Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:24][CH:25]=[O:26])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][Mg+].[Br-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:24][CH:25]([OH:26])[CH3:27])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(F)cc1)N1CC[C@](CC=O)(c2ccc(F)cc2)OC1=O
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(F)cc2)C(=O)O1
Temperature: -78 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
To a solution of 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-fluorophenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetaldehyde (500 mg, 1.40 mmol) in anhydrous THF (100 mL) was added CH3MgBr (5 mL, 3 mol/L) at −78° C. under nitrogen. The formed mixture was stirred for 3 h at −78° C. The reaction was quenched by water. The organic phase was separated and concentrated to give the crude product, which was purified by TLC and chiral preparative HPLC to afford (6S)-6-(4-fluorophenyl)-3-((S)-1-(4-fluorophenyl)ethyl)-6-(2-hydroxypropyl)-1,3-oxazinan-2-one (19 mg, 4%). LC-MS Method 2 tR=1.92 min, m/z=398; 1H NMR: (400 MHz, CDCl3): δ=1.02 (d, 3H), 1.48 (d, 3H), 1.84 (m, 4H), 2.01 (m, 1H), 2.14 (m, 1H), 2.29 (m, 1H), 2.84 (m, 1H), 3.83 (m, 1H), 5.54 (q, 1H), 6.74 (m, 2H), 6.82 (m, 2H), 6.99 (m, 2H), 7.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1C(O)=O.C(=O)(O)[O-].[Na+].[Br:32]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:32][C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:23])=[CH:10][N:9]=2)[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C(=O)O)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Combined 5-methoxy-1-(5-(((tetrahydro-2H-pyran-4-yl)methyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (329.5 mg, 0.914 mmol) and sodium bicarbonate (307 mg, 3.66 mmol) in DMF (3 mL) then added 1-bromopyrrolidine-2,5-dione (163 mg, 0.914 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 30 minutes and then diluted with water (15 mL) to give a suspension. The suspension was filtered, rinsed with water (3×5 mL), and dried in vacuo to give the title compound (302 mg, 84% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.28 (m, 2 H) 1.62 (dd, J=12.88, 1.77 Hz, 2 H) 1.80 (dddt, J=14.78, 11.12, 7.39, 3.44, 3.44 Hz, 1 H) 3.16-3.23 (m, 2 H) 3.23-3.31 (m, 2 H) 3.81-3.89 (m, 2 H) 4.05 (s, 3 H) 7.79 (dd, J=8.59, 0.76 Hz, 1 H) 7.84 (s, 1 H) 8.38 (dd, J=8.46, 2.40 Hz, 1 H) 8.75 (t, J=5.81 Hz, 1 H) 8.96 (dd, J=2.53, 0.76 Hz, 1 H). MS m/z [M+H]+ 395.3, 397.3.
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH:17]=1)=O.[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[CH3:18][C:2]1[N:21]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]2=[N:19][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH:17]=1
Reactant: Cc1ccnc(N)c1
Reactant: CCC1Oc2ccc(C(=O)C(C)Br)cc2NC1=O
Product: CCC1Oc2ccc(-c3nc4cc(C)ccn4c3C)cc2NC1=O
Yield: 25.5 %

Procedure:
6-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.82 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.12 g) and 2-amino-4-methylpyridine (3.24 g). mp. 194°-195° C (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][CH2:13][C:14]([NH2:16])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[S:11])[NH:12][CH2:13][C:14]([NH2:16])=[O:15]
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: NCC(N)=O
Product: Cc1cccc(Cl)c1NC(=S)NCC(N)=O

Procedure:
2-[3-(2-Chloro-6-methylphenyl)-thioureido]-acetamide was prepared by the procedure described in Example 2 using 18.3 g of 2-chloro-6-methylphenyl-isothiocyanate and 12.0 g of glycinamide. 22.8 Grams of the product was obtained, m.p. 161°-163° C. (dec.). This compound was used without further purification in the next paragraph.
