Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C1(O)C(O)C(O)C(O)C(O)C1O>OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>[C@H:5]1([OH:6])[CH:3]([OH:4])[C@@H:2]([OH:1])[C@H:11]([OH:12])[C:9](=[O:10])[C@@H:7]1[OH:8]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: OC1C(O)C(O)C(O)C(O)C1O
Product: O=C1[C@@H](O)[C@H](O)C(O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 835.5 %

Procedure:
Angyal, S. J. et al. Carbohydr. Res. 76:121 (1979); Posternak, T., Biochem. Prep. 2:57 (1952). A solution containing sorbitol (1.0 g) and yeast extract (0.05 g) in 10 mL distilled, deionized water was autoclaved for 25 min and cooled to room temperature. After inoculation with Gluconobacter oxydans ATCC 621 the culture was incubated in an orbital shaker at 200 rpm for 24, h at 30° C. This G. oxydans culture was subsequently added to a second sterile solution containing myo-inositol (12.0 g, 66.7 mmol), D-sorbitol (0.4 g), and yeast extract (2.0 g) in 400 mL distilled, deionized water. After incubation in an orbital shaker at 200 rpm for 48 h at 30° C., cells were removed by centrifugation. The resulting culture supernatant was concentrated to 75 mL, MeOH (400 mL) added, and the solution maintained at −20° C. for 12 h. Precipitate which formed was filtered, washed with MeOH, and dried to afford myo-2-inosose as a white powder (8.17 g, 69%). A second crop of myo-2-inosose (3.09 g, 26%) was obtained after maintaining the filtrate at −20° C. for an additional 12 h. mp 188-192° C. 1H NMR (D2O): δ4.25 (d,J=10 Hz, 2 H), 3.66 (dd, J=9, 9 Hz), 3.26 (m, 2 H). 13C NMR (D2O): δ206.0, 94.3, 76.2, 74.5, 74.1, 74.0, 73.3, 73.2.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]([CH3:42])[C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][C@@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN(C)[C@@H]1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (3R)Dimethyl-pyrrolidin-3-yl-amine following General Procedure C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]2[N:16]([CH3:19])[N:17]=[CH:18][C:10]=12>>[Cl:15][C:13]1[N:12]=[C:11]2[N:16]([CH3:19])[N:17]=[CH:18][C:10]2=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:14]=1
Reactant: CN1CCNCC1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Product: CN1CCN(c2nc(Cl)nc3c2cnn3C)CC1

Procedure:
Reaction of N-methylpiperazine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave 6-chloro-1-methyl-4-(4-methyl-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].O=S(Cl)[Cl:19]>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:5]=1[C:6]([Cl:19])=[O:7])[CH3:2]
Reactant: CCOc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCOc1ccc(C(F)(F)F)cc1C(=O)Cl
Temperature: 90 °C

Procedure:
A mixture of 2-ethoxy-5-(trifluoromethyl)benzoic acid (0.20 g, 0.84 mmol) and SOCl2 (5 mL) was warmed to 90° C. for 2 h and then was cooled to ambient temperature and concentrated under reduced pressure. The crude material was diluted with 10 mL toluene and was concentrated again. This dilution/concentration was repeated two additional times to provide 2-ethoxy-5-(trifluoromethyl)benzoyl chloride, that was used directly below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH2:16][CH2:15][CH2:14][N:12]3[CH:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]3[CH2:16][CH2:15][CH2:14][N:12]3[C:13]=2[Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cn3c(n2)CCC3)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(-c2ccc(OC)cc2)nc2n1CCC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To an ice cold (0° C.) solution of [16.8 g, 0.078 mol] 2-(4-methoxyphenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole in 200 ml of dry tetrahydrofuran under argon was added dropwise over 20 minutes 35 mL [0.0858 mol] of a 2.5M solution of n-butyl lithium in hexane. Once the addition was complete, the deep-red solution was stirred in the cold for five minutes and then a solution of the tributyltin chloride [26.4 g, 0.0975 mol] in 50 ml of dry tetrahydrofuran was added over 20 min. The reaction mixture was stirred at ice-bath temperatures for 1.5 hours and then saturated ammonium chloride was added. The layers were shaken together and separated and the organic extract was washed an additional time with saturated ammonium chloride and then dried with anhydrous potassium carbonate. The solvent was removed in vacuo to give 50 g of a crude oil, which was taken up twice in cold hexane, filtering off the unreacted 2-(4-methoxyphenyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole each time. The product was purified on a column of silica, eluting with 1:1 ethyl acetate/hexane in the presence of 1% diethylamine, to give 19.2 g (49% of a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(OC)(C)C.COC1C=CC=C(OC)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[C:30]([C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]5[CH:27]=[CH:26][N:25]=[CH:24][N:23]=5)(=[O:19])=[O:20])=[CH:15][CH:16]=4)[CH:11]=[CH:10][N:9]=3)=[C:4]([O:28][CH3:29])[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)#[N:31]
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd+]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: NCCc1[c-]cccc1
Solvent: COC(C)(C)C
Product: COc1cc(-c2cccc(C#N)c2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 120 °C
Yield: 60 %

