Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4]C>C(O)CC>[CH:1](=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:1]([OH:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCO
Solvent: CCCO
Product: CCCC=O
Product: CCCCO
Yield: 30 %
Yield: 15.8 %

Procedure:
In all representation examples of JP 6 2108-832, the hydrogenation is carried out using hydrogen at atmospheric pressure. Cycloaliphatic carboxylic acids such as cyclohexanecarboxylic acid are predominantly converted into cyclohexanecarbaldehyde with 98-99% selectivity using undoped zirconium dioxide at 300-350° C. and atmospheric pressure (Examples 1-7). The aliphatic carboxylic acid pivalic acid yields pivalaldehyde with 100% selectivity (Example 8). However, aliphatic carboxylic acids or their esters having two alpha hydrogen atoms are converted into the corresponding alcohols or mixtures of alcohols and aldehydes in moderate yields and selectivities using chromium-doped zirconium dioxide at 320° C. and atmospheric pressure. For instance, n-heptanoic acid and methyl n-heptanoate produce n-heptanol in a yield of 62% or 33.9%, respectively (Examples 9 and 10), propionic acid (Example 14) and valeric acid (Example 16) produce n-propanol in a yield of 34.6% and only traces of n-pentanol (37.1% n-valeraldehyde yield). Buteric acid (Example 15) produces a mixture of n-butyraldehyde (15.8% yield) and n-butanol (30% yield).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([CH3:10])[CH3:9])(=O)=O.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C@H:24]([NH2:26])[CH3:25])=[CH:15]1.C(N(C(C)C)C(C)C)C>O1CCOCC1.CCOC(C)=O>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C@H:24]([NH:26][CH2:7][C:8]([F:11])([CH3:10])[CH3:9])[CH3:25])=[CH:15]1
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(F)COS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F
Temperature: 90 °C
Yield: 91.1 %

Procedure:
2-Fluoro-2-methylpropyl trifluoromethanesulfonate (8.04 g, 35.87 mmol) was added to a solution of (R)-1-(1H-indol-3-yl)propan-2-amine (5.00 g, 28.70 mmol) and N-ethyl-N-isopropylpropan-2-amine (7.44 ml, 43.04 mmol) in dioxane (50 ml). The reaction was heated to 90° C. for 3 h. After cooling to room temperature, the reaction was diluted with EtOAc (200 ml) and washed with saturated. NaHCO3 solution (2×100 ml). The aqueous phase was extracted with EtOAc (150 ml), then the combined organics were dried over MgSO4 and concentrated. The crude product was purified by flash silica chromatography, elution gradient 100% EtOAc. Pure fractions were evaporated to dryness to afford (R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine (6.49 g, 91%) as a brown oil. 1H NMR (400 MHz, CDCl3, 27° C.) δ 1.14 (3H, d), 1.31 (3H, d) 1.37 (3H, d), 1.94 (1H, s), 2.63-2.87 (3H, m), 2.92 (1H, dd), 3.07 (1H, h), 7.07 (1H, d), 7.08-7.15 (1H, m), 7.16-7.24 (1H, m), 7.37 (1H, d), 7.62 (1H, d), 8.04 (1H, s). m/z: ES+ [M+H]+ 249
Reaction SMILES: [CH:1]1([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][C:13]([CH2:15][OH:16])=[CH:14][C:8]=3[N:7]=2)[CH2:5]CC[CH2:2]1.C1(C2NC3C=CC(CO)=CC=3N=2)CC1>>[CH3:5][CH:1]([C:6]1[NH:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][OH:16])=[CH:14][C:8]=2[N:7]=1)[CH3:2]
Reactant: OCc1ccc2[nH]c(C3CCCC3)nc2c1
Agent: OCc1ccc2[nH]c(C3CC3)nc2c1
Product: CC(C)c1nc2cc(CO)ccc2[nH]1

