Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.N[C:46]1[CH:53]=[CH:52]C=C[C:47]=1[CH2:48][OH:49].NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:52][CH:53]=[CH:46][C:47]=4[CH2:48][OH:49])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:35][CH2:36][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:38][CH2:39]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccccc1CO
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5ccccc5CO)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 2-aminobenzylalcohol as the aniline component. (12%, MS=613.3 (M+H))
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=O)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:38])([F:37])[C:27]1[N:28]=[C:29]2[C:34](=S)[NH:33][CH2:32][CH2:31][N:30]2[CH:36]=1>COCCO>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]1[N:33]2[C:34]([C:29]3[N:30]([CH:36]=[C:27]([C:26]([F:38])([F:25])[F:37])[N:28]=3)[CH2:31][CH2:32]2)=[N:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1cn2c(n1)C(=S)NCC2
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCn1cc(C(F)(F)F)nc1-2

Procedure:
A mixture of 129 mg (0.475 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 129 mg (0.583 mmol) of 2-(trifluoromethyl)-6,7-dihydroimidazo[1,2-a]pyrazine-8(5H)-thione (Intermediate 11), and 8.5 mL of 2-methoxyethanol was stirred at reflux for 3 days. The cooled solution was concentrated, and the residue was purified by preparative HPLC (C18 reverse phase column, 20-90% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the title compound as an oil. LC-MS 517 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:20])[CH2:17][C:18]#[N:19])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1>N.[Ni].CO>[NH2:19][CH2:18][CH2:17][C@H:16]([N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:20]
Reactant: COc1ccc(NC2CCN([C@H](C)CC#N)CC2)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1ccc(NC2CCN([C@H](C)CCN)CC2)cc1
Reaction time: 8 h

Procedure:
(R)-3-[4-(4-Methoxy-phenylamino)-piperidin-1-yl]-butyronitrile (0.53 g, 1.94 mmol) was dissolved in NH3 saturated MeOH (15 mL), treated with Raney nickel (excess), and placed under 45 psi H2 on a Parr shaker for 8 h. In a standard work-up the mixture was diluted with MeOH and filtered through celite. The cake was washed with MeOH and the combined filtrate was concentrated to give crude (R)-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-amine as a pale yellow oil (0.54 g, quant.). TLC analysis and 1H NMR confirmed the crude product to be pure with no further purification required. 1H NMR (CDCl3) δ 0.98 (d, 3H, J=6.0 Hz), 1.36 (m, 5H), 1.71 (m, 2H), 2.03 (d, 2H, J=12.0 Hz), 2.23 (br t, 1H), 2.42 (br t, 1H), 2.49-2.71 (m, 4H), 3.17 (m, 2H), 3.76 (s, 3H), 6.57 (d, 2H, J=9.0 Hz), 6.75 (d, 2H, J=9.0 Hz).
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:2]([CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)[OH:1]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(O)c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccccn1)C1CCCN1
Reaction time: 1 h

