Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:21][S:22]([N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1)(=[O:24])=[O:23]
Reactant: Cc1ccccc1C1CC(=O)c2c(C)c[nH]c2C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C1CC(=O)c2c(C)cn(S(C)(=O)=O)c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a suspension of 60% sodium hydride (0.12 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.60 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.43 g) in dimethylformamide (3 ml), and the mixture was stirred at the same temperature for 12 hours. To the mixture was added methanesulfonylchloride (0.74 g), and the mixture was stirred for 3 hours. To the mixture was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give crystals, which were recrystallized from ethyl acetate-hexane to give colorless crystals of 1-methanesulfonyl-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.35 g).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:32])[F:31])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1.[O:42]=[CH:43][CH:44](CO)O.C([BH3-])#N.[Na+]>CO>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([C:16]3[C:35]([N:36]4[CH2:37][CH2:38][N:39]([CH2:44][CH2:43][OH:42])[CH2:40][CH2:41]4)=[CH:34][C:19]4[NH:20][C:21]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:31])([F:32])[F:33])=[N:22][C:18]=4[CH:17]=3)=[O:15])[CH:11]=2)[CH:6]=[N:5]1
Reactant: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCNCC1
Reactant: O=CC(O)CO
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3ccccc3C(F)(F)F)[nH]c2cc1N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide trihydrochloride (0.2 mmol; see Example 88) in methanol (2 mL) was added glyceraldehyde (2 mmol), and the resulting mixture was stirred at RT for 60 min. The reaction mixture was then charged with solid sodium cyanoborohydride (1 mmol), and the stirring was continued at RT for 10h. The reaction mixture was then concentrated in vacuo, and the residue was suspended in water (10 mL) with vigorous stirring. After 30 min, the solid was filtered, washed with water, and dried under vacuum to afford 6-[4-(2-hydroxyethyl)-piperazin-1-yl]-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)amide as a white solid. MS: m/z 565 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(N(CC)CC)C>C(O)C>[C:14]1(=[O:23])[N:13]([CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-bromomethylphthalimide (5.28 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 4.29 g of the desired product (69.4%, pale yellow crystals).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCN2CCCCC2)c1
Yield: 94.8 %

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.68 mmol) and piperidine (1.33 ml, 13.46 mmol) in ethanol (5 ml). Purification by flash column chromatography (ethyl acetate/methanol, 100:0 to 85:15) gave the title compound (480 mg, 94.7%). The amine was converted to the hydrochloric acid salt and re-crystallized from methanol/diethyl ether: M.p. 194.6° C. MS m/z (relative intensity, 70 eV) 301(M+, 1), 99 (8), 98 (bp), 96 (4), 55 (5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:18]2[CH2:19][CH2:20][CH:15]([F:14])[CH2:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(F)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1 g, 5.84 mmol), 4-fluoropiperidine hydrochloride (0.97 g, 6.42 mmol) and 4 Å molecular sieves (10 g) in DCE (50 mL). The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (2.48 g, 11.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 0:100 to 100:0) then (Si—PPC, MeOH: DCM, 0:100 to 5:95) to give 3-(4-Fluoropiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.59 g, 39%). 1H NMR (CDCl3, 400 MHz) δ 4.80-4.58 (m, 1H); 3.97-3.89 (m, 2H); 3.85-3.76 (m, 2H); 3.08 (t, J=6.4 Hz, 1H); 2.50-2.28 (m, 4H); 1.99-1.82 (m, 4H); 1.48-1.38 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([N:18]=[C:19]=[S:20])=[O:17])=[CH:14][CH:13]=1>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][C:12]([CH3:11])=[CH:13][CH:14]=1)=[O:5]
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: CCOCC
Product: Cc1ccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)cc1
Yield: 98.2 %