Reaction SMILES: [F:1][C@:2]1([CH3:20])[C:6]([OH:8])([CH3:7])[C@@H:5]([CH2:9][OH:10])[O:4][CH:3]1[N:11]1[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[NH:13][C:12]1=[O:19].C(=NC1CCCCC1)=NC1CCCCC1.[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].O>O1CCCC1>[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45]([O:10][CH2:9][C@@H:5]1[C:6]([OH:8])([CH3:7])[C@:2]([F:1])([CH3:20])[CH:3]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[NH:13][C:12]2=[O:19])[O:4]1)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1cn(C2O[C@H](CO)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(C2O[C@H](COC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a stirred solution of 1-((3R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3,4-dimethyltetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (about 0.05 g, 0.17 mmol) in tetrahydrofuran (about 5 ml) was added N,N-dimethyl amino pyridine (about 0.06 g, 0.52 mmol), N,N′-methanediylidenedicyclohexanamine (about 0.071 g, 0.34 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (about 0.09 g, 0.52 mmol) at about 0° C. and stirred at room temperature for about 1 hour. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 1.5% methanol in dichloromethane as eluent furnished title compound (0.03 g) as a colorless solid. Yield: 46.8%; 1H NMR (300 MHz, CDCl3): δ 8.08 (bs, 1H), 7.23-7.22 (m, 1H), 6.37 (d, 1H, J=23.4 Hz), 4.95 (bs, 1H), 4.45-4.25 (m, 3H), 3.40-3.34 (m, 1H), 1.95 (s, 3H), 1.45 (d, 3H, J=22.8 Hz), 1.44 (s, 9H), 1.41 (m, 3H), 1.27 (s, 3H), ES Mass: [M+Na] 482 (100%).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH:15]=2)[C:10]([CH3:36])=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:36][C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])=[CH:13][CH:12]=2)[N:8]([CH2:7][C:6]([OH:37])=[O:5])[CH:9]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(C)cn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(C)cn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], (3-methyl-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (3-methyl-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid as off-white solid.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:4]=1SC)#[N:2].[CH3:27][NH2:28]>C(O)C>[C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:4]=1[NH:28][CH3:27])#[N:2]
Reactant: CSc1ccc(-n2c(-c3ccc(F)cc3)nc(SC)c(C#N)c2=O)cc1
Reactant: CN
Solvent: CCO
Product: CNc1nc(-c2ccc(F)cc2)n(-c2ccc(SC)cc2)c(=O)c1C#N
Yield: 42 %

Procedure:
The title compound was prepared from 5-cyano-2-(4-fluorophenyl)-1-[4-(methylthio)phenyl)-4-(methylthio)-6-oxo-1,6-dihydropyrimidine (1 g, 2.6 mmol, prepared according to the procedure disclosed in example 2) in ethanol (10 ml) with methylamine (0.16 g, 5 mmol) was refluxed for 2 hr. Then the reaction mass poured on to ice and the resulted solid filtered, washed thoroughly with water. The solid thus obtained was purified by column chromatography using ethyl acetate and hexane mixture as eluent to yield title compound (0.4 g, yield 42%, mp 219-222° C. purity 95.3% by HPLC). 1H-NMR (CDCl3):δ 2.45 (s, 3H), 3.17-3.18 (d, 3H), 6.0 (s, 1H, NH, D2O exchangeable), 6.91-6.99 (m, 4H), 7.14-7.16 (d, 2H), 7.31-7.34 (m, 2H). IR (KBr) cm−1: 3279, 2981, 2931, 2208, 1736, 1651, 1604 (—C═O). MS m/z: 367.1 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[C:15]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:15]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][N:24]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1ccc(CCNCc2ccc(C(C)(C)C)cc2)cc1
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
87 mg (0.44 mol) of 5,6-difluoro-1H-indol-7-carboxylic acid, 113 mg (0.40 mmol) of (4-tert-butyl-benzyl)-[2-(4-methyl-phenyl)-ethyl]-amine and 84 mg (0.44 mmol) of EDC.HCl were dissolved in 4 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 69 mg (38%) product as a colorless viscous oil. MS (ISP) 461.3 (M+H)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]3)[CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:29][CH2:28][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH2:16][CH2:17]1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)ccn2)CC1
Reactant: NCC1CCCCC1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCCCC4)n3)ccn2)CC1
Temperature: 105 °C

Procedure:
A mixture of trans-N1-(6-fluoro-2,4′-bipyridin-2′-yl)cyclohexane-1,4-diamine (15 mg, 0.052 mmol), DMSO (0.4 ml), and cyclohexylmethanamine (59.3 mg, 0.524 mmol) was heated at about 105° C. for about 24 hours, or until the product pormation was completed, as indicated by LCMS. The excess amine was removed under reduced pressure to yield a residue. The residue was mixed with 0.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 11.3 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 380.3 (MH+), retention time=0.61 min. 1H NMR (400 MHz, METHANOL-d4, 45° C.) δ ppm 0.97-1.11 (m, 2 H) 1.17-1.36 (m, 3 H) 1.49-1.72 (m, 6 H) 1.71-1.80 (m, 2 H) 1.84 (d, J=12.91 Hz, 2 H) 2.11-2.28 (m, 4 H) 3.13-3.25 (m, 1 H) 3.28 (d, 2 H, App.) 3.65-3.75 (m, 1 H) 6.65 (d, J=8.61 Hz, 1 H) 7.16 (d, J=7.43 Hz, 1 H) 7.43-7.48 (m, 1 H) 7.52 (t, J=7.83 Hz, 1 H) 7.64 (s, 1 H) 7.85 (d, J=7.04 Hz, 1 H)
