Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:5][CH:4]=1.C=O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:9][CH2:10][CH2:11][N:12]([C:13]([O:14][CH3:15])=[O:16])[CH2:19][C:7]=2[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)NCCSc1ccc(OC)cc1
Agent: C=O
Solvent: c1ccccc1
Product: COC(=O)N1CCSc2ccc(OC)cc2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 208.5 %

Procedure:
A mixture of compound 7 (95 mg), paraformaldehyde (95 mg, excess), p-toluenesulfonic acid (30 mg) in benzene (4 mL) was stirred at 60° C. overnight. Analysis by TLC showed a new spot and the complete disappearance of the starting material. Filtration, followed by concentration and chromatography on SiO2 gave 92 mg of pure product 8. Yield: 95%.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[S:8][C:9]2[C:15]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:14][C:13]([O:21][CH3:22])=[CH:12][C:10]=2[N:11]=1>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCOCC1>[CH2:19]([NH:18][C:16]([C:15]1[C:9]2[S:8][C:7]([NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])=[N:11][C:10]=2[CH:12]=[C:13]([O:21][CH3:22])[CH:14]=1)=[O:17])[CH3:20]
Reactant: CCNC(=O)c1cc(OC)cc2nc(N)sc12
Reactant: CCN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(OC)cc(C(=O)NCC)c2s1
Temperature: 60 °C

Procedure:
Ethyl isocyanate (0.87 mL, 10.9 mmol) was added to a suspension of 2-amino-N-ethyl-5-methoxy-1,3-benzothiazole-7-carboxamide (549 mg, 2.18 mmol) and dibutyl tin diacetate (4 drops, catalytic amount) in dioxane (12 mL). The reaction was heated to 60° C. for 8 hours after which time LCMS indicated clean conversion to the desired product. The reaction solvent was removed in vacuo and the crude material used directly in the next step.
Reaction SMILES: [I-:1].[Na+].C(N(C(C)C)CC)(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([N:21]2[CH2:26][CH2:25][CH2:24]/[C:23](=[CH:27]\[C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:30]([O:40][CH3:41])[CH:29]=3)/[C:22]2=[O:42])[CH3:20])=[CH:15][CH:14]=1.[C:43]([O:46][CH2:47]Cl)(=[O:45])[CH3:44]>COCCOC>[I-:1].[C:43]([O:46][CH2:47][N+:36]1[C:37]([CH3:39])=[CH:38][N:34]([C:31]2[CH:32]=[CH:33][C:28](/[CH:27]=[C:23]3/[C:22](=[O:42])[N:21]([C@H:19]([C:16]4[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=4)[CH3:20])[CH2:26][CH2:25][CH2:24]/3)=[CH:29][C:30]=2[O:40][CH3:41])[CH:35]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)OCCl
Reactant: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: COc1cc(/C=C2\CCCN([C@@H](C)c3ccc(F)cc3)C2=O)ccc1-n1cc(C)[n+](COC(C)=O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Sodium iodide (54 mg) and IPEA (0.05 mL) were added to a DME solution (2 mL) of (E)-1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one (CAS Registry No. 870843-42-8, 100 mg) and chloromethyl acetate (0.03 mL), and the resulting reaction solution was stirred at 80° C. for 1 hr. The reaction solution was allowed to cool to room temperature, and the precipitated solid was collected by filtration. The obtained solid was washed with diethylether and dried in air to give 70 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[C:35]1([C:41]2([C:47]([OH:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C@:10]([CH2:13][CH2:14][N:44]2[CH2:43][CH2:42][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:47]([OH:49])=[O:48])[CH2:46][CH2:45]2)([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Alternately prepare by a method similar to Example 5.4.1 using (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-phenylpiperidine-4-carboxylic acid to give the title compound.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:36]=[C:35]3[C:30]([C:31]([NH2:37])=[N:32][CH:33]=[N:34]3)=[CH:29][CH:28]=2)[CH:21]([C:38]([O:40][CH3:41])=[O:39])[CH2:20]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:41][O:40][C:38]([CH:21]1[CH2:20][N:19]([CH2:18][C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[CH2:24][C:23](=[O:25])[N:22]1[CH2:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH2:37])=[N:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1)=[O:39]
