Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([O:25]C)=[O:24])=[CH:16][C:15]=2[CH:27]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16][C:15]=2[CH:27]=1)[CH3:2]
Reactant: CCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCOc1ccccc1COc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 62.1 %

Procedure:
Into a solution of methyl 7-[[2-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.64 g) in THF-methanol (6-3 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (2.9 ml), and the resulting mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[2-(2-ethoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (385 mg) as light yellow crystals.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22](=[O:25])(=[O:24])[NH2:23])=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[N:35]([CH3:36])[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[N:32]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:41]1([N:47]=[C:48]=[O:49])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>N1C=CC=CC=1>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22]([NH:23][C:48]([NH:47][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[O:49])(=[O:24])=[O:25])=[CH:14][CH:15]=2)[C:7]2[CH:26]=[C:27]([C:31]3[N:35]([CH3:36])[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[N:32]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NC2CCCCC2)cc1

Procedure:
0.275 g of 4'-[(2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-sulphamoyl-biphenyl is refluxed for 20 hours in 2 ml of pyridine with 0.5 ml of cyclohexylisocyanate. The mixture is then evaporated down, the residue is suspended in acetone and the insoluble solid is filtered off. After the filtrate has been evaporated down the crude produce thus obtained is purified by column chromatography over silica gel (eluant: dichloromethane/ethanol=50:1).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]CC)=O)[CH:4]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][CH3:17].[H-].[Na+]>COCCOC>[CH3:14][N:2]([CH3:1])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9](=[O:11])[CH:16]([CH3:17])[C:15]([O:19][CH2:20][CH3:21])=[O:18])[CH:4]=1
Reactant: CCOC(=O)CC
Reactant: CCOC(=O)c1cc(N(C)C)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C)C(=O)c1cc(N(C)C)ncn1
Yield: 60.6 %

Procedure:
A solution of 6-dimethylamino-4-ethoxycarbonyl-pyrimidine (19.5 g) and ethyl propionate (11.2 g) in 1,2-dimethoxyethane (75 cc) is added to a suspension of sodium hydride (9.6 g) (50% in mineral oil) in 1,2-dimethoxyethane (25 cc), and the reaction mixture is refluxed. Refluxing is maintained for a further 30 minutes. The solvent is evaporated, and then the residue is taken up in diethyl ether (350 cc) and 4N hydrochloric acid (70 cc). After decanting, the aqueous phase is again extracted with diethyl ether (450 cc). The combined organic phases are washed with an 8% (w/v) sodium bicarbonate solution (120 cc). They are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure to give ethyl 3-(6-dimethylaminopyrimidin-4-yl)-2-methyl-3-oxopropionate (15.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][CH:5]([CH3:13])[C:6](=O)[CH:7]=[CH:8][N:9](C)[CH3:10].[NH2:19][C:20]1N=C[NH:22][N:21]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][CH:5]([C:6]1[N:22]2[N:21]=[CH:20][N:19]=[C:10]2[N:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: Nc1nc[nH]n1
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)C=CN(C)C
Solvent: CC(=O)O
Product: CC(Oc1ccc(Cl)cc1Cl)c1ccnc2ncnn12
Temperature: 25 °C

