Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:15]=1)[N:12]=[CH:11][CH:10]=[C:9]2[CH3:29].CC(O)C.[OH-].[NH4+].[C:36]([N:38]=[C:39](SC)[S:40][CH3:41])#[N:37]>O.C1(C)C=CC=CC=1>[C:36]([N:38]=[C:39]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]2[CH:15]=[C:6]([O:5][CH3:4])[CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[C:9]3[CH3:29])[CH2:28][CH2:27]1)[S:40][CH3:41])#[N:37]
Reactant: CSC(=NC#N)SC
Reactant: COc1cc(NCCCCCCN2CCNCC2)c2nccc(C)c2c1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: COc1cc(NCCCCCCN2CCN(C(=NC#N)SC)CC2)c2nccc(C)c2c1
Yield: 66 %

Procedure:
A solution of 5.5 g (0.009 mole) of 6-methoxy-4-methyl-N-[6-(1-piperazinyl)hexyl]-8-quinolinamine, trihydrobromide, compd. with 2-propanol (1:0.3), hemihydrate in 100 ml of water was made basic with concentrated ammonium hydroxide and extracted with dichloromethane. The extract was washed, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under vacuum. A solution of the concentrate and 1.8 g (0.012 mole) of cyanodithioimidocarbonic acid, dimethyl ester in 100 ml of toluene was stirred at room temperature for 64 hours, then washed with water, dried, and concentrated to dryness. Recrystallization from 2-propanol afforded 2.7 g (66%) of the title compound as yellow needles, mp 97°-99°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([C:72]2[NH:76][N:75]=[CH:74][N:73]=2)=[CH:68][CH:67]=1>C(Cl)Cl>[N:75]1[NH:76][C:72]([C:69]2[CH:70]=[CH:71][C:66]([NH:65][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]3)=[O:30])=[CH:67][CH:68]=2)=[N:73][CH:74]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(-c2ncn[nH]2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3ncn[nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.32 mmol) in methylene chloride (5 mL), HATU (Aldrich, 152 mg, 0.4 mmol) was added followed by the addition of DIPEA (0.1 mL) and 5-(4-amino-phenyl)-1H-[1,2,4]triazole (made above, 64 mg, 0.4 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 70% EtOAc/hexanes) to give a white solid. 140 mg.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])=[CH:27][CH:26]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:33][CH2:32][C:31]([C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=3)([CH3:35])[CH3:34])=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CC(C)(CN)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: CC(C)(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(Cl)cc1

Procedure:
2-(Benzo[2,5]thiadiazole-4-sulfonylamino)-4-chloro-N-[2-(4-chloro-phenyl)-2-methyl-propyl]-benzamide. 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid was coupled with 2-(4-chloro-phenyl)-2-methyl-propylamine as in EXAMPLE 1, Part C. HPLC: RT=11.08 min. MS (ESI−): mass calcd. for C23H20Cl2N4O3S2, 534.04; m/z found, 533/535 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.53 (s, 1H), 8.35 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.71 (dd, J=8.8, 7.0, 1H), 7.70 (d, J=1.8, 1H), 7.35-7.31 (m, 2H), 7.30-7.26 (m, 2H), 6.89 (d, J=8.3 1H), 6.86 (dd, J=8.4, 1.8, 1H), 5.58-5.52 (m, 1H), 3.56 (d, J=6.1, 2H), 1.36 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18]C(OCC2C=CC=CC=2)=O)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C1CC=CCC=1.CO>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1)[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: C1=CCC=CC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(CCN)cc1

Procedure:
The mixture of {1-[4-(2-benzyloxycarbonylamino-ethyl)-phenyl]-ethyl}carbamic acid tert-butyl ester (0.80 g, 2.0 mmol), 1,4-cyclohexadiene (0.96 mL, 10 mmol) and palladium on carbon (100 mg) in ethanol (20 mL)-methanol (5 mL) was heated to reflux for 2 h and brought to room temperature. The mixture was filtered through celite and concentrated to afford a white solid. M+1=265.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=O)(=O)[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([Li])CCC.[CH:35]([CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)=[O:36]>O1CCCC1.[Cl-].[NH4+]>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH2:23][N:17]([C:4]2[CH:3]=[C:2]([CH:35]([OH:36])[CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:30])[CH:10]=3)[N:5]=2)[CH2:18][CH2:19]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(C(O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 0.08 h
Yield: 69.3 %

