Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.C(#N)C.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]>C(N(CC)CC)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH:9]([NH2:8])[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH2:17]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:45])[C:28]([C:42]([OH:44])=[O:43])=[CH:29][N:30]2[C@@H:38]1[CH2:40][C@@H:39]1[F:41]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)NC(c1cccnc1)[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CC[C@@H](C(N)c3cccnc3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Yield: 32.8 %

Procedure:
3-(R)-[1Tert-butoxycarbonylamino-1-(3-pyridyl)methyl)pyrrolidine [F2] (0.461 mmol) was added to an acetonitrile suspension (5 ml) of 5-amino-6,7,8-trifluoro-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (156 mg, 0.493 mmol) and the mixture was heated under reflux for 19 hours in the presence of triethylamine (0.5 ml). After cooling, the solvent of the reaction solution was evaporated under a reduced pressure. The resulting residue use dissolved in chloroform (50 ml) this was washed with 10% citric acid (40 ml) and saturated brine (40 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was mixed with concentrated hydrochloric acid (5 ml) under ice-cooling, further mixed with 1 mol/l hydrochloric acid aqueous solution (5 ml) at room temperature and then washed with chloroform (50 ml×5). This hydrochloric acid aqueous solution was adjusted to an alkaline liquid property by adding 10 mol/l sodium hydroxide aqueous solution, further adjusted to a liquid property of pH 7.4 by adding concentrated hydrochloric acid and 1 mol/l hydrochloric acid and then extracted with chloroform (150 ml×3). The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under a reduced pressure to obtain the crude title compound as light yellow crystals. This was purified by recrystallizing from ethanol to obtain 71.5 mg (32%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:4]([O:21][CH3:22])[CH:3]=1.FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:39](=[O:54])[C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:41]=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:39](=[O:54])[C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:43]=[C:42]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:41]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCCS(C)(=O)=O
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(F)ccc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 4-(4-fluoro-2-methoxyphenyl)-N-(2-(methylsulfonyl)ethyl)pyridin-3-amine (0.08 g, 247 μmol, example 192, intermediate a) and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (177 mg, 617 μmol, example 223, intermediate d) in CH2Cl2 (2 mL) was added DIPEA (128 mg, 172 μL, 987 μmol) and the clear solution was stirred at room temperature for 19 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (0.075 g; 52%). MS (ESI): m/z=575.09 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][C:13]3[C:14]([CH2:38][OH:39])=[C:15]([O:30]CC4C=CC=CC=4)[C:16]([C:19]([NH:21][O:22]CC4C=CC=CC=4)=[O:20])=[N:17][CH:18]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>[Pd].CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][C:13]3[C:14]([CH2:38][OH:39])=[C:15]([OH:30])[C:16]([C:19]([NH:21][OH:22])=[O:20])=[N:17][CH:18]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(NOCc1ccccc1)c1ncc(CNCc2ccc3c(c2)OCO3)c(CO)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NO)c1ncc(CNCc2ccc3c(c2)OCO3)c(CO)c1O
Yield: 81.2 %

Procedure:
Compound 11a (0.024 g, 0.039 mmol, 1 eq) and 10% Pd/C catalyst (5 mg) were stirred in 4.0 mL of methanol overnight under an atmosphere of hydrogen. The catalyst was filtered and the reaction mixture was concentrated under vacuum yielding 0.011 g of 5-((benzo[d][1,3]-dioxol-5-ylmethylamino)methyl)-N,3-dihydroxy-4-(hydroxymethyl)picolinamide (69% yield) as a white solid; MS-ESI m/z 348 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:25]2[CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: C[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (52 g, 0.15 mol, 1.0 eq) prepared in accordance of the procedures set forth in Intermediate (i), (2S)-2-methyl pyrrolidine (25.2 g, 0.3 mol, 2.0 eq), anhydrous CH3CN (500 ml), and dry K2CO3 powder (50 g, 36 mmol, 2.4 eq) were added to a 2 L round-bottom flask equipped with a mechanical stirrer and a reflux condenser. The resulting suspension was stirred at 75° C. for 2 h. The heating block was set at 88° C. LC/MS showed a trivial amount of starting material at m/z 363. The reaction mixture was concentrated in vacuo. The residue was partitioned between 200 ml of water and 400 ml of DCM. The aqueous layer was washed with 50 ml of DCM twice. The organic extracts were combined and washed with 150 ml of saturated NaHCO3 solution, 150 ml of brine, and dried over K2CO3. The crude was purified by silica gel column, eluted with 5-10% MeOH in DCM. The product still had weak UV absorptions at 254 nm and 280 nm. A pale yellow oil was obtained, yield: 24.5 g (64%).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH2:30][CH3:31])[C:25]([CH3:32])=[CH:24][N:23]=1.[OH-].[Na+]>O>[CH2:30]([O:29][C:26]1[C:25]([CH3:32])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[C:27]=1[CH3:28])[CH3:31]
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Reactant: CCOc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C

