Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH2:27])[CH2:16][CH2:15]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:28](=S)=[S:29].[OH-].[K+].[ClH:33]>O.C(O)C>[ClH:33].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13][N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[NH:27][C:28]4=[S:29])[CH2:18][CH2:19]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1NC1CCN(CC2COC(c3ccc(F)cc3)C2)CC1
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1ccc(C2CC(CN3CCC(n4c(=S)[nH]c5ccccc54)CC3)CO2)cc1
Reaction time: 3.5 h

Procedure:
A mixture of 13.7 g of 1-[2-(4-fluorophenyl)-tetrahydro-4-furylmethyl]-4-(2-aminoanilino)piperidine, 18 g of carbon disulfide and 4.2 g of potassium hydroxide is heated under reflux with stirring for 3.5 hours and then cooled. To the mixture are added 200 ml of ethanol, 126 ml of water and 32 ml of concentrated hydrochloric acid, and the whole is heated under reflux for 20 minutes. The solvent is then distilled off under reduced pressure. The residue is made alkaline with aqueous ammonia and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant. To the thus obtained oil is added ethanolic hydrochloric acid. The crystals precipitated are collected by filtration and recrystallized from methanol-isopropyl ether to give 1-[1-(2-(4-fluorophenyl)-tetrahydro-4-furylmethyl)-4-piperidyl]benzimidazoline-2-thione hydrochloride as colorless needles, melting at 269°-270° C. with decomposition.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:6][O:7][C:8]=1[C:9]([OH:11])=O)[CH2:2][CH3:3].[Li].O[N:20]=[C:21]([C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)[NH2:22].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1.C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([C:4]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:6][O:7][C:8]=1[C:9]1[O:11][N:22]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([CH2:27][N:28]3[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]3)=[CH:39][CH:40]=2)[N:20]=1)[CH2:2][CH3:3]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Reactant: CCCc1c(-c2ccccn2)noc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C1CN(Cc2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1c(-c2ccccn2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1

Procedure:
A mixture of 4-propyl-3-(pyridin-2-yl)isoxazole-5-carboxylic acid, lithium salt (13.5 mg, 0.058 mmol), tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (7.8 mg, 0.058 mmol), HOBt (16.02 mg, 0.105 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (26.1 mg, 0.136 mmol), and diisopropylethylamine (0.041 mL, 0.233 mmol) in acetonitrile (1 mL) was stirred at 80° C. for 2 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (3 mL), washed a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by preparative HPLC afforded tert-butyl 1-(4-(5-(4-propyl-3-(pyridin-2-yl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1C(O)=O.Cl.[NH2:15]O>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:15]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: NO
Agent: Cl
Product: Nc1ccc2ccccc2c1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 33.1 %

Procedure:
Polyphosphoric acid (7.5 g) was added to a mixture of 2-naphthoic acid (600 mg, 3.48 mmol) and hydroxylamine hydrochloride (254 mg, 3.66 mmol) at room temperature and heated slowly to 160° C. The reaction mixture was stirred for 90 min and then allowed to cool to ambient temperature and quenched with crushed ice (50 g). The resultant solid was filtered and washed with water (2×20 mL). The combined filtrate and washings were basified with 10% potassium hydroxide solution (100 mL). The precipitated solid was filtered, washed with water (2×25 mL), petroleum ether (2×20 mL), diethyl ether (2×20 mL) and dried in vacuo to afford naphthalen-2-amine (165 mg, 34%) as a light pink solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][S:2][C:3]1[O:7][C:6]([CH:8]=[N:11][OH:12])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=O)o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(C=NO)o1
Temperature: 23 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
To a solution of 5-(methylthio)furan-2-carbaldehyde (1.0 g, 7.04 mmol) in ethanol (10 mL) was added an aqueous solution of hydroxylamine hydrochloride (3.75M) (2.26 mL, 8.45 mmol) and an aqueous solution of sodium acetate (1.5 M) (3.78 mL, 5.63 mmol). The reaction mixture was stirred a 23° C. for 18 hours. The ethanol was concentrated in vacuo, H2O was added (50 mL) and the precipitate was filtered and dried in oven (60° C.) for 10 minutes to afford 277 mg (25%) of the title compound. LCMS (+ESI, M+H+) m/z 158.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]O)[CH:2]=1.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH3:15])[CH:2]=1
Reactant: OCc1cccnc1
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccccc1Cc1cccnc1

