Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].Cl.[OH-].[Na+]>O>[NH2:11][C:10]1[C:2]([Cl:1])=[C:3]([C:7]([Cl:14])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Cl)c(C(=O)O)c1Cl
Temperature: 60 °C

Procedure:
2,6-Dichloro-3-nitro-benzoic acid (10 g, 42 mmol, Step a) was added to concentrated hydrochloric acid (100 mL) followed by stannous chloride dihydrate (38 g, 169 mmol). The reaction mixture was heated at 60° C. for 1 hour. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to afford the sticky material. The sticky material (crude product) was dissolved in water (turbid solution, 200 mL) and treated slowly with aqueous sodium hydroxide (20%) solution till precipitation while maintaining the pH 1-2 (dense precipitate was observed). The precipitate was filtered and the filtrate was extracted with ethyl acetate (2×200 mL) and dried over anhydrous sodium sulphate and concentrated under vacuum to yield 3-amino-2,6-dichlorobenzoic acid as a creamish solid (6 gm, 69%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:3][C:4]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc2nc(N3CCNCC3)sc2c1

Procedure:
A mixture of 10 mmol 2,6-dichlorobenzothiazole, 12.3 mmol of piperazine and 20 mmol of potassium carbonate in 50 ml of acetonitrile was refluxed for 3 hours. The reaction mixture was concentrated and treated with 25 ml of water. Extraction with ethyl acetate, drying over magnesium sulfate, and evaporation of the solvent yielded the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH2:10][OH:11].O>C(O)C>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[N:10][OH:11])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC1(C)CCC(=O)CC1
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(=NO)CC1
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of 4,4-dimethylcyclohexanone (0.511 g, 4.049 mmol) in 95% ethanol (20 ml) was added 50% hydroxylamine in water (2.481 ml, 40.49 mmol), and the reaction was heated to reflux for 2 hours. The reaction was cooled to ambient temperature, and the product was precipitated by the addition of water. The solids were collected by vacuum filtration to yield 202 mg of the title compound (35% yield).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:9])[CH3:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[CH3:8])=[CH:14][CH:13]=1
Reactant: CC(=O)c1sccc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2ccsc2C(C)=O)cc1
Temperature: 80 °C
Yield: 45.1 %

Procedure:
A flask was charged with 1-(3-bromothiophen-2-yl)ethanone (1.00 g, 4.88 mmol), 4-methoxyphenylboronic acid (0.740 g, 4.88 mmol), tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol), dimethoxyethane (50 mL), and 2 N aqueous Na2CO3 (7.3 mL) and then warmed to 80° C. for 7 h. At that time the reaction mixture was poured into H20 and extracted with EtOAc. The organic phase was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified via flash chromatography, eluting with 5-15% EtOAc/hexanes to afford the product (0.50 g, 2.2 mmol). MS (M+H)+ 233.
Reaction SMILES: [O-2].[Mg+2].[CH:3](O)=[O:4].C(OC(=O)C)(=O)C.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16]([OH:18])=O>>[CH:3]([NH:13][C@@H:14]1[C:19](=[O:20])[O:21][C:16](=[O:18])[CH2:15]1)=[O:4]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: O=CO
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@H]1CC(=O)OC1=O
Reaction time: 0.21 h