Procedure:
7.8 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were suspended in 200 ml of alcohol and treated while cooling with ice with 7.1 g of 2-chloromethyl-4-ethoxy-3,5-dimethylpyridine hydrochloride. Thereafter, a solution of 2.4 g of sodium hydroxide in 100 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 500 ml of methylene chloride. The solution was washed firstly with 250 ml of 1.5N sodium hydroxide solution and then with 3×250 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 150 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 5,7-dihydro-2-[[(4-ethoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 179°-180°.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:29])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[CH:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:8]([C:10]([O:12]CC)=[O:11])[CH3:9].[OH-].[Na+]>CO>[CH3:1][NH:2][C:3](=[O:29])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[NH:5][C:6](=[O:19])[CH:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH:8]([C:10]([OH:12])=[O:11])[CH3:9]
Reactant: CCOC(=O)C(C)C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(C)C(=O)O

Procedure:
N-[3-(Ethoxycarbonyl)-2-(2-methylpropyl)butanoyl]-O-methyl-L-tyrosine N-methylamide (2.0 g., 0.0051 mol.) was hydrolysed upon the addition of methanol (30 mls.) containing 0.1M sodium hydroxide solution (6 mls., 0.006 mol.). The solvent was removed by evaporation in vacuo and the resulting gum washed with diethyl ether (2×25 mls.) The gum was acidified with 0.1M hydrochloric acid solution and the mixture was extracted with dichloromethane (2×50 mls.). The combined extracts were dried over anhydrous sodium sulfate and the solvent was removed by evaporation in vacuo to yield N-[3-carboxy-2-(2-methylpropyl)butanoyl]-O-methyl-L-tyrosine N-methylamide as a mixture of isomers as an off-white solid (1.9 g., 0.0052 mol.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: OCCCCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
300 mg (1 mmol) 5-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-pentan-1-ol in 10 ml CH2Cl2 were treated with 0.1 ml (1.2 mmol) methane sulfonyl chloride and 0.41 ml (3 mmol) triethyl amine at 0° C. The solution was stirred at RT for 2 h, was diluted with CH2Cl2 and extracted with 1M HCl and water, and dried over Na2SO4. Evaporation yielded 310 mg (83%) Methanesulfonic acid 5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pentyl ester as light brown oil, MS: 376 (MH+).
Reaction SMILES: C(O[CH:9]([C:11]1([NH:14][C:15]([C:17]2[C:18]([O:35][CH3:36])=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[O:16])[CH2:13][CH2:12]1)C)C1C=CC=CC=1.C[Si](I)(C)C.[CH3:42][OH:43]>ClCCl>[OH:43][CH2:42][CH2:9][C:11]1([NH:14][C:15]([C:17]2[C:18]([O:35][CH3:36])=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[C:20]3/[CH:26]=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)=[O:16])[CH2:13][CH2:12]1
Reactant: COc1c(C(=O)NC2(C(C)OCc3ccccc3)CC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Reactant: CO
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: COc1c(C(=O)NC2(CCO)CC2)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Reaction time: 2 h