Procedure:
2-cyclopentyl-1H-benzimidazole-5-methanol as a residue; and 2-cyclopropyl-1H-benzimidazole-5-methanol as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=3)[CH:11]([CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]2=[O:32])=[CH:5][CH:4]=1.O.[NH2:34][NH2:35].NN.CCOC(C)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:12]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([NH:34][NH2:35])=[O:18])=[CH:15][CH:14]=3)[CH:11]([CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]2=[O:32])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C2C(CCCc3ccccc3)C(=O)N2c2ccc(OC)cc2)cc1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(N2C(=O)C(CCCc3ccccc3)C2c2ccc(C(=O)NN)cc2)cc1
Yield: 50.6 %

Procedure:
Reflux a mixture of the product of Step 1 (7.5 g, 17.5 mmol, 12/1 trans/cis mixture) and hydrazine hydrate (4.7 mL, 87.3 mmol) in CH3OH (40 mL) overnight, monitoring the reaction by TLC (30% EtOAc/hexanes) and adding additional hydrazine and refluxing further as necessary. Evaporate most of the solvent in vacuo and partition the resultant residue between water and EtOAc. Wash with water and brine, dry over Na2SO4 and concentrate onto silica gel to obtain a free-flowing powder. Load the powder onto a chromatography column packed with silica and EtOAc. Elute with EtOAc to obtain 3.8 g (50%) of the title compound as a 6/1 trans/cis mixture. 1H NMR (400 MHz, CDCl3, trans isomer) 7.74(2H, d, J=8.2 Hz), 7.39(2H, d, J=8.2 Hz), 7.28(2H, m), 7.16(5H, m), 6.76(2H, d, J=9.1 Hz), 4.63(1H, d, J=2.1 Hz), 3.73(3H, s), 3.06(1H, m), 2.65(2H, m), 1.98(1H, m), 1.85(3H, m). Diagnostic C-4 proton for cis diastereomer 5.16(J=5.6 Hz). MS(EI): 429(M+,74), 249(100), 149(35). HRMS calculated for C26H27N3O3 : 429.2052; found 429.2052.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.[F:64][C:65]1[CH:70]=[C:69](/[CH:71]=[CH:72]/[CH3:73])[CH:68]=[C:67]([F:74])[C:66]=1[F:75].S([O-])([O-])=O.[Na+].[Na+].[OH2:82]>C(O)(C)(C)C>[F:64][C:65]1[CH:70]=[C:69]([C@H:71]([OH:22])[C@@H:72]([OH:82])[CH3:73])[CH:68]=[C:67]([F:74])[C:66]=1[F:75]
Reactant: C/C=C/c1cc(F)c(F)c(F)c1
Reactant: O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: C[C@H](O)[C@@H](O)c1cc(F)c(F)c(F)c1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution mixture of tert-butanol (170 mL) and water (170 mL) of AD-Mix-α (47.5 g) and methanesulfonamide (3.22 g), 1,2,3-trifluoro-5-((E)-propenyl)benzene (5.83 g) was added. The resulting reaction solution was stirred at 5° C. overnight, and then sodium sulfite (51 g) was added thereto. The resulting reaction solution was stirred at room temperature for 1 hr, and then extracted with methylene chloride three times. The organic layers were combined and washed with a 2 N sodium hydroxide aqueous solution. The sodium hydroxide layer was re-extracted with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 1:1) to give 5.54 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].O=S(Cl)Cl.[CH3:15]O>>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:15])=[O:9]
Reactant: O=C(O)c1ccccc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1O
Temperature: 25 °C

Procedure:
To a ice cold solution of salicylic acid (10 g, 0.072 mol) in methanol (100 mL), was added drop wise SOCl2 (12.8 g, 0.1 mol). After the addition, the mixture was warmed to room temperature and heated to reflux for 12 h. After reaction is completed the reaction mixture was cooled to room temperature and the excess methanol was evaporated under reduced pressure to obtain 9 g of methyl 2-hydroxybenzoate as a white solid. (81%). A solution of methyl 2-hydroxybenzoate (9 g, 0.059 mol) in glacial acetic acid (90 mL) was cooled to 15° C., fuming nitric acid (11.2 mL) was added drop wise. The reaction mixture was warmed to room temperature and stirred for 4 h. When the reaction is completed, the reaction mixture was poured into crushed ice. The precipitate was collected by filtration and washed several times with chilled water, then dried in a vacuum oven to the required product as a yellow coloured solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:17](=O)[CH3:18]>C(OCC)C>[CH3:17][CH:18]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: Nc1ccccc1
Solvent: CCOCC
Product: CC(Nc1ccccc1)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 869.3 %

