Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:28])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (2.00 g, 6.40 mmol) in methylene chloride (100 mL) was cooled in an ice/salt bath and a solution of diethylaminosulfur trifluoride (1.24 g, 7.68 mmol) in methylene chloride (10 mL) added drop-wise over 1 hour. The resulting solution was then stirred for 14 hours during which time it slowly warmed to room temperature. After this time the reaction was quenched by the cautious addition of saturated sodium bicarbonate (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organics dried over magnesium sulfate. Subsequent filtration and concentration under reduced pressure afforded crude tert-butyl 4-(4-chlorophenyl)-4-fluoropiperidine-1-carboxylate as a viscous yellow oil. This material was immediately dissolved in 10% methanolic hydrogen chloride (100 mL) and the resulting yellow solution stirred at room temperature for 64 hours then concentrated under reduced pressure. The resulting dark yellow oil was triturated with ethyl acetate (100 mL) for 4 hours after which time a white crystalline solid resulted. This material was isolated by filtration and vacuum dried for 3 hours to afford 4-(4-chlorophenyl)-4-fluoropiperidine hydrochloride in 73% overall yield.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.CS(C)=O.F[C:21]1[C:22]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:23]([CH3:38])[C:24]([C:36]#[N:37])=[C:25]2[C:29]=1[O:28][C:27]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[N:26]2>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:21]2[C:22]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:23]([CH3:38])[C:24]([C:36]#[N:37])=[C:25]3[C:29]=2[O:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:26]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CCOCC3)nc2c1C#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CCOCC3)nc2c1C#N
Temperature: 150 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (55 μl, 0.435 mmol) and triethylamine (70 μl, 0.502 mmol) were added to a dimethyl sulfoxide (3 ml) solution of 7-fluoro-5-methyl-2-morpholin-4-yl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-283) (113 mg, 0.335 mmol), followed by stirring in an oil bath at 150° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform and washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was recrystallized from hot ethanol to obtain the entitled compound (33.0 mg, 22%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:14](=[CH:23]\[CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)/[C:15]([NH:17][C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1.[Br:31]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:31][C:20]1[S:19][C:18]([NH:17][C:15](=[O:16])/[C:14](/[C:4]2[CH:5]=[CH:6][C:7]([N:8]3[C:12]([CH3:13])=[N:11][N:10]=[N:9]3)=[C:2]([Cl:1])[CH:3]=2)=[CH:23]/[CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2ncc(Br)s2)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A suspension of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cycloheptyl-N-thiazol-2-yl-acrylamide (300 mg, 0.69 mmol) and N-bromosuccinimide (123 mg, 0.69 mmol) in carbon tetrachloride (3 mL) at 25° C. was treated with benzoyl peroxide (8.4 mg, 0.035 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL). The organic phase was then washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 hexanes/ethyl acetate) afforded (E)-N-(5-bromo-thiazol-2-yl)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3cycloheptyl-acrylamide (118 mg, 33%) as an amorphous solid: EI-HRMS m/e calcd for C21H22BrClN6OS (M+) 520.0448, found 520.0448.