Procedure:
20 mg of 3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic acid (1-benzyloxyethyl-cyclopropyl)-amide obtained by Example 814 was dissolved in 1 mL of dichloromethane, added with 6.4 μl of trimethylsilyliodide at 0° C. under nitrogen atmosphere, and stirred at this temperature for 2 hours. The reaction solution was added with methanol to stop the reaction, and the solvent was concentrated, followed by purification by LC-MS, to afford 1.7 mg of the title compound.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:21][C:22]([S:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>ClC(Cl)C.S([O-])([O-])(=O)=O.[Cu+2]>[C:22]([S:25](/[N:27]=[CH:2]/[CH2:3][C:4]1([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[O:26])([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(C)(C)S(N)=O
Reactant: COC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Product: COC(=O)C1(C/C=N/S(=O)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Yield: 80.4 %

Procedure:
A solution of 1-tert-butyl 4-methyl 4-(2-oxoethyl)piperidine-1,4-dicarboxylate (822 mg, 2.88 mmol), copper(II) sulfate (1.38 g, 8.64 mmol) and 2-methyl-2-propanesulfinamide (354 mg, 3.17 mmol) in dichloroethane (15 mL) was heated at 65° C. for 24 h. The reaction was cooled, filtered and concentrated. The residue was partitioned between saturated aqueous NaHCO3 and dichloromethane, separated, the organic layer dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 7% methanol:dichloromethane to give the title compound (0.9 g). MS: m/z=389.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[C:4]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.C(O)=[O:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:31])[CH2:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[C:4]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Reactant: O=CO
Solvent: ClCCl
Product: O=C(CCN1C(=O)c2ccccc2C1=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 20 g (50 mmole) of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne, 1.0 g (3 mmole) of mercuric sulfate and 55 ml of formic acid in 50 ml of methylene chloride was stirred at room temperature for 30 min. The mixture was poured over ice and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ethyl acetate and ether to give a colorless solid. Recrystallization from acetone gave colorless prisms, mp 163°-164° C.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[N:10][C:9]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:15][C:9]1[N:10]=[N:11][C:12]([Cl:14])=[CH:13][C:8]=1[N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1
Reactant: Clc1cc(Br)c(Cl)nn1
Reactant: C1=CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(N2CC=CCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
1,2,3,6-Tetrahydropyridine, (1.04 ml) was added to a stirred solution/suspension of 4-bromo-3,6-dichloropyridazine (2.0 g, 8.8 mmol) and potassium carbonate (2.4 g) in dry DMF (10 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 5 hours. The reaction was poured into water (100 ml) and extracted with ethyl acetate (×3). The combined extracts were washed with water (200 ml), brine, dried (MgSO4), filtered and evaporated. The residue was triturated with ether/petroleum ether to afford a white powder (1.96 g, 97%). 1H NMR (250 MHz, CDCl3) 6.82 (1H, s), 5.97 (1H, m), 5.80 (1H, m), 3.77 (2H, m), 3.59 (2H, m), 2.38 (2H, m). MS (ES+) 232 [MH]+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[CH:9]=2)[N:4]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[O:7]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[CH:9]=2)=[N:6]1
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(-c3noc(C(Cl)(Cl)Cl)n3)ccn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)COC(=O)N1CCN(c2cc(-c3ncon3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
2,2-Dimethylpropyl 4-[4-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl]-1-piperazinecarboxylate (23.1 mg) obtained in Example 32 was dissolved in methanol (2 mL), and sodium borohydride (10 mg) was added thereto and stirred at room temperature for 10 minutes. Then, the reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=7/3) to obtain 9.1 mg of the entitled compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:24].[K+].[K+].OO>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH2:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cn2)CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(N)=O)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 193.1 %