Reaction SMILES: [O-]S([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[C:18]([CH3:20])[CH:19]=1.Cl[CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32]>O.CN(C=O)C>[CH3:13][C:14]1[CH:15]=[C:16]([S:21]([CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])(=[O:23])=[O:22])[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3cc(C)cc(C)c3)c(C)o2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A solution of Na2SO3 (308 mg, 2.4 mmol) and Na2CO3 (259 mg, 2.4 mmol) in water (5 mL) was added to a suspension of 3,5-dimethylbenzenesulfonyl chloride (500 mg, 2.4 mmol) in water (5 mL) and the mixture was stirred at 100° C. for 2 h. The mixture was cooled, filtered, and the filtrate was made acidic with 1 M HCl and chilled at 0° C. for 2 h. The precipitate was filtered, washed with water (1 mL) and dried. A mixture of chloride 2 (289 mg, 1.08 mmol) and crude sulfinic acid (184 mg, 1.08 mmol) in dry DMF (10 mL) was stirred at 100° C. for 16 h. The mixture was cooled and diluted with ice/water (50 mL) and stirred for 15 min. The precipitate was filtered, washed with water (5 mL). The residue purified by column chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether, to give benzoate 25 (388 mg, 90%) as a white powder: mp (EtOAc) 141-143° C.; 1H NMR (CDCl3) δ 8.03 (ddd, J=8.6, 1.8, 1.5Hz, 2 H, H-2, H-6), 7.94 (ddd, J=8.6, 1.8, 1.5Hz, 2 H, H-3, H-5), 7.42 (br s, 2 H, H-2′, H-6′), 7.25 (br s, 1 H, H-4′), 4.28 (s, 2 H, CH2SO2), 3.94 (s, 3 H, OCH3), 2.35 (s, 3 H, CH3), 2.33 (s, 6 H, 2×CH3); MS m/z 400.5 (MH+, 100%). Anal. calcd for C21H21NO5S: C, 63.14; H, 5.30; N, 3.51. Found: C, 63.23; H, 5.28; N, 3.46%.
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[O:22])=[CH:14][CH:13]=3)[C:8]([CH2:10][CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].CS(C)=[O:38].OO.[OH-].[Na+]>O.CO>[CH2:10]([C:8]1[N:7]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:25])=[O:26])=[O:22])=[CH:16][CH:17]=2)[C:6]2[CH:34]=[CH:35][C:3]([C:1]([NH2:2])=[O:38])=[CH:4][C:5]=2[N:9]=1)[CH3:11]
Reactant: CS(C)=O
Reactant: CCc1nc2cc(C#N)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1nc2cc(C(N)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-[4-(5-cyano-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethanol (step 4 of Example 82, 200 mg, 0.68 mmol), DMSO (0.06 mL, 0.82 mmol) and methanol (10 mL) was added 30% aqueous solution of hydrogen peroxide (0.12 mL, 1.0 mmol) and 0.2 M aqueous NaOH (0.06 mL). The mixture was stirred at 50° C. for 4 h, then cooled. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous NaOH (50 mL) and brine (50 mL), then dried (Na2SO4), and concentrated to afford the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 8.23 (1H, d, J=1.1 Hz), 7.96 (1H, br.s), 7.76 (1H, dd, J=1.1 Hz, 8.4 Hz), 7.42-7.51 (4H, m), 7.25 (1H, br.s), 7.09 (1H, d, J=8.4 Hz), 3.70 (2H, t, J=6.6 Hz), 2.85 (2H, t, J=6.9 Hz), 2.76 (2H, q, J=7.4 Hz), 1.24 (3H, t, J=7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=O)[C:8]([CH3:14])=[C:7]2[C:3]=1[C:4]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:5]=1[NH:6]2.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)=[O:13])[C:8]([CH3:14])=[C:7]2[C:3]=1[C:4]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:5]=1[NH:6]2
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)O)cc(Cl)c3c2c1
Reactant: CN1CCC(N)CC1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NC4CCN(C)CC4)cc(Cl)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylic acid and 1-methylpiperidin-4-amine using an analogous procedure to that described in the preparation of Compound 88. 1H NMR (400 MHz, DMSO-d6 with TFD) δ ppm 1.70-2.2 (m, 4H) 2.53 (br. s., 3H) 2.58 (s, 3H) 2.74-2.82 (m, 3H) 2.80-4.10 (m, 5H) 7.29 (s, 1H) 8.47 (s, 1H) 8.70 (s, 1H). [M+H] calc'd for C20H18N2O2S 371; found, 371.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:28]1(CS(Cl)(=O)=O)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH2:26][CH:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)(=[O:24])=[O:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: O=S(=O)(Cl)CC1CCCC1
Product: O=S(=O)(CC1CCCC1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 58 %

Procedure:
According to the procedure for compound 398 using cyclopentylmethyl sulfonyl chloride (30 mg, 0.16 mmol) afforded 26.7 mg (58% yield) of 479, as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[CH:6]=[O:7].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.[Cl-].[NH4+]>C1COCC1>[CH:11]1([CH:6]([C:5]2[CH:8]=[CH:9][N:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[OH:7])[CH2:13][CH2:12]1
Reactant: Br[Mg]C1CC1
Reactant: COc1cc(C=O)ccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(O)C2CC2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a solution of 2-methoxyisonicotinaldehyde (4.33 g) in THF (100 mL) was added 0.60 M cyclopropylmagnesium bromide (63.1 mL) at 0° C., and the mixture was stirred at 0° C. for 10 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (5.30 g) as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>CCCCCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:19])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
13bk) 49.4 g of 4-bromo-2-chloro-benzoic acid were suspended in 60 ml of hexane, treated with 0.2 ml of N,N-dimethylformamide and 18.5 ml of thionyl chloride and boiled at reflux under argon for 15 hrs. The resulting solution was cooled to room temperature, filtered, evaporated and the residue was again evaporated with 60 ml of toluene. There were obtained 53 g (99%) of 4-bromo-2-chloro-benzoylchloride as a crude oil which crystallized upon standing, but which was used directly in the next step without further manipulation.