Reactant: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3[nH]2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Reaction time: 4 h
Yield: 69.6 %

Procedure:
To a solution containing (±)-2-[4-(4-amino-quinazolin-7-ylmethyl)-3-methoxycarbonyl-5-oxo-piperazin-1-ylmethyl]-5-chloro-indole-1-carboxylic acid tert-butyl ester (26 mg, 0.03 mmol) in CH2Cl2 (4 mL) is added trifluoroacetic acid (1 mL) at ambient temperature. After 4 h, the reaction mixture is concentrated in vacuo and then dissolved in water/CH3CN and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 10 mg (47%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ2.62 (m, 1H), 3.05-3.51 (m, 4H), 3.59 (s, 3H), 3.81 (d, J=14.0 Hz, 1H), 4.26 (m, 1H), 4.69 (ABq, ΔAB=310 Hz, JAB=16.4 Hz, 2H), 6.26 (s, 1H), 7.02 (dd, J=8.6, 2.0 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.61 (d, J=8.7 Hz, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.47 (s, 1H), 8.77 (s, 1H), 9.69 (br s, 2H), 11.17 (s, 1H) ppm; MS (ion spray): m/z 479 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:18])([F:30])[F:31])(=[O:28])=[O:27])[N:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: Brc1n[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1C(F)(F)F)n1nc(Br)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a suspension of 3-bromoindazole (500 mg, 2.54 mmol) in 8 ml CH2Cl2 was added triethyl amine (1.06 ml, 7.61 mmol) at room temperature. To this yellow solution was added 2-(trifluoromethyl)benzenesulfonyl chloride (0.392 ml, 2.54 mmol) and the reaction mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified on SiO2 using 5% to 20% ethyl acetate in heptane to give 3-bromo-1-(2-(trifluoromethyl)phenylsulfonyl)-1H-indazole (894 mg)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1([F:29])[CH2:19][CH2:18][C:17]([CH2:27][NH2:28])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:29][C:14]1([F:13])[CH2:15][CH2:16][C:17]([CH2:27][NH:28][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=2[F:1])([C:20]2[CH:21]=[N:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: COc1ccc(F)c(C(=O)O)c1
Product: COc1ccc(F)c(C(=O)NCC2(c3ccc(F)nc3)CCC(F)(F)CC2)c1

Procedure:
From 2-fluoro-5-methoxybenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=397.1, tR (minutes, Method D)=0.71
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([C@H:19]1[CH2:24][C@H:23]([OH:25])[CH2:22][CH2:21][O:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:6]([C@H:19]1[CH2:24][C@H:23]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][CH2:21][O:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Methanesulfonyl chloride (0.62 g, 5.41 mmol) in dry methylene chloride (10 ml) was added dropwise to a mixture of trans-2-diphenylmethyl-4-hydroxypyran 3a (0.73 g, 2.70 mmol), triethylamine (0.41 g, 4.06 mmol) in methylene chloride (10 ml) and was cooled to 0° C. After one hour, the reaction was gradually allowed to reach room temperature over a period of four hours. Additional methylene chloride (20 ml) was added to the reaction mixture, and the mixture was washed in turn with saturated aqueous sodium bicarbonate, brine and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and purification by flash chromatography gave compound 4a (0.93 g, 99.9% yield) as an oil.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:29]I>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH3:29])[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: CI
Agent: Cl
Product: CN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m.p. 248° C. (dec.) and MS: m/e=384.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4 ,5]decan-4-one hydrochloride and methyl iodide.