Procedure:
To a solution of 4-(4-bromo-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (385 mg, 1.0 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in tetrahydrofuran (10 mL) which was cooled to −78° C., butyl lithium (0.8 mL, 1.3 mmol) was added slowly and the mixture was stirred for 5 minutes, followed by the addition of a solution of tert-butyl 4-formylpiperidine-1-carboxylate (153 mg, 1.3 mmol) in tetrahydrofuran (5 mL) slowly. After being stirred further at −78° C. for 2 hours, the reaction mixture was diluted with a saturated aqueous solution of ammonium chloride (10 mL) and extracted with dichloromethane (20 mL×2). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20-40% ethyl acetate in petroleum ether) to afford 360 mg of the desired product (yield was 70%). MS (ESI+) [(M+H)+] 520.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])=[N+:2]=[N-:3].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.2 %

Procedure:
A solution of 2-(2-azido-ethoxy)-ethanol 2 (14.1 g, 0.108 mol) and pyridine (13 ml, 1.5 equiv.) in CH2Cl2 (150 ml) was cooled in an ice bath. p-Toluenesulfonyl chloride (30.7 g, 1.5 equiv.) then DMAP (173 mg, 0.01 equiv.) were added. The reaction mixture was stirred at RT for 72 h, then washed with a 1 M HCl aqueous solution (3×50 ml), dried over MgSO4, filtrated then concentrated under reduced pressure. Purification by flash column chromatography (eluent: pet. ether/AcOEt 9:1 then 7:3) afforded tosylate 3 as a colorless oil (23.8 g, 78%). 1H and 13C NMR spectra matched the literature data (Gill, H. et al. J. Med. Chem. 2009, 52, 5816-5825).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH2:27])[C:5]2=3)[CH:14]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[C:5]2=3)[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c3c(c1)c1c(OCCN)cccc1n3C(c1ccccc1)CO2
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NCCOc1cccc2c1c1cc(C)cc3c1n2C(c1ccccc1)CO3
Temperature: 95 °C
Yield: 99.5 %

Procedure:
To a mixture of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine (0.0.442 g, 1.23 mmol) in DMF (10 mL) is added acetic anhydride (0.126 g, 1.23 mmol) and DMAP (0.08 g, 0.66 mmol). The mixture is heated at 95° C. for 1 h and then partitioned between water and ether after cooling. The organic layer is washed three times with water (60 mL), dried over magnesium sulfate and concentrated to give 0.49 g (99%) of N-{2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}acetamide.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23])=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:2]=1.[C-:27]#[N:28].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[C:1]1([CH3:26])[CH:2]=[CH:3][C:4]([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]([C:27]#[N:28])=[C:21]([C:24]#[N:25])[C:22]#[N:23])=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][CH:6]=1
Reactant: [C-]#N
Reactant: Cc1ccc(-n2c3ccccc3c3cc(C=C(C#N)C#N)ccc32)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(-n2c3ccccc3c3cc(C(C#N)=C(C#N)C#N)ccc32)cc1
Reaction time: 0.17 h
Yield: 21.5 %

