Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][C@H:3]1[CH2:17][OH:18]>[Pd].C(O)C>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C@H:3]([CH2:17][OH:18])[CH2:4]2)=[CH:13][CH:12]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)C[C@H]1CO
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2ccc(N)cc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a mixture of [(2S)-1-methyl-4-(4-nitrophenyl)piperazin-2-yl]methanol (315 mg) and ethanol (5.081 mL) was added 10% palladium-supported carbon (53% wet product) (267 mg), followed by stirring at room temperature for 4 hours under a hydrogen gas atmosphere (1 atm). The reactant was filtered through celite and then the solvent was evaporated under reduced pressure to obtain [(2S)-4-(4-aminophenyl)-1-methylpiperazin-2-yl]methanol (278 mg) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:17])[C:15]#[N:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[NH2:16][CH2:15][CH:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=2)=[O:7])[CH2:9][CH2:10]1)[CH3:17]
Reactant: [H][H]
Reactant: CC(C#N)N1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CN)N1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 100 %

Procedure:
A mixture of 32 parts of 4-(4-fluorobenzoyl)-α-methyl-1-piperidineacetonitrile and 400 parts of methanol, saturated with ammonia is hydrogenated in the Parr-apparatus at 25° C. with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methylbenzene and the latter is evaporated again. The residue is dissolved in 2,2'-oxybispropane and the solution is filtered till clear. The solvent is evaporated, yielding 32 parts (100%) of [1-(2-amino-1-methylethyl)-4-piperidinyl](4-fluorophenyl)methanone as an oily residue.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:18][CH2:19][O:20][CH3:21])[CH3:17])[CH:12]=[C:11]([Cl:22])[C:10]=1[F:23])(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:22])[C:10]=1[F:23])[CH2:15][N:16]([CH2:18][CH2:19][O:20][CH3:21])[CH3:17]
Reactant: COCCN(C)Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: COCCN(C)Cc1cc(Cl)c(F)c(CN)c1

Procedure:
was prepared according to Scheme C2 (step D) from (3-chloro-2-fluoro-5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (222 mg, 0.47 mmol) and 4N HCl in dioxane. MS (LC-MS): 261.0 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Si:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6](Br)[CH:7]=1.[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[O:33][C:32]=2[C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([Si:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[C:6]([C:40]2[C:34]3[O:33][C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:36]=4[C:35]=3[CH:37]=[CH:38][CH:39]=2)[CH:7]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Brc1cc(Br)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cc(-c2cccc3c2oc2ccccc23)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 63.8 %

Procedure:
A solution of (3,5-dibromophenyl)triphenylsilane (4.66 g, 9.43 mmol), dibenzo[b,d]furan-4-ylboronic acid (1.00 g, 4.72 mmol), Pd(PPh3)4 (0.109 g, 0.094 mmol) and potassium carbonate (1.304 g, 9.43 mmol) in toluene (150 mL) and water (25 mL) was refluxed under nitrogen overnight. The organic phase was isolated, filtered and evaporated. The residue was purified by column chromatography on silica gel with hexane/DCM (4/1, v/v) as eluent to yield (3-bromo-5-(dibenzo[b,d]furan-4-yl)phenyl)triphenylsilane (1.75 g, 64% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:17])[NH:9]2)[C:5]([OH:18])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:25])[CH:23]=O)[CH3:20].S(O)(C)(=O)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:23]([C:22]([O:21][CH2:19][CH3:20])=[O:25])[N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:17])[C:15]=4[CH2:16][CH:8]3[C:6]=2[N:7]=1
Reactant: Oc1ccc(Cl)nc1C1Cc2c(F)cccc2N1
Reactant: CCOC(=O)C=O
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1Oc2ccc(Cl)nc2C2Cc3c(F)cccc3N12
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (8.53 g, 32.31 mmol) and Glyoxylic acid ethyl ester (6.59 g, 64.59 mmol) in THF (80 mL), MsOH (0.31 g, 3.23 mmol) was added. The mixture was stirred at 50° C. for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=10:1) to provide ethyl 2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (10.2 g, yield: 90.3%). 1H-NMR (CDCl3, 400 MHz) δ 7.04˜7.13 (m, 3H), 6.63 (d, J=8.0 Hz, 1H), 6.55 (t, J=8.4 Hz, 1H), 6.03 (s, 1H), 5.09 (d, J=8.8 Hz, 1H), 4.22˜4.34 (m, 2H), 3.73 (d, J=16.4 Hz, 1H), 3.44˜3.51 (m, 1H), 1.29 (d, J=7.2 Hz, 3H). MS (M+H)+: 349.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([NH2:25])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[C@H:40]([CH3:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])(=O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([NH:25][C@H:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:46])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
To a solution of (S)-2-amino-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (10.0 g, 24.9 mmol) in dichloromethane (100 mL) was added triethylamine (10.4 mL, 74.6 mmol) at 0° C. After stirred for 10 min, ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) was added at room temperature and stirred for 1 hour. Additional triethylamine (10.4 mL, 74.6 mmol) and ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) were added at room temperature and stirred for additional 2 hours. The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/heptane) to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-1-ethoxycarbonyl-ethylamino)-propionic acid benzyl ester (10.6 g). 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H, J=7.3 Hz), 1.27 (d, 3H, J=6.8 Hz), 1.89 (bs, 1H), 2.95-3.07 (m, 2H), 3.38 (dd, 1H, J=6.8, 14.8 Hz), 3.69 (dd, 1H, J=7.1, 7.1 Hz), 4.06-4.17 (m, 2H), 5.06 (d, 1H, J=12.1 Hz), 5.12 (d, 1H, J=12.1 Hz), 7.20-7.25 (m, 4H), 7.28-7.34 (m, 4H), 7.35 (dd, 1H, J=7.6, 7.6 Hz), 7.41-7.46 (m, 3H), 7.53 (dd, 1H, J=1.5, 1.5 Hz); MS: m/z (MW) 466.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:24])[CH2:6][N:7]([C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([Cl:23])[N:15]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)C>C(O)(=O)C.[Fe]>[Cl:23][C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:4](=[O:3])[CH:5]([CH3:24])[CH2:6][N:7]([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[C:14]=2[N:15]=1
Reactant: CCOC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1CN(C2CCCCC2)c2nc(Cl)ncc2NC1=O
Yield: 82.3 %