Procedure:
To a stirred mixture of 5.4 g of 2-aminobenzamide and 200 ml of ether was added dropwise, a solution of 7.5 g of 4-methylbenzoyl isothiocyanate in 100 ml of ether over 30 minutes. After 48 hours the solid was collected, giving 12.2 g of N-[[[2-(aminocarbonyl)phenyl]amino]thioxomethyl]-4-methylbenzamide.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)=O)=[N:6][CH:7]=[N:8][CH:9]=1)(=[O:3])[NH2:2]>CN(C)C(=O)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:15]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:13]([C:11]2[N:2]=[C:1]([OH:3])[C:4]3[C:5]([N:10]=2)=[N:6][CH:7]=[N:8][CH:9]=3)=[N:14]1
Reactant: NC(=O)c1cncnc1NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: CC(=O)N(C)C
Product: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2ncncc12
Temperature: 220 °C
Reaction time: 0.5 h

Procedure:
246 mg (0.629 mmol) of the compound from example 48A were initially charged in N,N-dimethylacetamide (22 ml) and stirred in a microwave at 220° C. for 30 min. The reaction mixture was poured onto ice-water and filtered. The filter residue was washed with water and dried under high vacuum at 50° C. overnight. This gave 142 mg (57% of theory) of the title compound in solid form.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22]C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.Br[C:41]1[C:46]([CH:47]([CH3:49])[CH3:48])=[CH:45][C:44]([CH:50]([CH3:52])[CH3:51])=[CH:43][C:42]=1[CH:53]([CH3:55])[CH3:54]>>[CH:53]([C:42]1[CH:43]=[C:44]([CH:50]([CH3:52])[CH3:51])[CH:45]=[C:46]([CH:47]([CH3:49])[CH3:48])[C:41]=1[O:22][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])([CH3:55])[CH3:54]
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Product: CC(C)c1cc(C(C)C)c(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c(C(C)C)c1

Procedure:
The title compound is prepared in a manner substantially similar to Example 359 starting from 3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 2-bromo-1,3,5-triisopropyl-benzene. MS: 610.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:20][CH:21]2[CH2:23][CH2:22]2)=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>N1C=CC=CC=1>[CH:21]1([S:20][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:6]=2[C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(N)ccc1SC1CC1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(SC2CC2)c([C@H]2CCCN2C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 109 %

Procedure:
To 85G (1.25 g, 3.74 mmol) in pyridine (8.0 mL) at 0° C. was added methyl chloroformate (0.4 mL, 5.23 mmol). After 30 min, the reaction was quenched by MeOH (2.0 mL). Pyridine was removed under high vacuum. The crude was suspended in EtOAc and washed by 1.0 N HCl (2×20 mL), sat. NaHCO3 and brine. The organic layer was dried over Na2SO4. After evaporation of solvent, 85H (1.6 g, 95% yield) was obtained as a solid used for next step without purification. 1H NMR (400 MHz, DMSO-d6, 100° C.) δ ppm 0.52-0.64 (m, 2H) 0.94-1.05 (m, 2H) 1.17-1.28 (s, 9H) 1.54-1.63 (m, 1H) 1.77-1.86 (m, 2H) 2.18-2.29 (m, 2H) 3.46-3.57 (m, 2H) 3.62-3.68 (s, 3H) 5.05 (dd, J=7.70, 3.85 Hz, 1H) 7.23 (s, 1H) 7.32-7.40 (m, 1H) 7.40-7.47 (m, 1H) 9.26 (s, 1H), LC-MS 293 (M-Boc).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[CH3:20][O:19][C:17](=[O:18])[NH:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCCOc1ccc2nc(N)sc2c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCOc1ccc2nc(NC(=O)OC)sc2c1
Temperature: 25 °C

Procedure:
To a stirring solution of 24.45 g. of 2-amino-6-n-propyloxybenzothiazole-hydrochloride in 100 ml of pyridine maintained at 0° C. by an ice bath, is slowly added 9.45 g. of methyl chloroformate. After the addition is completed the mixture is allowed to warm up to room temperature. It is then poured on 300 g. of ice water. A solid is formed which is isolated by filtration and crystallized from ethanol yield 20 g m.p. 178°-180° C.
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20]>>[N:3]1([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[NH:14][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:17]=2[C:16]([F:15])([F:30])[F:31])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: Cl
Product: O=C(NC1CCCCC1N1CCCC1)c1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, white solid, MS: m/e=409.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2,4-bis(trifluoromethyl)benzoic acid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:11]1[CH:29]=[C:14]2[C:15]([C:21]3[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[N:13]2[N:12]=1)[CH3:10]>CS(C)=O>[C:9]([C:11]1[CH:29]=[C:14]2[C:15]([C:21]3[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[N:13]2[N:12]=1)(=[O:8])[CH3:10]
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)O)nn12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)=O)nn12
Temperature: 25 °C
Yield: 59.8 %

