Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([C:4]2[N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][CH:21]=3)[N:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(N)nc(Cl)n1
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(Cl)cc2)n1

Procedure:
To a stirred suspension of the hydrochloride salt of 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-4-yl-amine (0.023 g, 0.075 mmol) in ethanol (7.0 ml) was added 4-chloroaniline (0.025 g, 0.20 mmol). The mixture was stirred under reflux for 6 hours. After evaporation of the solvent under reduced pressure, the residue was treated with hydrochloric acid (1.0 M, 10 ml) and stirred for 30 minutes. Filtration provided the hydrochloride salt of 6-(5-chloro-2-methoxy-phenyl)-N*2*-(4-chloro-phenyl)-pyrimidine-2,4-diamine which was treated with methanol (10 ml) and stirred while a solution of sodium carbonate in water (1.0 M, 1 ml) was added. After stirring for 1 hour, solvents were evaporated under reduced pressure. The residual solid was treated with water (10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.019 g, 70% yield) as a white powder. 1H NMR (CDCl3) δ 4.80 (s, 2H, NH2), 6.62 (s, 1H, Ar), 6.94 (d, 1H, J=8.8 Hz, Ar), 6.98 (s, 1H, NH), 7.27-7.30 (m, 2H, Ar), 7.36 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.61-7.63 (m, 2H, Ar), 7.93 (d, 1H, J=2.8 Hz, Ar),
Reaction SMILES: [C@@H:1]12[O:6][C@@H:5]1[CH2:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]2.[OH2:11].[Na+].[Cl-]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[OH:6][C@H:1]1[C@H:5]([OH:11])[CH2:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: O
Reactant: COC(=O)C1C[C@@H]2O[C@@H]2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)C1C[C@@H](O)[C@H](O)C1
Reaction time: 48 h

Procedure:
Methyl (1S,5R)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (8 g, 56.3 mmol) and tetrabutylammonium bisulfate (1.911 g, 5.63 mmol) were suspended in THF (5 ml) and water (75 ml) and allowed to stir for 48 hrs. Added solid NaCl and extracted with three 250 ml portions of EtOAc. Added 100 ml Hexane washed with brine and dryed over sodium sulfate. Silca gel chromatography on a 50 g Biotage SNAP cartridge with 40-60% acetone-hexane to give title product as a clear oil. 1H NMR (500 MHz, CDCl3) δ 1.89-2.03 (m, 3H), δ 2.26-2.42 (m, 3H), δ 3.08-3.15 (m, 1H), δ 3.74 (s, 3H), δ 4.06 (m, 1H), δ 4.23 (m, 1H)
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:7]
Reactant: NCCCC(=O)O
Reactant: CCCCOC(=O)c1ncc2ccc(Oc3ccccc3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCCNC(=O)c1ncc2ccc(Oc3ccccc3)cc2c1O
Yield: 91.1 %

Procedure:
A mixture of 4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (150 mg, 0.45 mmol) and 4-amino-butyric acid (688 mg, 6.68 mmol) in 0.5 M NaOMe/MeOH (8.9 mL, 4.45 mmol) was refluxed overnight. Reaction mixture was concentrated and residue was dissolved in water (150 mL). It was acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 151 mg (0.41 mmol) in 92% yield. LC-MS ESI−: 365.08 (M−1)−.
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6](=O)[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[CH3:8].[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.CCCCCC.CCOCC>[Cl:1][C:2]1[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[CH3:8]
Reactant: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Reaction time: 1.5 h