Procedure:
A microwave vial was charged with 1-(4-chloro-2-methoxyphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (53.42 mg, 0.125 mmol), (3-cyanophenyl)boronic acid (55.2 mg, 0.375 mmol), potassium phosphate (106 mg, 0.501 mmol), and chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) methyl-t-butylether adduct (Strem Chemical, Newburyport, Mass.) (9.52 mg, 0.013 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (501 μl) and water (125 μl) were added. The vial was sealed and heated to 120° C. for 30 min in a microwave reactor. The mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated. The crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-(3′-cyano-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (37.15 mg, 0.075 mmol, 60.2% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=13.00 (br. s., 1H), 8.70 (d, J=5.7 Hz, 1H), 8.66 (d, J=1.4 Hz, 1H), 8.58 (s, 1H), 8.37 (d, J=1.6 Hz, 1H), 8.30-8.17 (m, 2H), 8.15-8.05 (m, 1H), 8.01-7.94 (m, 1H), 7.92-7.86 (m, 1H), 7.81-7.70 (m, 2H), 7.60-7.43 (m, 3H), 7.03 (d, J=6.5 Hz, 1H), 3.78 (s, 3H); m/z (ESI) 494.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH:9]([CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: BrCc1cscn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(Cc1cscn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35 %

Procedure:
To a solution of tert-butyl diethylphosphonoacetate (15.6 g, 62 mmol) in dimethylformamide (50 mL) was added sodiumhydride (60% dispersion in mineral oil, 2.48 g, 62 mmol) at 0° C. under nitrogen atmosphere. After 45 min, to the mixture was added a solution of 4-(bromomethyl)-1,3-thiazole in toluene (27 g). The mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with toluene/ethyl acetate (1/3). The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1/2 to 100% ethyl acetate) to afford 7.17 g (35%) of the title compound as a colorless oil:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH:17]([CH3:19])[CH3:18])=[O:5])[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH:17]([CH3:19])[CH3:18])=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(C(C)C)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(C(C)C)cccc2c1NC1CCCC1

Procedure:
4-Chloro-8-isopropyl-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.9 mmol) was treated with cyclopentylamine following general procedure B to afford 4-cyclopentylamino-8-isopropyl-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (165 mg) following general procedure E.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>CCCCCC>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: COc1cc(S(N)(=O)=O)cc(C(=O)Cl)c1OC
Yield: 94.7 %

Procedure:
419 g (1.6 mole) of 2,3-dimethoxy-5-sulphamoyl benzoic acid and 1,351 g (11.35 moles) of thionyl chloride are placed in a 2 liter flask fitted with an agitator, a thermometer and a condenser connected to a soda bubbler. The mixture is brought to reflux for 1 hour, after which the excess thionyl chloride is expelled under vacuum. The residue is dissolved in 1,000 ml of hexane, filtered, washed twice with 500 ml of petroleum ether and dried in a desiccator under vacuum. 424 g (yield 94.8%) of 2,3-dimethoxy-5-sulphamoyl benzoyl chloride is obtained, with a melting point of 153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[C:18]1[N:22]([CH:23]([CH3:25])[CH3:24])[CH:21]=[N:20][N:19]=1.O=S(Cl)[Cl:28]>C(Cl)Cl.CN(C=O)C>[Cl:28][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([C:18]2[N:22]([CH:23]([CH3:25])[CH3:24])[CH:21]=[N:20][N:19]=2)[CH:12]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2-c2nncn2C(C)C)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2-c2nncn2C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a room temperature solution of 29.5 (60 mg, 176 μmol) in DCM was added one drop of DMF followed by SOCl2(63 mg, 527 μmol). The mixture was stirred at room temperature for 2.0 hours. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-5% MeOH/EtOAc provided 29.6 as a colorless oil (44 mg, 70%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10])=[N:2]1.C1C=CC=CC=1.S(Cl)([Cl:28])=O>N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:28])=[O:10])=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1C1=NOCC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1C1=NOCC1

