Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:12][CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][S:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:28])=[O:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCCCO)c1cc(F)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
The 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-1-pentanol (115 mg, 0.307 mmol) obtained in Example 29, t-butyl N-methylsulfonylcarbamate (120 mg, 0.614 mmol), and triphenylphosphine (163 mg, 0.614 mmol) were dissolved in tetrahydrofuran (3 ml). At room temperature, diisopropyl azodicarboxylate (120 μl, 0.614 mmol) was added to the resulting solution. After stirring the resulting mixture for 18 hours at room temperature, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated, whereby the title compound (168 mg, 0.304 mmol, 99%) was obtained as a colorless amorphous substance.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[NH2:20][C:21]1[S:25][CH:24]=[C:23]([C:26]#[N:27])[C:22]=1[C:28]1[N:29]=[CH:30][S:31][CH:32]=1>>[C:26]([C:23]1[C:22]([C:28]2[N:29]=[CH:30][S:31][CH:32]=2)=[C:21]([NH:20][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:24]=1)#[N:27]
Reactant: N#Cc1csc(N)c1-c1cscn1
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-c1cscn1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.047 g, 0.17 mmol) and 5-amino-4-(thiazol-4-yl)thiophene-3-carbonitrile (0.024 g, 0.12 mmol) according to protocol A. The desired product was submitted to prep HPLC for further purification. Retention time (min)=7.57, method [7], MS(ESI) 461.1 (M+H). 1H NMR (CDCl3) δ 12.73 (s, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.92-7.89 (m, 2H), 7.89 (d, J=9.3 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J=8.9 Hz, 1H), 6.96 (d, J=9.3 Hz, 1H), 5.30 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:15]=[C:14]([CH3:16])[S:13][C:4]=2[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22]N[CH2:20][CH2:19]1.CC(O)C>O>[CH3:16][C:14]1[S:13][C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=[C:2]([N:1]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)[C:3]=2[CH:15]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: CC(C)O
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 102 °C
Yield: 86.5 %

Procedure:
4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepine (100 g, 0.38 mol), N-methylpiperazine (250 mL, 2.5 vol) and 2-propanol (200 mL, 2 vol) were charged into a three-necked round bottom flask equipped with reflux condenser, overhead stirrer, and thermometer. The reaction mixture was heated to reflux at 102° C. under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to below 55° C. whereupon water (250 mL, 2.5 volumes) was added to precipitate out the solid. The light yellow solid was isolated by Buchner filtration and twice washed with 25% aqueous 2-propanol (100 mL) and then once with 2-propanol (100 mL). It was dried in vacuo to provide olanzapine in 86.5% yield (101.7 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][N:2]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:3][N:2]=1
Reactant: NC1CCCC1
Reactant: O=C(Nc1ccnnc1)Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccnnc1)NC1CCCC1

Procedure:
A stirred solution of 2.0 grams (0.009 mole) of phenyl N-(4-pyridazinyl)carbamate and 1.0 ml of cyclopentylamine in tetrahydrofuran was heated under reflux for 18 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel. Elution was accomplished with 10% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure to yield 0.2 gram of N-(4-pyridazinyl)-N'-cyclopentylurea. This material were combined with the identical product from a previous reaction to yield 0.5 gram; m.p. 192°-195° C. dec. The nmr spectrum was consistent with the proposed structure. The reaction was repeated several times.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1NC1CCCCC1
Yield: 61.5 %

