Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH:5]1[O:10][C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:7]=2[O:6]1)=[O:4].O.[NH2:29][NH2:30]>C(O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:7]2[O:6][CH:5]([C:3]([NH:29][NH2:30])=[O:4])[O:10][C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:8]=2[CH:23]=1
Reactant: NN
Reactant: COC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Solvent: CCO
Solvent: O
Product: NNC(=O)C1Oc2ccc(Cl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Temperature: 25 °C

Procedure:
A solution of 2.47 g 6-chloro-4,4-dicyclohexyl-4H-benzo[1,3]dioxine-2-carboxylic acid methyl ester in 9 ml ethanol was added to a solution of 0.61 ml hydrazine monohydrate in 9 ml ethanol. The reaction mixture was refluxed for 1 h. After cooling to room temperature, the solvent was removed in vacuo. The crude product was purified by preparative HPLC (C18 reverse phase column, elution with water/TFA gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a solid. Yield: 1.1 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]([S:38](Cl)(=[O:40])=[O:39])([CH3:37])[CH3:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:38]([CH:35]([CH3:37])[CH3:36])(=[O:40])=[O:39])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)S(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, isopropylsulfonyl chloride.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH2:27][OH:28])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH2:27][O:28][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][O:26][S:39]([CH3:38])(=[O:41])=[O:40])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(CO)CO)cc2OCC3)n(C(C)C)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(COS(C)(=O)=O)COS(C)(=O)=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropane-1,3-diol (79.4 mg, 0.192 mmol) and Et3N (80 uL, 0.574 mmol) in DCM (10 mL) cooled at 0° C. was added methanesulfonyl chloride (37.4 uL, 0.48 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless gum (quantitative). LCMS (Method J): RT 2.98 min [M+H]+ 570.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[CH3:35][NH:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][C:47](O)=[O:48])[CH2:41][CH2:40]1)=[O:38]>>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:47](=[O:48])[CH2:46][CH2:45][N:42]1[CH2:43][CH2:44][N:39]([C:37]([NH:36][CH3:35])=[O:38])[CH2:40][CH2:41]1
Reactant: CNC(=O)N1CCN(CCC(=O)O)CC1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Product: CNC(=O)N1CCN(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)CC1

Procedure:
A mixture of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 3-(4-(methylcarbamoyl)piperazin-1-yl)propanoic acid was coupled as described for the preparation of 2 to give 4-(3-((2-((2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)(methyl)amino)-2-oxoethyl)amino)-3-oxopropyl)-N-methylpiperazine-1-carboxamide (7).
Reaction SMILES: C(O[C:4]1[N:14](CC2C=CC3NC4C=CC=CC=4CCC=3C=2)[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)C.[CH2:31](OC1NC2=NC(C)=CC(C)=C2N=1)[CH3:32]>>[CH2:31]([C:4]1[NH:14][C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:32]
Reactant: CCOc1nc2c(C)cc(C)nc2[nH]1
Reactant: CCOc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2
Product: CCc1nc2c(C)cc(C)nc2[nH]1

Procedure:
[step 1] 2-(2-Ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (324 mg, 33%) was obtained in the same manner as in step 1 of Example 1, using 2-ethoxy-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (478 mg, 2.50 mmol), obtained in Reference Example 2, instead of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:22][NH2:23]>C1C=CC=CC=1.CO>[CH3:22][N:23]=[CH:1][CH:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CN
Reactant: O=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Solvent: CO
Solvent: c1ccccc1
Product: CN=CC1CCSc2c1c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-formyl-9-phenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (1.4 g) in absolute benzene (20 ml) is added a 30% solution (1.5 ml) of methylamine in methanol. The mixture is stirred at room temperature for 3 hours and evaporated to give 4-methyliminomethyl-9-phenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole as orange solid. The product is dissolved in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) and sodium borohydride (274 mg) is added thereto. The mixture is stirred at room temperature for 1 hour and evaporated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](N(OC)C)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:14]2[CH2:16][CH2:15]2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)c1ccnc(Cl)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccnc(Cl)n1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a solution of 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (893 mg, 4.43 mmol) in THF (9 mL) at −78° C. under nitrogen atmosphere was added cyclopropyl magnesium bromide (0.5 M in THF, 13.3 mL, 6.64 mmol) dropwise. The solution was warmed to 0° C. and stirred for an additional 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness. Purification on silica gel by flash chromatography (0-100% EtOAc/hexanes) afforded (2-chloropyrimidin-4-yl)(cyclopropyl)methanone (360 mg, 1.97 mmol, 45% yield) as a colorless oil. MS ESI: [M+H]+ m/z 183.1. 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=4.9, 1H); 7.82 (d, J=4.9, 1H), 3.45-3.31 (m, 1H), 1.30 (m, 2H), 1.22 (m, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[C:5]([CH3:12])=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].O>CN1C(=O)CCC1>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:13]#[N:14])=[CH:3][CH:4]=[C:5]2[CH3:12])=[N:9]1
Reactant: Cc1ccc(Br)c2nn(C)cc12
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(C#N)c2nn(C)cc12
Temperature: 130 °C
Yield: 40 %

