Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)[CH3:2].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:18][CH2:10][C:7]1[CH:6]=[N:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cnc(C)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cnc(CBr)cn1
Temperature: 80 °C
Yield: 31.8 %

Procedure:
A mixture of 2-ethoxy-5-methylpyrazine (0.86 g, 6.22 mmol), NBS (1.440 g, 8.09 mmol), and diphenylperoxyanhydride (0.151 g, 0.622 mmol) in carbon tetrachloride (20 mL) was heated to 80° C. overnight. Cooled to RT, diluted with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated NaCl (2×), dried over Na2SO4, filtered, and concentrated. The residue was purified via ISCO (40 g silica, 40 mL/min, 0-30% EtOAc/Hexanes over 25 min) to afford 2-(bromomethyl)-5-ethoxypyrazine (430 mg, 32%). MS (m/z) 217.0 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C@H:8]([O:10][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@@H:7]([N:11]=[N+:12]=[N-:13])[CH2:6]1)=[O:4]
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Product: COC(=O)C1C[C@H](N=[N+]=[N-])[C@@H](OCCOC2CCCCO2)C1

Procedure:
In analogy to example 11A (1R,3S,4S)-3-azido-4-hydroxy-cyclopentanecarboxylic acid methyl ester (CAS 213742-85-9) was reacted with 2-(2-bromoethoxy)tetrahydro-2H-pyran to give (3S,4S)-3-azido-4-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-cyclopentanecarboxylic acid methyl ester. Light yellow oil. MS 336.3 ([M+H]+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COc1cccc(N)c1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: COc1cccc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)c1
Yield: 82 %

Procedure:
4-Hydroxy-N-(3-methoxyphenyl)-2-methyl-2H -naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 3-methyoxy-aniline. Yield: 82% of theory; m.p. 242°-244° C (decomp.; from xylene).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([NH:16][C@H:17]4[CH2:18][CH2:19][C@H:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]4)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=3)[N:3]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, 6-chloro-N-{trans-4-[(dimethylamino)methyl]-cyclohexyl}-3-(methylsulfonyl)-1,5-naphthyridin-4-amine (56 mg, 0.14 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (61 mg, 0.21 mmol) followed by formation of the dihydrochloride salt to afford the desired product (43 mg, 51%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.90 (s, 1H), 8.51 (d, J=9.0 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.14 (s, 2H), 5.76-5.66 (m, 1H), 3.38 (s, 3H), 3.09 (d, J=6.7 Hz, 2H), 2.94 (s, 6H), 2.50-2.43 (m, 2H), 2.08-1.96 (m, 3H), 1.74-1.64 (m, 2H), 1.47-1.35 (m, 2H). ESI MS m/z 523 [M+H]+; HPLC>99% (AUC), tR=10.04 min.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][OH:7])(=[O:5])[CH3:4].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([O:7][NH:6][C:3](=[O:5])[CH3:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)NO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
60% sodium hydride (11.68 g, 0.292 mol) was added to a dimethyliformamide solution (200 ml) of acetohydroxamic acid (21.9 g, 0.292 mol) with cooling in an ice bath. After stirring for 1 hour at room temperature, benzylbromide (50 g, 0.292 mol) was added thereto and allowed to react for 24 hours at room temperature. The reaction solution was poured into 500 ml of water. and extracted with ethyl acetate. The organic layer was rinsed with water and dried. After removing the solvent by evaporation, the residue was purified with silica gel chromatography to obtain 31.3 g of N-benzyloxyacetamide (yield: 65%). The proton NMR spectrum of the compound is 1.85 s (3H); 4.89 bs (2H); 7.37 s (5H); 8.30 bs, 8.81 bs (1H) (solvent: CDCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([Cl:20])=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Product: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (prepared according to: J. Med. Chem. (2008), 51, 5330-5341) (0.257 g, 1.1 mmol) in SOCl2 (2.409 mL, 33.0 mmol) was heated to 60° C. for 35 min, cooled to RT and concentrated to dryness. The residue was co-evaporated with toluene (2×) to afford 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (100% yield assumed) as a yellow solid.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12][C:13](=N)N)[CH:6]=1.BrC[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:13][S:12][CH2:11][C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCCBr
Reactant: N=C(N)SCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCCSCc1cccnc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 70.8 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (144 cc) is added dropwise, in the course of 25 minutes and whilst keeping the temperature below 12° C., to a solution of 2-(pyrid-3-ylmethyl)-isothiourea dihydrochloride (173 g) in distilled water (330 cc), cooled to 4° C. After heating for 25 minutes at 70° C. and then cooling to 11° C., a 10 N aqueous solution of sodium hydroxide (89 cc) and then 1-bromo-4-chlorobutane (123.5 g) are added, whilst stirring, and stirring is continued for 15 hours at a temperature of about 20° C. The reaction mixture is then extracted four times with methylene chloride (560 cc in total); the organic extracts are combined, washed twice with distilled water (800 cc in total), dried over anhydrous sodium sulphate and filtered. The solution is poured onto neutral silica gel (150 g) contained in a column of diameter 3.7 cm; the column is eluted with methylene chloride (2500 cc). The first fraction (600 cc) is discarded. The second (2500 cc) is concentrated to dryness under reduced pressure (25 mm Hg; 3.4 kPa) without exceeding 30° C. Pyrid-3-ylmethyl 4-chlorobutyl sulphide (110 g) is thus obtained.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17]O)[C:9]#[N:10]>C(Cl)(Cl)(Cl)Cl>[Br:2][CH2:17][CH2:16][CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:5]
Reactant: N#Cc1ccc(OCCCO)c(F)c1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(OCCCBr)c(F)c1