Procedure:
A solution of N-(2-chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide (265 mg, 0.7 mmole) in 40 mL of toluene was treated with diisobutyl aluminum hydride (5 mL of a 1N solution in hexane), and the reaction was stirred for 90 minutes. The reaction was diluted with 20 mL of Et2O, a concentrated aqueous solution of Rochelle salt was added, and the mixture stirred for 60 minutes, at which time the emulsion had broken apart. The organic layer was separated, washed with H2O, aqueous Rochelle salt, dried and the solvent removed, and gave the titled compound, 221 mg (87%). MS (ESI) 362 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=O.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH:26]([NH:29][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:2])([CH3:28])[CH3:27]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC(C)C)n(C)n1
Yield: 88 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using isopropylamine instead of N,N-dimethylhydrazine, to the title compound (95 mg, 88%) which was obtained as a colorless oil. MS: m/e=373.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[C:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:17]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=[CH:19][C:20]([O:23][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(COc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A solution of alpha-bromo-p-tolunitrile (5.00 g, 25.5 mmol), 4-phenylphenol (4.56 g, 26.8 mmol), and potassium carbonate (10.6 g, 76.5 mmol) in N,N-dimethylformamide (75 mL) was stirred vigorously for 16 hours at room temperature. Water (75 mL) was added and the mixture was stirred at room temperature for 1 hour. The precipitate was filtered off and washed with thoroughly with water. Drying in vacuo over night at 50° C. afforded 7.09 g (97%) of 4-(biphenyl-4-yloxymethyl)benzonitrile as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:13]([CH2:16][CH3:17])[CH:14]=[O:15])[CH3:12].[C:18]1([C@H:24]2[CH2:26][C@H:25]2[CH2:27][OH:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.C(Cl)(Cl)Cl>[CH2:11]([N:13]([CH2:16][CH3:17])[CH:14]=[O:15])[CH3:12].[C:18]1([C@H:24]2[CH2:26][C@H:25]2[CH:27]=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC[C@@H]1C[C@@H]1c1ccccc1
Agent: CCN(C=O)CC
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C[C@@H]1C[C@@H]1c1ccccc1
Yield: 99 %

Procedure:
0.55 ml (6.40 mmol) of oxalylchloride was dissolved in 4 ml of anhydrous dichloromethane. To the resultant solution was dropwise added a solution of 0.91 ml (12.8 mmol) of dimethylsulfoxide in 4 ml of anhydrous dichloromethane in a stream of argon gas at -78° C., and the resultant mixture was stirred for 30 minutes. To the mixture was dropwise added a solution of 805 mg (3.26 mmol) of compound 26 obtained in Reference Example 18 in 4 ml of anhydrous dichloromethane, and the resultant mixture was stirred for 2 hours to effect a reaction. To the reaction mixture was added 1.9 ml (25.6 mmol) of triethylamine, and the resultant mixture was stirred for 1 hour to effect a reaction. To the obtained mixture was added a saturated aqueous ammonium chloride solution to thereby terminate the reaction. To the obtained reaction mixture was added chloroform for extraction to obtain an organic layer. The organic layer was separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography (the composition of the developing solvent was; ethyl acetate:hexane=2:1). As a result, compound 27 (yield: 99%) was obtained as a white crystalline product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Sc1nc(CCO)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.9 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (8.4 g) obtained in Example 4 was dissolved in dichloromethane (50 mL), trifluoroacetic acid (50 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethanol (100 mL). Thionyl chloride (8 mL) was added under ice-cooling, and the mixture was refluxed for 4 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was concentrated under reduced pressure. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (6.7 g) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:7])[CH:5]=[CH2:6])C.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[CH2:8]([O:15][CH2:6][CH2:5][C:4]([OH:7])=[O:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CC(=O)OCC
Reactant: OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a stirred solution of ethylacrylate (0.5 mol, 50.0 g) in benzylalcohol (2 mol, 216 g), KtBu (5 mmol, 0.61 g) was added at room temperature. After standing overnight, NaOH (0.55 mol, 22 g) in water (100 ml) was added. The solution was stirred for 2 hrs. at 50° C. and cooled to room temperature. Water (300 ml) was added and the mixture extracted with CH2Cl2 (1×500 ml, 4×150 ml). The aqueous layer was evaporated and the residue washed with diethylether (4×100 ml). The white solid was dissolved in water (300 ml) and acidified with 33% HCl up to a pH of 2. On cooling (0° C.), the acid solidified. It was filtrated, rinsed with cold water, and dissolved in diethylether. After drying over MgSO4, the ether was evaporated. The acid was recrystallized from pentane/toluene and dried in a stream of nitrogen, resulting in 64.3 g (71%) of product.
Reaction SMILES: CCO.[Na].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]([CH3:18])=[O:17]>>[O:8]=[C:6]([CH2:15][C:16](=[O:17])[CH3:18])[C:5]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a 100 mL two neck RB flask fitted with magnetic stirrer was charged with 25 mL of ethanol. To the stirred solvent was added sodium metal pieces (0.86 g, 37 mmol) slowly at 0° C. under nitrogen atmosphere and stirred for 30 minutes at room temperature. After 30 minutes, diethyl oxalate (5 g, 34.2 mmol) in acetone (10 mL) was added drop wise. During addition, the reaction mixture was changed to yellow color. After addition, thick mass was observed, was added ethanol (10 mL) to the reaction mixture and stirred at room temperature for 1 h. Then, the reaction mixture was filtered; the solids were dissolved in ice-cold water (50 mL), acidified with concentrated sulfuric acid and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure and the solvent traces were removed by triturated with n-hexane. The product was obtained as brown liquid (3.2 g, yield: 59.2%). 1H NMR (300 MHz, DMSO-d6): δ 5.46 (s, 2H), 4.02-4.09 (q, 2H), 1.89 (s, 3H), 1.18-1.22 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH:8]([OH:11])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])([CH3:10])[CH3:9]
Reactant: CC(C)O
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CS(=O)(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Chloroethylsulfonyl chloride (2 g, 12.3 mmol), isopropanol (1 mL), and pyridine (2.7 mL) were dissolved in dichloromethane (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid and water, and the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered, and the solvent was evaporated to give the title compound (1.06 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]([NH:13][C:14]3C=CC=CC=3O)=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:31](N1C=CN=C1)(N1C=CN=C1)=S.[NH2+]1C2C=CC=CC=2N=N1.F[B-](F)(F)F.CNC>ClCCl.O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:25])[CH3:26])[C:11]([N:13]([CH3:14])[CH3:31])=[O:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](CC(C)C)N[C@@H](C(=O)Nc1ccccc1O)c1ccc2occc2c1
Agent: CNC
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)N=N[NH2+]2
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc2occc2c1
Reaction time: 18 h
Yield: 40.5 %

