Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[CH:6]([CH3:14])[C:5]1=[O:15])(=[O:3])[CH3:2].[H-].[Na+].CI.[CH2:20]1COCC1>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[C:6]([CH3:20])([CH3:14])[C:5]1=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)C(C)c2ccc(Br)cc21
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)N1C(=O)C(C)(C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-acetyl-6-bromo-3-methyl-1,3-dihydro-2H-indol-2-one (9.5 g) were added NaH (1.57 g), methyl iodide (2.45 ml) and THF (70 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (5.2 g) as a colorless crystal.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:28]1CCN2C(=NCCC2)CC1.C1COCC1.C=O>C1COCC1>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([CH2:17][C:11](=[CH2:28])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccnc2ccccc12)P(=O)(OCC)OCC
Reactant: C1CCC2=NCCCN2CC1
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Cc1ccnc2ccccc12)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
140 mg of anhydrous lithium chloride was dissolved in 7 ml of dry THF, and 3 ml of a THF solution of 1.04 g of ethyl 2-diethylphosphono-3-(4-quinolyl)propionate was added thereto. Then, 1.7 ml of DBU/THF (12/25) was added, and then a 3 ml of a THF solution of 0.14 g of paraformaldehyde was added thereto. The mixture was stirred at room temperature for one hour, and then the insoluble materials were removed by filtration. The product collected by filtration was washed with a small amount of benzene, and the washed solution was combined with the filtrate. The combined filtrate was diluted with 60 ml of ethyl acetate and washed with 40 ml of water and then with 40 ml of a saturated sodium chloride aqueous solution. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to obtain 601 mg of the above identified compound as syrup.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])(O)[CH2:9][CH3:10].ClC1C(OC)=C(C(C2C=CC=CC=2OC)C)C=CC=1OC.ClC1C(OCOC)=C(C(C2C=CC=CC=2OC)(O)C)C=CC=1>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[CH2:9][CH3:10]
Reactant: CCC(O)(c1ccccc1O)c1ccccc1O
Agent: COCOc1c(Cl)cccc1C(C)(O)c1ccccc1OC
Agent: COc1ccccc1C(C)c1ccc(OC)c(Cl)c1OC
Product: CCC(c1ccccc1O)c1ccccc1O

Procedure:
1,1-Bis(2-hydroxyphenyl)propane was prepared similarly from 1,1-bis(2-hydroxyphenyl)propanol and 1-(3-chloro-2-methoxy-methoxyphenyl)-1-(2-methoxyphenyl)ethane was prepared similarly from 1-(3-chloro-2-methoxymethoxyphenyl)-1-(2-methoxyphenyl)ethanol.
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][C:8]([C:12]([OH:14])=O)=[C:9]([CH3:11])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(NC1SC(C(Cl)=O)=C(C)N=1)(C)(C)C.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:36][CH:37]([C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)[C:38]#[N:39]>C(N(CC)CC)C>[C:38]([CH:37]([NH:36][C:12]([C:8]1[S:7][C:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:10][C:9]=1[CH3:11])=[O:14])[C:40]1[S:41][CH:42]=[CH:43][CH:44]=1)#[N:39]
Reactant: N#CC(N)c1cccs1
Reactant: Cc1nc(NC(C)(C)C)sc1C(=O)O
Agent: Cc1nc(NC(C)(C)C)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(NC(C)(C)C)sc1C(=O)NC(C#N)c1cccs1
Yield: 41 %

Procedure:
1.5g of 2-t-butylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-t-butylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.6g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.4g of amino-thiophen-2-yl-acetonitrile hydrochloride and 3.3ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.96g (Yield 41%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:41]([O-])=O.C(O)(=O)C>C1COCC1.[Fe]>[NH2:41][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:13]=1[C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:3]=1[O:2][CH3:1])=[CH:21][CH:20]=[C:19]([S:23]([N:26]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[C:27]1[S:28][CH:29]=[CH:30][N:31]=1)(=[O:24])=[O:25])[CH:18]=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)c([N+](=O)[O-])cnc3c2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)c(N)cnc3c2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 98.8 %

