Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[C@@H:14]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:13][C@H:12]([C:31](O)=[O:32])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CCOC(C)=O>[OH:32][CH2:31][C@@H:12]1[CH2:11][C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[C@@H:14]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=[O:29])=[CH:19][CH:18]=2)[CH2:13]1
Reactant: O=C(N[C@H]1C[C@H](C(=O)O)C[C@H]1NC(=O)c1ccc(Cl)s1)c1ccc(-n2ccccc2=O)cc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[C@H](CO)C[C@H]1NC(=O)c1ccc(Cl)s1)c1ccc(-n2ccccc2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Example 94 (0.22 g, 0.45 mmol) was stirred in THF (10 mL) at 0° C., Et3N (0.095 mL, 0.68 mmol, 1.5 eq) was added followed by dropwise addition of ClCOOEt (0.051 mL, 0.54 mmol, 1.2 eq). The mixture was stirred at 0° C. for 1 h. It was filtered and rinsed with THF (10 mL). The THF solution was stirred at 0° C. MeOH (5 mL) was added followed by addition of NaBH4 (0.25 mg, 6.6 mmol). The resulting mixture was stirred at 0° C. for 1 h. LC/MS showed completion of the reaction. EtOAc was added, it was washed with NH4Cl, H2O, and brine. The organic layer was concentrated, and purified by reverse phase HPLC (MeOH/H2O in 0.1% TFA) to give pure title compound. LC-MS (ESI) 472.12, 474.04 (M+H), 488.06 (M+Na), tR=2.54 min (10–90% MeOH in H2O with 0.1% TFA in a 4-min run).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:47]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH:57]2[CH2:62][CH2:61][CH:60]([O:63][CH2:64][C:65](O)=[O:66])[CH2:59][CH2:58]2)=[CH:52][C:51]=1[C:68]([F:71])([F:70])[F:69])([O-:49])=[O:48]>ClCCl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:65](=[O:66])[CH2:64][O:63][CH:60]3[CH2:61][CH2:62][CH:57]([NH:56][C:53]4[CH:54]=[CH:55][C:50]([N+:47]([O-:49])=[O:48])=[C:51]([C:68]([F:70])([F:69])[F:71])[CH:52]=4)[CH2:58][CH2:59]3)[CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1cc(N2CCNCC2)nc2ccccc12
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(C(=O)COC3CCC(Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of 4-methyl-2-(piperazin-1-yl)quinoline (100 mg, 0.44 mmol) in dichloromethane (20 ml) was added EDAC.HCl (126 mg, 0.66 mmol, 1.5 eq), HOBt (88.8 mg, 0.66 mmol, 1.5 eq), triethylamine (133 mg, 1.31 mmol, 3 eq) and 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (190 mg, 0.52 mmol, 1.2 eq). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to give a residue. The crude material was purified by Pre-TLC with 50% ethyl acetate in dichloromethane to afford 1-[4-(4-methylquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoro-methyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (117 mg, 47%); (ES, m/z) [M+H]+ 572.20; 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=9.0 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.54-7.62 (m, 1H), 7.32-7.38 (m, 1H), 6.87 (s, 2H), 6.63-6.67 (m, 1H), 4.48 (d, J=7.5 Hz, 1H), 4.28 (s, 2H), 3.75-3.85 (m, 7H), 3.39-3.52 (m, 2H), 2.65 (s, 3H), 2.16 (d, J=9.9 Hz, 1H), 1.46-1.53 (m, 2H), 1.25-1.36 (m, 2H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[C:24]4[CH2:31][CH2:32][C:33]([O:35]C(C)C)=[O:34])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH:28]([CH3:29])[CH3:30])[CH:25]=[C:24]4[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)OC(=O)CCc1cn(C(C)C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C(C)C)c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.9 %