Procedure:
N-Boc-pyrrolidine (5.0 g) is dissolved in diethyl ether (60 mL) and the solution is cooled to −78° C. N,N,N′,N′-Tetramethylenediamine (TMEDA) (4.4 mL) is added to the mixture followed by sec-butyl lithium (27.0 mL, 1.3 M in cyclohexane) maintaining the temperature below −60° C. After 2 h, 2-pyridine carboxaldehyde (3.3 mL) is added and the mixture is stirred at −70° C. for an additional 30 min. The reaction mixture is allowed to warm to room temperature and is then quenched with water (25 mL) and poured into EtOAc (250 mL). The separated organic layer is washed with water (2×50 mL) followed by brine (50 mL), dried (Na2SO4), and concentrated. The crude product is purified by column chromatography (heptane/EtOAc, 4/1; 2/1, 1/1) to afford 4.79 g of tert-butyl 2-(hydroxy(pyridin-2-yl)methyl)pyrrolidine-1-carboxylate as a mixture of diastereomers. The resulting alcohol is dissolved in dichloromethane (10 mL) and trifluoroacetic acid (80 mL) is added with ice bathe cooling. After 1 h, the reaction mixture is concentrated and added to 1 N sodium hydroxide solution (200 mL). The mixture is extracted with CH2Cl2 (3×100 mL). The combined organic layers are dried (Na2SO4) and concentrated. The resulting oil is distilled in a Kugelrohr apparatus (175-200° C., 0.2 Torr) to afford 2.04 g of the title compound as a mixture of diastereomers. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 8.47, 7.76, 7.46, 7.24, 5.27, 4.50, 4.34, 3.32, 3.22, 2.83, 2.68, 1.62-1.36; MS (ESI+) m/z 179 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[S:3][C:4]=3[N:5]=2)[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc4nc(N)sc4n3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Nc3ncc4nc(NC(=O)C5CC5)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (139 mg, 324 μmol) in pyridine (4 mL) was added cyclopropanecarbonyl chloride (59 μL, 648 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→30/70), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (96 mg, 59%) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6].O.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:18]1([CH2:24][C:25]([NH:2][CH:3]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[CH2:4][C:5]([OH:7])=[O:6])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(CC(=O)O)c1ccc2c(c1)OCO2
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CC(NC(=O)Cc1ccccc1)c1ccc2c(c1)OCO2
Temperature: -5 °C
Reaction time: 2 h

Procedure:
20 g of 3-amino-3-(benzo[1,3]dioxol-5-yl)propionic acid hydrochloride are placed in 10 ml of acetone, 30 ml of water and 38 ml of TEA at −5° C. and 14 ml of phenylacetyl chloride in 20 ml of acetone are added dropwise, followed by stirring for 2 hours at −5° C. The acetone is concentrated. The aqueous phase is washed with Et2O and the insoluble material is removed by filtration. The phases are separated again by settling and the aqueous phase is washed with Et2O and then acidified with 1N HCl to pH 2. The resulting phase is poured into DCM and a precipitate forms. The precipitate is filtered off by suction and rinsed with DCM. 24 g of the expected compound are obtained.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl.C(=O)(O)[O-].[Na+]>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][N:12]([C:27](=[O:29])[CH3:28])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNC(c2ccccc2)C1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a mixture of tert-butyl 3-phenylpiperazine-1-carboxylate (400 mg, 1.52 mmol) and triethyl amine (309 mg, 3.05 mmol) in dichloromethane (5 mL) was added acetyl chloride (156 mg, 1.98 mmol) at 0° C. After stirring for 3 h at room temperature, the reaction mixture was diluted with saturated sodium bicarbonate solution and dichloromethane. The aqueous part was extracted with dichloromethane and the combined organic part was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (20/1 dichloromethane/methanol) to afford 4-acetyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 54%). [M-BOC]H+=205.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([OH:17])[C:8]([CH3:16])([CH3:15])[CH2:9]OS(C)(=O)=O)(=O)=O.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([N:25]1[CH2:9][C:8]([CH3:16])([CH3:15])[C@H:7]([OH:17])[CH2:6]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(COS(C)(=O)=O)[C@H](O)COS(C)(=O)=O
Solvent: CCO
Product: CC1(C)CN(Cc2ccccc2)C[C@H]1O
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of 21.7 g (75 mmol) of (2S)-2-hydroxy-3,3-dimethyl-4-[(methylsulfonyl)oxy]butyl methanesulfonate and 24.4 mL (228 mmol) of benzylamine in 200 mL of ethanol was heated at 120° C. for 18 h in a 400 mL capacity bomb. The reaction mixture was allowed to cool to room temperature, the bomb was vented, and the reaction mixture was concentrated under reduced pressure to 100 mL. The reaction was diluted with 50 mL of water and made acidic with concentrated hydrochloric acid. The aqueous phase was then washed with ether, made basic with 5M aqueous sodium hydroxide, and extracted with ether. The ether extract was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 0.25:9.75 2M ammonia in methanol:ethyl acetate to afford 13.8 g (90%) of (3S)-1-benzyl-4,4-dimethyl-3-pyrrolidinol. 1H NMR (300 MHz, CDCl3) δ 7.30-7.36 (m, 5H), 3.77 (br s, 1H), 3.65 (s, 2H), 2.93-2.99 (m, 1H), 2.55-2.64 (m, 2H), 2.31 (d, J=9 Hz, 1H), 1.76 (d, J=7 Hz, 1H), 1.09 (d, J=1 Hz, 6H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=O.[CH3:12][NH2:13].[BH4-].[Na+]>CO>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:1][NH:13][CH3:12])[CH:8]=[CH:9]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of 7-formyl-1H-indole (0.23 g, 1.6 mmol) in methanol (10 mL) was added with a 40% solution of methylamine in methanol (0.6 mL, 6.4 mmol), and the mixture was stirred at room temperature for 1 hour. Then, the mixture was added portionwise with sodium borohydride (0.060 g, 4.8 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, then the residue was added with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (99:1→95:5)) to obtain 1-(1H-indole-7-yl)-N-methylmethanamine (0.23 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.Cl.Cl.CC([OH:22])C>C(OCC)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]3[O:22][CH:10]3[C:4]=2[CH:3]=1
Reactant: CC(C)O
Reactant: Fc1ccc2c(c1)C=Cc1ccccc1C2
Agent: Cl
Solvent: CCOCC
Product: Fc1ccc2c(c1)C1OC1c1ccccc1C2
Yield: 43 %