Procedure:
A quantity of 1.2 g 3-pyridyl carbinol in 15 ml 1.8 M aluminum chloride in nitrobenzene was reacted with 10 ml of toluene during 3 days at 80° C. The reaction mixture was poured on HCl/ice and extracted with toluene. The organic phase was washed with water, dried and the solvent was evaporated. The desired product was obtained as viscous oil, containg 8.5% nitrogen.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1>>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[N:3]1[CH2:4][C@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[O:1][C:2]1=[O:13]
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1ccco1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccco1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-bromofuran. The title compound (1.49 g) was obtained as a pale-yellow solid, m/z 249 (MH+).
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:3]=1[CH2:4][N:5]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15](C(F)(F)F)[CH:14]=1)[C:6]1[N:7]=[N:8][N:9]([CH3:11])[N:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C[N:42]([CH3:46])C(=O)C>C(OCC)C.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.O.O.O.[K+].[K+].[K+].[Fe+3].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:19]([F:22])([F:20])[C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=1)[CH2:12][N:5]([CH2:4][C:3]1[CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=[CH:30][C:2]=1[C:46]#[N:42])[C:6]1[N:7]=[N:8][N:9]([CH3:11])[N:10]=1
Reactant: CC(=O)N(C)C
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2Br)n1
Agent: [Fe+3]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C#N)n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
A mixture of N-(2-bromo-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (10.4 g; 18.5 mmol), potassium hexacyanoferrate trihydrate (1.9 G; 4.49 mmol) and sodium carbonate (2.4 g; 22.6 mmol) was stirred in N,N-dimethylacetamide (32 mL). Palladium acetate was added (0.48 g; 2.13 mmol). The reaction was stirred at 120° C. for 16 hours. The reaction was diluted with diethyl ether and filtered over a pad of silica gel and celite. The mother liquor was washed with water (3×) and brine. It was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified over a 330 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-30% ethyl acetate in heptane) to give 8.45 g (89.9%) of title compound as a tan solid. MS (ES+): Calc: 508.3, Found: 509.2 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.76 (s, 1H), 7.75 (d, J=8.30 Hz, 1H), 7.68 (s, 3H), 7.62 (dd, J=8.30 Hz, 1H), 4.96 (s, 2H), 4.89 (s, 2H), 4.22 (s, 3H).
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:17][CH:16]1[CH:18]1[CH2:20][CH2:19]1)C1C=CC=CC=1>O1CCCC1.[Pd]>[CH:16]1([CH:18]2[CH2:20][CH2:19]2)[CH2:17][CH:15]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: c1ccc(CNc2ccccc2C2CC2C2CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccccc1C1CC1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
1 g of benzyl(2-bicyclopropyl-2-yl-phenyl)amine (3.8 mmol, trans/cis ratio of about 3:1) is dissolved in 15 ml of absolute tetrahydrofuran. Then 50 mg of Pd (5%) on activated carbon are added. Hydrogenation is then carried out, with stirring, for 1 hour at room temperature. After completion of the reaction, the catalyst is filtered off and the solvent is removed using a water jet vacuum. The product is purified by chromatography on silica gel (eluant:ethyl acetate/hexane 1/15). 0.61 g of 2-bicyclopropyl-2-ylphenylamine (92% of theory) is obtained in the form of a brownish liquid (trans/cis ratio of about 3:1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C1(OC)C=CC=CC=1.C([NH:35][C:36]1[S:37][CH:38]=[C:39](/[C:41](=[N:73]/[O:74]CC2C=CC(OC)=CC=2OC)/[C:42]([NH:44][C@@H:45]2[C:71](=[O:72])[N:47]3[C:48]([C:59]([O:61]CC4C=CC(OC)=CC=4)=[O:60])=[C:49]([S:52]/[CH:53]=[CH:54]\[C:55]([O:57][CH3:58])=[O:56])[CH2:50][S:51][C@H:46]23)=[O:43])[N:40]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>CCCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:35][C:36]1[S:37][CH:38]=[C:39](/[C:41](=[N:73]/[OH:74])/[C:42]([NH:44][C@@H:45]2[C:71](=[O:72])[N:47]3[C:48]([C:59]([OH:61])=[O:60])=[C:49]([S:52]/[CH:53]=[CH:54]\[C:55]([O:57][CH3:58])=[O:56])[CH2:50][S:51][C@H:46]23)=[O:43])[N:40]=1
Reactant: COC(=O)/C=C\SC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](NC(=O)/C(=N\OCc3ccc(OC)cc3OC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: CCCCCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)/C=C\SC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Reaction time: 0.67 h