Procedure:
To a solution of 2.27 g (0.0061 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclohexyl-amino]-2-methyl-propanoic acid ethyl ester in 40 mL of acetic acid was added 2.0 g (0.0358 g-atom) of iron powder. The mixture was heated at 80 degrees for 2 hours, and then filtered through Celite while still hot. The filtercake was washed with 100 mL of ethyl acetate and the combined filtrate was washed successively with 100 mL of water, 100 mL of 7.4 M ammonium hydroxide, 50 mL of water and then 100 mL of brine. The aqueous layers were back washed with 100 mL of ethyl acetate and the combined ethyl acetate layers dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-dichloromethane (1:1), followed by crystallization from dichloromethane-hexanes to give 1.48 g of (rac)-2-chloro-9-cyclohexyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-18) as white needles.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[O:28][CH2:29][C:30](O)=[O:31]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30](=[O:31])[CH2:29][O:28][C:27]5[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=5[O:25][CH3:24])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: COc1ccccc1OCC(=O)O
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)COc4ccccc4OC)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-(2-methoxy-phenoxy)-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and (2-methoxyphenoxy)acetic acid (161 mg, 0.88 mmol). The title compound was obtained as yellow powder (28 mg, 7%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1Br.[CH3:18][N:19]1CCCC1=O>>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: Nc1c(Br)cc(-n2cnnc2)cc1C(F)(F)F
Reactant: CN1CCCC1=O
Product: N#Cc1cc(-n2cnnc2)cc(C(F)(F)F)c1N

Procedure:
The following compound, m.p. 283°, was similarly prepared to the prevous Preparation using 4-(4-amino-3-bromo-5-trifluoromethylphenyl)-1,2,4-triazole, cuprous cyanide and 1-methyl-2-pyrrolidone as the starting materials: ##STR148##
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[NH2:14][NH2:15]>C(O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([NH:14][NH2:15])=[O:2])[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: NN
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: NNC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A solution of (3,4-dichloro-phenyl)-acetic acid methyl ester (44.7 mmol) and hydrazine (447 mmol) in ethanol (100 mL) was stirred at 80° C. for 18 h. After it was cooled to room temperature and concentrated in vacuo, the crude product was purified by crystallization in ethanol to give (3,4-dichloro-phenyl)-acetic acid hydrazide (43 mmol).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=4[Cl:30])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>CS(C)=O.C(OCC)C>[Cl:30][C:24]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][NH:32][CH3:31])[CH2:22][CH2:21]2
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Solvent: CCOCC
Solvent: CS(C)=O
Product: CNC[C@H]1CCc2cccc(-c3cc(Cl)ccc3Cl)c2O1
Temperature: 60 °C