Procedure:
PBr3 (8.14 g, 0.03 mol) was added drop by drop at 0° C. to a solution of 3-fluoro-4-(3-hydroxypropoxy)-benzonitrile (5.5 g, 0.028 mol, from step (i) above in carbon tetrachloride (50 ml) and stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with water, and extracted with dichloromethane. Organic layer was washed with water, brine, dried over sodium sulfate and solvent evaporated under reduced pressure. The residue was purified by column chromatography over silica gel using 6% ethyl acetate in petroleum ether as eluent to yield (4.3 g) of the title compound as a liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OCCCCc1cccc(F)c1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(CCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a solution of 0.18 g of 4-(3-fluorophenyl)-1-butanol, 0.30 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol and 0.27 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran, a solution of 0.20 ml of N,N-diisopropylazodicarboxylate dissolved in 5 ml of tetrahydrofuran was added dropwise, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to obtain a residue. The residue was subjected to silica gel chromatography, which afforded 0.38 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-fluorophenyl) butyloxy)benzene (83% yield), nD25.0 1.5620.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7.18 mL (48.0 mmol) benzyl chloroformate in 50 mL DCM was added dropwise to 12.3 g (45.7 mmol) tert-butyl 4-piperidin-4-yl-piperazine-1-carboxylate and 8.2 mL (50 mmol) N-ethyldiisopropylamine in 200 mL DCM while cooling with ice and the reaction mixture was stirred overnight at RT. It was washed with 200 mL of 15% K2CO3 solution, the organic phase was separated off and dried over Na2SO4. After elimination of the desiccant and solvent the residue was further reacted without any further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)=[CH:25][N:24]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cn1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cn1
Yield: 23.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-5-(3-fluorobenzyl)picolinamide was prepared according to Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.140 g; 0.605 mmol), 5-(3-fluorobenzyl)picolinic acid (0.139 g; 0.605 mmol), HATU (0.254 g; 0.668 mmol) and N,N-diisopropylethylamine (0.262 mL; 1.52 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.057 g (23%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][CH:12]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH3:1][C:2]1[C:7]([O:8][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(C)n1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(C)nc3C)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
2,6-Dimethylpyridin-3-ol (165 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-(N,N-dimethylamino)pyridine (164 mg) were dissolved in 1,2-dichlorobenzene (4.5 ml) to prepare a solution which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give the title compound (116 mg, yield 83%).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]1>>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[C:4]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C(O)C1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Yield: 42.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with morpholine-2-carboxylic acid (0.26 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.35 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:15](=[O:16])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:4][CH:3]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cc1cnc(N)o1
Product: Cc1cnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, off-white solid, m.p. 166-168° C. and MS: m/e=292.2 (M+) was prepared in accordance with the general method of example 44a from 5-methyl-oxazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:12]=[CH:13][C:14]=1F)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[N:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=12.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([O:26][C:14]3[CH:13]=[CH:12][C:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[C:3]([F:16])[C:2]=3[Cl:1])=[CH:22][C:21]=12
Reactant: Oc1ccn2ncnc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccn3ncnc3c2)c(Cl)c1F
Temperature: 80 °C