Reaction SMILES: C[O-].[Na+].[C:4]1([CH3:26])[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[C:27]1([CH3:56])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]([C:41]1[CH:55]=[CH:54][C:44]([CH2:45]P(=O)(OCC)OCC)=[CH:43][CH:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]>CN(C=O)C>[C:4]1([CH3:26])[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:18]1[CH:25]=[CH:24][C:21](/[CH:22]=[CH:45]/[C:44]2[CH:43]=[CH:42][C:41]([N:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH3:56])=[CH:55][CH:54]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccccc1N(c1ccc(C=O)cc1)c1ccccc1C
Reactant: CCOP(=O)(Cc1ccc(N(c2ccccc2C)c2ccccc2C)cc1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N(c1ccc(/C=C/c2ccc(N(c3ccccc3C)c3ccccc3C)cc2)cc1)c1ccccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Sodium methoxide (4.9 mmol) was added to a stirring solution of 4-(N,N-di-tolylamino)benzaldehyde (3.78 mmol) and diethyl 4-(N,N-di-tolylamino)-benzylphosphonate (3.78 mmol) in 15 mL of DMF at 25° C. The mixture stirred for 4 h at 25° C., producing a yellow precipitate. The solid was collected, and then slurried in warm water. The solid was collected again, and crystallized from ethanol/toluene to yield 1.5 g of the stilbene, (E)-4,4′-bis-(N,N-di-tolylamino)stilbene (Inv-5). H1 NMR and mass spectra data were consistent with the structure.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:30])([CH3:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2([C:17]3[CH:18]=[C:19]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:20]=[CH:21][CH:22]=3)SCCCS2)[CH:8]=[CH:9][CH:10]=1.CC(C)=[O:33]>CN(C=O)C.[Cu]=O.[Cu](Cl)Cl>[OH:1][CH2:2][C:3]([CH3:30])([CH3:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:18]=2)=[O:33])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(CO)Cc1cccc(C2(c3cccc(CC(C)(C)CO)c3)SCCCS2)c1
Reactant: CC(C)=O
Agent: Cl[Cu]Cl
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: CC(C)(CO)Cc1cccc(C(=O)c2cccc(CC(C)(C)CO)c2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A suspension of copper(II) oxide (0.96 g, 12.1 mmol) and anhydrous copper(II) chloride (3.2 g, 23.8 mmol) in acetone (80 mL) was heated to reflux. A solution of 230 (4.44 g, 10.0 mmol) in acetone (20 mL) and DMF (1.2 mL) was added dropwise over 5 min. After 90 min at reflux temperature, the reaction mixture was cooled to room temperature and filtered. The insoluble material was washed with CH2Cl2 (3×20 mL). The combined organic solutions were washed with aqueous 2 N Na2CO3 solution (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; hexanes/acetone=80/20) to give 232 (2.5 g, 71%) as an oil. 1H NMR (CDCl3): δ 7.68-7.30 (m, 8 H), 3.31 (s, 4 H), 3.03 (s br., 2 H), 2.65 (s, 4 H), 0.88 (s; 12 H). 13C NMR (CDCl3=77.00 ppm): δ 197.42, 139.06, 136.96, 134.60, 131.88, 127.78, 127.55, 70.39, 44.07, 36.30, 23.80. HRMS nba): Calcd for C23 H31O3 (MH+): 355.2273, found: 355.2263. HPLC: 94.5% pure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22]C(C)C)=[C:18]([O:26]C(C)C)[CH:17]=1)=[CH:13][C:12]([O:30][CH3:31])=[C:11]([O:32][CH3:33])[CH:10]=2)=[O:5])[CH3:2].O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:26])[CH:17]=1)=[CH:13][C:12]([O:30][CH3:31])=[C:11]([O:32][CH3:33])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC(C)C)c(OC(C)C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(O)c(O)c1
Reaction time: 6 h
Yield: 21 %

Procedure:
To a solution of 4-(3,4-diisopropoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (116.0 rag) in dichloromethane (2.5 ml), titanium tetrachloride (TICl4) (288 mg) was added at 0° C., followed by stirring at the same temperature for 6 hours. The reaction mixture was poured over water and extracted with chloroform. The chloroform layer was washed by sequential additions of a saturated aqueous sodium hydrogen carbonate solution and water and then dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (7:3, v/v) to yield 4-(3,4-dihydroxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (20.0 mg, 21%) having a melting point of 122° to 124° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CCOCC>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([Cl:29])=[CH:31][CH:32]=1
Reactant: COC(=O)CCCCCCCCNc1ccc(OC)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
As described in example 3(b) the reaction is carried out with 2 g. (6.8 mmol) of 9-(4-methoxyphenylamino)-pelargonic acid methyl ester, 0.75 g (7.5 mmol) of triethylamine, 1.2 g (6.8 mmol) of 4-chlorobenzoic acid chloride and 80 cc. of ether. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [C:1]([C:3]([CH3:12])([CH2:9][CH2:10][CH3:11])[C:4]([O:6]CC)=[O:5])#[N:2].C(O)C.[OH-].[Na+]>O>[C:1]([C:3]([CH3:12])([CH2:9][CH2:10][CH3:11])[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCCC(C)(C#N)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(C)(C#N)C(=O)O