Reaction SMILES: S([O-])(O[O-])(=O)=[O:2].[K+].[K+].[CH3:9][C:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][CH2:20][N+:21]([O-:23])=[O:22])[C:12]=2[S:13][CH:14]=1>O.COCCOC>[CH3:9][C:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:20][N+:21]([O-:23])=[O:22])=[O:2])[C:12]=2[S:13][CH:14]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: Cc1csc2c(SC[N+](=O)[O-])cccc12
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1csc2c(S(=O)C[N+](=O)[O-])cccc12
Temperature: 5 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A solution of potassium peroxymonosulphate (`oxane` trade mark; 1.0 g, 1.63 mmol) in water (20 ml) was added in one portion to a stirred solution of 3-methyl-7-(nitromethylthio)benzo[b]thiophene (0.7 g, 2.93 mmol) in 1,2-dimethoxyethane (40 ml) cooled to 5° C. The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). These extracts were washed with water, dried (MgSO4), and evaporated to leave an oil, which was purified by flash chromatography using 4:1 v/v dichloromethane/hexane as eluant, to give 3-methyl-7-(nitromethylsulphinyl)benzo[b]thiophene as a pale yellow solid (0.35 g); NMR:2.5(s, 3H), 5.55(s, 2H), 7.25(s, 1H), 7.6-8.0(m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[Cl:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[C:3]([Cl:19])[CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1Cl
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(Cl)c2)c1[N+](=O)[O-]
Yield: 74 %

Procedure:
Method H3 was used with 4-(4-amino-3-chlorophenoxy)-3-nitropyridin-2-amine and 4-chloro-3-trifluoromethyl-phenyl isocyanate to afford the title compound (530 mg, 74%). 1H-NMR (δ, ppm, DMSO-d6): 6.05 (d, 1H, HPy,5, J=5.7 Hz), 7.19 (m, 3H, Harom), 7.43 (d, 1H, HPh,11or12, J=2.7 Hz), 7.61 (s, 2H, NH2,Py), 8.01 (d, 1H, HPy,6, J=5.7 Hz), 8.09 (s, 1H, Harom), 8.17 (d, 1H, Harom, J=9.1 Hz), 8.49 (s, 1H, NHurea1), 9.85 (s, 1H, NHurea3). LC-MS (m/z): 502 (M+H, 100).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19](O)=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a suspension of 60% sodium hydride (361 mg, 9 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (865 mg, 9.1 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A62. A solution of 6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (520 mg, 1.3 mmol) and 1,1′-carbonyldiimidazole (422 mg, 2.6 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B62. Solution B62 was added to Solution A62 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (50 mg, 8%) as a white solid: MS (ESI) M+1=478.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[C:7]=1[C:8]([F:11])([F:10])[F:9].[F:26][C:27]1[CH:32]=[C:31]([N:33]2[CH:37]=[N:36][N:35]=[N:34]2)[CH:30]=[CH:29][C:28]=1[OH:38]>>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:6]3[C:7]([C:8]([F:9])([F:10])[F:11])=[C:3]([CH2:2][O:38][C:28]4[CH:29]=[CH:30][C:31]([N:33]5[CH:37]=[N:36][N:35]=[N:34]5)=[CH:32][C:27]=4[F:26])[CH:4]=[N:5]3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC(n3ncc(CCl)c3C(F)(F)F)CC2)nc1
Reactant: Oc1ccc(-n2cnnn2)cc1F
Product: CCc1cnc(N2CCC(n3ncc(COc4ccc(-n5cnnn5)cc4F)c3C(F)(F)F)CC2)nc1

Procedure:
The title compound was synthesized using 2-(4-(4-(chloromethyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)piperidin-1-yl)-5-ethylpyrimidine and 2-fluoro-4-(1H-tetrazol-1-yl)phenol in manner similar to that described in Example 1. 1H NMR (CDCl3): δ 8.95 (1H, s), 8.18 (2H, s), 7.64 (1H, s), 7.52 (1H, m), 7.43 (1H, m), 7.19 (1H, m), 5.16 (2H, s), 4.92 (2H, m), 4.50 (1H, m), 3.02 (2H, m), 2.47 (2H, q), 2.22 (2H, m), 2.01 (2H, m), 1.19 (3H, t).
Reaction SMILES: C1(NC(C)C)CCCCC1.C([Li])CCC.[I:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].Cl.[C:27]([O:30][CH2:31][CH3:32])(=[O:29])[CH3:28]>O1CCCC1.CCCCCC>[I:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([CH2:28][C:27]([O:30][CH2:31][CH3:32])=[O:29])=[O:20]
Reactant: CCOC(C)=O
Reactant: O=C(Cl)c1ccccc1I
Agent: CC(C)NC1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccccc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Cyclohexyl isopropylamine (10.6 grams) is dissolved in 80 ml of tetrahydrofuran and the solution is cooled to -78° C. In a nitrogen stream, a solution of n-butyl lithium (about 15%) in hexane solution (26 ml) is added thereto, and the mixture temperature is raised to -40° C. Then it is cooled to -78° C. once again, 3.3 grams of ethyl acetate is gradually added thereto and, ten minutes thereafter, a solution of 10 grams of o-iodobenzoyl chloride in tetrahydrofuran is dropped thereinto gradually. The mixture is stirred at -78° C. for one hour, then gradually warmed up to 0° C. within two to three hours, 20 ml of 20% hydrochloric acid solution is added thereto, the mixture is poured into ice water, and extracted with ether. The extract is washed with a saturated aqueous solution of sodium bicarbonate, dried with anhydrous magnesium sulfate, ether is evaporated therefrom, and the resulting oil is purified by distilling in vacuo to give 8.5 grams of pale yellow oil, b.p. 142° C./3 mmHg.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:3]1.[CH2:18]([Li])CCC.CI>O1CCCC1>[CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][C:12]=2[CH3:18])=[N:3]1
Reactant: [Li]CCCC
Reactant: CC1(C)COC(c2ccc(C(F)(F)F)cc2)=N1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)ccc1C1=NC(C)(C)CO1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
To a solution of the product from step (i) (9.5 g) in tetrahydrofuran (40ml) at -60° C. was added n-butyllithium (17 ml of a 2.5M solution in hexanes) dropwise. The mixture was stirred at -65° C. for 1 hour and methyl iodide (12 ml) was added. The mixture was stirred at room temperature for 1 hour and quenched with brine. The organic phase was dried (MgSO4) and evaporated. Yield 9.56 g. Used directly in the next step.
