Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9]1[N:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O.[CH3:19]OC(OC)OC.C(O)(C(F)(F)F)=O>CO.[Ni]>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:9]2=[N:14][C:13]([OH:15])=[CH:12][CH:11]=[C:10]2[N:16]=[CH:19]1
Reactant: COC(OC)OC
Reactant: CC1CCCCC1Nc1nc(O)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC1CCCCC1n1cnc2ccc(O)nc21
Yield: 40.2 %

Procedure:
6-(2-Methylcyclohexylamino)-5-nitropyridin-2-ol (100 mg, 0.398 mmol) and nickel (11.68 mg, 0.199 mmol) in MeOH (10 mL) were stirred at 22° C. for 24 hr under H2. After filtration through Celite®, the solution was concentrated in the presence of a few drops of TFA. The residue was dissolved in trimethoxymethane (2112 mg, 19.90 mmol) and stirred overnight with a drop of TFA. The mixture was concentrated. The residue was diluted with water, neutralized with NaHCO3 solution and extracted with EtOAC. The EtOAc extract was concentrated and the residue was purified by column chromatography to give the title compound as a brown oil (37 mg). LCMS m/z=232.10 [M+H]+, 1H NMR (400 MHz, CDCl3) major isomer; δ ppm 0.75 (d, J=6.3 Hz, 3H), 1.22-2.20 (m, 9H), 4.18-4.27 (m, 1H), 6.89 (d, J=8.9 Hz, 1H), 8.17 (d, J=8.9 Hz, 1H), 8.52 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[NH:9]C(=O)O[C:12](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH3:16]>CN(C=O)C>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[C:12]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([CH:15]([CH2:17][CH3:18])[CH3:16])=[CH:20][CH:21]=1)=[O:13]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: COc1cccc2c(=O)oc(=O)[nH]c12
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2cccc(OC)c2N)cc1

Procedure:
A solution of 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (0.50 g, 2.6 mmol) and 4-sec-butylaniline (0.42 g, 2.8 mmol) in DMF (4.0 mL) were stirred at 110° C. under N2 for 24 hours. The mixture was concentrated to dryness then purified by column chromatography on silica gel using ½ EtOAc/hexane as eluent to afford 2-amino-N-(4-sec-butyl-phenyl)-3-methoxy-benzamide as white solid. Yield: 0.533 g (69%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]([OH:17])=[O:16])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N(CC(=O)O)Cc2ccc(Cl)cc2)C1
Temperature: 80 °C

Procedure:
A solution of 3-[(4-chloro-benzyl)-methoxycarbonylmethyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.31 mmol) in methanol (4.00 mL) and 1.0 N NaOH (aqueous) (4.00 mL) was heated to reflux at 80° C. for 2.5 h. The reaction mixture was concentrated, acidified to pH 5.0 using 1.0 N HCl and extracted with dichloromethane (3×). The product was used for the next step without further purification. ESI-MS m/z: 369 (M+1), UV retention time: 1.85 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.[H-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][O:7]2)[CH:6]=1
Reactant: Cc1cn[nH]c1
Reactant: C1=COCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn(C2CCCCO2)c1
Temperature: 90 °C
Reaction time: 20 h
Yield: 83.2 %