Procedure:
Magnesium oxide (0.121 grams; 0.003 mole) was dissolved in 19.3 grams (0.4 mole) of 95% formic acid under nitrogen. Acetic anhydride (69.3 grams; 0.655 mole) was then added to the solution which was stirred for 10-15 minutes. The temperature of the mixture rose to 40° C. L-aspartic acid (39.93 grams; 0.30 mole) was added to the mixture and the resulting slurry was stirred at about 50° C. for about 6 hours. N-formyl-L-aspartic anhydride was formed at this point as shown by high performance liquid chromatography (HPLC). The mixture was then filtered and washed with 30 grams of acetic acid in order to isolate the N-formyl-L-aspartic anhydride. The yield of the N-formyl-L-aspartic anhydride from the L-aspartic acid was 80%. The N-formyl-L-aspartic anhydride will include some acetic acid, which remains for use as a solvent in the coupling step.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[NH:17]C(=O)OC>C(O)C>[F:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 110 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Ethyl alcohol (30 ml) and a 2N aqueous solution of sodium hydroxide (50 ml) were added to methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate obtained above, and the mixture was stirred For 4 hours while heating on an oil bath at 110° C. After completion of the reaction, the solvent was distilled off, and the residue was extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and the solvent was distilled off under reduced pressure to obtain oily 2-fluoro-4-chloro-5-cyclopentyloxyaniline (4.38 g, 19.0 mmol, 95.0% yield). The spectral data and the like are as shown in Reference Example 1.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[C:25]([CH3:27])[C:21]2[N:22]=[CH:23][NH:24][C:20]=2[C:19]=1[CH3:28]>CN(C)C1C=CN=CC=1.ClCl.CO>[CH3:28][C:19]1[C:20]2[NH:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:27])=[CH:26][C:18]=1[N:17]=[C:8]=[S:9]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1cc(N)c(C)c2[nH]cnc12
Agent: CN(C)c1ccncc1
Agent: ClCl
Solvent: CO
Product: Cc1cc(N=C=S)c(C)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (2.29 g) and 4-dimethylaminopyridine (0.03 g) in CH2 Cl2 (150 mL) is added dropwise over 30 minutes a solution of 5-amino-4,7-dimethylbenzimidazole (0.816 g) in methanol (50 mL). The mixture is stirred for 3 hours at room temperature, then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with a gradient of 50% to 80% ethyl acetate/hexane to afford 4,7-dimethyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.Cl.[NH2:14][OH:15].C(O)(=O)C>O>[Cl:1][C:2]1[C:7]([CH:8]=[N:14][OH:15])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc(Cl)c(C=NO)c(Cl)n1
Temperature: 60 °C

Procedure:
4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (7.34 g, 33.09 mmol), hydroxylamine hydrochloride (2.31 g, 33.33 mmol), acetic acid (49.6 mL), and water (3.3 mL) were mixed, and heated to 60° C. for 2 hours. The reaction mixture was diluted with water and cooled under ice bath. The precipitate was collected and dried (Yield=6.41 g, 82%). MS (m/z): 238 (M+H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]1([CH3:21])[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:20][C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:21])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilyl chloride (83.6 g, 0.55 mol) and imidazole (78.69 g, 1.15 mol) were added to a solution of o-cresol (50 g, 0.46mol) in dry DMF (200 mL). The reaction mixture was stirred for 3 h, treated with a 5% aqueous NaHCO3 solution, extracted with petroleum ether and concentrated to obtain the title compound as an oil. Yield: 102 g, (100%); 1H NMR (CDCl3): δ 0.20 (s, 6H, 2CH3), 1.0 (s, 9H, 3CH3), 2.2 (s, 3H, CH3), 6.75 (d, 1H, Ar), 6.85 (q, 1H, Ar), 7.18 (q, 1H, Ar), 7.25 (d, 1H, Ar).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29])=[O:24])(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 25 °C
Yield: 74.6 %

Procedure:
Piperidine (0.96 mL, 9.7 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (1.6 g, 9.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.9 g, 8.6 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 4 h, then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5.0 mL) and water (2.0 mL) at 40° C. and the solution was acidified with concentrated HCl. The precipitate was filtered, providing (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (tranilast) (2.1 g, 74%) as a yellow crystalline solid; mp 208-209° C., lit.2 206° C.; δH (500 MHz, DMSO-d6) 3.79 (s, 3H, OCH3), 3.82 (s, 3H; OCH3), 6.79 (d, J=15.5 Hz, 1H, CH═CHCO), 6.99 (d, J5′,4′=8.5 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=7.9 Hz, 1H, H4), 7.25 (d, J5′,6′=8.5 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.56 (d, J=15.5 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=7.9 Hz, 1H, H5), 8.00 (d, J3,4=7.9 Hz, 1H, H3), 8.62 (d, J5,6=7.9 Hz, 1H, H6), 11.30 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OCC(C)(C)CO2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Br[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:22]#[N:23])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: N#Cc1ccccc1Br
Reactant: CC1(C)COB(c2cc(F)cc([N+](=O)[O-])c2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cc(F)cc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 72.1 %