Reaction SMILES: O[CH2:2][N:3]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:4]1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][CH2:2][N:3]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:4]1
Reactant: N#Cc1cn(CO)cc1-c1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1cn(CCl)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
With efficient stirring, 48 g of N-hydroxymethyl-3-(2-chlorophenyl)-4-cyanopyrrole are added in several portions to 60 ml of thionyl chloride such that moderate gas evolution is maintained. When the evolution of gas ceases, the mixture is stirred for 2 hours at room temperature and then for 21/2 hours at 35°-40° C. After cooling to room temperature, toluene is added and the mixture is concentrated. The residue is recrystallised from diethyl ether/petroleum, affording the title compound in the form of beige crystals with a melting point of 97°-99° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.[CH2:23](O)[C:24]#[CH:25].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:25][C:24]#[CH:23])[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: C#CCO
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CCOc1cc(OC)cc2oc(-c3cn4nc(OC)sc4n3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 205 mgs, 0.646 mmol) in THF (10 mL) was treated at r.t. and under a nitrogen atmosphere, with propargyl alcohol (0.096 mL, 1.615 mmol), tri-n-butylphosphine (0.398 mL, 1.615 mmol) and dropwise, over a 25 min period with a solution of 1,1′-(azodicarbonyl)dipiperidine (408 mgs, 1.615 mmol) in THF (10 mL). The mixture was sonicated in a bath for 30 min and stirred at r.t. for another 30 min. The mixture was then dissolved in dichloromethane (50 mL) and washed with sat. aqueous NaHCO3, brine and dried (MgSO4). Evaporation of the solvent gave a solid that was purified by silica gel column chromatography ISCO to give the title material (180 mg, 0.507 mmol, 78% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.38 (s, 1H), 6.92 (s, 1H), 6.86 (dd, J=1.8, 1.0 Hz, 1H), 6.53 (d, J=1.6 Hz, 1H), 4.94 (d, J=2.7 Hz, 2H), 4.21 (s, 3H), 3.77-3.84 (m, 3H), 3.60-3.66 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[CH:16][CH:15]=1>>[C:8]([C:7]1[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:18][CH:19]=2)=[N:3][C:4]([S:11][CH3:12])=[N:5][C:6]=1[CH3:10])#[N:9]
Reactant: Nc1ccc(NC(=O)N2CCCC2)cc1
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Product: CSc1nc(C)c(C#N)c(Nc2ccc(NC(=O)N3CCCC3)cc2)n1

Procedure:
The compound was prepared from 4-chloro-6-methyl-2-(methylthio)-5-pyrimidinecarbonitrile and N-(4-aminophenyl)-1-pyrrolidinecarboxamide following procedure similar to that described for Intermediate 23.