Procedure:
Trifluoroacetic acid (40.0 uL, 0.519 mmol) was added to a solution of 4-methylpyrazole (0.901 g, 11.0 mmol) in dihydropyran (2.0 mL, 22 mmol). The reaction mixture was stirred at 90° C. for 20 hours. The mixture was cooled to room temperature, and then quenched with Sodium hydride (92 mg, 2.3 mmol). After stirring at room temperature for 10 minutes more, the solvent was removed under vacuum. The residue was suspended in dichloromethane, and passed through a short plug of silica, rinsed with dichloromethane. The filtrate was evaporated in vacuo to yield 1.5213 g (83%) of 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole. LCMS (ESI): M+H=167.4; 1H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 7.27 (s, 1H), 5.29 (d, J=9.9 Hz, 1H), 3.89 (d, J=11.2 Hz, 1H), 3.64-3.51 (m, 1H), 2.00 (overlapping s and m, 4H), 1.88 (dd, J=27.1, 13.0 Hz, 1H), 1.64 (m, 1H), 1.51 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:5].O.NN>C(O)C.[Ni]>[CH3:16][N:2]([CH3:1])[CH2:3][CH:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:5]
Reactant: CC(CN(C)C)Nc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(CN(C)C)Nc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of N1,N1-Dimethyl-N2-(4-nitro-phenyl)-propane-1,2-diamine (446 mg, 2 mmol) in absolute ethanol (20 mL) was added hydrazine monohydrate (0.78 mL, 8 equiv.) followed by the addition of a small portion of Raney nickel. The reaction mixture was heated to 50° C. with stirring for 2 h at which point all gas evolution had ceased. The reaction mixture was filtered through celite to remove the Raney nickel. The filtrate was concentrated under reduced pressure to give the N-(2-Dimethylamino-1-methyl-ethyl)-benzene-1,4-diamine as a brown oil. This material was carried on in subsequent steps without purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=O.[NH3:17]>>[NH2:17][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:2]
Reactant: N
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Product: NC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
4-(Methoxycarbonyl)-3-nitrobenzoic acid (100 g, 0.44 mol) was taken into concentrated aqueous ammonia (37w %, 500 mL), and the resulting yellow solution was allowed to stir at room temperature over 12 hours. The solution was then reduced in volume to approximately 300 mL by rotary evaporation, and the solution was acidified to pH 2 by portion-wise addition of concentrated aqueous hydrochloric acid. The thick precipitate was collected by filtration and dried in vacuo to afford 4-(aminocarbonyl)-3-nitrobenzoic acid (51 g, 60% yield). 1H-NMR (d6-DMSO): 8.42 (d, 1H), 8.27 (dd, 1H), 8.26 (br s, 1H), 7.86 (br s, 1H), 7.76 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]#[N:14])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH:11]=[O:12])=[CH:7]2.[C-]#N.[Na+].[CH3:18][OH:19]>[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([C:13]#[N:14])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:19][CH3:18])=[O:12])=[CH:7]2
Reactant: CO
Reactant: N#Cc1cc(Br)c2[nH]c(C=O)cc2c1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Product: COC(=O)c1cc2cc(C#N)cc(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 17 h
Yield: 55 %

Procedure:
To a stirred solution of 7-bromo-2-formyl-1H-indole-5-carbonitrile (0.17 g, 683 μmol) in MeOH (6.03 ml) was added sodium cyanide (167 mg, 3.41 mmol) and manganese dioxide (297 mg, 3.41 mmol) and the reaction mixture was allowed to stir for 17 h at room temperature. The mixture was evaporated, water (20 ml) was added and the mixture was extracted with ethyl acetate (2×15 ml). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The crude product (0.11 g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) to yield methyl 7-bromo-5-cyano-1H-indole-2-carboxylate (0.105 g, 55%) as an orange solid, MS (ISN) m/z=279.3 [(M−H)+], mp 248° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[S:37][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:40]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:39][CH:40]=1)(=[O:34])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-Trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic-acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.4) (0.405 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.414 g, 1.2 mmol) according to the general procedure III. Obtained as an off-white solid (0.44 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][C:32]([O:34]C)=[O:33])[C:6]=2[CH:36]=1.[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]=2[CH:36]=1
Reactant: COC(=O)COC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
To a suspension of 7-chloro-5-methoxycarbonylmethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in ethanol (5 ml) is added 5N aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction mixture, and the mixture is made weak acidic by adding thereto diluted hydrochloric acid, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from diethyl ether to give 7-chloro-5-carboxymethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.38 g) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([C:14]2[C:15]([CH3:21])([CH3:20])[C:16](=[O:19])[NH:17][N:18]=2)=[CH:5][CH:4]=1.CC1C=CC(S(O[CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([C:14]2[C:15]([CH3:21])([CH3:20])[C:16](=[O:19])[N:17]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[N:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NNC(=O)C2(C)C)c2c1OC(C)(C)C2
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C5) and tert-butyl 4-{[(4-methylphenyl)sulfonyl]oxy}piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B5*HCl)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=O)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:40])[CH2:21][N:22](C(C1C2C(=CC(OC)=CC=2)C(OC)=CC=1)=S)[CH3:23]>>[CH3:18][O:19][C:20](=[O:40])[CH2:21][N:22]([C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17])[CH3:23]
Reactant: COc1ccc2c(C(=O)O)ccc(OC)c2c1
Reactant: COC(=O)CN(C)C(=S)c1ccc(OC)c2cc(OC)ccc12
Product: COC(=O)CN(C)C(=O)c1ccc(OC)c2cc(OC)ccc12