Procedure:
A mixture of 2-(3-fluoro-5-nitrophenyl)-5,5-dimethyl-[1,3,2]dioxaborinane (15 g, 59 mmol) and 2-bromobenzonitrile (12.4 g, 68.2 mmol) in 1,2-dimethoxyethane (125 ml) and 2M aqueous sodium carbonate (50 ml) was degassed with nitrogen for 30 min then treated with tetrakis(triphenylphosphine)palladium(0) (2.06 g, 1.8 mmol). The reaction was then heated at 90° C. for 16 h, cooled to ambient temperature and partitioned between ethyl acetate and water. The organics were washed with brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by dry flash chromatography on silica, eluting with isohexane (containing 1% methanol) on a gradient of ethyl acetate (10-40%) afforded 3′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a cream-coloured solid (10.3 g, 72%): δH (400 MHz, CDCl3) 7.54-7.61 (2H, m), 7.65 (1H, ddd, J 8, 2 and 2), 7.74 (1H, ddd, J 8, 8 and 2), 7.84 (1H, dd, J 8 and 2), 8.03 (1H, ddd, J 8, 8 and 2), 8.22-8.24 (1H, m).
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].C(N(C(C)C)CC)(C)C>O1CCCC1>[O:3]1[CH2:4][CH2:5][N:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=3[N+:27]([O-:29])=[O:28])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N[C@H]2CC[C@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of EXAMPLE 324J (1.00 g) and 4-fluoro-3-nitrobenzenesulfonamide (0.90 g) in tetrahydrofuran (15 mL) was added diisopropylethylamine (4.75 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered and the solid washed with dichloromethane. The reaction mixture was combined with the washings were concentrated. The resulting solid was triturated with dichloromethane and filtered to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.Cl[CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:22][C:23]2[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2.8 g), ethyl 5-chloromethyl-2-furancarboxylate (1.8 g), sodium hydrogencarbonate (1 g) and N,N-dimethylformamide (120 ml) was heated while stirring at 80° C. for 12 hours. The mixture thus obtained was concentrated under reduced pressure. To the resultant residue, water was added. After extraction was performed with ethyl acetate, an organic phase was dried over anhydrous sodium sulfate and evaporated. The resultant residue was purified by column chromatography to obtain a target substance (0.8 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[CH2:29][C:30]1[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:29][C:30]2[O:34][C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:32][CH:31]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Reaction time: 10 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2 g), triethylamine (0.76 g), ethyl 5-chloromethyl-2-furancarboxylate (1.4 g) and toluene (60 ml) was heated to reflux while stirring for 10 hours. The mixture thus obtained was concentrated under reduced pressure. After the resultant residue was washed with water added thereto, an organic phase was dried over anhydrous sodium sulfate and evaporated. The resultant residue was purified by column chromatography to obtain a target substance (0.6 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[S:1]1[C:5]([CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:17])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1ccccc1
Product: OC(c1ccccc1)c1cc2ccccc2s1

Procedure:
Using general procedure B, benzo[b]thiophene was reacted with benzaldehyde to give benzo[b]thiophen-2-yl-phenyl-methanol as a colorless solid. MS: 223.1 ([M+H—H2O]+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH2:17]([NH2:19])[CH3:18].O1CCCC1.[BH4-].[Na+]>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:19][CH2:17][CH3:18]
Reactant: CCN
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 20 ml of methanol was dissolved 24.5 g of 3,5-bistrifluoromethylbenzaldehyde, and under ice-cooling, added thereto was 60 ml of ethylamine (a 2M tetrahydrofuran solution). Subsequently, 4.38 g of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added distilled water and concentrated under reduced pressure. The residue was extracted with dichloromethane, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→chloroform:methanol=9:1), to give 6.35 g of N-(3,5-bistrifluoromethylbenzyl)-N-ethylamine as shown in Table 135 below.
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.CN(C)C(=O)C.[C:26]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])#[N:27].[H-].[Na+]>O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:27]=[C:26]([N:28]([S:29]([CH3:32])(=[O:31])=[O:30])[CH3:33])[N:1]=2)=[CH:4][CH:5]=1
Reactant: CN(C#N)S(C)(=O)=O
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reaction time: 6 h
Yield: 29.1 %