Procedure:
A solution of 4-(2,4-dichlorophenoxy)-1-(dimethylamino)-1-penten-3-one (2.9 g) in glacial acetic acid (25 ml) was added to a stirred solution of 3-amino-1,2,4-triazole (0.93 g) also in glacial acetic acid (25 ml). The mixture was heated under reflux for 5 hours and then cooled to room temperature. The mixture was then poured into 200 ml of ice-water and extracted with toluene. The toluene extracts were washed with a 10% aqueous solution of sodium hydrogen carbonate followed by water, then dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was triturated with cold diethyl ether and the solid was collected by filtration, followed by recrystallisation from a mixture of ethyl acetate and petroleum ether (b.p. 40°-60° C.) to give 7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.02 g, (mp 137°-138° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[C@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:24](=[O:26])[CH3:25])[C@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](O)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 0 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of (±)-cis-3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (50.0 mmol, 11.6 g) in anhydrous DCM (500 mL) at room temperature was added triethylamine (100 mmol, 14.0 mL). The reaction mixture was cooled to 0° C. using an ice bath. To this was added acetic anhydride (50.0 mmol, 4.72 mL) dropwise over 10 minutes. After completion of addition, the reaction was stirred for 12 hours while slowly coming to room temperature. All volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (250 mL) and washed with saturated NaHCO3 (2×50 mL), water (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 110 g SiO2 cartridge using ethyl acetate/hexanes gradient to provide (±)-cis-4-acetoxymethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (12.3 g).
Reaction SMILES: [NH:1]1[C:6]2=[N:7][C:8]([CH:11]=O)=[CH:9][CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:20]([NH2:23])([CH3:22])[CH3:21].C(O)(=O)C>ClCCl>[CH3:21][CH:20]([NH:23][CH2:11][C:8]1[N:7]=[C:6]2[NH:1][CH2:2][CH2:3][CH2:4][C:5]2=[CH:10][CH:9]=1)[CH3:22]
Reactant: CC(C)N
Reactant: O=Cc1ccc2c(n1)NCCC2
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)NCc1ccc2c(n1)NCCC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2,3,4-tetrahydropyridino[2,3-b]pyridine-7-carbaldehyde in dry dichloromethane (32 mL) were added 4° A seives, sodium sulfate and isopropyl amine. The mixture was cooled to 0° C. followed by the addition of acetic acid (300 μL). The resulting mixture was stirred at room temperature under nitrogen for 18 hrs. The mixture was filtered through celite, diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, evaporated concentrated in vacuo and purified by flash chromatography(10% MeOH/CH2Cl2 ). EI-MS m/z 206 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>C(#N)C>[F:1][C:2]1[CH:3]=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:6]=1
Reactant: Fc1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cc(F)cn2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of 4-fluoro-1H-pyrazole (250 mg, 2.90 mmol) and potassium carbonate (803 mg, 5.81 mmol) in acetonitrile (3 mL) was added 4-fluoronitrobenzene (430 mg, 3.05 mmol). The resulting mixture was stirred at 70° C. for 2 hours. The reaction was then filtered and concentrated. Purification by column chromatography gave 4-fluoro-1-(4-nitrophenyl)-1H-pyrazole (400 mg, 67%). 1H NMR (400 MHz, CDCl3, δ): 8.34 (d, 2H), 7.91 (d, 1H), 7.81 (d, 2H), 7.67 (d, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([OH:11])=O)[CH:5]=[N:4][N:3]=[N:2]1.ClC(OCC)=O.CCN(CC)CC.[K+].[C:29]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:30]C([O-])=O.[Mg+2].[Cl-].[Cl-]>CC#N.CCN(CC)CC>[CH2:36]([O:35][C:29](=[O:34])[CH2:30][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([N:1]2[CH:5]=[N:4][N:3]=[N:2]2)[CH:7]=1)[CH3:37]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccc(-n2cnnn2)c1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cccc(-n2cnnn2)c1

Procedure:
Prepared from 3-tetrazol-1-yl-benzoic acid [CAS-No. 204196-80-5] by activation with ethyl chloroformate/Et3N and reaction with ethyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure H (method a). Obtained as a light yellow solid (211 mg).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl[CH2:27][C:28]#[N:29].C(N(CC)CC)C>CC(C)=O>[C:28]([CH2:27][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1)#[N:29]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCNc1cc(C(=O)OCC#N)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g), chloroacetonitrile (0.625 g), triethylamine (0.28 g), and dry acetone (10 ml) was refluxed for 19 hours. After cooling, the precipitated triethylamine hydrochloride was removed by filtration, and the filtrate was evaporated in vacuo. To the residue, water (20 ml) and ethylacetate (50 ml) were added, and the pH of the aqueous layer was adjusted to pH 7.5. The organic layer was then separated, washed with dilute sosium hydrogen carbonate, dried, and evaporated in vacuo. The residue was recrystallized several times from chloroform/petroleum ether. Thereby the cyanomethyl-3-n-butylamino-4-phenoxy-5-sulphamyl-benzoate was obtained with a melting point of 159°-161°C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[Cl:11])=[O:3].[Br-:12].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:12][CH2:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[Cl:11])=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To 2,5-dichloroacetophenone (5.0 g, 26.45 mmol) in anhydrous tetrahydrofuran (53 mL) under argon was added phenyltrimethylammonium tribromide (9.94 g, 26.45 mmol, 1.0 eq) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h, concentrated, and re-dissolved in ethyl acetate. The organic layer was washed with water (2×250 mL) and brine (1×150 mL), dried (MgSO4), filtered, and evaporated in vacuo. Purification using MPLC chromatography (Biotage) gave 3.47 g (52.5%) of 2-bromo-1-(2,5-dichlorophenyl)ethanone as a clear oil. 1H-NMR (DMSO-d6) δ 7.93 (dd, J=2.1 Hz, 0.9 Hz, 1H), 7.61 to 7.60 (m, 2H), 4.86 (s, 2H);
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][CH:36]1[CH2:40][CH2:39][CH2:38][NH:37]1.C(OCC)(=O)C>C(#N)C>[CH3:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:16]=2)=[CH:8][CH:7]=1
Reactant: CC1CCCN1
Reactant: CCOC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1CN1CCCCC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A solution of ethyl 2-[4-(3-chloropropoxy)phenyl]-4-(piperidin-1-ylmethyl)-1,3-oxazole-5-carboxylate i95 (0.22 g, 0.56 mmol, 1 eq) in acetonitrile (10 ml) is treated with potassium carbonate (0.31 g, 2.24 mmol, 4 eq) and 2-methylpyrrolidine (60 μl, 0.67 mmol, 1.2 eq) and the resulting mixture is stirred at 110° C. overnight. Ethyl acetate is then added and the organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Purification over silicagel (eluent: dichloromethane/methanol/ammonia) affords 90 mg of ethyl 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4-(piperidin-1-ylmethyl)-1,3-oxazole-5-carboxylate i96.
Reaction SMILES: [NH:1]=[C:2]([C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]=1[OH:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.[C:38](Cl)(Cl)=[O:39]>C1C=CC=CC=1>[CH3:22][N:11]1[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][C:14]2[O:15][C:38](=[O:39])[N:1]=[C:2]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:9]=2[C:10]1=[O:23]
Reactant: O=C(Cl)Cl
Reactant: Cn1c(-c2ccccc2)cc(O)c(C(=N)c2ccccc2)c1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1c(-c2ccccc2)cc2oc(=O)nc(-c3ccccc3)c2c1=O
Reaction time: 18 h

