Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=[CH:6][C:5]([O:8]C(C)C)=[C:4](C(C2C=CC(C)=CC=2)=C)C=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[CH2:30])[CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([O:8][CH:5]([CH3:6])[CH3:4])([OH:28])[CH:24]([C:29]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[CH2:30])[CH:23]=1
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1OC(C)C
Reactant: C=C(c1cccc(C)c1)c1cc(Br)ccc1O
Product: C=C(c1cccc(C)c1)C1C=C(Br)C=CC1(O)OC(C)C

Procedure:
Employing the same general procedure as for the preparation of 4-bromo-1-isopropoxy-2-[(1-p-tolyl)vinyl]benzene (Compound S), 81.5 mg (0.3 mmol) of 4-bromo-2-[(1-m-tolyl)vinyl]phenol (Compound N) was converted into the title compound using 164 mg (0.6 mmol) of triphenylphosphine, 0.10 mL (108 mg, 0.6 mmol) of diethylazodicarboxylate, 0.05 mL (39 mg, 0.6 mmol) of isopropanol and 3 mL of tetrahydrofuran. The reaction was sluggish necessitating addition (after 23 hours of stirring at ambient temperature) of another equivalent of reagents (initially only ½ of the above amounts were added) and stirring for 4 additional days. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a pink oil.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]Br)=[O:8])=[CH:5][CH:4]=[C:3]([Cl:11])[CH:2]=1.[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH2:15]>C(O)C>[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1[NH:15][CH2:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([Cl:11])=[CH:2][CH:1]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Cc1cccc(C)c1N
Solvent: CCO
Product: Cc1cccc(C)c1NCC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
46.7 g (0.2 mole) of ω-bromo-4-chloroacetophenone in 40 ml of ethanol were added to 48.4 g (0.4 mole) of 2,6-dimethylaniline in 40 ml of ethanol and the mixture was warmed to 50° C. for 20 minutes. Thereafter, it was cooled to 0° C. and the crystals which had formed were filtered off and rinsed with a little ethanol. 30 g (55% of theory) of 2,6-dimethyl-N-(4-chlorobenzoylmethyl)-aniline of melting point 82° C. were obtained.
Reaction SMILES: [CH:1]1([N:4]([CH3:13])[C:5]2[N:9]=[C:8]([CH:10]=O)[N:7]([CH3:12])[N:6]=2)[CH2:3][CH2:2]1.[Cl-].[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]2[N:23]=[C:24]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:18]2[N:17]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:1]1([N:4]([C:5]2[N:9]=[C:8]([CH:10]=[CH:26][C:24]3[N:25]=[C:18]4[N:17]=[C:16]([CH3:15])[CH:21]=[C:20]([CH3:22])[N:19]4[N:23]=3)[N:7]([CH3:12])[N:6]=2)[CH3:13])[CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1
Reactant: CN(c1nc(C=O)n(C)n1)C1CC1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(C=Cc3nc(N(C)C4CC4)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a solution of 3-(cyclopropyl(methyl)amino)-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (45 mg, 250 μmol, Eq: 1.00) in tetrahydrofuran (2.3 ml) were added ((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (115 mg, 250 μmol, Eq: 1.00) and DBU (95.0 mg, 94.1 μl, 624 μmol, Eq: 2.5). The resulting mixture was stirred for 18 hours at 25° C. TLC (Hep/EtOAC 1:1/UV 254 nm) showed no starting material left and new product spot. MS showed product peak also. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 1:1 as eluent to give Cyclopropyl-{5-[2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-vinyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-methyl-amine (30 mg, 37%) as light yellow waxy solid
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reaction time: 48 h
Yield: 77.6 %