Procedure:
A solution of methyl N-{(1R)-1-(benzofuran-5-yl)-2-[(2-hydroxyphenyl)amino]-2-oxoethyl}-L-leucinate (410 mg) and 1,1′-thiocarbonyldiimidazole (196 mg) in dichloromethane (5 ml) was left to stand for 18 hours. Water (20 l) was added to the reaction mixture and this was then stirred rapidly for 30 minutes. After this, 1H-Benzotriazolium, 1-[bis(dimethylamino)methylene]-, tetrafluoroborate (1-), 3-oxide (TBTU, 710 mg) and a solution of dimethylamine in tetrahydrofuran (3 ml of 2M solution) were added. The reaction mixture was stirred for a further 18 hours and was then passed down an SPE (5 g, silica) eluting with a gradient (3:1 to 1:2 cyclohexane:ethyl acetate). The required fractions were combined and evaporated to furnish methyl N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (140 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C=CC=CC=1.[CH:18]([C:20]([CH3:22])=[O:21])=[CH2:19]>C(N(CC)CC)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:19][CH2:18][C:20](=[O:21])[CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=CC(C)=O
Reactant: CCOC(=O)C1CCCC1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1(CCC(C)=O)CCCC1=O

Procedure:
A mixture of 102.0 g of ethyl 2-oxocyclopentanecarboxylate, 300 ml of benzene, 67 ml of methyl vinyl ketone and 20 ml of triethylamine was allowed to stir magnetically at reflux for 2.5 hours. Concentration followed by Claisen distillation gave 128 g of product.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1)=O.[CH3:25][NH:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[CH2:33]2)(=[O:29])=[O:28]>>[CH3:25][NH:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])/[C:33]/2=[CH:1]\[C:3]1[NH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1)(=[O:29])=[O:28]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(CC(=O)O)CC1)CCCC2
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(CC(=O)O)CC1)CCCC3)C(=O)N2
Yield: 80 %

Procedure:
{(4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-acetic acid (50 mg, 0.15 mmol) was condensed with 5-methylaminosulfonyloxindole (40 mg, 0.15 mmol) following the procedure used in Example 1. The formed solid was purified by flash chromatography, eluting with (dichloromethane: methanol 6:1 followed by 4:1:0.01 acetic acid) to give 65 mg of the desired product.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12](F)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]#[N:20])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:23][O:24][CH2:25][CH2:26][OH:27]>>[CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH2:26][CH2:25][O:24][CH3:23])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:19]#[N:20])[CH2:2][CH2:3][CH3:4]
Reactant: COCCO
Reactant: CCCCNc1c(C#N)cnc2cc(F)c(OC)cc12
Agent: [H-]
Agent: [Na+]
Product: CCCCNc1c(C#N)cnc2cc(OCCOC)c(OC)cc12
Temperature: 25 °C