Procedure:
A mixture of 10 g. (0.0348 mole) of 3-(α-iminobenzyl)-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone and 7.3 g. (0.0724 mole) triethylamine in 200 ml. toluene is treated portionwise with 30 ml. (27.8 g., 0.0348 mole) of a 12.5% solution of phosgene in benzene. The resulting mixture becomes warm and the solids are separated out. The mixture is then stirred at room temperture for 18 hours and then poured onto water and filtered. The solids are washed with toluene. The toluene and water filtrate is separated and the toluene dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting solid is recrystallized with hot toluene to give 6-methyl-4,7-diphenyl-2H-pyrido[3,4-e]-1,3-oxazine-2,5-dione, m.p. 178°-179° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[O:4][C:5]2[C:10]([C:11]=1[CH2:12]Cl)=[CH:9][C:8]([Br:14])=[C:7]([OH:15])[C:6]=2[Br:16].ClC1C=C2C(=CC=1O)[O:25][C:24](=[O:30])[CH:23]=C2CCl>>[C:24]([O:30][CH2:12][C:11]1[C:10]2[C:5](=[C:6]([Br:16])[C:7]([OH:15])=[C:8]([Br:14])[CH:9]=2)[O:4][C:3](=[O:17])[C:2]=1[Br:1])(=[O:25])[CH3:23]
Reactant: O=c1oc2c(Br)c(O)c(Br)cc2c(CCl)c1Br
Reactant: O=c1cc(CCl)c2cc(Cl)c(O)cc2o1
Product: CC(=O)OCc1c(Br)c(=O)oc2c(Br)c(O)c(Br)cc12
Yield: 30 %

Procedure:
This compound was prepared by the same method as compound 4, starting with compound 13 rather than compound 12, to yield 34.5 mg (73.3 mmol, 30% yield) of compound 6 as an oil. 1H NMR (CDCl3+5% CD3OD) δ 7.88 (1H, s), 5.42 (2H, s), 2.11 (3H, s); MS (ES, negative) 466.9, 468.9, 470.9 and 472.9; UV (KMOPS, pH 7.2) λmax (ε) 397 nm (15,900 M−1cm−1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[N:12]=1>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:15]2[N:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[CH:23][CH:24]=1
Reactant: Nc1ccc2ccc(Oc3ccc(Cl)cc3)nc2n1
Reactant: O=C(O)c1ccccc1
Solvent: O
Product: O=C(Nc1ccc2ccc(Oc3ccc(Cl)cc3)nc2n1)c1ccccc1
Temperature: 0 °C
Yield: 23 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with benzoic acid (12.6 g), N,N'-carbonyldiimidazole (7.45 g) and 2-amino-7-(4-chlorophenoxy)-1,8-naphthyridine (12.6 g). The product obtained by precipitation in water (13 g; m.p. 100° C.) is purified by chromatography on a 4-cm-diameter column containing silica (0.040-0.063 mm; 200 g), eluting with methylene chloride and collecting 100-cc fractions. The fractions 10 to 25 are concentrated to 9/10 of the initial volume. After cooling for 2 hours at 0° C., the crystallized solid is separated by filtration, washed with diethyl ether (2×5 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-chlorophenoxy)-1,8-naphthyridin-2-yl]benzamide (4 g), m.p. 148° C., is obtained.
Reaction SMILES: ClC1C=C(O)C=CC=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1.CCOC(C)=O>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]=[CH:12][N:11]=[CH:10]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Oc1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2cncnc2cc1OC
Temperature: 25 °C

