Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.C[O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:47]=[C:46]3[C:42]=2[CH:43]=[CH:44][NH:45]3)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:48]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[C:41]([NH:40][S:37]([C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:49]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cc3[nH]ccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(=O)(=O)c4ccc(O)cc4)c4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.18 mmol) were added 4-methoxy-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-4-yl)benzenesulfonamide (137 mg, 0.27 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (14 mg, 0.02 mmol) and 182 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified using SP1® Purification System (50% to 100%, hexane-ethyl acetate) to obtain 27 mg (21% yield, 95% purity) and 98 mg (72% yield, 88% purity) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
4-Nitrophenyl sulfonyl chloride (1.1 g, 5.4 mmol) was added in one portion to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.9 mmol) and diisopropylethylamine in THF (10 ml). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, after which time the solvent was removed under vacuum to give the title compound (1.92 g, 100% yield) as an orange solid which was used without further purification. Tr=2.00 min m/z (ES+) (M+Na+) 408.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH2:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:17][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([C:8]3[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N)cc1-c1ccnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1ccnn1C(C)C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 4-fluoro phenyl isocyanate (0.0652 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 44 as a colorless solid (0.050 g, 30%). LCMS m/z (%)=369 M+H+, (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (bs, 1H), 8.52 (bs, 1H), 7.42-7.35 (m, 4H), 7.28-7.27 (d, J=2.7 Hz, 1H), 7.057 (m, 3H), 6.07 (d, J=1.76 Hz, 1H), 4.10 (m, 1H), 3.66 (s, 3H), 1.24 (d, J=6.56 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[CH:9]=2)[O:6][C:5](=[O:7])[N:4]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3]1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C2(C)CNC(=O)O2)cc1OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)CN(Cc3ccccc3)C(=O)O2)cc1OCC1CC1
Reaction time: 2 h
Yield: 52.6 %

Procedure:
500 mg (1.8 mmol) of 5-methyl-5-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxazolidinone was first agitated with 75 mg (3.1 mmol) of sodium hydride in 17 ml of dimethylformamide for 30 minutes and, after adding 0.32 ml (2.7 mmol) of benzyl bromide, for 2 hours at room temperature. The procedure was continued analogously to Example 10, thus obtaining 348 mg of 5-methyl-5(3-cyclopropylmethoxy-4-methoxyphenyl)-3-benzyl-2-oxazolidinone as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])O)[CH2:10][CH2:9]1.[CH3:24][S:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2>ClCCl>[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[C:32]2[C:31]3[C:35](=[C:27]([CH2:26][S:25][CH3:24])[CH:28]=[CH:29][CH:30]=3)[NH:34][CH:33]=2)[CH2:10][CH2:9]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(C(F)(F)F)cc1F)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.66 ml (8.61 mmol) of trifluoroacetic acid was added to 1.68 g (7.18 mmol) of the compound from Example 148A and 1.27 g (7.18 mmol) of the compound from Example 8A in 80 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 80.0 mg (3% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][N:29]([C@H:11]([CH3:12])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:10])[CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH2:30][CH:31]=2)=[N:24][CH:25]=1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Clc1ccc(C2=CCNCC2)nc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](N1CC=C(c2ccc(Cl)cn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 63.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-chloro-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (1.31 g, 6.7 mmol) were dissolved in acetonitrile (20 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.88 g of the intended substance (yield 63.8%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21](O)=[O:22])=[CH:15]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21]([C:16]3[CH:17]=[CH:18][C:19](=[O:20])[N:14]([CH3:13])[CH:15]=3)=[O:22])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1cc(C(=O)O)ccc1=O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1cc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 0.87 mmol, Example 1, Step H), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.17 g, 1.13 mmol) and BOP-Cl (0.33 g, 1.30 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.22 g, 69% yield) as a solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.C(N(CC)CC)C.[C:16](=O)([O-:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1.ClCCl>[OH:8][CH2:7][CH2:6][C:4]1[CH:5]=[N:1][N:2]([C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH:3]=1
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: OCCc1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(CCO)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.10 g (9.81 mmol) 2-(1H-pyrazol-4-yl)-ethanol, 0.20 g (1.64 mmol) 4-dimethylaminopyridine and 1.50 ml (10.3 mmol) triethylamine were placed in 30 ml dichloromethane, the reaction mixture was cooled to 0° C. and 2.20 g (9.88 mmol) tert. butyl carbonate was slowly added. The mixture was stirred for 2 h at ambient temperature and then overnight at ambient temperature. It was diluted with 50 ml dichloromethane and washed with 10% citric acid solution and 15% potassium carbonate solution, the organic phase was dried, filtered and the solvent was eliminated from the filtrate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[C:23]([F:26])([F:25])[F:24]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([C:23]([F:26])([F:24])[F:25])[CH:15]=2)(=[O:21])=[O:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1nccnc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
To a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester (153 mg, 1.0 mmol) in 2.0 mL of pyridine was added 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (279 mg, 1.0 mmol) in 1.0 mL of pyridine. The mixture was stirred at room temperature for 16 h, diluted with 15 mL of ethyl acetate, washed twice with 1M HCl (15 mL), dried on MgSO4 and the solvent was evaporated. The product was purified on silica gel column (15% ethyl acetate in hexane) to afford 185 mg of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylic acid methyl ester as white powder. MS: (M+H)/z=396.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:19][CH:18]=3)[C:12]([CH2:14][CH3:15])=[N:13][C:8]2=[C:7]([CH3:34])[CH:6]=1.[C:35](Cl)([CH3:37])=[O:36].C(N(CC)CC)C>C1COCC1>[C:35]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:21][CH:22]=3)[C:12]([CH2:14][CH3:15])=[N:13][C:8]2=[C:7]([CH3:34])[CH:6]=1)(=[O:36])[CH3:37]
Reactant: CCc1nc2c(C)cc(NCCN)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(NCCNC(C)=O)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h