Procedure:
Triethylamine (1.46 mL) was added to a solution of the compound of Example 238 (315 mg) in DMSO (10 mL). While the mixture was stirred at room temperature, sulfur trioxide-pyridine complex (829 mg) was added at once and the mixture was further stirred at room temperature for 1 hour. Subsequently, the reaction was quenched by adding water (100 mL). Filtration of the resulting crystals afforded the title compound as a colorless powder (187 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][C:20]([CH3:30])([C:26]([O:28][CH3:29])=[O:27])[CH2:21]2.O>N1C=CC=CC=1>[CH3:30][C:20]1([C:26]([O:28][CH3:29])=[O:27])[CH2:21][C:22]2[C:18](=[CH:17][CH:25]=[CH:24][C:23]=2[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:19]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1(C)Cc2cccc(O)c2C1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C1(C)Cc2cccc(OS(=O)(=O)C(F)(F)F)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At −15° C., 1.5 ml (8.7 mmol) of trifluoromethanesulfonic anhydride were slowly added dropwise to a solution of 897 mg (4.35 mmol) of methyl 4-hydroxy-2-methyl-2,3-dihydro-1H-indene-2-carboxylate in 20 ml of pyridine. After warming to room temperature, the reaction mixture was stirred for another 2 h. 20 ml of water were then added and, after phase separation, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 1100 mg (3.25 mmol, 75% of theory) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)O)[CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:19])CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)[F:19])[CH:5]=[CH:4][N:3]=1
Reactant: OC(c1ccnc(Cl)n1)C1CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC(c1ccnc(Cl)n1)C1CC1
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
To a solution of (2-chloropyrimidin-4-yl)(cyclopropyl)methanol (75 mg, 0.406 mmol) in dichloromethane (2 mL) at 0° C. was added diethylaminosulfur trifluoride (66 mg, 0.410 mmol) and stirred for 30 min. The solution was concentrated to dryness and purified by flash chromatography on silica gel (0-100% EtOAc/hexanes) to afford 2-chloro-4-[cyclopropyl(fluoro)methyl]pyrimidine (20 mg, 0.107 mmol, 26% yield) as a colorless oil. MS ESI: [M+H]+ m/z 187.1. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=5.0, 1H), 7.43 (d, J=5.0, 1H), 4.93 (dd, J=7.4, 47.5, 1H), 1.13 (m, 1H), 0.70-0.60 (m, 4H).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O-])=[O:10])=[C:7]([CH2:12][CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.B.O>O1CCCC1>[F:23][CH:2]([F:1])[C:3]1[N:4]=[C:5]([C:19]([F:22])([F:20])[F:21])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([CH2:12][CH3:13])[C:8]=1[CH2:9][OH:10]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)[O-])c1CC
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(CO)c1CC
Temperature: 10 °C
Reaction time: 160 h
Yield: 84.9 %