Procedure:
Sodium hydroxide (93 mg) was added to a solution of 1-methylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(1-methylethyl)-1H-indol-3-yl]propanoate (D122) (60 mg) in THF (5 mL), isopropanol (4 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 2 days. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-(1-methylethyl)-1H-indol-3-yl]propanoic acid (E28) (28 mg). δH (DMSO-d6, 400 MHz): 1.30 (6H, d), 1.37 (6H, d), 2.64 (2H, t), 3.00 (2H, t), 4.56 (1H, m), 4.89 (1H, m), 7.16 (1H, t), 7.37 (1H, dd), 7.46 (2H, m), 7.79 (1H, dd), 8.12 (1H, dd), 8.18 (1H, d), 12.07 (1H, br s); MS (ES): C26H26ClN3O4 requires 467; found 468.2 (M+H+).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([OH:32])=O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1.[O:33]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[NH:36][CH:35]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH2:34]1>CCOC(C)=O>[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([N:36]3[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:33][CH2:34][CH:35]3[CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:32])[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1
Reactant: COC(=O)CC1COc2ccccc2N1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: COC(=O)CC1COc2ccccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 75 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
T3P (50% solution in EtOAc, 61.5 g, 96.6 mmol) was added to 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (10.3 g, 53.1 mmol), methyl 3,4-dihydro-2H-1,4-benzoxazin-3-ylacetate (Intermediate 2, 10.0 g, 48.3 mmol) and TEA (26.8 mL, 193.2 mmol) in EtOAc (125 mL) at rt. The resulting mixture was stirred at 75° C. for 16 h. The resulting solution was diluted with 350 mL of EtOAc and washed with sat. aq. NaHCO3 solution (160 mL), 0.5 M HCl solution (160 mL) and brine (160 mL). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by re-crystallization from MeOH to afford the title compound (10.1 g, 55%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.C(OC[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C1OC1.O1CC1COC1CC2C(=CC=CC=2)C1>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:14][CH2:13]1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Agent: c1ccc2c(c1)CC(OCC1CO1)C2
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccccc2)CC1

Procedure:
Compound 11 was prepared in a similar manner to compound 7, substituting the commercially available benzyl glycidyl ether for 2-(oxiran-2-ylmethoxy)indane in part D to afford 11. Mass Spectrum (M+1)=412.36.
Reaction SMILES: B.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH:13][CH3:14])=O)=[CH:5][CH:4]=1.CO.Cl>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][NH:13][CH3:14])=[CH:7][CH:8]=1
Reactant: CNC(=O)CCc1ccc(Br)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNCCCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Borane in THF (1.0 M, 28 mL, 28 mmol) was added dropwise to a solution of 22A (1.6 g, 7.0 mmol) in THF (17.5 mL). After stirring the reaction mixture for 30 min at 0° C. the mixture was refluxed for 4 h. Methanol (20 mL) was added to the mixture at 0° C. followed by the addition of 20 mL 6.0 M HCl dropwise. After refluxing for 30 min the volatiles were removed in vacuo. 50% NaOH (12 mL) was added dropwise while maintaining the temperature below 30° C. The resulting mixture was diluted with water (100 mL) and extracted with diethyl ether (3×100 mL). The organics were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 22B (1.57 g, 97%) as a clear oil. MS (ESI) m/z 227.99/229.99 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ccc2ccn(Cc3ccccc3)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: Clc1cccc(-c2ccc3ccn(Cc4ccccc4)c3c2)c1
Temperature: 70 °C
Yield: 50 %