Procedure:
By following serially the procedures of examples 2 and 3 and using an equivalent amount of 4,6-dimethoxy-1-naphthalenecarboxylic acid of example 61 instead of 5-bromo-1-naphthalenecarboxylic acid; N-[(4,6-dimethoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester (I, R1 and R2 =CH3, R3 =4-CH3O, R4 =6-CH3O and R5 =H); mp 105°-107° C.; NMR (CDCl3) δ 3.05 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 4.0 (s, 3H), 4.8 (2d, J=20 Hz, 2H), 7.3 (m, 5H); was obtained via N-[(4,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester; NMR (CDCl3) δ 2.75 (s, 1H), 3.7 (s, 3H), 3.9 (s, 3H), 4.0 (s, 3H), 4.35 (s, 2H), 7.4 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][C@@H:28]([O:32]C(=O)C5C=CC([N+]([O-])=O)=CC=5)[C:24]=4[N:25]=[CH:26][N:27]=3)[C:5]2=[CH:6][CH:7]=1.C(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][C@@H:28]([OH:32])[C:24]=4[N:25]=[CH:26][N:27]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)C4)c4cc(Cl)ccc43)c21
Agent: CC(C)(C)OC=O
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)C4)c4cc(Cl)ccc43)c21

Procedure:
tert-butyl 5-chloro-1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was prepared by the procedures described in Example 3, Step 12, substituting tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate with tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate. LCMS (APCI+) m/z 357.1 [M+H-Boc]+; Rt=3.86.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:24][CH2:25]1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: c1cnc(N2CCNCC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3cnccn3)CC2)cc1
Yield: 69.9 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.6 g), 1-(pyrazin-2-yl)piperazine (1.3 g) and potassium carbonate (1.6 g) in dimethylformamide (20 ml) was stirred at 70-80° C. for 7 hr. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give a pale-yellow solid (1.8 g). The obtained pale-yellow solid was crystallized from hexane-ethyl acetate to give the title compound (1.2 g) as pale-yellow crystals, m.p.=118-119° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.C([Sn](CCCC)(CCCC)[C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccco2)c2c1C(=O)NC2
Yield: 54.8 %

Procedure:
In a similar manner to Step 1 of Example 10, 7-amino-4-bromoisoindolinone (234 mg, 1.03 mmol) was dissolved in THF (11.6 mL), and the solution was treated with 2-(tributylstannyl)furane (0.649 mL, 2.06 mmol) and bis(triphenylphosphine)dichloropalladium (58 mg, 0.082 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetone=4/1, chloroform/methanol=12/1) to obtain 7-amino-4-(furan-2-yl)isoindolinone (121 mg, yield 55%).
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[CH:11]=[C:12]([C:21]([O:23]CC)=[O:22])[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:15]=1)([O:6]CC)=[O:5])C>Cl>[P:4]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=1)([OH:6])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(CP(=O)(OCC)OCC)cc(C(=O)OCC)c1
Agent: Cl
Product: O=C(O)c1cc(CP(=O)(O)O)cc(C(=O)O)c1
Yield: 43.8 %

Procedure:
A solution of diethyl 5-[(diethoxyphosphinyl) methyl]-1,3-benzenedicarboxylate (0.186 g, 0.5 mmol) in 12 N HCl (2.5 mL) was heated at 100° C. for 24 hours. The resulting precipitate was washed with water and dried under vacuum to give 0.057 g of white powder: 1H NMR (D2O) δ 3.11 (d, 2H), 7.93 (s, 2H), 8.19 (s, 1H). TLC: Rf 0.20 (EtOAc/Hexanes 1/1). Elemental analysis calculated for C9H7O7P.H2O: C, 38.86; H, 3.99. Found: C, 38.74; H, 4.08.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1([C:18]([O:20]CC)=O)[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O>[Ni].C(O)C>[CH2:11]([N:7]1[CH2:8][CH2:9][CH2:10][C:6]21[C:18](=[O:20])[NH:1][CH2:4][CH2:5]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1(CC[N+](=O)[O-])CCCN1Cc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: O=C1NCCC12CCCN2Cc1ccccc1
Reaction time: 12 h
Yield: 93 %