Procedure:
To a mixture of 3.5 ml of trifluoroacetic acid and 0.7 ml of anisole was added under ice-cooling 250 mg (0.25 mM) of 4-methoxybenzyl 7β-{2-(2-tritylaminothiazol-4yl)-2-[(Z)-2,4-dimethoxybenzyloxyimino]acetamido}-3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylate, and the mixture was stirred for 40 minutes and then at room temperature for 10 minutes. After the reaction, the reaction solution was slowly added dropwise to a mixture of diethyl ether and n-hexane (1:2, 30 ml), and the formed crystals were collected by filtration to give 150 mg of 7β-{2-(2-aminothiazol-4-yl)-2-[(Z)-hydroxyimino]acetamido}-3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylic acid trifluoroacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]2[CH:9]=[C:8]([C:11]([NH:13][CH2:14][CH:15]=[CH2:16])=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH3:18]>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]1[C:10]2[CH2:9][CH2:16][C@H:15]3[C@@H:8]([C:11](=[O:12])[NH:13][CH2:14]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH3:18]
Reactant: C=CCNC(=O)C1=Cc2c1ccc(OC)c2OC
Solvent: Clc1ccccc1Cl
Product: COc1ccc2c(c1OC)CC[C@@H]1CNC(=O)[C@@H]21
Yield: 51.9 %

Procedure:
A solution of 3,4-dimethoxy-N-(2-propenyl)benzocyclobutene-1-carboxamide (13.2 g, 0.053 mole) and o-dichlorobenzene (600 mL) was stirred at reflux for 15 hours. After cooling to 0°, a solid was filtered, washed with hexane, and dried (in-vacuo) to yield 6.8 g white solid. cis And trans isomers were separated by HPLC to obtain: 1.80 g trans isomer; mp 185°-7°; M+ 247; and 3.50 g cis isomer; mp 219°-21°; M+ 247.
Reaction SMILES: OS(O)(=O)=O.O.[CH2:7]([OH:9])[CH3:8].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18](=[CH2:22])[C:19](N)=[O:20]>C(Cl)Cl.[Cu]>[CH2:7]([O:9][C:19](=[O:20])[C:18]([C:12]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=1[Cl:10])=[CH2:22])[CH3:8]
Reactant: CCO
Reactant: C=C(C(N)=O)c1ccc(Cl)cc1Cl
Agent: [Cu]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: C=C(C(=O)OCC)c1ccc(Cl)cc1Cl
Temperature: 100 °C