Procedure:
Benzotriazole (5.0 g, 4.20 mmol) and aniline (3.91 g, 4.20 mmol) were dissolved in diethyl ether (85 ml), and acetaldehyde (2.03 g, 4.62 mmol) was added dropwise thereto on ice. The reaction mixture was stirred at room temperature for 15 minutes and then allowed to stand overnight at −20° C. The crystallized product was collected by filtration, washed with diethyl ether and then dried to give α-methyl-N-phenyl-1H-benzotriazole-1-methanamine (8.7 g) as a white crystal. The resulting α-methyl-N-phenyl-1H-benzotriazole-1-methanamine (2.86 g, 12 mmol) and vinylphthalimide (2860 mg, 12.0 mmol) were suspended in chloroform (10 ml), to which p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol) was then added and stirred at room temperature for 10 hours. After addition of water, the reaction mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium carbonate and water, and then concentrated. The residue was applied to silica gel column chromatography to give the titled compound (1.03 g, yield over 2 steps: 25%) as a white crystal.
Reaction SMILES: O=[C:2]1[N:7]([C@H:8]2[C@@H:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:16]3[CH:15]=[C:14]([O:26][CH2:27][CH2:28][NH:29][S:30]([C:33]4[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=4)(=[O:32])=[O:31])[CH:13]=[CH:12][C:11]=3[CH2:10][CH2:9]2)[C:6](=O)[CH:5]2[CH:3]1[CH2:4]2.CO>O1CCCC1.ClCCl>[CH:5]12[CH2:4][CH:3]1[CH2:2][N:7]([C@H:8]1[C@@H:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:16]3[CH:15]=[C:14]([O:26][CH2:27][CH2:28][NH:29][S:30]([C:33]4[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=4)(=[O:32])=[O:31])[CH:13]=[CH:12][C:11]=3[CH2:10][CH2:9]1)[CH2:6]2
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N2C(=O)C4CC4C2=O)CC3)c1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N2CC4CC4C2)CC3)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
cis-N-(2-{[7-(2,4-Dioxo-3-azabicyclo[3.1.0]hex-3-yl)-8-(2-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide (38 mg, 0.069 mmol) was dissolved in tetrahydrofuran (2 mL) and borane tetrahydrofuran complex was added (1 N, 0.4 mL, 0.4 mmol). The reaction mixture was heated to 50° C. for 3.5 h. After cooling to room temperature methanol (0.2 mL) was added dropwise and stirring was continued for 30 min. The reaction mixture was diluted with dichloromethane, washed with saturated sodium chloride solution and dried (magnesium sulfate). The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane/methanol). Yield: 4 mg (7.6 μmol, 11%, colorless oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2([C:13]3([CH3:21])[CH2:16][C:15]([F:18])([F:17])[C:14]3([F:20])[Cl:19])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([C:13]2([CH3:21])[CH2:16][C:15]([F:18])([F:17])[C:14]2([F:20])[Cl:19])([OH:11])[CH2:12][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CC1(C2(C#Cc3ccc(Cl)cc3)CO2)CC(F)(F)C1(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C(O)(C#Cc2ccc(Cl)cc2)Cn2cncn2)CC(F)(F)C1(F)Cl
Yield: 77.4 %

