Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][SH:9].Cl[CH2:11][CH2:12][CH2:13][C:14]#[N:15]>O.C(O)C>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][S:9][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCl
Reactant: SCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CCCCSCc1ccco1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 94.1 %

Procedure:
A solution of sodium hydroxide (12.7 g) in water (50 ml) and ethanol (50 ml) was added dropwise over 30 minutes to a solution of furanylmethyl mercaptan (34.25 g) and 4-chlorobutyronitrile (31.58 g) in ethanol (150 ml) under nitrogen at 10° C. (ice-bath). The temperature rose slightly (to 18° C.) and the solution went cloudy. It was stirred at room temperature for 6.5 hours and allowed to stand for 20 hours. Ethanol was removed by evaporation at reduced pressure. The residue was dissolved in water (100 ml) and the solution was extracted with chloroform . The combined extracts were washed with water, dried (MgSO4) and chloroform evaporated at reduced pressure. The residual light-brown liquid was vacuum-distilled to give 4-(2-furanylmethylthio)butyronitrile (51.16 g), b.p.0.05 mm 112°-5° C.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:19])[NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].CN(C)[CH:22]=[O:23]>C1COCC1>[C:6]([O:10][C:11](=[O:19])[NH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:22]=[O:23])([CH3:9])([CH3:7])[CH3:8]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyllithium (1.7 M, 14.5 mL, 24.6 mmol, 2.39 equiv) was added to a solution of pyridin-3-yl-carbamic acid tert-butyl ester (6-1, 4.00 g, 20.6 mmol, 1 equiv) in THF (100 mL) at −78° C., and the resulting mixture stirred for 1 h. N,N-dimethylformamide (8.00 mL, 103 mmol, 5 equiv) was added, and the reaction mixture was warmed to 0° C. and stirred for 30 min. The mixture was partitioned between water (400 mL) and ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (20% ethyl acetate in hexanes, grading to 40% ethyl acetate in hexanes) to afford (4-formyl-pyridin-3-yl)-carbamic acid tert-butyl ester (6-2) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 9.89 (br s, 1H), 9.84 (s, 1H), 8.53 (d, 1H, J=4.8 Hz), 7.49 (d, 1H, J=4.8 Hz), 1.55 (s, 9H); TLC (EtOAc), Rf=0.47.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([OH:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[N:12][C:11]([O:15][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClCCN1CCCCC1
Reactant: Cc1nc(O)nn1-c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1nc(OCCN2CCCCC2)nn1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
1-(3,4-Dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ol (0.41 mmol) was dissolved in methanol (150 mL) at room temperature. A solution of potassium carbonate in water (30 mL) was added dropwise until pH 9. After 15 min under stirring a solution of 1-(2 chloroethyl) piperidine hydrochloride (0.62 mmol) in water (100 mL) was added. The reaction was stirred at room temperature overnight. The methanol was evaporated and after extraction with CH2Cl2 the organic layer was dried over MgSO4 then evaporated and finally purified by chromatography in silica gel to give 1-{2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yloxy]ethyl}piperidine (0.03 g, yield 20%) as a dark orange oil. H1NMR (300 MHz, CDCl3, 25° C.) δ: 7.53 (d, J=2.4 Hz, 1H); 7.48 (d, J=8.6 Hz, 1H); 7.23 (dd, J=2.4 Hz, 1H); 4.33 (t, J=5.9 Hz, 2H); 2.71 (t, J=5.9 Hz, 2H); 2.44 (t, J=4.9 Hz, 4H); 2.40 (s, 3H); 1.51 (q, J=5.5 Hz, 4H); 1.34 (m, 2H) ppm. EM (ES+) m/z=355 (100%) [M+H]+. C16H20Cl2N4O (355.26) calc. C, 54.09%; H, 5.67%; N, 15.77%. found C, 53.80%; H, 5.72%; N, 15.48%.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH2:16])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C(N(CC)CC)C.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(O)C>O1CCCC1>[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH:16][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc2c([C@H]3C[C@@H]3CN)cccn2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c([C@H]3C[C@@H]3CNC(=O)C3CC3)cccn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a suspension of 1-[(1S,2S)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine dihydrochloride (750 mg, 2.74 mmol) and triethylamine (1.52 mL, 10.9 mmol) in tetrahydrofuran (27 mL) was added cyclopropanecarbonyl chloride (372 μL, 4.10 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Ethanol was added to the reaction solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (646 mg, yield 88%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[S:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:4].[C:22](=O)([O-])[O-].[K+].[K+].IC.[NH4+].[Cl-]>CC(C)=O>[F:21][C:2]([F:20])([F:1])[C:3]([N:5]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[S:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:22])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1sc2nccnc2c1NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1sc2nccnc2c1N(C)C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 7-(2,2,2-trifluoroacetamido)thieno[2,3-b]pyrazine-6-carboxylate 10 (9.22 g, 28.9 mmol) and potassium carbonate (7.98 g, 57.8 mmol) in acetone (140 mL) was added iodomethane (3.60 mL, 57.8 mmol). The reaction was stirred at 50° C. for 1 h. NH4Cl solution(aq) was added and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated to give crude ethyl 7-(2,2,2-trifluoro-N-methylacetamido)thieno[2,3-b]pyrazine-6-carboxylate 11 (9.1 g, 95%). (m/z)=334 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[N:17]1([CH2:23][CH2:24][CH2:25][C:26]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[NH:28][C:27]=2[CH:35]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][CH2:25][C:26]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[NH:28][C:27]=2[CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:8]=1[N:14]([C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:9][C:8]=1[N:14]([C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COC[C@H](C)N(C(=O)C(F)(F)F)c1cc(F)ccc1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC[C@H](C)N(C(=O)C(F)(F)F)c1cc(N2CCN(C)CC2)ccc1C(=O)OC(C)(C)C
Yield: 84.1 %