Procedure:
Compound 1 was dissolved in diethyl ether (20 ml) and converted into the hydrochloric acid salt (1:1) by dropwise addition of 6 N HCl/2-propanol. The solvent was evaporated. The residue was triturated under boiling 2-propanone, filtered off and dried, yielding 2.17 g (43%) of (±)-(2α,3aβ,12bα)-11-fluoro-3,3a,8,12b-tetrahydro N,N-dimethyl-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-methanamine hydrochloride (compound 2; mp. 239. 1° C.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>C(O)(=O)C>[C:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Yield: 97 %

Procedure:
18.8 g of 2-hydroxynaphthalene-6-carboxylic acid was reacted with 94 g of acetic anhydride in 94 g of acetic acid at 80° C. for 4 hours. The reaction liquid was poured to 500 g of water and the precipitate was filtrated and washed thoroughly with methanol and water and then dried to give 22.3 g of 2-acetoxynaphthalene-6-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl.[CH3:23][N:24](C)[CH2:25][CH2:26][CH2:27]Cl>CN(C)C=O.C(OCC)(=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([N:8]2[CH2:27][CH2:26][CH2:25][N:24]([CH3:23])[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]2=3)=[O:19])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: CN(C)CCCCl
Reactant: O=C(Nc1cccnc1Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc21
Temperature: 0 °C
Yield: 20.7 %

Procedure:
To a solution of 2-chloro-3-(4-nitrobenzoyl)aminopyridine (1.93 g) in N,N-dimethylformamide (13 ml) was added sodium hydride (60 % in oil, 585 mg) and the solution was stirred at 0° C. for ten minutes. 3-Dimethylaminopropyl chloride hydrochloride (1.16 g) was added to the solution and the mixture was stirred for 3 hours at 150° C. The solution was diluted with ethyl acetate and the solution was washed with successively with water, saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (80 g, ethyl acetate:n-hexane =1:3) to give 1-(4-nitrobenzoyl)-5-methyl-2,3,4,5-tetrahydropyrido [3,2 -b][1,4]diazepine (450 mg).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.IC1C2C(=CC([C:42]([F:45])([F:44])[F:43])=CC=2)N(S(C2C=CC=CC=2)(=O)=O)C=1>>[C:14]1([S:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:42]([F:45])([F:44])[F:43])[CH:10]=3)[C:6]([C:20]3[CH:21]=[N:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:24]=3)=[CH:7]2)(=[O:12])=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2ccc(C(F)(F)F)cc21
Reactant: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Product: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(C(F)(F)F)ccc23)cn1

Procedure:
Following the general method as outlined in Intermediate 4, starting from 3-iodo-1-(phenylsulfonyl)-6-(trifluoromethyl)-1H-indole (Intermediate 40; 300 mg; 0.66 mmol) 0.40 g (94%) of the title compound was obtained as a black oil, which was used directly without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Yield: 94.6 %