Procedure:
Add the cyanohydrin prepared in Example 5(a), 2,4-dichloroacetophenone cyanohydrin-O-trimethylsilylether, (75 g) dropwise to a solution of concentrated H2SO4 containing 4% SO3 (60 mL) and 250 mg of copper powder at 40° C. During the addition, maintain the reaction temperature between 80°-85° C. (water bath). After all cyanohydrin is added, raise the temperature to 100° C. and heat the reaction mixture at this temperature for 30 min. Cool the reaction mixture to 90° C. and carefully treat with water (26 mL) and ethanol (60 mL). Heat the mixture at 100° C. for 15 hrs, cool and dilute with ice cold water (200 mL). Separate the organic layer, dilute with CH2Cl2 (100 mL) and wash with brine (100 mL). Extract the combined aqueous phase containing solids twice with EtOAc (400 mL), wash with saturated NaHCO3, water (100 mL each) and dry over Na2SO4. Eyaporate EtOAc in vacuo to give an oil containing a crystalline solid. Dilute this residue with a small yolume of CH2Cl2 -separated crystals of α-(2,4-dichlorophenyl)-α-methyleneacetamide which were collected by filtration (26 g). Combine the filtrate with the organic layer obtained earlier and chromatograph the concentrate on silica gel (300 g) to provide ethyl-α-(2,4-dichlorophenyl)-α-methyleneacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:28])=[O:6].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[C:16]([F:17])([F:18])[F:19])=[CH:10][C:9]=1[CH3:28])=[O:6])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-amino-N-{2,6-dimethyl-4-[2,2,2-trifluoro-1-(4-fluoro-phenyl)-1-hydroxy-ethyl]-phenyl}-benzamide (0.064 g, 0.15 mmol) (Example I4) in absolute dichloromethane (2 ml), at 20° C., was added a solution of benzoyl chloride (0.021 g, 0.15 mmol) in dichloromethane (0.5 ml). After 10 minutes, the suspension was treated with a solution of pyridine (0.016 g, 0.2 mmol) in dichloromethane (0.5 ml). The solution was stirred at 20° C. for 2 hours. The reaction mixture was quenched by addition of water (2 ml) and a few drops of aqueous hydrochloric acid (1M). The phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were dried over sodium sulfate, filtered through a plug silica gel which was further washed with ethyl acetate and concentrated. The residue was triturated in hexanes, filtered, washed with pentane and dried to yield the title compound as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15]Br>CC(O)=O>[C:1]([C:5]1[NH:6][C:7]2[C:13]([Br:15])=[C:12]([NH2:14])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2ccc(N)cc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)c1nc2ccc(N)c(Br)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 0.53 g (2.8 mmol) of 2-tert-butyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.05 ml (1.0 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (CHCl3, neat) to yield 0.18 g (0.67 mmol, 67%) of the desired product.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH3:10]>C1C=CC=CC=1>[CH:9]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:10])[CH3:8].[C:1]1([CH:9]([CH3:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: C=CC
Solvent: c1ccccc1
Product: CC(C)c1ccccc1

Procedure:
The phenol producing apparatus 10, from an upstream side (the left side in the drawing), has a reaction tower 11 in which benzene reacts with propylene as raw materials to form so-called cumene isopropylbenzene, an oxidation tower 14 which oxidizes therein the cumene via a benzene tower 12 and a cumene tower 13 to form cumene hydroperoxide (CHP), a sodium removing apparatus 30 which separates and removes sodium mixed into for neutralization , a concentration tower 15 which concentrates cumene hydroperoxide, a sodium removing apparatus 31 provided on the way back from the concentration tower 15 to the upstream side of the oxidation tower 14, a disintegration tower 16 which disintegrates the concentrated cumene hydroperoxide by an acid material to form coarse phenol and coarse acetone, a sodium removing apparatus 32, and a coarse acetone tower 17, a refined acetone tower 18, a phenol tower 19 which are each kinds of distilled tower for separating and refining phenol and acetone.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:20](OCC)=O)[N:14]2[CH2:17][C:18]#[N:19])=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]=[C:13]3[CH2:20][NH:19][CH2:18][CH2:17][N:14]3[C:15]=2[N:16]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)nc2n1CC#N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: Clc1ccc2cc3n(c2n1)CCNC3
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a stirred suspension of lithium aluminum hydride (0.16 g, 4.2 mmol) in ether (20 mL) at 0° C. under Ar was added ethyl 6-chloro-1-(cyanomethyl)-7-azaindole-2-carboxylate (0.45 g, 1.7 mmol). The mixture was heated under reflux for 18 h, cooled to room temperature and treated with sodium sulfate decahydrate (2.8 g, 8.4 mmol). The mixture was stirred for 30 nun, filtered through kieselguhr, concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-methanol (9:1)] to give the product as a yellow oil (0.10 g, 27%). IR νmax (Nujol)/cm−1 3230, 2925, 2855, 1594, 1561, 1528, 1466, 1429, 1397, 1342, 1306, 1257, 1121, 1100, 1022, 948, 901, 874, 822, 810, 746, 546 and 509; NMR δH (400 M CDCl3), 3.31 (2H, t, J 6 Hz), 4.15 (2H, t, J 6 Hz), 4.19 (2H, s), 6.11 (1H, s), 7.03 (1H, d, J 8 Hz), 7.72 (1H, d, J 8 Hz)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11](CC3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43]Br)[CH:38]=1>>[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:11]2[C:10](=[O:33])[CH:9]=[C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@@H:2]([NH2:1])[CH2:3]3)[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12]2=[O:23])[CH:38]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: COC(=O)c1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1