Procedure:
To a mixture of 5.5 g of dry tert.-butanol and 7.08 g of dry pyridine is added a solution of 9.79 g of 4-bromobenzoyl chloride in 20 ml of anhydrous methylene chloride. The mixture is stirred under nitrogen for 2 days. The reaction mixture is then diluted with methylene chloride, and the organic solution extracted with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual oil is distilled under reduced pressure to give 8.9 g (70%) of tert.-butyl 4-bromobenzoate as a colorless oil: b.p. 91°-92° C./1.2 mm; NMR (CDCl3, 80 MHz) delta 1.59 (s, 9H), 7.53 (d, 2H, J=8.7 Hz); IR (neat) 2970, 1710, 1585, 1475, 1390, 1290, 1160, 1110, 1070, 845 and 745 cm-1.
Reaction SMILES: [F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:3]2=S.[NH3:16]>>[NH2:16][C:3]1[C:2]2([F:1])[CH2:14][CH2:13][CH2:12][CH:11]2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: FC12CCCC1c1ccccc1NC2=S
Reactant: N
Product: NC1=Nc2ccccc2C2CCCC12F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
142 mg (0.64 mmol) of 3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione is dissolved in 50 ml of 7 M methanolic ammonia solution. After 1 hour of stirring at room temperature, the batch is concentrated by evaporation in a vacuum, and the residue is purified by column chromatography on silica gel with dichloromethane-ethanol as an eluant: 108 mg of product, melting point 174-6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17](=O)([O:23]C(C)(C)C)[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 5-amino-2-methoxypyridine (8.00 g, 64.4 mmol) and triethylamine (11.7 mL, 83.8 mmol) in dioxane (32 mL) at 0° C. was added a solution of di-tert-butyl carbonate in dioxane (20 mL). The reaction mixture was allowed to warm to RT, stirred for 16 h. After concentration in vacuo, the residue was dissolved in 65 mL of EtOAc and 32 mL of a saturated aqueous NaHCO3 solution and stirred at RT for 2 h. The layers were separated. The organic layer was washed with water and dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)C>C(O)C.C1COCC1.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N1CCc2cc(N)ccc21
Yield: 67.9 %

Procedure:
The solution of 1-acetyl-5-nitroindoline (1.0 g, 4.85 mmol) in ethanol-THF (100 mL: 30 mL) was hydrogenated over 5% Pd/C (600 mg) at atmosphere pressure for 2 h, filtered through Celite and concentrated in vacuo to give a white solid which was recrystalllized from ethanol. White crystalline solid (580 mg, 68%) was obtained. Mp 185-186.5° C. (lit 184-185° C., [21]); 1H NMR (270 MHz, DMSO): δ 7.73 (1H, d, J=8.6 Hz, ArH), 6.45 (1H, s broad, w1/2=1.8 Hz, ArH), 6.33 (1H, dd, J=8.6, 1.8 Hz, ArH), 4.82 (2H, s, NH2), 3.97 (2H, t, J=8.4 Hz, CH2), 2.99 (2H, t, J=8.4 Hz, CH2), 2.07 (3H, s, CH3); APCI-MS 175 (M−H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])=[CH:31][CH:30]=1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: Nc1ccc(Cl)cc1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)Nc3ccc(Cl)cc3)c(=O)n12
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -10° C. and -12° C. during 20 minutes. After stirring for 5 minutes, 11.23 g (0.088 mol) of 4-chloroaniline dissolved in 80 ml of chloroform are dropped to the above solution at -10° C. during 35 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 18.5 g (73.7%) of the named compound as yellow crystals after recrystallization from ethanol, m.p.: 202°-204° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:10](=[O:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Brc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccn2)C(=O)C1
Temperature: 25 °C
Yield: 22.1 %

Procedure:
To 1-Boc-3-oxopiperazine 3a (390 mg, 1.95 mmol) in DMF (5 mL) at 0° C. was added NaH (60% in oil, 97 mg, 2.44 mmol). The reaction was stirred at 0° C. for 25 min before a solution of 2-bromopyrimidine 1i (465 mg, 2.92 mmol) in DMF (2 mL) was added. The reaction was slowly warmed up to room temperature overnight. To the reaction mixture was added H2O, and the resulting mixture was extracted with EtOAc. The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 3% MeOH/CH2Cl2) gave 3b as yellow oil (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19]Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Clc1ccc(SCc2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 128.5 %