Procedure:
A round-bottom flask was charged with 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-3-nitro-N-(thiazol-2-yl)quinoline-7-sulfonamide (0.759 g, 1.204 mmol), THF (2.006 ml), and acetic acid (2.006 ml) to give a yellow solution. Iron (0.672 g, 12.04 mmol) powder was added, and the flask was fitted with a reflux condenser and placed in a 60° C. heating bath. The mixture was stirred for 50 min, then cooled to room temperature, diluted with THF, and filtered through diatomaceous earth with the aid of THF. The filtrate was concentrated. The residue was concentrated from DCM/heptane (2×), then concentrated from DCM to give 3-amino-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)quinoline-7-sulfonamide (0.714 g, 1.189 mmol, 99% yield) as a tan foam. m/z (ESI) 601.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[CH2:12]=[O:13].[OH-].[Na+].S(=O)(=O)(O)O>>[CH3:10][O:9][C:5]1[CH:6]=[C:7]([CH2:12][OH:13])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[OH:11]
Reactant: COc1cccc(OC)c1O
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CO)cc(OC)c1O

Procedure:
310 g of 2,6-dimethoxyphenol, 300 g of 38 wt% formalin, and 810 g of 10% wt% aqueous sodium hydroxide were reacted for 60 hours at 25° C. under a pressure of 0 kg/cm2 -G, the reaction mixture was and then neutralized with sulfuric acid, to obtain 80 g of 2,6-dimethoxy-4-(hydroxymethyl)phenol. (Yield: 22 mol%) 25 g of the obtained 2,6-dimethoxy-4-(hydroxymethyl)phenol was reacted in 320 ml of methanol in the presence of 0.375 wt% of platinum-alumina catalyst and hydrogen for 4 hours at 200° C. at 199 kg/cm2 -G, and 15 g of 2,6-dimethoxy-4-methylphenol was obtained. (Yield: 66 mol%) The yield on the basis of the amount of the raw material was 15 mol%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:15]([C:13]2[S:14][C:10]([Br:9])=[CH:11][CH:12]=2)(=[O:17])=[O:16])=[CH:4][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: NCc1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1ccncc1)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a stirred solution of 4-aminomethyl-pyridine (1.24 g, 11.5 mmol) in THF (8 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) dissolved in THF (8 ml) and triethylamine (0.59 ml, 4.21 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (dichloromethane/methanol) and crystallization from dichloromethane/hexane to yield the title compound (1.21 g, 95%) as a white solid. MS (ISN) 330.8 [(M−H)−], mp 159° C.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:12][N:11]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[C:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][C:35]3[C:30](=[CH:31][C:32]([N:49]4[CH2:54][CH2:53][O:52][CH2:51][CH2:50]4)=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:10]1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[NH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[CH2:12][N:11]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[C:37]([NH:38][C:39](=[O:48])[O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][C:35]3[C:30](=[CH:31][C:32]([N:49]4[CH2:50][CH2:51][O:52][CH2:53][CH2:54]4)=[CH:33][CH:34]=3)[N:29]=2)=[O:27])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the amide intermediate, 1 mL of 4N HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure to give a crude product which was used directly in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16]>CO>[CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]([NH2:17])[S:16][CH:2]=2)=[CH:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: NC(N)=S
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Solvent: CO
Product: CC(C)c1ccc(-c2csc(N)n2)cc1

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-ylamine was prepared (0.41 g) following general procedure B using 2-bromo-1-(4-isopropyl-phenyl)-ethanone (0.5 g, 2.07 mmol), thiourea (173 mg, 2.28 mmol) and MeOH (10 mL). LCMS m/z: 219 (M+1)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23])#[N:2].[Cl-].[OH:29][NH3+:30].C(=O)([O-])O.[Na+]>CS(C)=O.[Cl-].[Na+].O>[NH2:2]/[C:1](=[N:30]\[OH:29])/[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:16]=2)[N:9]=[N:8][C:7]=1[C:22]([NH:24][CH:25]1[CH2:26][CH2:27]1)=[O:23]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCC#N)cc1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC/C(N)=N/O)cc1
Yield: 78.9 %

Procedure:
A solution of 5-(3-cyanopropyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (366 mg, 1.0 mmol) obtained in Example 1207, hydroxyammonium chloride (139 mg, 2.0 mmol, 2.0 eq.) and sodium hydrogen carbonate (168 mg, 2.0 mmol, 2.0 eq.) in DMSO (5 ml) was stirred at 90° C. for 5 hr. Saturated brine (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 ml×3), and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (315 mg, 79%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[SH:19])=[CH:16][CH:15]=[CH:14][CH:13]=2.[OH-].[Na+]>C(OCC(O)=O)C>[CH2:1]([O:3][CH2:4][C:5]1[S:19][C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1S
Agent: CCOCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1nc2cnc3ccccc3c2s1
Temperature: 60 °C