Procedure:
To 5-(2-aminoethyl)amino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (20 mg) in THF (1 mL) at °C. was added AcCl (3.4 μL) and triethylamine (18 μL). After 1 h, the solvent was evaporated and the residue was purified (SiO2, 80:20:1CHCl3, MeOH, NH4OH) to give 17 mg of the title compound. 1H NMR (300 MHz, CD3OD) δ 7.63-7.45 (m, 4H), 7.18-7.04 (AB q, 4H), 6.33 (s, 1H), 5.43 (s, 2H), 3.47 (t, 2H J=5 Hz), 3.38 (t, 2H J=5 Hz), 2.86 (q, 2H, J=7.8 Hz), 2.47 (s, 3H), 1.90 (s, 3H), 1.22 (t, 3H, J=7.8 Hz).
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][CH2:23]C#N>>[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][CH2:23][C:13]1[NH:2][C:3](=[O:12])[C:4]2[C:5]([CH:11]=1)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2
Reactant: N#CCCN1CCCCC1CO
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CCCCC3CO)cc12
Yield: 9.9 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (3.17 g) and 3-(2-hydroxymethylpiperidin-1-yl)propionitrile (1.51 g), 3-[2-(2-hydroxymethylpiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (268 mg) was obtained.
Reaction SMILES: [CH:1]([N:14]1[C:18]2[CH:19]=[C:20]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[O:30]CC3C=CC=CC=3)[CH:21]=[CH:22][C:17]=2[O:16][C:15]1=[O:38])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C.CO>[CH:1]([N:14]1[C:18]2[CH:19]=[C:20]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[OH:30])[CH:21]=[CH:22][C:17]=2[O:16][C:15]1=[O:38])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c(-c2ccc3oc(=O)n(C(c4ccccc4)c4ccccc4)c3c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(O)c(-c2ccc3oc(=O)n(C(c4ccccc4)c4ccccc4)c3c2)c1
Reaction time: 16 h
Yield: 98 %

Procedure:
A mixture of 3-benzhydryl-5-(2-(benzyloxy)-5-methylphenyl)benzo[d]oxazol-2(3H)-one (1.0 g, 2.0 mmol) and palladium on activated charcoal (10% w/w, 0.20 g) in ethyl acetate/methanol (1:1 v/v, 20 mL) was stirred under an atmosphere of hydrogen (1 atm) for 16 h. The reaction mixture was filtered through a pad of diatomaceous earth and the pad was washed with ethyl acetate/methanol (1:1 v/v, 20 mL). The filtrate and washes were combined and concentrated in vacuo. The residue was purified by column chromatography eluting with a 20-65% gradient of ethyl acetate in hexanes to afford 3-benzhydryl-5-(2-hydroxy-5-methylphenyl)benzo[d]oxazol-2(3H)-one as a colorless solid in 98% yield (0.80 g): 1H NMR (300 MHz, CDCl3) δ 7.38-7.32 (m, 6H), 7.30-7.24 (m, 5H), 7.17-7.12 (m, 1H), 6.99 (dd, J=8.2, 1.6 Hz, 1H), 6.84 (s, 1H), 6.79-6.73 (m, 2H), 6.51 (s, 1H), 4.68 (s, 1H), 2.24 (s, 3H); MS (ES+) m/z 407.8 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27](O)=[O:28])[N:11]=1.CCN(CC)CC.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]([N:56]2[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]2)=[O:28])[N:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1cccc(C)c1Nc1nn(CC(=O)O)c2cc(Nc3ccccc3)ccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1Nc1nn(CC(=O)N2CCN(C)CC2)c2cc(Nc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 100 mg (0.26 mmol) of 2-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-indazol-1-yl)acetic acid 69 (Example 34) in DCM (10 mL) at room temperature was treated with Et3N (43 μL, 1.2 eq) followed with Bop-Cl (73 mg, 1.1 eq) and 1-methylpiperazine (35 μL, 1.2 eq). The mixture was stirred at room temperature for 3 hours before it was quenched with water (5 mL). The organic layer was separated and washed with water, brine, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (eluens: DCM:MeOH:NH4OH, 20:1:0.2) to give the title compound 70. 1H-NMR (CDCl3) δ 2.28 (s, 6H), 2.32 (s, 3H), 2.35-2.45 (m, 4H), 3.59-3.69 (m, 4H), 4.98 (s, 2H), 5.91 (s, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.08-7.16 (m, 3H), 7.19 (s, 1H), 7.32 (t, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.58 (d, J=7.7 Hz, 2H). Mass Spectrum (ESI) m/e=471 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])=[O:10]
Reactant: COCCOCCO
Reactant: O=C(O)CCCCCCCBr
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)CCCCCCCBr
Yield: 78.4 %