Procedure:
3,4-Dichlorobenzenethiol (5 g) was added to a solution of sodium hydroxide (2.25 g) in ethanol (50 ml) and the resulting solution was treated with 2-picolyl chloride, hydrochloride (4.6 g) in ethanol (25 ml). After stirring for 4 hours at ambient temperature the mixture was filtered and the solvent removed by evaporation. The residue was converted into the hydrochloride with ethereal HCl and this was recrystallised from ethanol/ether to give 2-(((3,4-dichlorophenyl)thio)methyl)pyridine, hydrochloride (5.5 g) mp 213°-4° C. (Found: C,46.7; H,3.3; N,4.4 C12H9Cl2NS.HCl requires C,47.0; H,3.3; N,4.6%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6](I)[CH:7]=1.C([Mg]Cl)(C)C.B(OC)(OC)[O:20]C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([OH:20])[CH:5]=[N:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1
Reactant: COB(OC)OC
Reactant: Brc1cc(I)cnc1OCC1CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Oc1cnc(OCC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-bromo-2-(cyclopropylmethoxy)-5-iodopyridine (12.5 g) in dry THF (300 mL) was added i-PrMgCl*LiCl (30 mL, 38.3 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 20 min and then B(OMe)3 (5.5 g) was added at 0° C. The mixture was allowed to warm to r.t. and stirred for 3 h. The mixture was quenched by the addition of brine (50 mL). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×3). The organic phases were combined and the solvent was removed under reduced pressure. The residue was treated according Typical Procedure 5a to obtain the title compound. MS ESI+: m/z=244 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:12]1([S:18]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of ethyl piperidine-3-carboxylate (1.00 g, 6.36 mmol), benzenesulfonyl chloride (0.812 mL, 6.36 mmol), and triethylamine (2.66 mL, 19.1 mmol) in methylene chloride (10.0 mL) was stirred at r.t. for 2 hours. The mixture was quenched with water, then extracted with ethyl acetate. The extract was washed with 1N HCl solution, water, sat'd sodium bicarbonate solution, water, and brine, successively. Then, the extract was dried over sodium sulfate (anhydrous). After filtration, the filtrate was concentrated to yield 1.79 g (94%) of ethyl 1-(phenylsulfonyl)piperidine-3-carboxylate.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([S:12][CH2:13][CH2:14]O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:5]1([S:12][CH2:13][CH2:14][Cl:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: OCCSC1CCCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: ClCCSC1CCCCCC1
Reaction time: 0.25 h

Procedure:
5.11 cm3 of thionyl chloride were added dropwise, with stirring and under an inert atmosphere, at a temperature in the region of 20° C. to a solution of 1.74 g of 2-hydroxyethyl cycloheptyl sulfide in 30 cm3 of chloroform. After the addition, the reaction mixture was first stirred for 15 minutes at the same temperature and then for 1 hour at a temperature in the region of 600° C. The mixture was evaporated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C., then the residue obtained was taken up with 2 times 50 cm3 of water and then 1 times 50 cm3 of a saturated sodium hydrogencarbonate solution. The ethereal solution, separated by settling, was dried over magnesium sulfate, filtered, and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 400° C. 1.89 g of 2-chloroethyl cycloheptyl sulfide were obtained in the form of an oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[CH2:9]([N:11]([CH2:22][CH3:23])[C:12](=[O:21])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[CH3:10].[I:24]I>O1CCCC1>[CH2:22]([N:11]([CH2:9][CH3:10])[C:12](=[O:21])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[I:24])[CH3:23]
Reactant: CCN(CC)C(=O)Oc1cccc(Cl)c1
Reactant: II
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCN(CC)C(=O)Oc1cccc(Cl)c1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of lithium diisopropylamine (2M in THF) (21.40 ml; 42.8 mmol) in dry tetrahydrofuran (117 ml) under nitrogen atmosphere at −78° C. was added 3-chlorophenyl diethylcarbamate (8.86 g; 38.91 mmol). The reaction mixture was stirred for 30 min at −78° C., and iodine (0.669 g; 46.7 mmol) was added. The solution was stirred for 30 min. at 0° C. and was then allowed to warm up to room temperature for 2 h. The reaction mixture was quenched by adding water and the organics were removed under reduced pressure. The aqueous phase was extracted with ethyl acetate, washed with a solution of hydrochloric acid 1 N, dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford 8.32 g (55%) of 3-chloro-2-iodophenyl diethylcarbamate as brown solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([NH:1][C@@H:2]2[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:6][CH2:7]2)=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CC1
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)C5CC5)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[C:10]([OH:12])=O)=[CH:4][C:3]=1[F:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[CH:50]([NH2:59])[C:51]1[S:52][C:53]([CH2:57][OH:58])=[C:54]([CH3:56])[N:55]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[C:10]([NH:59][CH:50]([C:51]2[S:52][C:53]([CH2:57][OH:58])=[C:54]([CH3:56])[N:55]=2)[CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49][N:44]2[C:42]([O:41][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:43])=[O:12])=[CH:4][C:3]=1[F:14]
Reactant: O=C(O)C(=O)Nc1ccc(Cl)c(F)c1
Reactant: Cc1nc(C(N)C2CCCCN2C(=O)OC(C)(C)C)sc1CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nc(C(NC(=O)C(=O)Nc2ccc(Cl)c(F)c2)C2CCCCN2C(=O)OC(C)(C)C)sc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-chloro-3-fluorophenylamino)-2-oxoacetic acid (3′) (0.3 g, 1.378 mmol), TBTU (0.530 g 1.65 mmol) and TEA (0.166 g, 1.65 mmol) in DCM (20 ml) was stirred at RT for 1 h, then 2-[amino-(5-hydroxymethyl-4-methyl-thiazol-2-yl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.470 g, 1.378 mmol) was added and stirring was continued for 6 h. Reaction mixture was washed with 25% aqueous solution of K2CO3 (2×50 ml) and water (50 ml). The product was dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (EtOAc/hexane1/1) to afford tert-butyl 2-((2-(4-chloro-3-fluorophenylamino)-2-oxoacetamido)(5-(hydroxymethyl)-4-methylthiazol-2-yl)methyl)piperidine-1-carboxylate (4′) (0.53 g, 72%) as a white solid; LC-MS (APCI+) m/z: calcd for C24H30ClFN4O5S: 540.16. found: 541 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:22].[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35].C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:15][CH2:16][C:17]([F:20])([F:21])[CH2:18][CH2:19]4)[C:10]3=[O:22])=[C:6]([Cl:23])[CH:5]=2)=[CH:38][CH:37]=1)=[O:35]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCC(F)(F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCC(F)(F)CC4)C3=O)c(Cl)c2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Treat a solution of Trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (1.8 g, 3.5 mmol), 4-Methoxycarbonylphenylboronic acid (1.3 g, 7.0 mmol), and Tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.4 mmol) in DME (20 mL) with 2M aqueous K2CO3 (5.2 mL). Heat the reaction to 80° C. and stir overnight. Cool the reaction and quench with 1N HCl. Extract the aqueous with EtOAc. Wash the organic with brine, dried over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 1.0 g (57%) of desired product. MS (m/e): 498 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[C:10]2[C:15]([C:16]=1[CH:17]([C:28]1[CH:33]=[CH:32][C:31]([O:34]COC)=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7].Cl.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C>[CH3:43][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[C:10]2[C:15]([C:16]=1[CH:17]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7]
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)NCCN(C)C)n(CCN(C)C)c3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)CCNC(=O)c1c(C(c2ccc(O)cc2)c2ccc(O)cc2)c2ccccc2n1CCN(C)C
Temperature: 25 °C
Yield: 75.9 %