Procedure:
To 2.75 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 30 ml of benzene, then 1.7 ml of thionyl chloride and a drop of pyridine to heat at reflux for 3 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 2.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride. Separately 0.93 g of 1-ethyl-5-hydroxypyrazole hydrochloride was dissolved in 20 ml of chloroform, and 1.60 g of triethylamine was added, while cooling with ice. Into the obtained solution was added dropwise 10 ml of a chloroform solution containing 1.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride to stir at room temperature for 30 minutes, and 0.76 g of triethylamine and 0.16 g of acetone cyanohydrin were added to further stir overnight. The reaction solution was washed with dilute hydrochloric acid, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 1.59 g of the title compound as white crystals. m.p. 183~184.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[N:37]1([C:43](=[S:45])[NH2:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.ClC1N=C(C2SC(C(C)(C)C)=NC=2C2C=C(NS(C3C=C(F)C=CC=3F)(=O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:45][C:43]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[N:44][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)N1CCOCC1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1cc(F)ccc1F
Agent: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1)c1cc(F)ccc1F

Procedure:
The title compound was prepared from N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,5-difluorobenzenesulfonamide (1.5 g, 3.54 mmol), NBS (0.630 g, 3.54 mmol) and 4-morpholinecarbothioamide (0.517 g, 3.54 mmol) by a procedure analogous to Intermediate 9. The title compound was obtained as a yellow solid (1.8 g, 90% yield). ES-LCMS m/z 549.7 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][OH:14])[N:8]=2)[N:3]=1.[ClH:15].[ClH:16].NC1N(N)C(N)=C(N)C=N1.[S:27](=[O:30])(O)[O-].OCC(CO)=O.[Se](=O)=O>N[C@H](C(O)=O)CS>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][OH:14])[N:8]=2)[N:3]=1.[S:27]([Cl:16])([Cl:15])=[O:30]
Reactant: O=S([O-])O
Reactant: Cl
Agent: NC1=C(N)N(N)C(N)N=C1
Agent: N[C@@H](CS)C(=O)O
Agent: Nc1nc(N)c2nc(CO)cnc2n1
Product: O=S(Cl)Cl

Procedure:
A three-step process is provided for preparing the L,D and DL isomers of N[p-{[(2,4-diamino-6-pteridyl)-methyl]N10 -methylamino}-benzoyl]-glutamic acid. The first step produces: 2,4-diamino-6-hydroxymethyl pteridine by condensation in a buffered aqueous media of 2,3,4,5-tetraminopyrimidine dihydrochloride with the bisulphite addition product of 1,3-dihydroxyacetone in the presence of cysteine as catalyst and using selenium dioxide and a continuous air bubbling as oxidation agents. In the next step, 2,4-diamino-6-halomethylpteridine is obtained by halogenation of the previously obtained 2,4-diamino-6-hydroxymethylpteridine in an inert media with a halogenation agent such as thionyl chloride, in the presence of a basic catalyst such as pyridine or triethylamine. In the third step, N[p-{[(2,4-diamino-6-pteridyl)-methyl]-N10 -methylamino}-benzoyl-]-glutamic acid is produced by condensation of the 2,4-diamino-6-halomethylpteridine with N[p-(N-methylamino)-benzoyl]-glutamic acid at pH 3-4 in an aqueous buffered solution.
Reaction SMILES: [C:1]1([Bi:7](C2C=CC=CC=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][Bi](Br)Br>C1COCC1>[C:1]1([Bi:7]([Br:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc([Bi](c2ccccc2)c2ccccc2)cc1
Reactant: Br[Bi](Br)Br
Solvent: C1CCOC1
Product: Br[Bi](c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
In 400 ml of THF was dissolved 22.014 g (50 mmol) of triphenylbismuthine (Tokyo Kasei Co., Ltd.) under nitrogen atmosphere. The solution was cooled to 0° C. and thereto was slowly added dropwise 11.231 g (25 mmol) of tribromobismuthine (Aldrich Corp.) (30 minutes). The mixture was stirred to room temperature for 1 hour. The yellow precipitate was filtered and dried in a vacuum. The obtained precipitate was recrystallized from benzene, giving 27.422 g (62 mmol: yield 83%) of yellow powdery product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18](Cl)=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3N3CCCC3)ccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a mixture of ethyl(6-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (90 mg), pyrrolidine (59.6 mg) and DMF (dry) (10 mL) was added K2CO3 (57.9 mg). The mixture was stirred at 80° C. under argon atmosphere overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give title compound (46.0 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[F:15]C1C(C(C)C)=C(C#N)C(=O)NC=1C>>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]([F:14])([F:12])[F:13])[CH:3]=1.[F:15][C:3]1[C:4]([C:11]([F:14])([F:12])[F:13])=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1]
Reactant: Cc1[nH]c(=O)c(C#N)c(C(C)C)c1F
Agent: Cc1cc(C(F)(F)F)c(C#N)c(=O)[nH]1
Product: Cc1[nH]c(=O)c(C#N)c(C(F)(F)F)c1F