Procedure:
3-Chlorophenylboronic acid (1.21 g, 7.76 mmol) was added in four poritions to the mixture of 1-benzyl-6-bromo-1H-indole (1.12 g, 3.91 mmol), palladium(II) acetate (0.0191 g, 0,0850 mmol), and tetrabutylammonium bromide (1.26 g, 3.91 mmol) in water (22.5 mL) and THF (2.5 mL) while heating at 70° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and 2N hydrochloric acid was slowly added. The mixture was extracted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using 0-100% ethyl acetate in hexane as an eluant. Drying at 60° C. for 40 minutes yielded (0.621 g, 50%) of 1-benzyl-6-(3-chlorophenyl)-1H-indole as a yellow gum. Mass spectrum (+ESI, [M+H]+) m/z 318; 1HNMR (500 MHz, DMSO-d6): δ 7.85 (s, 1H), 7.75 (t, 1H, J=1.8 Hz), 7.6-7.65 (m, 2H), 7.55 (d, 1H, J=3.1 Hz), 7.45 (t, 1H, J=7.8 Hz), 7.25-7.35 (m, 4H), 7.2-7.25 (m, 3H), 6.5 (d, 1H, J=3.1 Hz), and 5.5 ppm (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:30][CH3:31])([CH3:29])[CH3:28])=[CH:23][C:22]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1.[C:36](Cl)([Cl:38])=[O:37]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:36]([Cl:38])=[O:37])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:30][CH3:31])([CH3:28])[CH3:29])=[CH:23][C:22]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-methoxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[CH:23]2[C:28]3([C:36]4[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH:27]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[CH2:26][C:25](=[O:46])[NH:24]2)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[Cl:37][C:33]1[CH:32]=[C:31]2[NH:30][C:29](=[O:38])[C:28]3([CH:27]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=4)[CH2:26][C:25](=[O:46])[NH:24][CH:23]3[C:17]3[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=3[O:15][CH:12]3[CH2:13][CH2:14][N:9]([CH2:8][C:6]([OH:7])=[O:5])[CH2:10][CH2:11]3)[C:36]2=[CH:35][CH:34]=1.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]
Reactant: CC(C)(C)OC(=O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-2′-[2-(1-tert-butoxycarbonylmethyl-4-piperidinyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.22 g, 0.28 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was triturated with dichlormethane and hexanes to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(1-hydroxycarbonylmethyl-4-piperidinyloxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as trifluoroacetic acid salt: yellow solid (Yield 0.18 g)
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[C@H:32]12[CH2:38][C@H:35]([NH:36][CH2:37]1)[CH2:34][N:33]2C(OC(C)(C)C)=O>>[C@H:32]12[CH2:38][C@H:35]([NH:36][CH2:37]1)[CH2:34][N:33]2[CH2:29][C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=3[CH3:13])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:31])[CH:15]=2)[C:20](=[O:24])[N:19]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3C[C@@H]4C[C@H]3CN4)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid, tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:22]([CH:25]=O)=[CH:23][CH:24]=3)[N:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.Cl.[NH2:28]O.C([O-])=O.[Na+]>C(O)=O>[C:25]([C:22]1[N:10]2[N:11]=[C:12]([CH:19]([CH3:20])[CH3:21])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]2=[CH:24][CH:23]=1)#[N:28]
Reactant: NO
Reactant: CCOC(=O)c1c(C(C)C)nn2c(C=O)ccc2c1-c1ccc(F)cc1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCOC(=O)c1c(C(C)C)nn2c(C#N)ccc2c1-c1ccc(F)cc1
Yield: 72.7 %

Procedure:
A solution of ethyl 4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (200 mg, 0.564 mmol), hydroxylamine hydrochloride (51.0 mg, 0.734 mmol), and sodium formate (69.1 mg, 1.02 mmol) in formic acid (2 mL) were refluxed for 2 h. The mixture was evaporated to give a green gum. The gum was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate (5 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a green gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 1-8 gave ethyl 7-cyano-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow crystal (144 mg, 72.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22][CH3:23])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([OH:26])=O.C(Cl)CCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([N:22]([CH3:23])[CH:24]=[O:26])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: CNc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CN(C=O)c1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To 7-(benzyloxy)-N-methyl-9H-carbazol-2-amine (120 mg, 0.4 mmol), formic acid (55 mg, 1.2 mmol) and DMAP (5 mg, 0.04 mmol) in 3 mL of pyridine was added portionwise EDC (230 mg, 1.2 mmol). The mixture was stirred at rt for 3 h under Ar atmosphere and concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with water (2×50 mL), 0.5 M HCl(2×50 mL), and brine (50 mL), and dried over MgSO4. After solvent removal, the crude product was purified with chromatography (hexane/EtOAc) to afford N-(7-(benzyloxy)-9H-carbazol-2-yl)-N-methylformamide as a white solid (110 mg, 83%). 1H NMR (400 MHz, acetone-d6) δ 10.34 (s, 1H), 8.49 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.51 (d, J=7.2 Hz, 2H), 7.39 (m, 2H), 7.34-7.28 (m, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.08 (dd, J=8.4, 2.4 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 5.19 (s, 2H), 3.31 (s, 3H); MS (ESI) m/z 331 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])=[CH:3][C:4]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]2)=[O:24])=[CH:18][CH:19]=1
Reactant: O=C1CCCN1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(N2CCCC2=O)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1