Procedure:
A solution of 4-fluoro-2-[((S)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl ester (2 g, 5.28 mmol) and N-methylpiperazine (5.86 mL, 52.8 mmol) in tetrahydrofuran (20 mL) was stirred at 60° C. for 7 days. The solution was then evaporated, NaHCO3 saturated solution was added and the mixture extracted with dichloromethane (3 times). The organic layer was washed with water, brine, dried over sodium sulfate filtered and evaporated to obtain a crude, which was purified by column chromatography on silica gel (dichloromethane-methanol 93:7). The title compound (2.04 g, 84%) was obtained as yellowish solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[C:37](=[O:39])=[O:38]>C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:37]([OH:39])=[O:38])=[N:3][CH:4]=1
Reactant: O=C=O
Reactant: Cc1cc(Br)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-fluorophenyl)thio]methyl ]-4-methylpyridine (1.39 g, 3.28 mmol) obtained in Example 10 in toluene (60 ml), a hexane solution of n-butyllithium (1.54 M, 2.55 ml, 3.93 mmol) was added in an argon atmosphere at −78° C. After stirring for 1 hour at the same temperature, carbon dioxide was bubbled thereinto the mixture. The reaction mixture was allowed to warm to room temperature over 2 hours, subsequently 0.1 N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with methylene chloride:methanol=10:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol, diethyl ether and hexane, and was collected by filtration, to obtain the title compound (815 mg, 2.09 mmol, 64%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19].C(OCC)C>C1COCC1>[CH3:21][O:20][C:18]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:19]
Reactant: NCCc1ccccc1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution of phenethylamine (75.2 mL, 0.6 mol) and triethylamine (83 mL, 0.6 mol) in THF (500 mL) was added slowly methyl chloroformate (46.2 mL, 0.6 mol) dissolved in THF (50 mL). After the reaction was stirred for an additional 1 h at room temperature, diethyl ether (2 L) and 1 N HC1 (800 mL) was added. The organic layer was washed with water, dried (MgSO4), and concentrated in vacuo to give a clear oil of pure title compound (102 g, 95%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[K+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a cooled (0° C.) solution of methyl 3-cyano-4-[(1-methylethyl)oxy]benzoate (100 g, 463 mmol) in tetrahydrofuran (500 mL) was added 10% potassium hydroxide (500 mL). The resulting solution was allowed to warm to room temperature and maintained for 16 h, at which time it was concentrated to remove the tetrahydrofuran. The residue was diluted with water (500 mL) and washed with ether (2×500 mL). The aqueous layer was then acidified with 3 N HCl and stood for 2 h. The solids were collected by filtration and washed several times with water, then dissolved in methylene chloride (1 L). The mostly homogeneous mixture was filtered through Celite® and concentrated to a minimal volume of methylene chloride. Collection of the solids by filtration gave 82 g (87%) of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid as a white solid.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:30][C@H:31]([C:35]([O:37][CH:38]([CH2:42][O:43][C:44](=[O:60])[C@H:45]([CH:57]([CH3:59])[CH3:58])[NH:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C:39](O)=[O:40])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:39](=[O:40])[CH:38]([O:37][C:35](=[O:36])[C@H:31]([CH:32]([CH3:34])[CH3:33])[NH:30][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:42][O:43][C:44](=[O:60])[C@H:45]([CH:57]([CH3:59])[CH3:58])[NH:46][C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (2.15 g, 8 mmole), 2,3-bis-(N-CBZ-L-valyloxy)-propanoic acid (6.2 g, 10.8 mmole), DMAP (244 mg, 2 mmole) and HOBT (1.46 g, 10.8 mmole) was coevaporated two times with DMF and reduced to about 120 ml. DCC (2.48 g, 12 mmole) was added and the mixture was stirred for two days at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. 150 ml ethyl acetate was added and the organic phase was washed twice with 5% acetic acid, with 5% sodium hydrogen carbonate and with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 2,25 g=35%
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][CH2:16][CH:17]([N:20]1[CH2:24][CH2:23][C@@H:22]([NH2:25])[CH2:21]1)[CH2:18][F:19].C(N(C(C)C)C(C)C)C>O1CCCC1>[F:19][CH2:18][CH:17]([N:20]1[CH2:24][CH2:23][C@@H:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:21]1)[CH2:16][F:15]
Reactant: N[C@@H]1CCN(C(CF)CF)C1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(N[C@@H]2CCN(C(CF)CF)C2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To 4-fluoro-3-nitrobenzenesulfonamide (0.272 g) and (R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-amine (0.195 g) in tetrahydrofuran (3.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.512 mL) and the reaction was stirred at room temperature. After stirring for 6 hours, the reaction was concentrated, loaded onto silica gel (Reveleris 40 g) and the product was purified by flash chromatography using a gradient of 25% to 100% ethyl acetate/hexanes over 30 minutes to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:46][N:47]([CH2:54][C@H:55]1[CH2:60][CH2:59][C@H:58]([NH2:61])[CH2:57][CH2:56]1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:61][C@H:58]4[CH2:57][CH2:56][C@H:55]([CH2:54][N:47]([CH3:46])[CH:48]5[CH2:53][CH2:52][O:51][CH2:50][CH2:49]5)[CH2:60][CH2:59]4)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)N[C@H]2CC[C@H](CN(C)C4CCOCC4)CC2)CCO3)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 7-(4-methylphenyl)-2,3-dihydrobenzooxepine-4-carboxylic acid (200 mg) and 1-hydroxybenzotriazole (145 mg) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (205 mg), and the resulting mixture was stirred for 2 hours. To the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (320 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (326 mg) and triethylamine (0.2 ml) in acetonitrile (10 ml), and the resulting mixture was stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent and the residue was then subjected to purification using column chromatography (ethanol/ethyl acetate 1:1) and to recrystallization (ethyl acetate/hexane) to obtain trans-7-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 63) (233 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:17]=2)[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:17]=2)[CH:12]=[C:11]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cccc(-c2ccc3cc(Cl)nc(OCc4ccccc4)c3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(OCc4ccccc4)c3c2)c1