Procedure:
To a solution of 7-bromo-2,4-dimethyl-2H-indazole (1 eq.) in NMP, was added CuCN (2 equiv.) and heated at 130° C. for 16 h. On completion, water was added to quench the reaction, solid precipitated was filtered and purified by column chromatography to afford the title compound (40-60% yield)
Reaction SMILES: Br[C:2]1C=C(NC2C=CC(N3CCN(C(C)C)CC3)=CN=2)C(=O)N(C)[CH:7]=1.[Br:26][C:27]1[N:28]=[C:29]([NH:35][C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH2:42][NH:41][CH2:40][CH2:39]3)[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1>>[Br:26][C:27]1[N:28]=[C:29]([NH:35][C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[CH2:42][N:41]([CH2:2][CH3:7])[CH2:40][CH2:39]3)[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCNC3)c1=O
Reactant: CC(C)N1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Product: CCN1CCc2cc(Nc3nc(Br)cn(C)c3=O)ccc2C1

Procedure:
Following the procedures as described for 220a and starting with 385 mg of 5-bromo-1-methyl-3-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one (221a), 248a was obtained as yellow solid (292 mg, 70%). MS: [M+H]+ 364.
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([N+:24]([O-])=O)[C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:19]1[C:3]([NH:4][C:5]2[S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([Cl:1])[C:22]([Cl:23])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(Nc2c([N+](=O)[O-])ccc(Cl)c2Cl)sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2c(N)ccc(Cl)c2Cl)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(2,3-dichloro-6-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(6-amino-2,3-dichloroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([CH2:26][CH3:27])[C:10]1=[O:28])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:26]([N:11]1[C:12]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([F:25])=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([OH:8])[C:10]1=[O:28])[CH3:27]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)nc21

Procedure:
Following the procedure of Example 32, hydrogenation of 3-benzyloxy-1-ethyl-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example X-2, 110 mg, 0.286 mmol) and 10% Pd/C (60 mg) in MeOH (2 mL) and ethyl acetate (3 mL) afforded 55 mg, of the title compound as a solid, mp 236-237° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[CH:29]([OH:31])[CH3:30])=[O:8].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:29]([C:10]1[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:12]2[C:17]([C:9]=1[C:7]([NH:6][CH2:5][C:4]1[CH:32]=[CH:33][C:34]([F:35])=[C:2]([F:1])[CH:3]=1)=[O:8])=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=2)(=[O:31])[CH3:30]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)O)n(Cc3ccccn3)c2c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-2-(1-hydroxyethyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 108, 8.0 mg, 0.017 mmol) in CH2Cl2 (1 ml) was added NMO (6.0 mg, 0.051 mmol) and TPAP (0.6 mg, 0.0017 mmol). The reaction was stirred at room temperature for 1 h and was purified directly by PTLC (75% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=C=O)=[CH:42][CH:41]=1>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([NH:46][C:43]4[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=4)=[O:7])[CH2:13][CH2:12]3)=[CH:15][C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:17]2)=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloroquinoline-2-carboxylate (1.0 g, 2.4 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (5 mL). After 1 h at room temp., the reaction mixture is adjusted to pH 10–11 with 10% aq. NaOH and extracted with EtOAc. The combined extracts are dried (Na2SO4) and concentrated. The residue is dissolved in CH2Cl2 (70 mL) and treated with 4-fluorophenyl isocyanate (0.32 mL, 2.8 mmol) for 15 h at room temp. The reaction mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography with CH2Cl2-MeOH yielding the title product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1.[ClH:15].[H][H]>CCO.CCOC(C)=O.[Pd]>[ClH:15].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:3]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(F)cc1-n1cccn1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCc1ccc(F)cc1-n1cccn1
Reaction time: 20 h
Yield: 58.6 %