Procedure:
Title compound 24 was prepared by the methods used in the preparation of compound 17, except that 3-bromomethyl-benzoic acid methyl ester was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.99 (s, 1 H), 7.91 (d, J=7.8 Hz, 1 H), 7.65 (d, J=7.6 Hz, 1 H), 7.56 (d, J=7.9 Hz, 1 H), 7.52 (d, J=7.6 Hz, 1 H), 7.39 (t, J=7.6 Hz, 1 H), 7.34 (t, J=7.6 Hz, 1 H), 7.23 (d, J=8.1 Hz, 1 H), 5.44 (s, 1 H), 5.12-5.31 (ABq, J=43.7, 15.9 Hz, 2 H), 5.08 (s, 2 H), 3.90 (s, 3 H), 3.31-3.39 (m, 2 H), 2.98 (d, J=11.9 Hz, 1 H), 2.87 (m, 1 H), 2.71 (m, 1 H), 2.11 (m, 1 H), 1.89 (m, 1 H), 1.73-1.59 (m, 2 H). MS (ES) [m+H] calc'd for C26H28N5O4, 474.2. found 474.2.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15](OC3C=CC=CC=3)=[S:16])[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O1CCOCC1>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[S:16])[C:11]([N:24]3[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:10][C:8]=2[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)Oc2ccccc2)CC1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)N2CCN(C)CC2)CC1

Procedure:
A solution of 0.5 g of 2-tert-butyl-5-(4-methyl-piperidin-1-yl)-6-phenoxythiocarbonylaminobenzothiazole and 0.11 g of 4-methylpiperazine in 20 ml of dioxane is refluxed for 16 hours. Evaporation of the solvent and chromatography of the residue over silica gel and elution with methylene dichloride-methanol (98:2) gives 2-tert-butyl-6-[(4-methylpiperazin-1-yl)thiocarbonylamino]-5-(4-methylpiperidin-1-yl)benzothiazole, identical with the compound described in Example 1.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: OCc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccc(Cn2nc(-c3ccccc3)cc2-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A mixture of 3,5-diphenylpyrazole (7.32 g, 33 mmol), [4-(chloromethyl)phenyl]methanol (5.00 g, 32 mmol), potassium carbonate (6.90 g, 50 mmol) and N,N-dimethylformamide (50 mL) was stirred at 120° C. for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (7.10 g, yield 63%) as colorless crystals.
Reaction SMILES: ClC1N=CC2C(=O)N3N=CC=C3NC=2C=1.CI.[Cl:18][C:19]1[N:28]=[CH:27][C:26]2[C:25](=[O:29])[N:24]3[N:30]=[C:31](C)[CH:32]=[C:23]3[N:22]([CH3:34])[C:21]=2[CH:20]=1>>[Cl:18][C:19]1[N:28]=[CH:27][C:26]2[C:25](=[O:29])[N:24]3[N:30]=[CH:31][CH:32]=[C:23]3[N:22]([CH3:34])[C:21]=2[CH:20]=1
Reactant: Cc1cc2n(C)c3cc(Cl)ncc3c(=O)n2n1
Agent: O=c1c2cnc(Cl)cc2[nH]c2ccnn12
Solvent: CI
Product: Cn1c2cc(Cl)ncc2c(=O)n2nccc12
Yield: 76 %

Procedure:
By treating 6-chloropyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 1 with methyl iodide according to the procedure of Example 5 for the preparation of 6-chloro-2,4-dimethylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one, 6-chloro-4-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is obtained, yield: 76%; m.p. >300°.