Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:6].[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)(Cl)Cl.C(N(CC)CC)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:31]1([CH:2]([O:1][C:37](=[O:39])[CH3:38])[CH2:3][NH:4][C:5]([C:7]2[N:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:29])[F:27])[CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[O:6])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCC(O)c1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OC(CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.5 %

Procedure:
To a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide (50 mg, 0.1 mmol) in chloroform (2 mL), acetic anhydride (0.25 mL), triethylamine (0.25 mL) and 4-dimethylaminopyridine (18 mg) were added. After stirred at ambient temperature for 6 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×10 mL) and dried over Na2SO4. The crude product obtained after removal of the solvent was purified by column chromatography eluted sequentially with hexane:ethyl acetate=1:1 and 1:2 to give a white powder (49.6 mg, 91.5% yield). 1H NMR (500 MHz, CDCl3) δ 8.10, 8.04, 7.75, 7.65, 7.57, 7.40-7.28, 7.00, 5.92, 4.07, 3.98, 3.90, 3.82-3.68, 3.36, 2.10. MS (ES+) m/z 508 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][NH:7]1.Br[CH2:26][C:27](Br)=[O:28].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:26][C:27]([NH:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1Br
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1Br

Procedure:
prepared by reaction of 1-(3-Bromo-4-methoxy-benzyl)6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[CH3:38][O:37][C:35]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9]1)=[O:36]
Reactant: COC(=O)Cl
Reactant: c1ccc(C(NC2CCCNC2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCCC(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 72.9 %

Procedure:
Add triethylamine (3.73 mL, 26.7 mmol) to a solution of piperidin-3-yl-trityl-amine (7.63 g, 22.3 mmol) in dichloromethane (125 mL), follow by dropwise addition of methyl chloroformate (1.76 mL, 22.7 mmol). Stir the reaction at room temperature under nitrogen overnight. Wash the reaction is wash with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–20% ethyl acetate/hexane) to give 6.51 g of the title compound as a white solid, 73% yield. 1H NMR: consistent with structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[CH:5]=1.[F:13][C:14]([F:50])([F:49])[C:15]1[CH:16]=[C:17]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:18][N:19]([C:36]1[N:37]=[N:38][N:39]([CH3:41])[N:40]=1)[C@H:20]1[CH2:26][CH2:25][CH2:24][NH:23][C:22]2[CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:29]([CH3:31])=[CH:30][C:21]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:23]2[CH2:24][CH2:25][CH2:26][C@H:20]([N:19]([CH2:18][C:17]3[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=[C:15]([C:14]([F:13])([F:50])[F:49])[CH:16]=3)[C:36]3[N:37]=[N:38][N:39]([CH3:41])[N:40]=3)[C:21]3[CH:30]=[C:29]([CH3:31])[C:28]([C:32]([F:34])([F:33])[F:35])=[CH:27][C:22]2=3)[CH:5]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1cccc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)c1
Reaction time: 2 h
Yield: 53 %

Procedure:
Add 3-formylbenzoic acid methyl ester (133 mg, 0.815 mmol) to a solution of (S)-(3,5-bis-trifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine (Example 3, Step 18) (150 mg, 0.272 mmol) in acetic acid (1 mL) and 1,2-dichloroethane (10 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxy borohydride (231 mg, 1.08 mmol) and stir for 3 h. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brined (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a white solid (101 mg, 53%): mp 62-65° C. dec; 1H NMR (CDCl3, 300 MHz) δ 1.50-1.70 (m, 2H), 2.07-2.25 (m, 2H), 2.29 (s, 3H), 2.73-2.85 (m, 1H), 2.95-3.09 (m, 1H), 3.89 (s, 3H), 4.18 (s, 3H), 4.31-4.40 (m, 2H), 4.81-5.02 (m, 2H), 6.93 (s, 1H), 7.31-7.42 (m, 2H), 7.55-7.63 (m, 4H), 7.79-7.82 (m, 1H), 7.89-7.92 (m, 1H), 8.10 (s, 1H); ESI MS m/z 701 [C32H29F9N6O2+H]+; HPLC 97.6%, tR 19.7 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])[NH:3]1.CCOC(C)=O.CC(O)=O>CCO.[Pd]>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:11][CH2:12][C:13]([OH:15])=[O:14])[NH:3]1
Reactant: O=C1Cc2c(NCC(=O)OCc3ccccc3)cccc2N1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)CNc1cccc2c1CC(=O)N2
Reaction time: 4 h