Procedure:
To a mixture of 1-(benzyloxy)-3-chloro-7-(3-methoxyphenyl)isoquinoline (150 mg, 0.40 mmol, 1.0 eq), pyridin-3-ylboronic acid (74 mg, 0.60 mmol, 1.5 eq), K2CO3 (166 mg, 1.20 mmol, 3.0 eq) in dioxane (2 ml) and H2O (1 mL) was added Pd(PPh3)2Cl2 (14 mg, 0.02 mmol, 0.05 eq) under N2 atmosphere. The sealed tube was irradiated in the CEM microwave at 130° C. for 1 h. After the reaction was completed, the volatiles were removed in vacuo and the residue was purified with chromatography on silica gel (hexane/ethyl acetate 50:1) to give 200 mg of crude lxvii-a as a brown oil, which was used directly in the next step without purification, LCMS m/z=419.0 (M+1) (Method B) (retention time=2.25 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[F:8].[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:11]=3[CH2:12][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCCC1c1ccc(F)c(F)c1
Reactant: O=C=NC(=O)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)c(F)c1)CC2
Temperature: 130 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A solution of 2-(3,4-difluorophenyl)cyclopentanone, (prepared in the manner of Intermediate P(1) and P(2)) (1.5 g, 7.65 mmol) and carbonisocyanatidic chloride (1.129 g, 10.70 mmol) was stirred at 58° C. in a high-pressure vessel for 1 h. The temperature was raised to 130° C. and the reaction mixture was stirred for an additional 2 h. After cooling to rt, the reaction mixture solidified. The solid residue was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuum and the oily residue was purified by column chromatography on silica gel to provide 7-(3,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (1.05 g, 3.96 mmol, 51.8% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=O)[CH:15]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CC(O)=O>[C:26]1([CH:15]([C:14]2[NH:1][C:2]3[CH:7]=[C:6]([C:8]4[S:9][CH:10]=[CH:11][CH:12]=4)[CH:5]=[CH:4][C:3]=3[N:13]=2)[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cc(-c2cccs2)ccc1NC(=O)C(C(=O)OCc1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)C(c1ccccc1)c1nc2ccc(-c3cccs3)cc2[nH]1
Temperature: 100 °C