Procedure:
To a suspension of [(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.324 mmol) in dimethylsulfoxide (0.5 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 1.62 mL, 3.24 mmol) and the mixture heated to 60° C. in a sealed vial for 24 hours. The cooled reaction mixture was then diluted with diethyl ether (10 mL), washed with 1.0 M aqueous sodium hydroxide solution (5 mL) and water (5×5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0.5 to 5% ammonia saturated methanol solution in dichloromethane gave {[(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}methylamine as a colorless syrup. The product was dissolved in diethyl ether (1 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.25 mL, 0.25 mmol) was added followed by 2-propanol (3 drops). The resulting white precipitate was filtered and the solid product triturated with diethyl ether (3×3 mL) to afford 56 mg (48%) of {[(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}methylamine hydrochloride as a white solid. MS (ESI) m/z 322.0 ([M+H]+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]2[CH:31]=[CH:30][C:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25][C:19]=3[CH:18]=2)[N:10]=1.C(N(CC)CC)C.[F:39][C:40]([F:47])([F:46])[CH2:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[Cl:15][C:14]1[C:9]([NH:8][C@@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH:1][S:42]([CH2:41][C:40]([F:47])([F:46])[F:39])(=[O:44])=[O:43])=[N:10][C:11]([NH:16][C:17]2[CH:31]=[CH:30][C:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25][C:19]=3[CH:18]=2)=[N:12][CH:13]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N)n3)cc2CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(=O)(=O)CC(F)(F)F)n3)cc2CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53 %

Procedure:
N*4*-((1R,2R)-2-Amino-cyclohexyl)-5-chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine was dissolved in Methylene chloride (5 mL) and Triethylamine (0.15 mL, 1.1 mmol) was added, followed by 2,2,2-Trifluoroethanesulfonyl chloride (0.025 mL, 0.23 mmol). Stir under an atmosphere of Nitrogen at room temperature for 45 min, then partition between 10 mL satd. sodium bicarbonate and 10 mL DCM. Separate and extract the aqueous layer, 3×10 mL DCM. Dry the combined organics over sodium sulfate, filter and concentrate in vacuo. The resultant oil was purified on a sulfonic acid resin cartridge, washing with methanol, eluting with ammonia/methanol. Conc. in vacuo reconcentrating from DCM afforded an oil. Subsequent purification on silica gel (0-10% MeOH:DCM, 12 g SiO2) gave 2,2,2-Trifluoro-ethanesulfonic acid ((1R,2R)-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-amide (55 mg, 53%) as a colorless film. LCMS (m/e) 591 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.21 (d, 1H, J=7.9 Hz), 7.18 (s, 1H), 7.01 (d, 1H, J=7.9 Hz), 6.97 (s, 1H), 5.36 (d, 1H, J=7.5 Hz), 5.31 (s, 1H), 3.84 (m, 1H), 3.61 (q, 2H, J=9.0 Hz), 3.55 (t, 2H, J=5.4 Hz), 3.36 (s, 3H), 3.29 (m, 1H), 2.9 (m, 4H), 2.72 (m, 6H), 2.17 (m, 2H), 1.82 (m, 2H), 1.34 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](ON2C(=O)CCC2=O)=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[C:9]1[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:31])[NH:41][CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])[CH:19]=[C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:40])[CH:8]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1
Reactant: NCCCC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)NCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1
Reaction time: 48 h