Procedure:
A mixture of 10% Pd/C (100 mg) and benzyl N-(2-oxo-2,3-dihydro-1H-indol-4-yl)glycinate from Step C (320 mg, 1.08 mmol) was stirred vigorously in EtOH (5 mL), EtOAc (5 mL), and AcOH (1 mL) under an atmosphere of hydrogen (ca. 1 atm). After 4 h, the mixture was filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated to give the title compound. MS: m/z=207 (M+1).
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-:7])=O)[CH:3]=1.[CH3:14][C:15]([O:18][C:19]([NH:21][CH2:22][CH2:23][NH2:24])=[O:20])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:13][O:12][C:1](=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH:24][CH2:23][CH2:22][NH:21][C:19]([O:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:20])=[O:7])[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)NCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
Mono-methyl isophthalate (10.0 g, 55.5 mmol), t-butyl n-(2-aminoethyl)carbamate (8.89 g, 55.5 mmol, 1.0 eq) and EDCI (12.2 g, 63.8 mmol, 1.15 eq) were dissolved in 270 mL DCM, followed by the addition of DIPEA (29.0 mL, 166 mmol, 3.0 eq). The reaction was allowed to stir at room temperature overnight. It was then taken up in 100 mL of DCM, washed with a 1:1 solution of 1.0 N HCl in brine, water, and a 1:1 solution of brine in saturated NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to afford the product as a light yellow solid (12.81 g, 72%).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:38]=[C:20]4[CH:21]([C:27]5[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=5)[CH2:22][C:23](=[O:26])[CH2:24][CH2:25][N:19]4[N:18]=3)=[CH:12][C:11]=2[O:39][CH3:40])[CH:9]=1>C1COCC1.[Cu]I>[Cl:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:38]=[C:20]4[C@@H:21]([C:27]5[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=5)[CH2:22][C@@:23]([CH3:1])([OH:26])[CH2:24][CH2:25][N:19]4[N:18]=3)=[CH:12][C:11]=2[O:39][CH3:40])[CH:9]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3n(n2)CC[C@](C)(O)C[C@@H]3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 4 %

Procedure:
A 25 mL round bottom flask was charged with copper (I) iodide (53.1 mg, 0.279 mmol) in THF (5 mL), and cooled to 0° C. A solution of methyl magnesium bromide (9.96 mL, 14.0 mmol) was added. The resulting mixture was stirred for 20 min. To the solution of methyl cuprate was added 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-(trifluoromethoxy)phenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (743 mg, 1.39 mmol) in THE (1 mL). The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with saturated ammonium chloride and diluted with EtOAc. The organic layer was collected and washed sequentially with H2O (100 mL), aq sat. NaHCO3 solution (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford rel-(7R,9R)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-methyl-9-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (43 mg, 4% yield, Example 152, first isomer to elute) and rel-(7S,9R)-2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-methyl-9-(4-(trifluoromethoxy)phenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (39.6 mg, 4% yield, Example 153, second isomer to elute). Data for Example 152: LC-MS (M+H)+ 549.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.09 (1 H, br. s.), 8.02 (1 H, d, J=1.5 Hz), 7.26-7.38 (5 H, m), 7.08-7.20 (3 H, m), 4.63-4.75 (2 H, m), 4.40 (1 H, ddd, J=14.9, 5.1, 2.3 Hz), 3.86 (3 H, s), 2.23-2.31 (1 H, m), 2.14-2.21 (1 H, m), 2.05-2.12 (1 H, m), 1.94-2.03 (1 H, m), 1.48 (3 H, s). Data for Example 153: LC-MS (M+H)+ 549.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.76 (1 H, s), 7.32 (1 H, d, J=2.4 Hz), 7.22-7.30 (5 H, m), 7.15 (1 H, d, J=8.5 Hz), 7.02-7.09 (2 H, m), 4.60 (1 H, ddd, J=14.7, 8.3, 2.6 Hz), 4.30 (1 H, ddd, J=14.9, 7.4, 2.4 Hz), 4.21 (1 H, dd, J=10.1, 1.8 Hz), 3.83-3.87 (3 H, m), 2.54 (1 H, dd, J=14.3, 10.4 Hz), 2.11-2.22 (3 H, m), 1.52 (3 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:26]N[CH2:24]3)[N:9]=2)=[CH:4][CH:3]=1.NC1(C(O)=O)C[O:30]C1.NC1(C(O)=O)CN(C(OC(C)(C)C)=O)C1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:26][O:30][CH2:24]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CNC1)c1nnc(C)n1-2
Reactant: NC1(C(=O)O)COC1
Agent: CC(C)(C)OC(=O)N1CC(N)(C(=O)O)C1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(COC1)c1nnc(C)n1-2