Procedure:
To a mixture of (4-bromo-2-methanesulfonylphenyl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (1.45 g) described in Preparation Example 191, pyrrolidin-2-one (0.24 mL), potassium carbonate (0.83 g) and copper(I) iodide (0.11 g) were added toluene (3 mL) and N,N′-dimethylethylenediamine (0.13 mL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 1-{4-[4-(4-chlorobenzoyl)piperidine-1-carbonyl]-3-methanesulfonylphenyl}pyrrolidin-2-one. To a mixture of the obtained 1-{4-[4-(4-chlorobenzoyl)piperidine-1-carbonyl]-3-methanesulfonylphenyl}pyrrolidin-2-one, palladium(II) acetate (34 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (123 mg), potassium fluoride (697 mg) and methylboronic acid (359 mg) was added tetrahydrofuran (9 mL), and the mixture was stirred with heating under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (408 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[NH2:19][CH:20]([CH2:34][CH3:35])[C@@H:21]([C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=1)[OH:22]>>[C:28]1([C:25]2[N:24]=[C:23]([C:21]([CH:20]([NH:19][C:5](=[O:7])[C@@H:4]([CH2:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:10])[CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])[CH2:34][CH3:35])=[O:22])[O:27][N:26]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)CC(CC(=O)N1CCOCC1)C(=O)O
Reactant: CCC(N)[C@H](O)c1nc(-c2ccccc2)no1
Product: CCC(NC(=O)[C@@H](CC(=O)N1CCOCC1)CC(C)(C)C)C(=O)c1nc(-c2ccccc2)no1

Procedure:
It is similarly prepared according to general procedure given for example 10 above but using 4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid and (S)-2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: C(=O)([O-])O.[Na+].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.CN(C=O)C.Cl[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([CH:28]=[C:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1>O>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:36]=[CH:35][C:27]([CH:28]=[C:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)C(C)=Cc1ccc(OCCCCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)=Cc1ccc(OCCCNc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
Sodium hydrogen carbonate (3.5 g), 4-chloroaniline (10.45 g) and DMF (50 ml) were added to methyl 4-(3-chloropropoxy)-α-methylcinnamate (11 g), and the mixture was stirred at 100° C. overnight. After the reaction mixture was allowed to cool, water (200 ml) was added thereto, and further the mixture was stirred at room temperature for 30 minutes. The insoluble product was collected by filtration, washed well with water, and was added cold methanol (20ml) thereto, and the mixture was stirred. The resulting crystal was collected by filtration to give methyl 4-[3-[N-(4chlorophenyl)amino]propoxy]-α-methylcinnamate (8 g). mp. 62°-64° C.
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:10]3[N:11]=[C:12](Cl)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]3=[N:8][CH:7]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1>CS(C)=O>[S:1]1[C:5]([C:6]2[N:10]3[N:11]=[C:12]([NH:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]4)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]3=[N:8][CH:7]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1c(Cl)nn2c(-c3cc4ccccc4s3)cnc2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: Cc1c(N[C@H]2CC[C@H](O)CC2)nn2c(-c3cc4ccccc4s3)cnc2c1C
Temperature: 100 °C

Procedure:
To a solution of 3-(benzo[b]thiophen-2-yl)-6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine (40 mg, 0.128 mmol, 1.0 equiv) in DMSO (1.00 mL) was added p-TSA (24 mg, 0.128 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (73 mg, 0.638 mmol, 5.0 equiv) and heated to 100° C. for 24 h. Purification by column chromatography using 5% methanol in dichloromethane elution gave 31 mg, 62%.