Procedure:
31.8 g of 2-[2-(4-chlorophenyl)-ethin-1-yl]-2-(2,3,3-trifluoro- 2-chloro-1-methylcyclobut-1-yl)-oxirane are added at room temperature to a stirred mixture of 6.4 g of 1,2,4-triazole, 12.6 g of ground potassium carbonate and 300 ml of acetonitrile. The reaction mixture is refluxed for 12 hours, and then cooled and filtered. The filtrate is concentrated under reduced pressure, and the remaining residue is purified by column chromatography (ethyl acetate) on silica gel. 29 g (75.5% of theory) of 1-(4-chlorophenyl)-3-(2,3,3-trifluoro-2-chloro-1-methyl-cyclo-but-1-yl)-4-(1,2,4-triazol-1-yl)-but-1-in-3-ol are obtained in form of a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17](Cl)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl.[N+](C1C=CC=CC=1)([O-])=[O:32]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:17](=[O:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCCCl
Reactant: O=[N+]([O-])c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Temperature: 5 °C
Reaction time: 12 h
Yield: 64.2 %

Procedure:
2-Methoxynaphthalene (30.1 g, 0.19 mol) was added to a solution of aluminum chloride (32.9 g, 0.25 mol) in anhydrous nitrobenzene under a nitrogen atmosphere. To the mixture was slowly added dropwise lauryl chloride (41.6 g, 0.19 mol) at 10-13° C. over 15 minutes. The resulting mixture was stirred at 5° C. for 2 hours and at room temperature for 12 hours. The reaction mixture was poured into 300 ml of 3M HCl at 0° C., extracted with chloroform, and sufficiently washed with brine. The solvents were removed by evaporation under reduced pressure. The residue was dissolved in chloroform and washed with 0.1M NaOH. The mixture was evaporated to remove the chloroform, followed by recrystallization from ethanol to give the title compound (41.5 g, yield: 64.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([CH3:18])[NH:15][N:14]=1)(=[O:12])=[O:11].[H-].[Na+].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24](Cl)[N:23]=1.O>CN(C)C=O.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([CH3:18])[N:15]([C:24]2[N:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[N:23]=2)[N:14]=1)(=[O:11])=[O:12]
Reactant: Cc1nc(S(=O)(=O)Nc2c(F)cccc2F)n[nH]1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(-n2nc(S(=O)(=O)Nc3c(F)cccc3F)nc2C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
N-(2,6-difluorophenyl)-5-methyl-1,2,4-triazole-3-sulphonamide (5 g) (Compound A81) was added in portions to a suspension of sodium hydride (1.37 g in 80% suspension in oil) in dry dimethylformamide (40 ml). The mixture was stirred for 30 minutes at 25° C., 4,6-dimethyl-2-chloropyrimidine (2.6 g) was added, and the mixture was then stirred at 100° C. for 18 hours. The cooled reaction mixture was poured into water, acidified with glacial acetic acid and then extracted with dichloromethane (3×100 ml). The organic phases were dried and evaporated, and the residue was chromatographed (silica/dichloromethane). The product was recrystallised from ethanol to give 0.8 g of the desired product, mp 228°-230° C., identical to that of Example A63.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([N:34]=[C:35]=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:16]([NH:34][C:35](=[O:36])[NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)Nc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 5-aminoisophthalate (obtained from Aldrich Chemical Co., Milwaukee, Wis., 0.441 g, 2.12 mmol) was dissolved in dry N,N-dimethylformamide (8 mL) in a 50 mL round-bottom flask under inert atmosphere. A 2.12 Molar solution of octadecylisocyanate (2.12 mmol) in dry N,N-dimethylformamide (1 mL) was then added dropwise. The residual octadecylisocyanate solution was quantitatively transferred with 2 portions of N,N-dimethylformamide (1 mL each) and the reaction was stirred overnight at room temperature. The reaction was then heated to 100° C. for 22 h, and thereafter cooled to room temperature to give a white slurry. The solid was then vacuum filtered, washed with fresh N,N-dimethylformamide, and then washed with deionized water. The filtrate was concentrated by rotary evaporation to give a white solid.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][C:20]([OH:22])=O)[CH2:13][CH2:12]1)[CH3:10].CN1CCOCC1.[NH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][C:35]([C:41]#[N:42])=[C:34]2[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Br:50])[CH:45]=1>O1CCCC1.N1C=CC=CC=1>[Br:50][C:46]1[CH:45]=[C:44]([NH:43][C:34]2[C:33]3[C:38](=[CH:39][CH:40]=[C:31]([NH:30][C:20](=[O:22])[C:19]#[C:18][CH2:17][N:14]4[CH2:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:16][CH2:15]4)[CH:32]=3)[N:37]=[CH:36][C:35]=2[C:41]#[N:42])[CH:49]=[CH:48][CH:47]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CCN1CCN(CC#CC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CCN1CCN(CC#CC(=O)Nc2ccc3ncc(C#N)c(Nc4cccc(Br)c4)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.785 g, 5.75 mmol) was dropwise added into an ice cold solution of 4-(N-ethylpiperazino)-2-butynoic acid (1.75 g, 8.85 mmol) and N-methylmorpholine (1.3453 g, 13.3 mmol) in 50 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 1.5 g (4.42 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by flash column chromatography. The product fractions were collected, and dried in vacuo to give 1.07 g (46%) of light brown solid; ESMS m/z 517.1, 519.1 (M+H+); mp 161° C. (dec).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCCC1>[CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:37])[NH2:14])=[CH:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h
Yield: 199.4 %