Procedure:
tert-Butyl 2-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]ethylcarbamate (40.0 g, 91.22 mmol) was dissolved in ethyl acetate (550 mL) and transferred to a Parr hydrogenation vessel charged with 5% platinum on carbon (10.68 g, 54.73 mmol, 0.03 eq). The vessel was purged with nitrogen gas and placed under hydrogen pressure (30 psi, 2.07×105 Pa) overnight. The catalyst was removed by filtration through a layer of CELITE filter aid, and the filter cake was rinsed with methanol and dichloromethane. The filtrate was concentrated under reduced pressure to provide 35.25 g tert-butyl 2-[(3-amino-7-benzyloxyquinolin-4-yl)amino]ethylcarbamate.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzamide from Example 247, step 2 (0.1 g, 0.41 mmol), benzylamine (0.040 g, 0.38 mmol), 4 {acute over (Å)} molecular sieves (1 g) in methanol (5 mL) and stir for 18 h at ambient temperature. Add sodium borohydride (0.058 g, 1.52 mmol), agitate 66 h at ambient temperature. Filter through a 5 g SCX column, eluting first with 1:1 dichloromethane/methanol. Discard the first washings, then elute with 1:1 dichloromethane/2 M ammonia in methanol. Collect the eluants and concentrate in vacuo. Purify by Chromatotron, on a 2 mm silica plate, eluting with 90:10:1 dichloromethane/ethanol/ammonium hydroxide to afford the title compound (0.058 g, 46%): mass spectrum (ion spray): m/z=333.06 (M+1); 1H NMR (DMSO-d6): 7.82 (m, 3H), 7.39-7.18 (m, 8H), 7.02-6.97 (m, 4H), 3.67-3.66 (2s, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>CC(O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][CH2:18][CH:16]([OH:17])[CH:8]([NH:7][C:6](=[O:19])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C1CO1
Reactant: COc1cccc(CN)c1
Solvent: CC(C)O
Product: COc1cccc(CNCC(O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Yield: 77 %

Procedure:
To a stirred solution of tert-butyl-(1-oxiranyl-2-phenylethyl)-carbamate (131.6 mg, 0.5 mmol), 3-methoxy-benzylamine (0.25 mL, 2 mmol) in 3 mL of 2-propanol was heated to reflux for 12 h to afford tert-butyl 4-(3-methoxybenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarba-mate. The solvent was evaporated and the crude product was purified by silica gel flash column chromatography (5-10% MeOH in CHCl3) to give 4 in 77% yield (154 mg) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:26][CH2:25][C@@H:24]([NH2:27])[CH2:23]2)=[O:21])=[CH:18][CH:17]=1.CCN(CC)CC>CN(C=O)C>[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([N:22]2[CH2:26][CH2:25][C@@H:24]([NH:27][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:23]2)=[O:21])=[CH:18][CH:17]=1
Reactant: N[C@@H]1CCN(C(=O)c2ccc(Cl)cc2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (500 mg) in DMF (5 mL) was added (3R)-1-(4-chlorobenzoyl)-3-pyrrolidinamine (951 mg) and Et3N (1.15 mL). After stirring for 3 hours at 120° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (601 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28]O>>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CCCCO1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2CCCCO2)c1

Procedure:
Mitsunobu reaction of phenol 58 with (tetrahydro-2H-pyran-2-yl)methanol gave 2-(3-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.2 g, 18%): 1H NMR (400 MHz, CDCl3) δ 7.81-7.84 (m, 2H), 7.69-7.72 (m, 2H), 7.12-7.16 (m, 1H), 6.76-6.79 (m, 2H), 6.81 (s, 1H), 6.69 (d, J=8.8 Hz, 1H), 4.17 (d, J=6.2 Hz, 2H), 3.76 (t, J=7.2 Hz, 2H), 3.60-3.66 (m, 1H), 3.44-3.52 (m, 2H), 2.69 (t, J=8.0 Hz, 2H), 1.98-2.06 (m, 2H), 1.86-1.92 (m, 2H), 1.60-1.72 (m, 2H), 1.24-1.40 (m, 2H).