Procedure:
2.66 g (10.0 mmol) of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate were introduced into 12 g of N,N-dimethylacetamide together with 2.70 g (20.0 mmol) of N-cyano-N-methylmethanesulphonamide. 440 mg (11.0 mmol) of sodium hydride (60% in oil) were added to this solution at room temperature over the course of 2 h. An orange-red clear solution was obtained. After 6 h at room temperature, the reaction solution was poured onto 25 ml of water. The suspension was stirred in an ice bath for 30 minutes, and the precipitate was filtered off and washed with water (2×10 ml). After drying in a high vacuum, 1.11 g (29.1%) of methyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate were obtained in the form of a pale beige solid. The product still contained traces of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate.
Reaction SMILES: O.[OH-].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:3]1([CH2:9][CH:10]([OH:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(O)Cc1ccccc1
Temperature: 80 °C

Procedure:
In a 4 liter three-necked flask fitted with a mechanical stirrer and a reflux condenser, were placed 1500 ml of water, 150 g ofsodium hydroxide (pellets), 190 ml of ethanol and 180 g of phenylacetone. The mixture was stirred and heated to 80° C., and 150 g of Raney alloy was added very cautiously by small amounts over about 1 hour. During the addition, heating was discontinued and the temperature was maintained at 85°-87° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C[C:14]([N:16](C)C)=O>>[CH:5]([C:4]1[CH:3]=[C:2]([C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=1)[C:14]#[N:16])=[O:6]
Reactant: COc1cc(C=O)cc(Br)c1O
Reactant: CC(=O)N(C)C
Product: COc1cc(C=O)cc(C#N)c1O

Procedure:
A mixture of 23.1 g of 3-bromo-4-hydroxy-5-methoxy benzaldehyde, 9.3 g of cuprous cyanide and 140 ml of dimethyl acetamide (DMA) was refluxed for 2 hours with stirring. After cooling, the mixture was poured over ice and extracted with an ethyl acetate—methanol mixture (90-10). The organic phase was washed and dried and the solvents were eliminated to obtain 18 g of crude product, which was used as is for the following step. It melted at 180° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(OC(=O)C)(=O)C.[Br:16]Br.S([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:16][C:5]1[CH:4]=[CH:3][C:2]([NH2:7])=[C:1]([NH2:8])[CH:6]=1
Reactant: Nc1ccccc1N
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1ccc(Br)cc1N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A mixture of o-phenylenediamine (5 g, 46.2 mmol), acetic acid (40 ml) and acetic anhydride (10.4 g, 102 mmol) was cooled in ice water, to which a solution of bromine (8.9 g, 55.4 mmol) in acetic acid (10 ml) was added and the reaction mixture was stirred for 40 minutes at 50°-55° C. and then the mixture was poured into a solution of sodium hydrogensulfite (1.5 g) in ice water (300 ml).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Br:11]Br.C(O)C.[O-]CC.[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([Br:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: BrBr
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(Br)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1H-Pyrrole-2-carboxylic acid ethyl ester (10 g) was dissolved in carbon tetrachloride (50 ml). A carbon tetrachloride solution (50 ml) of bromine was added dropwise thereto on ice over 30 minutes. The reaction mixture was stirred at 25° C. for one hour. The suspension of reaction mixture was added dropwise to an ethanol solution (100 ml) of 10% sodium ethoxide on ice over 20 minutes. The solvent was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (40 ml) and water (20 ml). The organic layer was washed with an aqueous solution saturated with sodium chloride (10 ml), and then concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane/ethyl acetate). Thus, a brown solid was obtained (10 g, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: OC1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: OC1CCN(c2ccc(Br)cn2)CC1
Reaction time: 3 h

Procedure:
In 100 ml of 1-methyl-2-pyrrolidone was dissolved 10 g of 2,5-dibromopyridine which was then added with 5.2 g of 4-hydroxypiperidine, along with 17.5 g of potassium carbonate at room temperature. Reaction was conducted at 100° C. for 3 hours with stirring. After completion of the reaction, the same post-treatment as in Preparation Example 13 was carried out to obtain the title compound. 9 g.