Procedure:
AcOH (3 mL) was added to compound 32 (463 mg, 1.04 mmol) and the reaction heated at 100° C. for 30 min. The solvent was evaporated under reduced pressure.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9](=[O:15])O[C:11]2=[O:14])=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)([CH3:3])[CH3:2].[NH2:19][CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27]>>[O:27]=[C:21]1[CH:20]([N:19]2[C:9](=[O:15])[C:8]3[C:12](=[CH:13][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][C:7]=3[N+:16]([O-:18])=[O:17])[C:11]2=[O:14])[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1
Reactant: NC1CCC(=O)NC1=O
Reactant: CC(C)Oc1cc2c(c([N+](=O)[O-])c1)C(=O)OC2=O
Product: CC(C)Oc1cc2c(c([N+](=O)[O-])c1)C(=O)N(C1CCC(=O)NC1=O)C2=O

Procedure:
reacting 6-isopropoxy-4-nitroisobenzofuran-1,3-dione with 3-aminopiperidine-2,6-dione to form 2-(2,6-dioxopiperidin-3-yl)-6-isopropoxy-4-nitroisoindoline-1,3-dione;
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[O:7]=[CH:8][C:9]([Cl:12])([Cl:11])[Cl:10].C(N(CC)CC)C>CCOCC>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:8]([OH:7])[C:9]([Cl:12])([Cl:11])[Cl:10]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Cn1cccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cn1cccc1C(O)C(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 102.4 %

Procedure:
To a solution of N-methylpyrrole (1.62 g, 20 mmol) in ether (10 ml) was added a solution of chloral (3.24 g, 22 mmol) in ether (10 ml). To this was added Amberlyst (160 mg) and the mixture was stirred under reflux for 18 hours. After cooling to room temperature and adding triethylamine (0.3 ml), the mixture was stirred for 5 minutes and filtered through a layer of Celite. The filtrate was concentrated under reduced pressure to afford the crude adduct 1-methyl-2-(2',2',2'-trichloro-1'-hydroxyethyl)pyrrole (4.68 g) as pale brown prisms.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH3:13])[CH:8]=[CH:9][C:10]=1[CH3:11].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:13])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(C)c(OCC(F)F)c1
Product: Cc1ccc(C(C)N[S@](=O)C(C)(C)C)cc1OCC(F)F
Yield: 66 %

Procedure:
The title compound is prepared in 66% yield (860 mg, clear colorless oil) from 1-(3-(2,2-difluoroethoxy)-4-methylphenyl)ethanone (880 mg, 4.1 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.