Procedure:
Combine a solution of 4-(5-cyano-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1630 mg, 5.38 mmol) in DMSO (50 mL) with potassium carbonate (371 mg, 2.69 mmol). Cool the solution to 0° C. and add slowly hydrogen peroxide (1.61 mL). After 10 min, stir the reaction mixture at room temperature for 2 h. Add water (25 mL) and extract twice with CH2Cl2 (30 mL). Dry the organic layer over sodium sulfate, filter and concentrate to provide the title compound (1669 mg, 97%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:29]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([O:14][CH3:29])=[O:13])=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn(-c2ccc(F)cc2)c(-c2ccc(N)cc2)cc1=O
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
In 50 ml of methanol was suspended 6.5 g of 6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid, and the suspension was cooled to 5° C., after which 3.9 g of thionyl chloride was added dropwise thereto over 10 minutes. After completion of the dropwise addition, the resulting mixture was refluxed for 6 hours, and then cooled to room temperature, after which the solvent was removed by distillation under reduced pressure. To the residue were added 30 ml of water and 30 ml of chloroform, and the resulting mixture was adjusted to a pH of 7 with sodium hydrogencarbonate, after which the aqueous layer was separated, washed with 30 ml of a saturated aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystalline substance was washed with 50 ml of diethyl ether to obtain 6.7 g of methyl 6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate having a melting point of 250° C. or more.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N+:7]([CH:10]=[CH:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)([O-])=O>>[C:17]1([C:14]2[O:13][C:12]([CH2:11][CH2:10][NH2:7])=[CH:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])C=Cc1ccc(-c2ccccc2)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCCc1ccc(-c2ccccc2)o1
Yield: 20.3 %

Procedure:
Cool lithium aluminum hydride (21 mL, 1.0 M solution in ether) to 0° C. and add 2-(2-nitrovinyl)-5-phenylfuran (760 mg, 3.53 mmol in 5 mL of ether). Stir reaction to room temperature for 15 hours. Re-cool reaction to 0° C. and quench with 0.80 mL of water, followed by 0.80 mL 1M sodium hydroxide and 0.80 mL of water (×3). Dilute reaction with additional tetrahydrofuran and stir at room temperature for 2 hours. Filter and dry over sodium sulfate and filter again. Concentrate and perform flash column chromatography (methylene chloride, MeOH, NH4OH) to give 134 mg (20% yield) of the title compound as a brown oil. MH+ 188.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:36])[O:32][CH:33]([CH3:35])[CH3:34])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:36])[O:32][CH:33]([CH3:34])[CH3:35])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 142 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.29–7.22 (m, 3H), 7.20–7.11 (m, 3H), 7.09–7.06 (m, 1H), 6.79 (d, 1H, J=7.6 Hz), 6.61 (s, 1H), 6.60–6.50 (m, 1H), 4.94 (septet, 1H, J=6.7 Hz), 4.05 (q, 1H, J=6.8 Hz), 3.24 (q, 2H, J=5.9 Hz), 2.86–2.79 (m, 2H), 2.36 (tt, 1H, J=11.9, 3.2 Hz), 2.27 (t, 2H, J=6.3 Hz), 1.85 (t, 2H, J=11.9 Hz), 1.72–1.66 (m, 2H), 1.60–1.52 (m, 3H), 1.48 (s, 6H), 1.23 (d, 6H, J=6.7 Hz); ESMS m/e: 500.2 (M+H)+.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH2:18][C:19]#[N:20].O>C1C=CC=CC=1>[CH:4]([CH:18]([C:11]1[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH3:9])[C:19]#[N:20])=[O:5]
Reactant: CCOC=O
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C)c(C(C#N)C=O)c(C)c1

Procedure:
To a stirred mixture of sodium methoxide (2.78 g, 51 mmol) and ethyl formate (4.0 g, 54 mmol) in 100 mL of benzene was added 2,4,6 trimethylphenylacetonitrile (8.0 g, 50 mmol) over 5 min. After stirring for an additional hour it was treated with water (100 mL) and the layers were separated. The aqueous layer was separated and acidified with 10% HCl and extracted with ethyl acetate. After drying the solvent was removed in vacuo to afford a-formyl-2,4,6-trimethylphenylacetonitrile as colorless crystals melting at 120°-122° C.
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:5]([CH3:9])[N:6]=[CH:7][N:8]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:5]([CH3:9])[N:6]=[CH:7][N:8]=1
Reactant: Cn1ncnc1SCCl
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1ncnc1SCI
Temperature: 50 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 3-chloromethylthio-2-methyl-1,2,4-triazole (981 mg: 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g: 12.0 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated to give 3-iodomethylthio-2-methyl-1,2,4-triazole (1.47 g) as yellow oil.