Reaction SMILES: ClC1C(OC)=CC2CCNCC(C)C=2C=1.C[N:17]1[CH2:23][CH:22]([CH3:24])[C:21]2[CH:25]=[C:26]([Br:31])[C:27]([O:29][CH3:30])=[CH:28][C:20]=2[CH2:19][CH2:18]1.BrC1C(OC)=CC2CCNCC(CC)C=2C=1.ClC1C(OC)=CC2CCNCC(CC)C=2C=1.IC1C(OC)=CC2CCNCC(CC)C=2C=1.COC1C(C(F)(F)F)=CC2C(C)CNCCC=2C=1.COC1C(C(F)(F)C(F)(F)F)=CC2C(C)CNCCC=2C=1>>[Br:31][C:26]1[C:27]([O:29][CH3:30])=[CH:28][C:20]2[CH2:19][CH2:18][NH:17][CH2:23][CH:22]([CH3:24])[C:21]=2[CH:25]=1
Reactant: COc1cc2c(cc1Br)C(C)CN(C)CC2
Agent: CCC1CNCCc2cc(OC)c(Br)cc21
Agent: CCC1CNCCc2cc(OC)c(Cl)cc21
Agent: CCC1CNCCc2cc(OC)c(I)cc21
Product: COc1cc2c(cc1Br)C(C)CNCC2

Procedure:
8-Chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Iodo-7-methoxy-1-methyl-2,3,4,5-taetrhydro-1H-3-benzazepine; N-Methyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Bromo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Chloro-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Iodo-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-Methoxy-1-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and 7-Methoxy-1-methyl-8-pentafluoroethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:11]2[CH2:12][CH2:13][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH2:9][CH2:10]2)[CH:15]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1cccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1

Procedure:
118.7 mg of the target compound (0.35 mmol, 42.3%) was obtained using 1-(3-methylphenyl)piperazine (289 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15](=[O:34])[CH2:16][CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+]>O1CCCC1.O>[OH:34][CH:15]([C:13]1[CH:12]=[CH:11][C:3]([O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]([CH3:1])[CH:14]=1)[CH2:16][CH2:17][C:18]1[S:22][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=2)=[N:20][C:19]=1[CH3:33]
Reactant: CCOC(=O)COc1ccc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1ccc(C(O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl [2-methyl-4-(3-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}propanoyl)phenoxy]acetate (intermediate11, 0.28 g) in tetrahydrofuran (8 ml) and water (8 ml) at 0° C. was treated portion-wise with sodium borohydride (0.043 g) and the mixture was stirred at 0° C. for 1 hour. The solvent was evaporated and the residue partitioned between water and ethyl acetate; the aqueous layer was separated and extracted twice more with ethyl acetate. The combined organic solutions were dried with brine and over magnesium sulfate and concentrated. The product isolated after evaporation of the solvent was further purified by flash column chromatography using cyclohexane:ethyl acetate (3:1) as eluent to give the title compound as a colourless gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([NH:30][C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[C:11]([N+:39]([O-:41])=[O:40])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:19][CH2:18][CH:17]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:37][CH:38]=1)[C:12]1[CH:13]=[C:14]([O:15][CH3:16])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[N+:39]([O-:41])=[O:40]
Reactant: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C(CN)Nc2ccc(C#N)cc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
4-[1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile (2.7 g, 5 mmoles) was dissolved in ethanol (100 ml) and hydrazine hydrate (0.65 ml, 20 mmoles) added. The reaction was heated to 60° C. for 3 hours then at room temperature for 48 hours. The solids that precipitated were filtered off and the residue submitted to flash chromatography to yield 4-[2-Amino-1-(4-benzyloxy-5-methoxy-2-nitro-phenyl)-ethylamino]-benzonitrile (1.5 g). 1HNMR(CDCl3): 7.75 (s,1H), 7.3-7.5 (m, 7H), 7.05 (s,1H), 6.45 (d, 2H), 5.80 (bs, 1H), 5.32 (m, 1H), 5.19 (s, 2H), 3.81 (s, 3H), 3.25 (dd, 1H), 3.0 (dd, 1H), 1.65 (bs, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[O:16][CH3:17])[CH3:2].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CCO.[Fe]>[CH2:18]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[O:16][CH3:17])[CH3:19]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1OC
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.77 g (2.87 mmol) of diethyl-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-amine was added to a suspension of 1.00 g (17.9 mmol) of iron powder in 7 mL EtOH and the mixture was stirred for 10 minutes at RT. 6.6 mL of conc. aqueous HCl was added dropwise within 15 minutes and the mixture was stirred for 1 hour. 100 ml of 2 M sodium carbonate solution was added and the mixture was exhaustively extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c2ccccc2n1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)nc4ccccc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
2-Methyl-quinolin-4-ol (213 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (110 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (7 mg, yield 2%).