Procedure:
8-Bromooctanoic acid (22.3 g), 2-(2-methoxyethoxy)-ethanol (14.08 g) and p-toluenesulphouic acid (0.1 g) were added to toluene (250 ml ) and the resulting soution heated at reflux temperature for 16 hours. Ethyl acetate (500 ml) was then added and the solution washed with aqueous K2CO3 solution and water, dried and evaporated. The residual oil was distilled to give 2-(2-methoxyethoxy)-ethyl 8-bromooctanoate (25.5 g), 77%) as a colourless oil, b.p. 126°-128° C./0.08 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH:37]=O)([CH3:32])([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:37][CH2:36][NH:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:39])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.7 %

Procedure:
To a solution of 2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (0.378 g, 1.00 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester (0.159 g, 1.00 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.223 g, 1.05 mmol). The mixture was stirred at room temperature for 15 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL). The extracts were dried over Na2SO4 and concentrated. Purification of the crude material by column chromatography on silica gel (98:1:1 CH2Cl2—CH3OH—NH4OH) provided 499 mg (96%) of 2-{[(2-tert-butoxycarbonylamino-ethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester as a yellow foam. 1H NMR (CDCl3) δ 1.48 (s, 9H), 1.64 (s, 9H), 1.69-1.85 (m, 2H), 1.94-1.99 (m, 1H), 2.24 (m,1H), 2.61-2.87 (m, 3H), 3.09-3.19 (m, 3H), 4.07 (dd, J=9.9 Hz, 5.7 Hz, 1H), 4.26 (d, J=16.2 Hz, 1H), 4.52 (d, J=16.2 Hz, 1H), 6.98 (dd, 1H, J=7.7 Hz, 4.7 Hz, 1H), 7.26-7.32 (m, 3H), 7.57 (brs, 1H), 7.74 (m, 1H), 7.86 (m, 1H), 8.41 (d, J=3.9 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:23]([C:29]2[N:33](COCC[Si](C)(C)C)[C:32]3[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:31]=3[N:30]=2)(O)[C:24]([F:27])([F:26])[F:25])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:7]=[CH:6]2)[CH3:2].C(C1C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)(O)C(F)(F)F)=C2C(=C(C)C=1)[N:55](S(C1C=CC(C)=CC=1)(=O)=O)[CH:54]=C2)C.CN>CO.C(O)C>[CH2:1]([C:3]1[C:4]([C:23]([C:29]2[NH:33][C:32]3[CH:42]=[CH:43][C:44]([C:46]#[N:47])=[CH:45][C:31]=3[N:30]=2)([NH:55][CH3:54])[C:24]([F:25])([F:27])[F:26])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:14])=[O:15])[CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CN
Solvent: CO
Solvent: CCO
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(NC)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F

Procedure:
The title compound was synthesized from a mixture of (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 105-A, methylamine in MeOH was used instead of ammonia in ethanol. MS (ESI+) m/z 566.79 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:29][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[C:12]([O:11][C:9]([N:5]1[CH2:6][C:7](=[O:29])[CH2:8][CH:4]1[C:3]([O:2][CH3:1])=[O:16])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 57 %

Procedure:
To a stirred solution of N-Boc proline methyl ester (2 .0 g, 8.15 mmol) in CH2Cl2 were added 3 A molecular sieves (2 g) and PDC (4.60 g, 12.2 mmol). The mixture was stirred for 3 days. The mixture was filtered through a Celiete pad and the filtrate was evaporated. The residue was chromatographed on silica gel with CHCl3—MeOH (10:1) as eluent to give methyl 1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylate (1.13 g, 57%) as a colorless oil. 1H-NMR (CDCl3) δ1.46-1.48 (m, 9 H), 2.56-2.61 (m, 1 H), 2.88-3.00 (m, 1 H), 3.77 (s, 3 H), 3.82-3.88 (m, 2 H), 4.71-4.83 (m, 1 H).