Procedure:
51.5 g (0.27 mol) of 2,5-dichloronitrobenzene, 22.3 g (0.27 mol) of cyclohexylamine, 74.6 g (0.54 mol) of potassium carbonate and 0.5 g of 18-crown-in 300 ml of dimethylformamide were heated at 100° C. for 4 h. The mixture was then poured into water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from i-propanol, resulting in 42.3 g (62%) of the product. Melting point 101°-103° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].[C:25]1([CH2:31][CH2:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:23]([O:22][C:19](=[O:21])[CH2:20][C:33]([OH:37])([CH2:32][CH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:34][CH2:35][CH3:36])[CH3:24]
Reactant: CCCC(=O)CCc1ccccc1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (32.2 ml, 230 mmol) in tetrahydrofuran (240 ml) at −58° is added 2.63 M n-butyl lithium in hexane (87.4 ml, 230 mmol) over one hour. Ethyl acetate (21.4 ml, 220 mmol) is then added and the reaction mixture stirred for 1 hour during which time the reaction mixture was cooled to −70°. 1-Phenyl-3-hexanone (I, 35.2 g, 200 mmol) is added slowly over 30 minutes and the reaction mixture stirred cold for 1 hour. The mixture was quenched with aqueous ammonium chloride (100 ml) and warmed to 20-25°. The mixture is then acidified with hydrochloric acid (4 M). The desired product is extracted into methyl t-butyl ether dried over magnesium sulfate and concentrated to give the title compound, TLC Rf=0.71 (ethyl acetate/hexane, 30/70); NMR (CDCl3) 7.28-7.12, 4.13, 3.60, 2.73-2.63, 2.50, 1.83-1.77, 1.58-1.53, 1.41-1.36, 1.24 and 0.93 L; CMR (CDCl3) 173.0, 143.2, 128.5, 128.4, 128.3, 128.1, 125.8, 72.8, 60.6, 42.9, 41.3, 30.1, 17.0, 14.6 and 14.2 L; MS (CI, ammonia) m/z (relative intensity) 282 (100), 264 (63), 247 (10), 194 (13), 172 (5), 159 (5).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.[BH4-].[Na+].CO.O>C1COCC1>[CH3:1][C:2]1([CH3:10])[CH2:3][CH:4]([OH:5])[CH2:6][CH:7]([OH:8])[CH2:9]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CC(O)CC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
14.0 g (0.1 mol) of dimedone were dissolved in 200 ml of THF. 3.8 g (0.1 mol) of NaBH4 and 5 mmol of CeCl3 dissolved in 50 ml of THF were then added at -30° C. The mixture was stirred at room temperature for another 2 hours and was hydrolyzed at 0° C. by means of methanol/water. The organic phase was separated off and the solvent was removed. The residue was extracted with ethanol and unreacted dimedone was removed by crystallization. This gave 11.5 g (80%) of 5,5-dimethylcyclohexane-1,3-diol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:18]=[C:19]([NH:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:20]=2)[C:14]([O:16]C)=[O:15])[CH3:9])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:18]=[C:19]([NH:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:20]=2)[C:14]([OH:16])=[O:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C[C@H](Nc1cc(C(=O)O)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 33.3 %

Procedure:
To 500 mg of methyl (S)-2-[1-(4-fluorophenyl)ethylamino](pyrazin-2-ylamino) isonicotinate (Example 134), was added 5 ml of methanol, and 2.7 ml of 2N sodium hydroxide aqueous solution was added subsequently, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate and water, and subjected to extraction, and 2N hydrochloric acid was added to the aqueous layer. The precipitated solid was filtered, and dried under reduced pressure to obtain 160 mg of the objective compound as white powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:38][CH:39]=1
Reactant: CCOC(=O)CCc1c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc3ccccc3c2CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a mixture of ethyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]propionate (1.16 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (1.03 g, 94%) of 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-1-naphthyl]propionic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 161-162° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#N)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1.Cl.[OH-:24].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:11]([C:12]([C:17]2[CH:18]=[CH:19][C:14]([CH3:22])=[CH:15][CH:16]=2)=[O:24])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1cc2ccccc2nc1N
Reactant: [OH-]
Reactant: Cc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cc3ccccc3nc2N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of 2-aminoquinoline-3-carbonitrile (1.86 g; 11 mmol) in dry tetrahydrofurane (110 mL) under a nitrogen atmosphere was slowly added a solution of p-tolylmagnesium bromide (1M in THF) (55 mL; 55 mmol). The resulting solution was stirred at room temperature for 4 h. A solution of hydrochloric acid 3N (220 mL) was added to hydrolyse the intermediate imine and the reaction mixture was heated to reflux for 2 h and then stirred at room temperature for 18 h. After cooling to 0° C., the reaction mixture was basified with a solution of sodium hydroxide 6N. The product was extracted with ethyl acetate (160 mL) and the organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-100%) in dichloromethane as eluent furnished 2.6 g (90%) of (2-aminoquinolin-3-yl)(p-tolyl)methanone as an ochre solid. ESI/APCI(+): 263 (M+H).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[CH3:32][C:33]1([N:37]([CH3:39])[CH3:38])[CH2:36][NH:35][CH2:34]1>>[F:1][C:2]1[C:20]([N:35]2[CH2:36][C:33]([CH3:32])([N:37]([CH3:39])[CH3:38])[CH2:34]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: CN(C)C1(C)CNC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Agent: CS(=O)(=O)O
Product: CN(C)C1(C)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)C1
Yield: 81.2 %