Procedure:
Ethoxyacetyl chloride (6 mL, 53.8 mmol) was added to a suspension of 3-aminoquinoline-4-thiol (4.6 g, 26.1 mmol) in ethoxyacetic acid (50 mL). The reaction mixture was heated at 60° C. overnight. The reaction mixture was concentrated under vacuum to remove a portion of the ethoxyacetic acid. The residue was combined with water (100 mL) and a precipitate formed. The mixture was made basic with 50% sodium hydroxide. The precipitate was isolated by filtration, washed with water and then dried to provide 2-(ethoxymethyl)thiazolo[4,5-c]quinoline as a fluffy green solid.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[CH2:31]([C:15]1([N:14]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18][O:17][C:16]1=[O:20])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OCCC1N=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCC1(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-[(diphenylmethylene)amino]dihydrofuran-2(3H)-one (1 g, 3.8 mmol) in DMF (10 mL) cooled to 0° C. was added NaHMDS (4.7 mL, 4.7 mmol, 1M THF) via serynge slowly. The resulting bright orange solution was stirred at 0° C. for 2 min at which point benzyl bromide (0.47 mL, 4 mmol) was addedvia serynge. After 5 min stirring at 0° C., the reaction was quenched with water, extracted with EtOAc, washed with aqueous LiCl, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (90 g silica gel, 0 to 40% EtOAc in hexane) to give 3-benzyl-3-[(diphenylmethylene)amino]dihydrofuran-2(3H)-one as a white solid. MS M+1=356.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc(C#N)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc(CN)c1
Reaction time: 2 h
Yield: 42.2 %

Procedure:
To a mixture consisting of crude tert-butyl 2-(3-cyanophenylsulfonamido)-ethylcarbamate (Compound 15, 1.52 g) in methanol (46 mL) under a nitrogen atmosphere was added 5% palladium on carbon (1 g). Hydrogen gas was applied via balloon at atmospheric pressure. The reaction mixture was stirred vigorously for two hours and was subsequently filtered over Celite and rinsed with additional methanol. The mixture was concentrated under reduced pressure and purified by silica chromatography (5:95 methanol-dichloromethane) to afford the title intermediate (650 mg, 42% over two steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[C:13]=2[CH3:14])=[O:17])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1)#[N:25]
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)c(F)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(F)c(F)c1
Yield: 53.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3,4-difluorophenyl)-5-methylpyrazole-4-carboxylic acid (0.7 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.0 g), the title compound (0.8 g) was obtained, melting point: 235° C.
Reaction SMILES: C(O)(=O)CC[C@H](NC(C1C=CC(NCC2N=C3C(N=C(NC3=O)N)=NC=2)=CC=1)=O)C(O)=O.BrC(CBr)C=O.NC1N=C(N)C(N)=C(O)N=1.NC1C=CC(CN[C@H](C(O)=O)CCC(O)=O)=CC=1.[OH-].[Na+].C([O-])(=O)CC[C@H](NC(C1C=CC(NCC2N=C3C(N=C(NC3=O)N)=NC=2)=CC=1)=O)C(O)=O.[Na+].[CH2:102]1[NH:107][C:106]2[NH:108][C:109]([NH2:113])=[N:110][C:111](=[O:112])[C:105]=2[N:104]([CH:114]=[O:115])[CH:103]1[CH2:116][NH:117][C:118]1[CH:123]=[CH:122][C:121]([C:124]([NH:126][C@H:127]([C:133]([O-:135])=[O:134])[CH2:128][CH2:129][C:130]([O-:132])=[O:131])=[O:125])=[CH:120][CH:119]=1.[Ca+2]>O.C(O)=O.[Pt]=O.O1CCOCC1>[CH:122]1[C:121]([C:124]([NH:126][C@H:127]([C:133]([OH:135])=[O:134])[CH2:128][CH2:129][C:130]([OH:132])=[O:131])=[O:125])=[CH:120][CH:119]=[C:118]([NH:117][CH2:116][CH:103]2[N:104]([CH:114]=[O:115])[C:105]3[C:111]([N:110]=[C:109]([NH2:113])[NH:108][C:106]=3[NH:107][CH2:102]2)=[O:112])[CH:123]=1
Reactant: Nc1nc(=O)c2c([nH]1)NCC(CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc1)N2C=O
Agent: O=[Pt]
Agent: Nc1ccc(CN[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: Nc1nc(N)c(N)c(O)n1
Solvent: O=CO
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(=O)c2c([nH]1)NCC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)N2C=O