Procedure:
THF (5 ml) and Nail (60% disp in oil, approx. 28 mg) is added to a dry flask maintained under inert atmosphere at room temperature. m-Chlorophenol (0.09 g) is added as a soln. in THF (1 mL) and stirring is continued until the solution became clear. 4-Chloro-6,7-dimethoxyquinazoline is added all at once (as the solid) and stirring was maintained overnight at RT. The solution is partitioned between CH2CL2 and 5% NaOH. The organic layer is washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (40% EtOAc/Hex) provided the pure compound. An analytical sample is obtained by recrystallization from EtOAc/Hex to provide 4-m-chlorophenoxy)-6,7-dimethoxyquinazoline (0.05 g, white needles, m.p. 152°-153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:20][C:19]([CH:21]=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Reactant: Nc1ccccc1O
Product: Oc1ccccc1N=Cc1ccc(-c2ccc(Cl)cc2)o1

Procedure:
Using 2-aminophenol and 5-(4-chlorophenyl)furan-2-carbaldehyde, 3.18 g of 2-{[5-(4-chlorophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 89%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(F)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(OCc2ccccc2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromo-2,5-difluoro-phenol (595, 0.90 g, 0.0043 mol, prepared as described in Example 34, Scheme 61) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (600, 0.84 g, 65.0%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[CH2:11][CH2:10][N:9]2[CH2:12][CH:13]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[NH:18][CH:19]=O)[N:14]=[C:8]12.[OH-].[Na+].[ClH:26]>CO.O.O1CCCC1>[ClH:26].[ClH:26].[CH3:19][NH:18][C:17]1[CH:16]=[C:15]([CH:13]2[CH2:12][N:9]3[C:8]([S:7][CH2:11][CH2:10]3)=[N:14]2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=CNc1cccc(C2CN3CCSC3=N2)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cccc(C2CN3CCSC3=N2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a stirred slurry of 1.15 g. (0.030 mole) of lithium aluminum hydride in 80 ml. of dry tetrahydrofuran is added 5.00 g. (0.0203 mole) of 3'-(2,3,5,6-tetrahydroimidazo[2,1-b]thiazol-6-yl)formanilide (Example 12) at a rate sufficient to keep the temperature at 40°-45°C. The reaction mixture is then stirred at room temperature for 3 hours and at 40°-50°C. for 30 minutes. After cooling the reaction, 1.8 ml. of water is cautiously added dropwise and then 2 ml. of 15% aqueous sodium hydroxide. The mixture is filtered and the filter cake washed with tetrahydrofuran. Evaporation of the solvent gives an oil which is dissolved in methanol and acidified with 2-propanolic hydrogen chloride. Filtration of the precipitate gives 4.18 g. (67% yield) of crude product which is recrystallized from methanol and has melting point 229°-231°C. Anal. Calcd. for C12H16N3SCl: C, 47.06; H, 5.60; N, 13.72; S, 10.47; Cl, 23.15. Found: C, 46.82; H, 5.56; N, 13.60; S, 10.40; Cl, 23.16.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C@@H:14]1[CH2:16][C@@H:15]1[F:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[C@@H:22]12[CH2:30][NH:29][CH2:28][C@@H:27]1[CH2:26][CH2:25][CH2:24][NH:23]2.C(N(CC)CC)C.O>C(#N)C>[C@@H:22]12[CH2:30][N:29]([C:11]3[C:10]([F:13])=[C:9]4[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]4[C@@H:14]4[CH2:16][C@@H:15]4[F:17])=[CH:3][C:2]=3[F:1])[CH2:28][C@@H:27]1[CH2:26][CH2:25][CH2:24][NH:23]2
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(N3C[C@@H]4CCCN[C@@H]4C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
A solution of 301 mg of 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (JP-A-5-163244), 463 mg of (S,S)-2,8-diazabicyclo[4.3.0]nonane, 1 ml of triethylamine in 10 ml of acetonitrile was heated under reflux for 15 hours. To the mixture was added 50 ml of water, and the solvent was removed under reduced pressure. The mixture was extracted from three 50 ml portions of chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. A residue was dissolved in 10 ml of trifluoroacetic acid, and the solution was stirred at room temperature for 2 hours. Trifluoracetic acid was removed under reduced pressure and to a residue was added 1N sodium hydroxide aqueous solution till a pH became 12. To the solution was added hydrochloric acid till the pH became 7.4. The solution was extracted with six 50 ml portions of chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and a residue was recrystallized from ethanol to yield 320 mg of the titled compound.