Yield: 94.5 %

Procedure:
In a 200 ml two-necked round-bottom flask with ground fitting, 16.00 g (94.7 mM) of ethyl 2-cyano-2-methylpentanoate and 90 ml of ethanol were placed. To the mixture under stirring with a magnetic stirrer, a solution of 10.8 g (270 mM) of sodium hydroxide in 35 ml of distilled water was added dropwise. The mixture was stirred for 5 hours at room temperature, followed by removal of the solvent and addition of 3N-HCl until the solution reacted pH 1. The reaction mixture was transferred to a separating funnel, followed by three times of extraction with 50 ml of diethyl ether and washing with 50 ml of distilled water. The organic layer was dried on anhydrous sodium sulfate, followed by distilling-off of the solvent and reduced-pressure distillation to obtain 12.61 g (89.4 mM) of 2-cyano-2-methylpentanoic acid. Yield:94.4%, b.p.:120° C./2 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].[CH2:16](N(CC)CC)C.[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:16][O:14][C:13](=[O:15])[CH2:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[Cl:1]
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
2-Chloro-4-(trifluoromethyl)-benzeneacetic acid (3 g) [CAS Reg. No. 601513-26-2] was dissolved in DCM (30 mL) and methyl chloroformiate (1.18 g, 0.97 mL) followed by triethylamine (1.4 g, 1.93 mL) were added drop by drop. To the mixture was added DMAP (0.154 g) and the yellow mixture was allowed to stir for 1 hour at 0° C. A clear solution was obtained. The mixture was diluted with DCM (30 mL) and was poured into sat. NH4Cl solution. The layers were separated and the aqueous phase was further extracted with 2 portions of DCM. The organic layers were washed with brine, dried over Na2SO4 and evaporated to give the title compound (3.0 g) that was used without further purification. NMR (□, CDCl3): 7.6-7.4 (m, 3H); 3.84 (s, 2H); 3.74 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7](C)[C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[CH2:13](O)C>[Pd]>[NH2:6][C:5]1[CH:7]=[C:8]([CH3:13])[C:2]([CH3:1])=[CH:3][C:4]=1[NH2:10]
Reactant: CCO
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Agent: [Pd]
Product: Cc1cc(N)c(N)cc1C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of 4,6-dimethyl-2-nitroaniline (1.66 g, 10.0 mmole) and 10% Pd/C (200 mg) in ethanol (35 mL) was hydrogenated for 2 h at room temperature under 25 psi H2. The catalyst was removed by filtration with celite and the solvent was removed by rota-evaporation to give 1.300 g (96%) of 1,2-diamino-4,5-dimethylbenzene as a brown solid. 1H NMR (CDCl3): 6.449 (s, 1 H), 6.469 (s, 1 H), 3.327 (br, 2 H), 3.259 (br, 2 H), 2.190 (s, 3 H), 2.159 (s, 3 H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:27]3[O:28][N:33]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1ccccc1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3)no2)C1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 49 mg (0.36 mmol, 1.5 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 58 mg (47% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)[NH:11][C:6]=2[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:20]
Reactant: COC(=O)c1cc(Cl)cc(N=Cc2cccc(Br)c2)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-7-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]([N:15]([CH:22]([CH3:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]=1)C.[OH:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([NH:35][NH2:36])=O>C(O)(=O)C>[OH:29][C:30]1[CH:31]=[C:32]([C:33]2[N:5]3[C:4]([CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]([N:15]([CH:22]([CH3:23])[CH3:24])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:14])[C:7]4[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=43)=[N:36][N:35]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: NNC(=O)c1cccc(O)c1
Reactant: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Solvent: CC(=O)O
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3cccc(O)c3)n2-c2ccccc21)c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 5(B) (177 mg, 0.466 mmol) in glacial acetic acid (4 mL) was added 3-hydroxy benzohydrazide (90 mg, 0.591 mmol). The reaction was heated to 120° C. for 3 hours, was cooled to room temperature, and was concentrated in vacuo. The residue was triturated with 50% Et2O in hexanes and the solids were filtered. The solids were dissolved in CH2Cl2 and the organic solution was washed with aqueous NaHCO3, dried (MgSO4) and concentrated to provide 244 mg of 2-[1-(3-hydroxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD3OD) δ 7.74 (s, 2H), 7.56-7.18 (m, 10H), 6.91 (m, 1H), 4.86 (m, 1H), 4.30-4.10 (m, 2H), 3.98 (d, 1H), 3.71 (d, 1H), 1.06 (m, 6H).