Procedure:
Folic acid and its salts can be prepared by any convenient method, for example 2,3-dibromopropionaldehyde, dissolved in a water miscible organic solvent (alcohol, dioxane), is added to a solution of equal molecular quantities of 2,4,5-triamino-6-hydroxypyrimidine and p-aminobenzylglutamic acid, maintaining a pH of about 4 by the controlled addition of alkali as the reaction progresses. If sodium hydroxide is used as the alkali, sodium folate is obtained. To make calcium leucovorin, folic acid is, for example simultaneously hydrogenated and formulated in 90 to 100% formic acid under the influence of platinum oxide catalyst to yield leucovorin. Conversion to the calcium salt may be accomplished by dissolving the leucovorin in sodium hydroxide solution, treating the calcium chloride, and precipitating with ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[C:15]1[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([Br:11])=[CH:13][CH:14]=1
Reactant: C#Cc1cccc(C)c1C
Reactant: SCc1ccc(Br)cc1
Agent: [Na]
Product: Cc1cccc(/C=C\C(SC(/C=C\c2cccc(C)c2C)c2ccc(Br)cc2)c2ccc(Br)cc2)c1C

Procedure:
A solution of 2,3-dimethylphenylacetylene (0.02 mol), 4-bromobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,3-dimethylstyryl-4-bromobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][N+:7]=1[O-:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccc(Cl)nc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Cl)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To methyl 2-(6-chloropyridin-3-yl)acetate (2.5 g) in DCM (100 mL) was added mCPBA (4.6 g). The resulting reaction mixture was stirred at room temperature for 4 hr. The organic phase was washed with sat. NaHCO3, dried over Na2SO4, and concentrated. The crude product was purified by flash chromatography to afford the title product (2.5 g).
Reaction SMILES: [CH:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[CH2:2]>[Pd].CO>[CH2:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CCc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Reaction time: 12 h
Yield: 73.8 %

Procedure:
A mixture of tert-butyl 9-ethenyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (349 mg, 1.27 mmol) and 10% palladium on carbon (50.0 mg) in methanol (6 ml) was stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated. The residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (260 mg, 73.9%) as an oil.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH3:29])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.CC1C2C(=NC=CC=2C2C=NC3C(C=2)=CC=CC=3)N(C2C=CC=CC=2C(N)=O)C=1>>[O:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:2]2[CH:9]=[C:8]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][C:18]([C:19]5[CH:20]=[N:21][C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[C:13]4[C:12]([CH3:29])=[CH:11]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:32][CH2:31]1
Reactant: NC1CCOCC1
Reactant: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: Cc1cn(-c2ccccc2C(N)=O)c2nccc(-c3cnc4ccccc4c3)c12
Product: Cc1cn(-c2ccc(C#N)c(NC3CCOCC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 4 %

Procedure:
According to Example 1(6), a crude product of 2-(tetrahydro-2H-pyran-4-ylamino)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile was prepared using compound (40f) instead of compound (1e) and using tetrahydro-2H-pyran-4-amine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (53) (the second stage yield: 4%) was prepared as a white solid using 2-(tetrahydro-2H-pyran-4-ylamino)-4-{(3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile instead of compound (1f). By this reaction, compound (54) (the second stage yield: 21%) was prepared as a white solid.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].C(O)(=O)C.[CH3:10][C:11]1[O:15][C:14]([CH:16]=[CH:17][CH2:18][CH2:19]O)=[CH:13][CH:12]=1.[Cl-].[Na+]>O>[CH2:17]([C:16]1[C:14](=[O:15])[CH2:13][CH:12]([OH:3])[C:11]=1[CH3:10])[CH:18]=[CH2:19]
Reactant: Cc1ccc(C=CCCO)o1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCC1=C(C)C(O)CC1=O
Reaction time: 0.58 h
Yield: 209.3 %

Procedure:
A buffer solution was prepared by dissolving sodium acetate (1.03 g) and MgCl2.6H2O (0.27 g) in water (200 ml) and adjusting the pH value to 6.0 (20° C.) with acetic acid. In a reaction vessel, 5-methyl-2-furylallylcarbinol (5 g) and the entire amount of the buffer solution as prepared above were charged, and the temperature was elevated up to 150° C. in 35 minutes while stirring. The mixture was stirred at the same temperature for 3 hours. After ice-cooling, sodium chloride (50 g) was added, and the mixture was extracted with methyl isobutyl ketone (100 ml) four times. The extract was concentrated at 60° C. under reduced pressure to remove methyl isobutyl ketone, whereby an oily substance (4.6 g) was obtained. The crude product was purified by column chromatography with silica gel (60 g) (developing solvent, ethyl acetate-n-hexane (1:2 by volume)) to obtain 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone (4.0 g). Yield, 80%.