Procedure:
To a solution of 4-fluoro-2-pyrazol-1-yl-benzonitrile (500 mg, 2.67 mmol) in EtOH (10 mL) and EtOAc (10 mL) was added conc-HCl (0.25 mL, 3 mmol) and 10% Pd—C (100 mg). The mixture was hydrogenated at 1 atmosphere hydrogen for 20 h. To the mixture was added additional conc-HCl (0.15 mL) and 10% Pd—C (100 mg) and the mixture was further hydrogenated for additional 20 h. The mixture was filtered over Celite, washed with EtOH, and the combined filtrate and washings were concentrated in vacuo. The residual material was triturated with EtOH to obtain 356 mg of the title compound as the hydrochloride salt as an off-white crystalline solid: HPLC rt=1.01 min. LC/MS m/z 192 (M+H); 1H NMR (DMSO-d6, 500 MHz) δ ppm 3.99 (2H, s, 7-CH2), 6.63 (1H, t, J=2 Hz, 9-CH), 7.40 (1H, dt, J=8.5, 2.5 Hz, 5-CH), 7.54 (1H, dd, J=10, 2.5 Hz, 3-CH) 7.81 (1H, dd, J=8.5, 6 Hz, 6-CH), 7.86 (1H, d, J=1.5 Hz, 10-CH) 8.35 (1H, d, J=2 Hz, 8-CH), 8.54 (3H, br.s, NH3+); 13C NMR (DMSO-d6, 125.8 Hz) δ ppm 38.8 (7-CH2), 107.7 (9-CH2), 111.6 (d, J=25 Hz, 3-CH), 114.6 (d, J=21 Hz, 5-CH), 123.7 (d, J=3 Hz, 1-C), 131.7 (8-CH), 134.0 (d, J=9 Hz, 6-CH), 140.4 (d, J=11 Hz, 2-C), 141.5 (10-CH), 161.9 (d, J=247 Hz, 6-CF); HRMS (ESI) calcd for C10H11FN3 (M+H) 192.0937. found 192.0930 (δ −3.6 ppm).
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:13]1=[O:26])=O)C1C=CC=CC=1.C(O)(=O)C.[BrH:31]>C(OCC)C>[BrH:31].[NH2:11][CH:12]1[CH2:16][C:15](=[O:17])[N:14]([C:18]2[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:13]1=[O:26]
Reactant: O=C(NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
85 g of 3-(N-benzyloxycarbonylamino)-1-(3,5-dichlorophenyl)pyrrolidine-2,5-dione are mixed with 200 ml of a solution of glacial acetic acid which is saturated with hydrobromic acid, and the mixture is then stirred for 11/2 hours at room temperature. Then 1 liter of diethyl ether is added and the precipitated crystals are rapidly collected by filtration, washed with diethyl ether and dried over potassium hydroxide in vacuo. The hydrobromide is obtained in the form of colourless crystals which melt at 278°-280° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Product: O=C(Cl)c1ccc(Cl)nc1Cl

Procedure:
A solution of commercially available (Aldrich) 2,6-dichloro-nicotinic acid (2.0 g, 10.4 mmol) in thionyl chloride (10 mL) was heated to 80° C. for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-nicotinoyl chloride as yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:17](SCCC)[C:18]([NH2:20])=[O:19]>O1CCCC1.[Ni]>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH2:20])=[O:19]
Reactant: CCCSC(C(N)=O)c1cccc(C(=O)c2ccc(F)cc2)c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: NC(=O)Cc1cccc(C(=O)c2ccc(F)cc2)c1N
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A solution of 24.2 g (0.07mole) of 2-amino-3-(4-fluorobenzoyl)-α-(n-propylthio)phenylacetamide in 300 mL of tetrahydrofuran was treated with an excess of wet Raney nickel (washed three times with water and three times with tetrahydrofuran). The mixture was stirred for 1 h and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from 95% ethanol to afford 14.8 g (78%) of yellow needles melting at 184°-186° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(-c2ccc(O)cc2)c2c1C(=O)NC2
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(N)c3c2CNC3=O)cc1
Yield: 67.5 %