Procedure:
A procedure analogous to the scheme set forth for the synthesis of Compound 224 was followed, with the exception that 3-aminooxetane-3-carboxylic acid was used as starting material instead of 3-amino-1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:17]3=[C:18]([CH2:20][CH2:21][N:16]3[CH2:15][C@@H:14]3[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][C@H:13]23)[CH:19]=1>>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:17]3=[C:18]([CH2:20][CH2:21][N:16]3[CH2:15][C@@H:14]3[CH2:22][NH:23][CH2:24][C@H:13]23)[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Reactant: O=Cc1ccccc1
Product: c1ccc(CNc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CC3)cc1

Procedure:
Using benzaldehyde and following the procedures described in EXAMPLE 76, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±)-cis-N-benzyl-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 118 as the free base. LRMS (ES)+: 306.3 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.C(OCC)(=O)C>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH2:20][C:21]3[N:22]=[C:23]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=4)[O:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Nc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(C=Cc2nc(CNc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
4-(4-[1,2,3]Triazol-1-yl-butyl)-phenylamine (0.304 g, 1 mmol) is dissolved in anhydrous N,N-dimethylformamide (5 ml) followed by the addition of sodium hydride (0.024 g, 1 mmol). After stirring for 15 min at room temperature 4-chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole (0.324 g, 1.5 mmol) is added and the mixture stirred for 16 h at 80° C. Ethyl acetate (25 ml) is added, the mixture is washed with brine, dried over sodium sulfate and concentrated in vacuo. After flash column chromatography (ethyl acetate/hexanes 1:1->2:1) [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-{2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethyl}-amine 1 can be isolated as a yellow solid. Yield 0.14 g (29%); m.p. 103–105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH2:10][CH3:11])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:15]([CH:17]1[O:19][CH2:18]1)Br.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[O:19]1[CH2:18][CH:17]1[CH2:15][CH:22]([C:21]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:23][CH2:24][O:20][CH2:11][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:15][CH:17]1[O:19][CH2:18]1
Reactant: CCC(O)c1ccc(OC)cc1
Reactant: BrCC1CO1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(CCOCCC(CC2CO2)c2ccc(OC)cc2)CC2CO2)cc1
Temperature: 60 °C
Reaction time: 65 h

Procedure:
4-Methoxyphenylpropanol (15 g, 0.090M) was added dropwise to a stirred slurry of sodium hydride (4.0 g of a 60% dispersion in oil, 0.10M) in dry tetrahydrofuran (100 ml) and the stirred mixture was heated at 60° C. for 1 hour under a gentle stream of dry nitrogen. On cooling, epibromohydrin (12.8 g, 0.0934M) was added and the mixture was stirred at ambient temperature for 65 hours. The solvent was evaporated off under reduced pressure and the residue was treated with water (800 ml) and extracted with dichloromethane. The combined extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crdue product which was further purified by chromotography (silica gel, dichloromethane) to give 2,3-epoxypropyl-4-methoxyphenylpropyl ether as a colourless oil.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[C:3]#[N:4].[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]2[C:19]([O:21][C:22](=O)[C:10]=12)=[O:20].N1C=CC(C)=CC=1.[OH-].[Na+].OO.S(=O)(=O)(O)[OH:36]>C1(C)C=CC=CC=1>[CH:5]([C:2]1([CH3:8])[C:3](=[O:36])[NH:4][C:22]([C:10]2[C:11]([C:19]([OH:21])=[O:20])=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=2)=[N:1]1)([CH3:7])[CH3:6]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C)(N)C#N
Reactant: O=C1OC(=O)c2nc3ccccc3cc21
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: Cc1ccncc1
Product: CC(C)C1(C)N=C(c2nc3ccccc3cc2C(=O)O)NC1=O
Reaction time: 1 h