Procedure:
5-[9-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-nonyloxy]-isophthalic acid di-tert-butyl ester (100 mg, 0.18 mmol) was dissolved in dry DMF (2 ml). 4-Aminobutyric acid (GABA, 23 mg, 0.2 mmol) and DIPEA (0.05 ml) was added. The mixture was stirred under nitrogen for 2 days. The mixture was concentrated. The residue was dissolved in EtOAc and washed with 0.1 N HCl (2×) and brine (1×), dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Br)(Br)(Br)[Br:20].O>C(Cl)Cl>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(=O)N(CCCCCO)C(C)C
Reactant: BrC(Br)(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCCCC(=O)N(CCCCCBr)C(C)C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
TPP (4.45 g, 9.34 mmol) was added to a 0° C. solution of alcohol 6 (2.00 g, 7.78 mmol) in dry CH2Cl2 (50 mL). After 10 min, CBr4 (3.10 g, 9.34 mmol) was added and the stirring was continued at 0° C. After 2 h, water (20 mL) was added and the reaction mixture was extracted with EtOAc (3×50 mL). The combined extracts were washed with water (2×20 mL), brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 30-35% ethyl acetate/hexane to afford 7 (2.20 g, 91%). TLC:EtOAc/hexanes (3:7), Rf˜0.40; 1H NMR (400 MHz, 45/55 mixture of rotamers) δ 4.60-4.70 and 3.96-4.10 (m, 1H, rotamers), 3.46 and 3.36 (t, J=5.8 Hz, rotamers), 3.02-3.10 (m, 2H), 2.30 and 2.22 (t, J=7.9 Hz, 2H), 1.80-1.97 (m, 2H), 1.40-1.70 (m, 6H), 1.20-1.40 (m, 6H), 1.16 and 1.10, (d, J=7.3 Hz, 6H, rotamers), 0.86 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, rotamers) δ 172.79, 172.39, 48.17, 45.47, 43.32, 40.70, 33.89, 33.87, 33.49, 32.48, 32.30, 31.81, 31.78, 30.78, 29.27, 28.74, 26.05, 25.84, 25.69, 25.54, 22.64, 21.47, 20.62, 14.17.
Reaction SMILES: Cl.[F:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)(=[O:21])=[O:20].C(N(CC)CC)C>C(#N)C>[C:28]([C:24]1[CH:23]=[C:22]([S:19]([NH:18][CH2:17][CH2:16][CH2:15][N:10]2[CH2:9][CH:8]([O:7][C:6]3[CH:12]=[CH:13][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:11]2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1)#[N:29]
Reactant: N#Cc1cccc(S(=O)(=O)NCCCBr)c1
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(S(=O)(=O)NCCCN2CC(Oc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A suspension of 3-(4-fluoro-phenoxy)-azetidine hydrochloride (0.049 g, 0.24 mmol) in acetonitrile (1.0 ml) is treated with the crude N-(3-bromo-propyl)-3-cyano-benzenesulfonamide (0.072 g) in acetonitrile (1.0 ml) and triethylamine (0.1 ml, 0.72 mmol). The resulting homogenous reaction mixture is stirred at ambient temperature for 70 hours, the solvent evaporated and the residue partitioned between ethylacetate and aqueous NaHCO3 solution. The ethylacetate phase is washed with brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution ethylacetate) to afford 3-cyano-N-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-benzenesulfonamide. [MH]+ 390.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([C:32](Cl)=[O:33])=[CH:24]1.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([C:32]([NH:1][C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)=[O:33])=[CH:24]1
Reactant: O=C(Cl)c1csc2ccccc12
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)c2csc3ccccc23)cc1Nc1ccc(F)cc1
Reaction time: 2 h

Procedure:
To dichloromethane 3.0 mL solution of tert-butyl 4-amino-2-(4-fluoroanilino)benzoate 40 mg were added triethylamine 0.064 mL, benzothiophene-3-carbonyl chloride 55 mg and dichloromethane 1.5 mL at room temperature, and it was stirred at same temperature for 2 hours. Aminomethylated-polystyrene 250 mg was added to the reaction mixture, and it was stirred at room temperature for 4 hours. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and insoluble matter was filtrated. The organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 4-(benzothiophene-3-carboxamido)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:11][CH:12]1[CH2:14][O:13]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:13]1[CH2:14][CH:12]1[CH2:11][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CNC2
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2c(c1)CN(CC1CO1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of isoindoline (200 mg, 1.68 mmol) and 2-(bromomethyl)oxirane (272 mg, 2.0 mmol) in CH3CN (10 mL) was added K2CO3 (690 mg, 5 mmol) and reaction mixture was stirred at 25° C. for 16 h. The mixture was filtered, concentrated and the crude product was used in the next step without further purification. (280 mg, yield 95%) MS (ESI+) e/z: 176.1 [M+1]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[CH:12]1.Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:10]([C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:3])[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[CH:12]1)[CH3:27]
Reactant: Cc1cn(Nc2ccncc2F)c2ccccc12
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1ccncc1F)n1cc(C)c2ccccc21
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% in oil, 1.48 g) in 10 ml of dimethylformamide (DMF) at ice bath temperature was added dropwise a solution of N-(3-fluoro-4-pyridinyl)-3-methyl-1H-indol-1-amine (8.5 g) in 40 ml of DMF. when addition was complete, the mixture was stirred for 15 minutes at ice bath temperature, and then cooled to -20° C. Ethyl chloroacetate (3.95 ml) was added dropwise in 10 ml of DMF. The mixture was stirred at -20° C. for one hour. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4). After filtering, the solvent was evaporated to yield an oil (12.2 g) which was eluted with 10% ethyl acetate/DCM on a silica gel column via HPLC. The desired fractions were evaporated to yield 6.9 g of a solid, m.p. 105°-108° C.