Procedure:
To a dry 500 ml four-necked flask is charged 30.6 g (0.09 mole) of the product of Example 28 and 40 ml of tetrahydrofuran under nitrogen. The reaction mixture is cooled to 10° C. with an ice-water bath. To the above solution is added via a syringe 180 ml (0.18 mole) of 1M borane in tetrahydrofuran. The reaction mixture is stirred for 160 hours and poured into water. The organics are extracted into 300 ml of ether and the ether extract washed with 200 ml of saturated sodium bicarbonate, dried (MgSO4), and concentrated. The residue is crystallized from petroleum ether to give 25 g (84.9%) of the desired product, m.p. 59.5°-60.5° C.
Reaction SMILES: [NH:1]1C=NC=N1.P(Cl)(Cl)(Cl)=O.[N:11]1([C:19]([CH2:21][C@H:22]([CH2:35][OH:36])[O:23][CH2:24][P:25]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])=[O:20])[CH:18]=[CH:17][C:15](=O)[NH:14][C:12]1=[O:13]>N1C=CC=CC=1>[N:11]1([C:19]([CH2:21][C@H:22]([CH2:35][OH:36])[O:23][CH2:24][P:25]([O:31][CH:32]([CH3:34])[CH3:33])([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])=[O:20])[CH:18]=[CH:17][C:15]([NH2:1])=[N:14][C:12]1=[O:13]
Reactant: CC(C)OP(=O)(CO[C@@H](CO)CC(=O)n1ccc(=O)[nH]c1=O)OC(C)C
Reactant: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)OP(=O)(CO[C@@H](CO)CC(=O)n1ccc(N)nc1=O)OC(C)C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
To the solution of 1,2,4-triazole (662 mg, 9.6 mmol) in 15 mL pyridine was added phosphorousoxychloride (223 μL, 2.4 mmol) at room temperature. The mixture was stirred for 10 minutes. Then the solution of 21 (289 mg, 0.80 mmol) was added to the mixture. The reaction mixture was stirred for 4 hours. Then ammonia gas was bubbled in to the reaction mixture for 1-3 hours and the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH=12:1) to give compound 22 (220 mg, 0.58 mmol) as a colorless foam, in 73% yield, which was characterized as follows:
Reaction SMILES: Cl[C:2]1=[N:3][C:4]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2=[N:3][C:4]3[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc2c(c1)N=C(Cl)c1ccccc1O2
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)N=C(N1CCN(C)CC1)c1ccccc1O2
Temperature: 110 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
Compound 549 (1.06 g, 3.68 mmol) and 1-methylpiperazine (0.818 mL, 7.37 mmol) were dissolved in toluene (40 mL) and stirred at 110° C. for 16 h. The toluene was removed on the rotary evaporator. The crude product was dissolved in ethyl acetate and washed with water. The organic layer was separated and dried with Na2SO4, filtered and concentrated via rotary evaporation. The residue was purified via Isco employing a 0 to 50% methanol:ethyl acetate solvent gradient to afford compound 550 (0.86 g, 66%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=1[F:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:12][C:11]=1[F:19]
Reactant: OB(O)c1ccc(Br)c(F)c1
Reactant: Nc1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2ccc(Br)c(F)c2)cn1
Temperature: 120 °C

Procedure:
To a solution of 5-bromopyrimidin-2-amine (2.1 g, 0.012 mol) in 1,4-dioxane (30 mL) was added (4-bromo-3-fluorophenyl)boronic acid (2.0 g, 0.0091 mol), potassium phosphate (6.4 g, 0.030 mol) and tetrakis(triphenylphosphine)palladium (700 mg, 0.6 mmol), water (5 mL). The solution was degassed with N2, and heated at 120° C. for 4 h. The mixture was cooled to RT, poured into water, and extracted with EtOAc. The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-30%) to afford the desired compound. LCMS: (M+H)=267.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:10]1[C:11]([CH3:24])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][S:22][CH3:23])=[O:17])=[N:14][CH:15]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)(=[O:26])=[O:27])[C:10]1[C:11]([CH3:24])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:23])=[O:43])=[O:17])=[N:14][CH:15]=1
Reactant: CSCCCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCCS(C)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methyl-N-[3-(methylthio)propyl]pyridine-2-carboxamide (149 mg, 0.293 mmol) in methylene chloride (5 ml), 3-chloroperbenzoic acid (51 mg, 0.293 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes. 3-Chloroperbenzoic acid (20 mg, 0.116 mmol) was added to the reaction solution under ice cooling, and the resulting mixture was stirred for 15 minutes. 1 N aqueous sodium hydroxide was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with methanol:methylene chloride (=1:30) was concentrated under reduced pressure. Ethylacetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (122 mg, 0.232 mmol, 79%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: CNCCc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)CCc4ccccc4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methyl-2-phenylethylamine. ES-MS m/e (%): 504 (M+H+, 100).