Procedure:
6-Methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile was fluorinated as described for 5-fluoro-4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile. The product was isolated as a 3:1 mixture of 6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile (starting material) and 5-fluoro-6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile. For 5-fluoro-6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridine-3-carbonitrile, LCMS E-S (M+H)=221.2. This mixture of nitriles was subjected to the reduction conditions as described above for 3-(Aminomethyl)-5-fluoro-4-isopropyl-6-methylpyridin-2(1H)-one. For fluorinated compound LCMS (ES) (M+H) showed 225.2 and for non-fluorinated analog LCMS (ES) (M+H) showed 207.2. Subsequent coupling reaction was performed with the crude mixture of amines without further purifications. For 3-(ethyl(1-methylpiperidin-4-yl)amino)-N-((5-fluoro-6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(trifluoromethyl)benzamide diformate; 1HNMR (400 MHz, CD3OD) δ ppm 8.32 (s, 2H), 7.50 (s, 1H), 7.34 (s, 1H), 4.59 (s, 2H), 3.40 (br, 2H), 3.18 (br, m, 1H), 3.09 (q, J=6.8, 2H), 2.96 (br, m, 2H), 2.78 (s, 3H), 2.35 (s, 3H), 2.29 (d, J=3.2 Hz, 3H), 1.98 (br, d, J=13.2 Hz, 2H), 1.80 (br, m, 2H), 0.84 (t, J=6.8 Hz, 3H); MS (ES) (M+H) 551.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH2:17])[C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[N+](=[CH2:20])=[N-].CCCCCC>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]2[CH2:20][CH2:17]2)[C:5]2[O:12][C:9]3([CH2:10][CH2:11]3)[CH2:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1
Reactant: C=[N+]=[N-]
Reactant: C=Cc1cc(Br)cc2c1OC1(CC1)CC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(Br)cc21

Procedure:
Following general procedure O and using A 6-bromo-3,4-dihydro-4,4-dimethyl-8-vinylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 41 1.36 g, 4.6 mmol), a solution of diazomethane in diethyl ether and palladium (II)acetate (˜30 mg) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent, the title compound was obtained as a clear oil (1.38 g, 100%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5].Cl.[CH3:12][C:13]1[N:14]=[C:15]([C:24](Cl)=[O:25])[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH:5][C:24]([C:15]1[S:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([CH3:12])[N:14]=1)=[O:25]
Reactant: Cc1cccc(C)c1N
Reactant: Cc1nc(C(=O)Cl)sc1-c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NC(=O)c1nc(C)c(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
2,6-Dimethyl aniline hydrochloride (230 mg) was added to a stirred suspension of 4-methyl-5-(4-pyridinyl)-thiazole-2-carbonylchloride hydrochloride (230 mg) in dry toluene (4 ml) at room temperature, and triethylamine (1.8 ml) was added to the mixture, and was stirred at room temperature for overnight. The mixture was diluted with chloroform, washed with water, dried over magnesium sulfate, and evaporated to dryness. The residue was recrystallized from iso-propanol to give 2',6'-dimethyl-4-methyl-5-(4-pyridinyl)-thiazole-2-carboxanilide (180 mg, yield 31%) as colorless plates.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.C([O-])(O)=O.[Na+].[CH3:22][CH2:23]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16][CH2:22][CH3:23])=[O:15])[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1cc(Cl)cc(OC(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 3-chloro-5-trifluoromethoxyphenylacetic acid (5.2 g, 20.4 mmol; see step (iii) above) in EtOH (600 mL) was added sulfuric acid (several drops). The solution was refluxed for 18 h, cooled to room temperature, neutralized with solid NaHCO3 and the EtOH removed in vacuo. The residue was diluted with EtOAc then washed with H2O (1×), aqueous NaHCO3 (1×) and brine (1×). The organics were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (5.5 g, 96%) as an oil which was used in the next step without further purification.