Procedure:
7-Fluoro-1-methyl-8-(3-methyl-3-dimethylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 1.45 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.45 g of 3-methyl-3-(dimethylamino)azetidine dimethanesulphonate. 1.56 g of 7-fluoro-1-methyl-8-(3-methyl-3-dimethylamino-1-azetidinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 274° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[C:5]2[B:6]([OH:13])[O:7][CH:8]([CH2:9][N+:10]([O-])=O)[C:4]=2[CH:3]=1.[H][H]>N.[Ni]>[ClH:1].[NH2:10][CH2:9][CH:8]1[O:7][B:6]([OH:13])[C:5]2[C:14]([O:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:15][C:2]([Cl:1])=[CH:3][C:4]1=2
Reactant: O=[N+]([O-])CC1OB(O)c2c(OCCCO)cc(Cl)cc21
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: Cl
Product: NCC1OB(O)c2c(OCCCO)cc(Cl)cc21
Yield: 190 %

Procedure:
To a 5-chloro-7-(3-hydroxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol 7 (80 mg, 0.27 mmol) in methanolic ammonia solution (2 M, 20 mL) was added Ra/Ni (˜0.1 g, 2800 Nickel slurry in water) and the reaction vessel was pressurized to 40 psi with hydrogen overnight at room temperature. The mixture was filtered through a pad of Celite® and washed with EtOAc. The filtrate was concentrated in vacuo and to the resulting residue was added water (1 mL), followed by conc HCl to pH 1. The heterogeneous mixture was lyophilized providing the title compound as a hygroscopic ivory solid (79 mg, quantitative). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20 (s, 1H), 6.99 (s, 1H), 5.28 (dd, J=8.0, 2.5 Hz, 1H), 4.13 (t, J=6.0 Hz, 2H), 3.59 (t, J=6.0 Hz, 2H), 3.47 (dd, J=13.0, 2.5 Hz, 1H), 2.89 (dd, J=13.2, 8.6 Hz, 1H), 1.89 (t, J=6.0 Hz, 2H); MS (ESI) m/z=272 (M+1, positive); HPLC purity: 96.83% (MaxPlot 200-400 nm), 95.40% (220 nm).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[N:14]=[CH:13][NH:12][C:11]2=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][C:11]1[C:10]2[C:15](=[CH:16][C:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Yield: 41 %

Procedure:
Phosphorus oxytrichloride (0.1 ml) was added to a mixture of 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (81 mg, 0.29 mmol) and N,N-dimethylaniline (0.1 ml) in toluene (5 ml), and the mixture heated at reflux for 1 hour. The volatiles were removed by evaporation and the residue partitioned between methylene chloride and aqueous ammnonia. The organic extract was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica eluting with ethyl acetate progressing through increasingly polar mixtures to methanol/methylene chloride (1/9) to give 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (40 mg, 41%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[N:19]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[N:23][C:18]2=[N:17][CH:16]=1)CCC>>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:21]=[CH:20][N:19]2[C:15]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)=[CH:16][N:17]=[C:18]2[N:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)nc1
Yield: 35.1 %