Procedure:
A mixture of 4-butylamino-7-fluoro-6-methoxy-3-quinolinecarbonitrile (150 mg, 0.55 mmol) and sodium hydride (55 mg, 2.29 mmol) in 1.7 mL of 2-methoxyethanol is heated at reflux for 30 minutes then cooled to room temperature. The reaction mixture is partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative thin layer chromatography, eluting with 5% methanol in dichloromethane, followed by trituration with ethyl acetate, provides 135 mg of 4-butylamino-6-methoxy-7-(2-methoxyethoxy)-3-quinolinecarbonitrile, mp 99-102° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:20]([O-])=O)[CH:3]=1.C1COCC1>[Pt].CO>[Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:20]
Reactant: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(Cl)cc1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4-chloro-N-methyl-2-nitro-5-(4-trifluoromethyl-piperidin-1-yl)aniline (1.07 g, 3.2 mmol), THF (20 mL), MeOH (30 mL) and Pt/C (100 mg) was stirred for 6 h at rt under a hydrogen atmosphere (3 bar). The catalyst was removed by filtration and the mixture was concentrated to give the sub-title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:9][CH:10]=[N:11][CH:12]1[C:20]2[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1([CH3:23])[CH3:22])#N.Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O>[CH3:29][O:28][C:26]([C:25]1[N:11]([CH:12]2[C:20]3[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]2([CH3:23])[CH3:22])[CH:10]=[N:9][CH:7]=1)=[O:27]
Reactant: CC1(C)Cc2c(Cl)cccc2C1N=CNC#N
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncn1C1c2cccc(Cl)c2CC1(C)C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
12.7 g of potassium carbonate are added to a solution of 21 g of N-cyano-N'-(2,2-dimethyl-4-chloroindan-1-yl)formamidine in 80 ml of dimethylformamide. 14.1 g of methyl bromoacetate are added dropwise. After the exothermic reaction has ceased the mixture is agitated for 1.5 hours at +50° C. another portion of 12.7 g of potassium carbonate is added and the mixture is stirred for 18 hours at +100° C. The precipitate is filtered off from the hot solution and washed with 30 g of hot dimethylformamide. The combined filtrates are dropwise added at +60° C. to a solution of 14.2 g of tert. butylnitrite in 30 ml of dimethylformamide. Immediate evolution of nitrogen is observed and the temperature of the mixture rises to +67° C. After 30 minutes the dropwise addition is completed. The mixture is maintained at +70° to +75° C. for 2.5 hours and then poured into ice-water and extracted with ethyl acetate. The organic phase is washed with brine, dried with sodium sulfate and concentrated to dryness. The residue is purified by chromatography at a silica gel column with an ethyl acetate/hexane mixture (1:2 by volume), affording 12.7 g of 1-(2,2-dimethyl-4-chloro-indan-1-yl)-5-imidazolecarboxylic acid methyl ester, having a melting point of 111°-113° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[NH:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1NCC(F)(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1NCC(F)(F)F
Yield: 77 %

Procedure:
The title compound is prepared in 77% yield (210 mg, yellow solid) from 4-chloro-2-(1-(5-methyl-6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (220 mg, 0.57 mmol, Intermediate-62, single enantiomer) and phenyl formate (140 mg, 1.1 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [C:1](=[S:6])([O:3]CC)[NH2:2].Br[CH2:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=O>O1CCOCC1>[CH2:15]([O:14][C:12]([C:11]1[S:6][C:1](=[O:3])[NH:2][C:9]=1[CH3:8])=[O:13])[CH3:16]
Reactant: CCOC(N)=S
Reactant: CCOC(=O)CC(=O)CBr
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(=O)[nH]c1C

Procedure:
84 g of ethyl thiocarbamate were added to 500 ml of dioxane and then 168 g of ethyl α-bromoacetylacetate was added thereto dropwise. The mixture was refluxed for 4 hours and the solvent was then evaporated under reduced pressure. The solid residue was crystallized from benzene to obtain 72g of 5-ethoxycarbonyl-4-methyl-4-thiazoline-2-one in the form of white crystals melting at 172°C.