Procedure:
6.50 g (19.5 mmol) of N-(p-tolyl)-3-(dicyanovinyl)carbazole and 60 ml of N,N-dimethylformamide as solvent were placed in a 500 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 1.05 g (21.4 mmol) of sodium cyanide and 5.0 ml of water, which was stirred for 10 minutes. Further, 8.64 g (19.5 mmol) of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 300 ml of chloroform was added. To the resultant solution was added 300 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain a red solid. The resultant solid was recrystallized in the presence of benzene to obtain 1.50 g of a red crystal.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C1N=CN([C:14](N2C=NC=C2)=[O:15])C=1.C1CCN2C(=NCCC2)CC1.[C@H:32]12[CH2:38][C@H:35]([NH:36][CH2:37]1)[CH2:34][N:33]2[C:39]1[N:44]=[CH:43][C:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:41][N:40]=1>C1COCC1.C(OCC)(=O)C>[CH2:48]([O:47][C:45]([C:42]1[CH:41]=[N:40][C:39]([N:33]2[CH2:34][C@@H:35]3[CH2:38][C@H:32]2[CH2:37][N:36]3[C:14]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:15])=[N:44][CH:43]=1)=[O:46])[CH3:49]
Reactant: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3)nc1
Reactant: OCc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N2C[C@@H]3C[C@H]2CN3C(=O)OCc2cccnc2)nc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution of pyridin-3-ylmethanol (0.086 mL, 0.878 mmol) in THF (2.5 mL) was added N,N-carbonyldiimidazole (0.142 g, 0.878 mmol). After stirring for 1 h a solution of TEA (0.245 mL, 1.756 mmol), DBU (0.132 mL, 0.878 mmol) and the title compound 212 (0.25 g, 0.878 mmol) in THF (2.5 mL) was added. The reaction mixture was stirred overnight at 45° C. The mixture was cooled down and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (twice): 40 SiO2, MeOH/EA 0% to 20% over 20 min to afford title compound 221 (80 mg, 24%) as an oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.81-8.77 (m, 2H), 8.60-8.57 (m, 2H), 7.83-7.76 (m, 1H), 7.42-7.35 (m, 1H), 5.21-5.05 (m, 1H), 5.21 (s, 2H), 4.79 (s, 1H), 4.72-4.64 (m, 1H), 4.31 (qd, J=7.1, 1.8 Hz, 2H), 3.69-3.41 (m, 3H), 1.98 (d, J=8.0 Hz, 2H), 1.34 (td, J=7.1, 2.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.Cl.[CH2:39]([O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45])[CH3:40].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:45][CH2:44][CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:46])=[O:34])=[CH:36][CH:37]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCOC(=O)CCN
Reactant: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(Nc1ccc(C(=O)NCCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
To a mixture of 4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]benzoic acid (250 mg) synthesized above, β-alanine ethyl ester hydrochloride (109 mg), 1-hydroxybenzotriazole monohydrate (109 mg), triethylamine (198 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (136 mg), and the mixture was stirred at room temperature for 3 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (272 mg, 92%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[C:13]2=[O:26])[CH2:6]1.[C:27](=O)([O-])[O-].[K+].[K+].[CH3:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1C)[NH:37][CH2:38][CH3:39]>CS(C)=O>[ClH:1].[ClH:1].[CH3:27][C:35]1[C:36]([NH:37][CH2:38][CH3:39])=[C:40]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=4)[C:13]3=[O:26])[CH2:6]2)[CH:41]=[CH:42][C:34]=1[CH3:33]
Reactant: CCNc1ccc(C)c(C)c1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCCCl)C1)CC2
Agent: [K+]
Solvent: CS(C)=O
Product: CCNc1c(CCCN2CCCC(CN3CCc4cc(OC)c(OC)cc4C3=O)C2)ccc(C)c1C
Product: Cl
Temperature: 120 °C