Procedure:
Raney nickel (˜2 g) was added to a solution of ethyl 2-(2-nitroethyl)-1-benzylpyrrolidine-2-carboxylate (6.00 g, 19.6 mmol) in absolute ethanol (200 mL) in a hydrogenation bottle. The mixture was shaken for 12 h under a hydrogen atmosphere (50 psi) in a Parr hydrogenation apparatus, filtered through a Celite pad and concentrated by rotary evaporation. GCMS analysis indicated that the hydrogenation product was a mixture of the primary amine and the lactam resulting from cyclization of the amine onto the ester. The mixture was dissolved in toluene (150 mL). A catalytic amount of p-toluenesulfonic acid (˜30 mg) was added and the mixture was heated at reflux under a nitrogen atmosphere for 24 h. Upon evaporation of the toluene, the residue (now entirely lactam, by GCMS) crystallized to give 4.20 g (93.1%) of tan solid (mp 152-153° C.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C([O:23][C:24](=O)[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[CH:32]=2)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[C:27](Br)[CH:26]=1)C>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:24](=[O:23])[C:25]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([Cl:38])[CH:32]=3)[C:28]([O:39][CH2:40][CH2:41][OH:42])=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Reactant: NCCCCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(NCCCCCCCCc1ccccc1)c1ccc(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a flamed dried round bottom flask charged with 8-phenyloctylamine (688 mg, 3.35 mmol, 6.68 μL) in 5 mL THF at −78° C. was added n-BuLi (2.2 mL, 4.4 mmol) as a solution in hexanes. The solution was stirred at −78° C. for 30 min then stirred at room temperature for 15 min. The solution was cooled back down to −40° C. and a cooled (-40° C.) solution of 3-bromo-4-(2-hydroxyethoxy)-5-(3-chloro-4-fluorophenyl)benzoic acid ethyl ester (400 mg, 0.957 mmol) in 10 mL THF via cannula. After the addition was completed, the reaction was warmed up to room temperature, stirred for 10 min, then worked up as in Step 2 of Example 135. The crude yellow oil that was obtained was dissolved in 1:1 EtOAc/Hexanes and filtered through a pad of silica gel with the same solvent system to yield 200 mg, 43% of the amide as a yellow oil. 1H NMR (CDCl3) 1.25-1.40 (m, 2H); 1.54-1.65 (m, 2H); 1.80 (bs, 1H); 2.57 (t, J=8.18, Hz, 2H); 3.41 (q, J=6.54 Hz, 2H); 3.90 (t, J=6.13, 2H); 4.12 (t, J=6.13 Hz, 2H); 6.07 (m, 1H); 6.99 (d, J=8.13 Hz, 1H); 7.08-7.18 (m, 3H); 7.20-7.27 (m, 2H); 7.33-7.40 (m, 1H); 7.56 (dd, J=6.54 Hz, 3.27 Hz, 1H); 7.65-7.69 (m, 1H); 7.73 (dd, J=8.13 Hz, 2.58 Hz, 1H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1)=[O:30])[CH2:24][CH2:23]2.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([C:31]1[N:32]=[CH:33][N:34]=[C:35]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:36]=1)=[O:30])[CH2:24][CH2:23]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(Br)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
70 mg (0.24 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride were added to 100 mg (0.30 mmol) (5-bromo-2,3-dihydroindol-1-yl)-(6-chloropyrimidin-4-yl)-methanone and 100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 22 h at RT and then evaporated down i. vac. The residue was combined with 20 mL water and stirred for 30 min at RT. The precipitated product was suction filtered. The purification was carried out using a silica gel column. The product fractions were combined and the solvent was eliminated using the rotary evaporator. The residue was stirred with water, suction filtered and dried at 40° C. in the CAD.
Reaction SMILES: CCOCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=O)=[CH:9][CH:8]=1.CCOCC.C1COCC1.[OH-].[Na+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][N:16]([CH3:17])[CH3:18])=[CH:11][CH:12]=1
Reactant: CN(C)C(=O)Cc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
To a suspension of LiAlH4in ether (5 mL) was added a solution of 2-(4-bromophenyl)-N,N-dimethylacetamide (1.1 g, 4.5 mmol) in 5:1 ether/THF (12 mL), giving a small exotherm. The mixture was stirred at room temperature for 3 h, refluxed overnight then cooled to 0° C. Water (0.5 mL) was added dropwise and the mixture stirred vigourously for 3 h, then poured into 1 M NaOH and extracted with ether. The organic phase was washed with brine and dried over MgSO4. Purification by flash chromatography (4% to 8% MeOH/dichloromethane+0.5% ammonium hydroxide) provided 132 mg of 2-(4-bromophenyl)-N,N-dimethylethanamine.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:26].CO.O1CCCC1.O.[OH-].[Li+]>CCCCCC.C(OCC)(=O)C.O>[F:26][C:6]1[CH:7]=[C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:27])=[O:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(CC(=O)O)c(F)c3)cc21

Procedure:
Following general procedure J and using [2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)phenyl]acetic acid methyl ester (Compound 14, 0.18 g, 0.48 mmol), methanol (4 mL), tetrahydrofuran (8 mL), water (2 mL) and lithium hydroxide monohydrate (0.2 g, 4.76 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 50-100% ethyl acetate in hexane as the eluent, the title compound was obtained as a dirty white solid (0.068 g, 41%).