Procedure:
Compound 49 (2.48 g, 4.21 mmol) obtained in Example 49 was dissolved in ethanol (50 ml), and 15 ml of 2N hydrochloric acid was added thereto, followed by heating under reflux for 2 hours. After cooling the reaction solution, a saturated aqueous solution of sodium bicarbonate was added thereto for neutralization. A little amount of ethyl acetate was added to the mixture followed by stirring at room temperature. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure to give 1.6 g (yield: 81%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].Br[C:12]1[CH:13]=[C:14]([C:18]2([CH3:31])[C:23]([CH3:25])([CH3:24])[O:22][C:21](OCC)=[N:20][S:19]2(=[O:30])=[O:29])[CH:15]=[CH:16][CH:17]=1>ClCCl.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:21]1[O:22][C:23]([CH3:25])([CH3:24])[C:18]([CH3:31])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:12][CH:13]=2)[S:19](=[O:30])(=[O:29])[N:20]=1)[CH3:9]
Reactant: C[C@H](N)c1ccccc1F
Reactant: CCOC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](NC1=NS(=O)(=O)C(C)(c2ccccc2)C(C)(C)O1)c1ccccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
In a round-bottom flask, 92 mg of 5-(3-bromophenyl)-2-ethoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide stereomer 1 were dissolved in 1.3 ml of dichloromethane and admixed with 45 mg of (S)-1-(2-fluorophenyl)ethylamine. After stirring at room temperature and under a gentle argon stream for 18 hours, the conversion was checked by LCMS. Since it was incomplete, the reaction mixture was taken up in 1.5 ml of THF and stirred at 50° C. for 5 hours. After the removal of the solvent under reduced pressure, the oily residue was stirred at 95° C. for 2 hours and then at room temperature for 48 hours. According to LCMS, the reaction remained incomplete. The residue was dissolved under inert gas in 2 ml of ethanol and, with addition of 50 mg of 10% Pd/C, stirred under a hydrogen atmosphere at room temperature for 16 hours. After the addition of a further 50 mg of 10% Pd/C, the reaction mixture was stirred under the same conditions for a further 24 hours. After filtration to remove solid constituents, the filtrate was concentrated by rotary evaporation and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was lyophilized. This gave the product (45.7 mg) with a molecular weight of 390.5 g/mol (C20H23FN2O3S); MS (ESI): m/e=391 (M+H+).