Procedure:
In a similar manner to Step 1 of Example 304, 7-amino-4-(4-hydroxyphenyl)isoindolinone (182 mg, 0.760 mmol) was dissolved in acetonitrile (9.1 mL), and the solution was treated with tert-butyldimethylsilyl chloride (206 mg, 1.37 mmol) and DBU (0.205 mL, 1.37 mmol), followed by purification by flash column chromatography (chloroform) to obtain 7-amino-4-(4-tert-butyldimethylsilyloxyphenyl)isoindolinone (182 mg, yield 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27](OC)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:31].CO.[C-]#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27]([NH2:31])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: N
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: NC(=O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A sealed tube was charged with methyl 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate (Example 59, Step A) (109 mg, 0.244 mmol), ammonia, 7N solution in methanol (2 ml, 14.00 mmol) and sodium cyanide (1.197 mg, 0.024 mmol). The tube was sealed and heated to 50° C. The pressure reached 35 kilopascals after 1 hour. The reaction was stirred at 50° C. for 18 h. The reaction was cooled to rt and anhydrous ammonia (gas) was bubbled through the solution for ten minutes at room temperature. The reaction mixture was capped and heated to 50° C. for 18 h. The reaction was cooled to rt and anhydrous ammonia (gas) was bubbled through the solution for twenty minutes at room temperature. The reaction mixture was capped and heated to 50° C. for 2 days. The crude reaction was concentrated under reduced pressure and purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[NH2:29][C@@H:30]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:31]([OH:42])[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([F:41])([F:40])[F:39].CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:29][C@@H:30]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C@H:31]([OH:42])[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]([F:41])([F:39])[F:40])=[O:16])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CN1CCC[C@H]1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1CCC[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 731 mg (3.12 mmol) of N-(tert-butoxycarbonyl)-L-asparagine in 6 ml of anhydrous DMF was treated at 0° C. with 530 mg (3.44 mmol) of HOBT and 1.39 g (3.28 mmol) of CMTC. A solution of 1,114 mg (2.84 mmol) of the compound from Example 3 and 1.6 ml (14.20 retool) of N-methylmorpholine in 8 ml of DMF was then added. The cooling bath was removed and the mixture was stirred at room temperature for 3 h. It was then concentrated in vacuo and the residue was partitioned between 40 ml of ethyl acetate and 40 ml of water. The water phase was extracted with 10 ml of ethyl acetate, and the combined extracts were washed with 50 ml of water and dried over MgSO4. After evaporation of the solvent in vacuo and chromatography of the crude product on 200 g of silica gel (dichloromethane:methanol 9:1), 1.42 g (89% of theory) of the title compound were obtained as crystals. Melting points: 104° C. Rf =0.15, I(9:1) MS(FAB): m/e=517 (M+H)+
Reaction SMILES: [C:1]([C:4]1[C:10]([F:11])=[CH:9][C:7]([NH2:8])=[C:6]([Cl:12])[CH:5]=1)(=[O:3])[CH3:2].[I:13]I>CC(O)=O>[C:1]([C:4]1[C:10]([F:11])=[C:9]([I:13])[C:7]([NH2:8])=[C:6]([Cl:12])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(N)cc1F
Reactant: II
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(N)c(I)c1F
Reaction time: 4 h

Procedure:
In 4.8 mL of HOAc, 0.5 g of 4-acetyl-2-chloro-5-fluoroaniline and 0.47 g of HgO are stirred under N2. At room temperature over 4 hours, 0.79 g of I2 is added and after stirring an additional hour, the mixture is filtered and the filter cake washed with 3 mL of AcOH To the filtrate and washed solution, 75 mL of H2O is added to precipitate the title compound, which is collected, washed with H2O and air dried to afford 0.83 g, m.p. 117°-119° C.