Procedure:
A vial charged with tert-butyl 3-chloro-2,4-difluorobenzoate (0.210 g, 0.845 mmol), [1,2,4]triazolo[1,5-a]pyridin-7-ol (0.114 g, 0.845 mmol), cesium carbonate (0.413 g, 1.27 mmol), and DMF (1.7 ml). The reaction was heated to 80° C. for 12 hours, then poured into ice water. The resulting solids were collected by filtration and purified by flash chromatography, eluting with gradient of 10% EtOAc/Hexanes to 50% EtOAc/Hexanes to provide the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[CH:5][C:4]=1[CH3:10].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[CH3:10][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH3:9])[C:3]=1[CH2:2][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1cncc(C)c1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2c(C)cncc2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a 0° C. mixture of 4-(bromomethyl)-3,5-dimethylpyridine (18.6 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.7 g, 12 mmol) in absolute ethanol (170 mL) was added triethylamine (8 mL, 57.4 mmol). The mixture was stirred at room temperature overnight. The solid precipitate was removed by filtration. Diethyl ether (300 mL) was added to the filtrate. The precipitate was removed by filtration. The filtrate was recovered, evaporated, and co-evaporated with EtOAc (1×50 mL). The residue was treated with water (300 mL). The solid material was recovered by filtration, washed with water (4×30 mL), diethyl ether (3×30 mL) and hexanes (2×30 mL), and dried in vacuo, affording 2-{[(3,5-dimethylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (1.78 g, 57% yield). The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(C)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27.7 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.03 g, 0.006 mol) in N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (3.22 g, 0.025 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-m-tolyloxy-but-2-enoic acid ethyl ester (1.50 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-(2-oxo-4-m-tolyloxy-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (495 mg, 25%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[N:7][CH:8]=1.[H][H]>C(OCC)(=O)C.[Pd]>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[N:7][CH:8]=1
Reactant: O=C1CCCC1=Cc1ccc(C(F)(F)F)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCCC1Cc1ccc(C(F)(F)F)cn1

Procedure:
A solution of 2-{[5-(trifluoromethyl)pyridin-2-yl]methylidene}cyclopentan-1-one (0.513 g, 2.13 mmol) in ethyl acetate (20 ml) was added palladium on carbon (10% wt, 50% wet, 0.226 g, 0.11 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-40% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: COc1cc(F)cc(B(O)O)c1
Product: COc1cc(F)cc(-c2nnc(N)nc2-c2ccccc2)c1
Yield: 32.7 %

Procedure:
6-(3-Fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (193 mg, 32%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-fluoro-5-methoxy phenylboronic acid (0.37 g, 2.19 mmol) according to the general procedure of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[N:19]=[C:20]=[O:21]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([NH:19][C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[F:11])=[O:21])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: ClCCl
Product: CCc1cc(Br)ccc1NC(=O)Nc1cc(C)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A solution of 4-bromo-2-ethylaniline (200 mg) in dichloromethane (10 mL) was treated with 1-fluoro-2-isocyanato-4-methylbenzene (151 mg), stirred at room temperature overnight, diluted with hexanes, and filtered. The filter cake provided 227 mg of the desired product. MS (ESI(+)) m/e 351,353 (M+H)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:13])[NH:8]3)=[CH:4][C:3]=2[O:2]1.ClS([N:18]=[C:19]=[O:20])(=O)=O>>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:13])[N:8]3[C:19]([NH2:18])=[O:20])=[CH:4][C:3]=2[O:2]1
Reactant: O=C1Cc2cc3c(cc2N1)OCO3
Reactant: O=C=NS(=O)(=O)Cl
Product: NC(=O)N1C(=O)Cc2cc3c(cc21)OCO3

Procedure:
5,6-Methylenedioxy-2-oxindole-1-carboxamide was prepared by reaction of 5,6-methylenedioxy-2-oxindole with chlorosulfonyl isocyanate, followed by hydrolysis, using the procedure of Example 19. The product melted at 237°-238° C. (dec.) after recrystallization from acetic acid.
Reaction SMILES: [Na].[OH:2][C:3]1[CH2:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7](=[O:9])[CH:8]=1.[Cl-].[C:14]1([N+:20]#[N:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[OH:2][C:3]1[CH2:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7](=[O:9])[C:8]=1[N:21]=[N:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C=C(O)CC(C(=O)O)C1
Reactant: N#[N+]c1ccccc1
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Product: O=C1CC(C(=O)O)CC(O)=C1N=Nc1ccccc1

Procedure:
13.8 g. of sodium were dissolved in 900 ml. of methanol and to this solution were added 46.8 g. of 3-hydroxy-5-keto-3-cyclohexene-carboxylic acid. The resulting mixture was stirred, maintained between -4° C. and -8° C. by means of a cooling bath and treated over a period of 30 minutes with a phenyl-diazonium chloride solution (prepared from 27.9 g. of aniline, 450 ml. of water, 72 ml. of concentrated hydrochloric acid and 21.0 g. of sodium nitrite in 90 ml. of water). The resulting mixture was stirred for an additional hour at -5° C. to -10° C. The precipitated red reaction product was removed by filtration with suction and washed with about 1000 ml. of water, whereby there was obtained 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-carboxylic acid having a melting point of 218° C.