Procedure:
6-Chloronicotinonitrile (295 mg, 2.13 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)nicotinonitrile (142 mg) as a white solid: δH (400 MHz, DMSO) 7.79 (1H, d, J 7), 8.35 (1H, m), 8.43 (1H, m), 9.06 (1H, s), 9.14 (1H, s), 10.41 (1H, d, J 7); m/z (ES+) 290 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1(O)[CH:42]=[CH:41]C=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][C:26]2[CH:41]=[CH:42][CH:37]=[CH:38][CH:39]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccccc1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Oc4ccccc4)cc3C)c2cc1OC
Yield: 50.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, phenol (44 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (69 mg, yield 50%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].CO/[CH:15]=[CH:16]/[C:17](=O)[CH2:18][CH3:19].N12CCN(CC1)CC2.Cl>COCCOCCO>[CH2:18]([C:17]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:15][CH:16]=1)[CH3:19]
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: CCC(=O)/C=C/OC
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: COCCOCCO
Product: CCc1ccc(C#N)c(=O)n1-c1ccccc1
Temperature: 120 °C
Yield: 27.3 %

Procedure:
A solution of 2-cyano-N-phenylacetamide (1.08 g, 6.73 mmol), (1E)-1-methoxypent-1-en-3-one (1.0 g, 8.76 mmol) and 1,4-diazabicyclo[2.2.2]octane (755 mg, 6.73 mmol) in 2-(2-methoxyethoxy)ethanol (10 mL) was stirred with heating at 120° C. for 7 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=2/1→4/1) to give the title compound (412 mg, 27%) as a pale-brown solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH:9](C)[C:8](=S)[NH:7][C:6]=2[CH:14]=1.[C:15]([NH:18][NH2:19])(=O)C>C(O)CCC>[CH:15]1[N:7]2[C:6]3[CH:14]=[CH:2][CH:3]=[CH:4][C:5]=3[N:11]=[CH:10][CH2:9][C:8]2=[N:19][N:18]=1
Reactant: CC1CNc2ccc(F)cc2NC1=S
Reactant: CC(=O)NN
Solvent: CCCCO
Product: C1=Nc2ccccc2-n2cnnc2C1

Procedure:
A solution of 8-fluoro-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (5.0 g, 23.8 mmol) and acetohydrazide (2.64 g, 35.7 mmol) in n-butanol (60 mL) was heated at 130° C. for 15 hours. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1-2:1) to afford 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine, 5,6-dihydro-1,4-dimethyl-9-fluoro-as an off-white solid (1.9 g, 34%). LRMS (M+H)+: calcd 232.11. found 232.
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.N1CCOCC1.Cl>O.CS(C)=O>[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[CH:2][C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[O:3]
Reactant: COc1cccc(C=O)c1O
Reactant: CC(=O)C1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCN1
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(C=CC(=O)C2C(=O)CCC2=O)c1O
Yield: 49 %

Procedure:
2-Acetyl-1,3-cyclopentanedione (4.26 g.) was treated with 4.94 g. of 2-hydroxy-3-methoxybenzaldehyde in 100 ml. of dimethylsulfoxide in the presence of 6 ml. of morpholine at 85° C for 40 minutes. After cooling, the reaction mixture was poured into 300 ml. of water containing 12 ml. of conc. hydrochloric acid. Deposited crystals were separated by filtration and washed with water, and dried. 2-(2-Hydroxy-3-methoxycinnamoyl)-1,3-cyclopentanedione (4.40 g., 49%) was obtained in yellow crystalline state, which showed mp. 198° - 200° C. after recrystallization from a mixed solvent of dioxane and ethanol.