Procedure:
A mixture of 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carboxamide (2.6 g), Lawesson's reagent (1.3 g) and tetrahydrofuran (50 mL) was stirred at 60° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from toluene to give the title compound (2.65 g, yield: 100%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:15]=2[N:14]([CH2:30][C:31](N(C)C2C=CC=CN=2)=[O:32])[C:13]1=[O:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:42]1([Mg]Cl)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]2[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:15]=2[N:14]([CH2:30][C:31]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:32])[C:13]1=[O:41])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c1N(CC(=O)N(C)c1ccccn1)C(=O)C(NC(=O)OCc1ccccc1)N=C2C1CCCCC1
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc2c1N(CC(=O)C1CCCCC1)C(=O)C(NC(=O)OCc1ccccc1)N=C2C1CCCCC1
Temperature: 0 °C

Procedure:
To a solution of (3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1-[N-methyl-N-(2-pyridyl)amino]carbonylmethyl-1H-1,4-benzodiazepin-2-one (400 mg) in tetrahydrofuran (4 ml) was added cyclohexyl magnesium chloride (1.08 ml) under stirring, at 0° C. The mixture was stirred for twenty minutes under the same conditions and at room temperature overnight. Ethyl acetate and a saturated aqueous solution of ammonium chloride were added to the reaction mixture. The separated organic layer was washed with 0.1N aqueous hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and brine successively and dried under magnesium sulfate. The solvent was removed in vacuo to afford a residue, which was subjected to column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (20:1) to give (3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-1-cyclohexylcarbonylmethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[N:14]=[C:13]([C:15]([O:17]C3CCCC3)=[O:16])[CH:12]=[CH:11][C:10]=2[O:23][CH3:24])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc(C(=O)OC2CCCC2)nc1OC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)nc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.3 %

Procedure:
Potassium hydroxide (1.98 g) in water (12 mL) is added to a solution of cyclopentyl 6-cyclopentyloxy-5-methoxypyridine-2-carboxylate (3.6 g) in methanol (35 mL) and the mixture stirred at room temperature for 2.5 hours. The solution is concentrated to half of the original volume and diluted with water. The solution is acidified to pH 4 with concentrated hydrochloric acid and the product extracted with ethyl acetate. The extracts are dried (MgSO4) and concentrated to give 6-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (1.38 g) as a yellow solid, m.p. 96–99° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CCC(c2ccc(N)nc2)CC1=O
Solvent: CC#N
Product: CN1CCC(c2cnc(N)c(Br)c2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (+/−)-4-(6-aminopyridin-3-yl)-1-methylpiperidin-2-one (291 mg, 1.418 mmol) in acetonitrile (14.200 mL) was added NBS (202 mg, 1.134 mmol) at 0° C. The reaction mixture was stirred for 30 min upon warming-up to room temperature. After quenched with Na2S2O3 solution, the reaction mixture was extracted with EtOAc, which was washed with NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered off, concentrated in vacuo. The crude product (+/−)-4-(6-amino-5-bromopyridin-3-yl)-1-methylpiperidin-2-one (98%) was used for the next step. LCMS (m/z): 284/286 (MH+), 0.34 min.