Procedure:
2-Amino-2,3-dimethylbutyronitrile (0.393 mol) is added over 40 minutes to a stirred solution of 2,3-quinolinedicarboxylic anhydride (0.376 mol) in 4-picoline (338 g, 3.63 mol) and toluene (52 g), while maintaining the temperature at 40° to 43° C. The reaction mixture is stirred at 40° to 43° C. for one hour. Aqueous sodium hydroxide (218 g, 25%, 1.36 mol) and then toluene 378 g) are added and the mixture stirred at 55° to 60° C. for approximately 15 minutes. The lower aqueous basic phase is separated off and the product extracted from organic phase with water. The aqueous phase is washed with toluene. A portion of the aqueous phase (25.8 g) is treated with 25% aqueous sodium hydroxide (10 g) and 3.7 equivalents of hydrogen peroxide at 65°-70° C. for one hour, then additional 50% aqueous sodium hydroxide (14.5 g) is added and the reaction mixture is allowed to stir for one hour at 65° to 70° C. The mixture is cooled to 25° to 30° C., and the pH of the mixture adjusted to 1.5 with concentrated sulfuric acid. The product 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid (17.3 g) is isolated by filtration.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[CH:13][N:14]([C:16]([N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:19])=[O:17])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])#[N:2].C([Sn](CCCC)=O)CCC.[N:36]([Si](C)(C)C)=[N+:37]=[N-:38]>C1(C)C=CC=CC=1>[CH:20]1([N:18]([CH3:19])[C:16]([N:14]2[CH:15]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([C:1]4[N:36]=[N:37][NH:38][N:2]=4)[CH:4]=3)[N:12]=[CH:13]2)=[O:17])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1C#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCCCC3)cn2)cc1-c1nn[nH]n1
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 4-(3-cyano-4-methoxyphenyl)-N-cyclohexyl-N-methyl-1H-imidazole-1-carboxamide (305 mg, 0.901 mmol), dibutylstannanone (28.0 mg, 0.113 mmol) and azidotrimethylsilane (0.239 ml, 1.803 mmol) was heated in toluene (8 mL) at 115° C. for 20 h. The mixture was then cooled to room temperature and evaporated to dryness. The crude product was chromatographed over silica using a mixture of dichlormethane/methanol (95:5). After evaporation of the homogenous fractions, the residual product was triturated with diethyl ether, filtered and dried to give the product as off-white crystals, (196 mg, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[C:15]2[O:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[CH2:37]([O:36][C:34]([CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]2[O:16][C:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:19]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35])[CH3:38]
Reactant: Oc1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1cccc(C[C@@H]2CCCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[2-[(3-hydroxyphenyl)methyl]-cyclohexyl]-4,5-diphenyloxazole (320 mg), ethyl bromoacetate (0.13 ml), and potassium carbonate (270 mg) in acetonitrile (3.0 ml) was stirred at room temperature overnight and a mixture of ethyl acetate and water was added thereto. The organic layer was separated, washed with water (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed over silica gel using n-hexane--ethyl acetate as an eluent. The first eluate gave cis- or trans-1-[(3-ethoxycarbonylmethoxyphenyl)methyl]-2-(4,5-diphenyloxazol-2-yl)cyclohexane (isomer A) (79 mg) as a powder.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].Cl>>[CH2:17]([N:12]1[CH2:11][CH2:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:14][CH2:13]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCBr
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Agent: Cl
Product: CCCCN1CCC(c2cccc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 4-(3-Trifluoromethyl-phenyl)-piperidine and n-Bu-Br: m.p. 222° C. (HCl), MS m/z (rel. intensity, 70 eV) 285 (M+, 3), 243 (12), 242 (bp), 70 (51), 56 (17).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[CH:15]([C:17]([O:19]CC)=[O:18])[CH2:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23].C(O)(=O)C.Cl>O>[F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]2[C:14](=[O:22])[C:15]([C:17]([OH:19])=[O:18])=[CH:16][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:23]
Reactant: CCOC(=O)C1CN2c3c(c(F)c(F)c(F)c3C1=O)CCN2C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2c(F)c(F)c(F)c3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 80.7 %

Procedure:
30 mg of the compound (198) obtained in Example 69 was added to 0.4 ml of acetic acid and 0.1 ml of 12N hydrochloric acid, and the solution was heated at 100° C. for 2 hours. After air-cooling, water was added to the reaction solution, and deposited solids were filtered off and washed with water, ethanol and ether in this order to obtain 22 mg of the subject compound (199) in a 81% yield.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:18]>C(O)(C(F)(F)F)=O>[ClH:18].[CH3:16][CH:11]1[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]1=[O:15]
Reactant: ClCCl
Reactant: CC1CCN(C(=O)OC(C)(C)C)CCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1CCNCCC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 4-methyl-5-oxo-azepane-1-carboxylic acid tert-butyl ester (700 mg, 3.083 mmol) was dissolved in 10% TFA in DCM (30 mL) and stirred at RT for 6 hours before being evaporated to give 0.74 g of 5-methyl-azepan-4-one hydrochloride.