Procedure:
A mixture of 1.3 g (0.0034 mol) of 2-[(N-(3-chloropropyl)-piperidine-3-yl)-methyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline, 15 ml of dimethylsulphoxide, 1.4 g (0.1 mol) of potassium carbonate and 1 g (0.0066 mol) of 3,4-dimethyl-N-ethylaniline is heated to 120° C. for 6 hours. The reaction mixture is poured onto ice water, extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulphate and evaporated down in vacuo. The residue obtained is purified over silica gel (0.036-0.2 mm) with 5% ethanol in methylene chloride.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[N:3]=[C:2]1[C:11]1[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=1)[C:16](OC)=[O:17].Cl.[CH:24]1(C2C(C3NC4CCNCCC=4N=3)=CC(C(OC)=O)=C(C)C=2)CCC1.Cl.[Cl:50][C:51]1[CH:56]=[CH:55][C:54]([CH:57]2[CH2:60][NH:59][CH2:58]2)=[CH:53][CH:52]=1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([CH:57]2[CH2:58][N:59]([C:16]([C:15]3[CH:20]=[C:11]([C:2]4[NH:1][C:5]5[CH2:6][CH2:7][N:8]([CH3:24])[CH2:9][CH2:10][C:4]=5[N:3]=4)[C:12]([CH3:22])=[CH:13][C:14]=3[CH3:21])=[O:17])[CH2:60]2)=[CH:55][CH:56]=1
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C2CCC2)cc1C
Reactant: Clc1ccc(C2CNC2)cc1
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C)cc1C
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1cc(C)c(-c2nc3c([nH]2)CCN(C)CC3)cc1C(=O)N1CC(c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 82, except methyl 5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoate (compound 83.4) was used in place of methyl 4-cyclobutyl-5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2-methylbenzoate hydrochloride (compound 82.7) and 3-(4-chlorophenyl)azetidine hydrochloride (compound 85.1) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 449 (M+H)+.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[CH:31]=[O:32])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH:30]2[C:31](=[O:32])[O:13][C:12]3[NH:11][C:10]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[F:21])=[N:9][C:8]=3[CH:1]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1ccc(Cl)cc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccc(Cl)cc1
Yield: 58 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(4-chlorophenyl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 12 as a white solid (78 mg, 58%). Analytical data for 12: 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J=7.9 Hz, 1H), 7.89 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.38-7.31 (m, 2H), 7.31-7.26 (m, 3H), 7.12-6.92 (m, 6H), 4.08 (d, J=6.8 Hz, 1H), 3.56 (ddd, J=9.8, 6.9, 4.9 Hz, 1H), 3.29 (dd, J=14.9, 5.0 Hz, 1H), 2.43 (dd, J=14.9, 9.8 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.7, 159.11 (d, JCF=244.0 Hz), 155.38 (d, JCF=242.2 Hz), 148.9, 136.8, 136.5, 136.3, 132.6, 130.4, 129.3, 128.8, 128.4, 127.9, 118.32 (dd, JCF=12.4, 9.3 Hz), 117.12 (dd, JCF=25.5, 8.6 Hz), 116.64 (dd, JCF=24.8, 9.2 Hz), 114.51 (dd, JCF=26.9, 3.7 Hz), 110.69 (d, JCF=3.8 Hz), 47.2, 38.6, 32.3; IR (film) cm−1 1769, 1638, 1492, 1481, 1462, 1239, 1171, 1118, 1096, 1032, 813, 766, 741, 699; LRMS (ESI): Mass calcd for [M+H]+ C25H18ClF2N2O2: 451.1. found 451.3; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 5% IPA/3% MeOH/hexanes 0.5 mL/min, 280 nm), Rt1 (major)=40.5, Rt2 (minor)=50.6 min; er=98:2.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH2:17][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:18]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1)=[O:4]>CO.C(O)(=O)C.[Pd]>[NH2:18][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]1[CH2:17][CH2:16][CH:14]2[CH2:15][N:5]([C:3](=[O:4])[C:2]([F:22])([F:1])[F:21])[CH2:6]1
Reactant: O=C(N1CC2CCC(C1)c1cc([N+](=O)[O-])ccc12)C(F)(F)F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
2,2,2-Trifluoro-1-(4-nitro-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-ethanone (1.227 g, 3.91 mmol) was placed in methanol (100 mL) and acetic acid (1 mL). 10% Palladium on carbon (6.8 mg) was then added. The reaction was hydrogenated at 20 psi for 30 minutes. The mixture was then filtered through celite and concentrated under reduced pressure to obtain 1-(4-amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone as a brown oil (1.110 g, 100%). LCMS (m/e) 285 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.92 (dd, 1H, J=8.0 and 10.9 Hz), 6.60-6.50 (m, 2H), 4.23-4.10 (m, 1H), 3.90-3.75 (m, 1H), 3.46-3.25 (m, 2H), 3.15-3.00 (m, 2H), 2.03-1.91 (m, 2H), 1.80-1.70 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[CH:5][C:3]=1[N:4]=[C:19]=[O:20]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)c(Br)cc1OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(Br)c(N=C=O)cc1OC
Temperature: 90 °C

Procedure:
2-Bromo-4,5-dimethoxyaniline (464 mg, 2.0 mmol) was dissolved in 10 ml of toluene at room temperature. DMAP (1 eq, 245 mg), and pyridine (1.3 eq, 0.22 ml) were added followed by phosgene (1.33 eq, 1.33 ml of a 20% solution in toluene). The mixture was heated to 90° C. for 4 hours. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuo to give 1-bromo-2-isocyanato-4,5-dimethoxy-benzene (542 mg, quantitative) as a light brown oil.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[S:14]1(=[O:25])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]1.[F:26][C@@H:27]1[CH2:31][NH:30][CH2:29][C@H:28]1[NH2:32]>>[F:26][C@@H:27]1[CH2:31][N:30]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=[C:2]([N:17]3[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[S:14](=[O:25])[CH2:15][CH2:16]3)[N:11]=2)[CH2:29][C@H:28]1[NH2:32]
Reactant: Cc1ccc2nc(Cl)[nH]c(=O)c2c1
Reactant: N[C@@H]1CNC[C@H]1F
Reactant: O=S1CCNCc2ccccc21
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(N3C[C@@H](N)[C@H](F)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 62-1 in Scheme 23 by using 2-chloro-6-methylquinazolin-4(3H)-one, 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide and trans-4-fluoropyrrolidin-3-amine. MS obsd. (ESI+) [(M+H)+] 426. 1H NMR (400 MHz, CD3OD) 7.82 (s, 1 H), 7.71 (d, J=6.8 Hz, 1 H), 7.42 (m, 4 H), 5.26 (d, J=15.2 Hz, 1 H), 5.07 (d, J=51.2 Hz, 1 H), 4.78 (brs, 1 H), 4.43 (m, 2 H), 4.29 (m, 1 H), 4.06 (t, J=11.2 Hz, 1 H), 3.86 (d, J=12 Hz, 1 H), 3.75 (m, 1 H), 3.40 (m, 2 H), 2.40 (s, 3 H).