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH:3]=[CH:4][CH2:5][OH:6]>CO.[Ni]>[F:1][C:2]([F:11])([C:7]([F:8])([F:9])[F:10])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: OCC=CC(F)(F)C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: OCCCC(F)(F)C(F)(F)F

Procedure:
10 g of 4,4,5,5,5-pentafluoro-2-penten-1-ol (obtained according to J. Am. Chem. Soc., 107, (1985), 5186-5191: T. Kitazume and N. Ishikawa) is dissolved in 100 cm3 of methanol, and hydrogenation is carried out in the presence of 0.5 g of Raney nickel. The catalyst is filtered, followed by washing with ethanol and after distillation at ordinary pressure, the expected alcohol is collected B.p.: 133° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:35][OH:36]>C(N=C=O)(C)C>[CH:3]([NH:11][C:35]([N:32]1[CH2:31][CH2:30][N:29]([C:25]2[CH:26]=[C:27]([CH3:28])[C:21]3[N:20]=[C:19]([C:13]4[C:14](=[O:18])[NH:15][CH:16]=[CH:17][C:12]=4[NH:11][C@H:3]([CH2:2][OH:1])[CH2:4][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:23][C:22]=3[CH:24]=2)[CH2:34][CH2:33]1)=[O:36])([CH3:4])[CH3:2]
Reactant: CO
Reactant: Cc1cc(N2CCNCC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Agent: CC(C)N=C=O
Product: Cc1cc(N2CCN(C(=O)NC(C)C)CC2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
To a solution of (S)-4-(1-hydroxymethyl-2-phenyl-ethylamino)-3-(4-methyl-6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one (30 mg, 0.063 mmol) in methanol (2 mL) was added isopropyl isocyanate (2 drops). The reaction mixture was stirred at room temperature for 5 min. Concentration gave the residue, which was purified by prep. HPLC to yield the title compound (23.8 mg, 69%). 1H NMR (400 MHz, CD3OD) δ 7.55 (1H, s), 7.14–7.28 (7H, m), 6.12 (1H, d, J=7.8 Hz), 4.01–4.03 (1H, m), 3.92 (quintet, J=6.6 Hz), 3.80 (4H, m), 3.76 (1H, dd, J=4.8, 11.2 Hz), 3.70 (1H, dd, J=5.2, 11.2 Hz), 3.61–3.64 (4H, m), 3.09 (11H, dd, J=5.6, 13.7 Hz), 2.91 (1H, dd, J=8.0, 13.7 Hz), 2.64 (3H, s), 1.19 (6H, d, J=6.8 Hz). LCMS (M+H)+ m/z 545 (t=1.99 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:22]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:26]([O:25][C:23]([CH:22]([N:8]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)C(Br)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.20 g (4.47 mmol) of tert-butyl 5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIa) were dissolved in dry DMF (15 ml) in a heat-dried flask under a nitrogen atmosphere. 187 mg (4.69 mmol) of sodium hydride (60% suspension in mineral oil) were added while stirring at 0° C., and the reaction solution was then stirred at room temperature for 30 min. After renewed cooling in an ice bath, 1.40 g (4.91 mmol) of tert-butyl 2-bromo-3-phenylpropionate were added, and the mixture was stirred while cooling in ice for 1 h and then at room temperature for 2 h. The reaction solution was diluted with ethyl acetate, mixed with 10% aqueous ammonium chloride solution and then extracted with ethyl acetate (3×). The combined organic phases were washed with water and saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 15-30% ethyl acetate in heptane). Yield: 1.3 g (62%) of colorless oil