Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])=[O:4].O[Li].O.Cl>C1COCC1.CO.O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([N:23]2[C:19]3[CH:20]=[N:21][CH:22]=[C:17]([C:15]([NH:14][CH:11]([C:7]4[O:8][C:9]([CH3:10])=[C:5]([C:3]([OH:4])=[O:2])[N:6]=4)[CH2:12][CH3:13])=[O:16])[C:18]=3[CH:25]=[N:24]2)=[CH:31][CH:30]=1
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)OC)c(C)o1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)O)c(C)o1
Reaction time: 3 h

Procedure:
To a solution of 2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-oxazole-4-carboxylic acid methyl ester (95.0 mg, 0.217 mmol) in a mixture of THF/Methanol/water (3 mL, 3:1:1) was added LiOH.H2O (36.5 mg, 0.869 mmol). After 3 hours, the reaction mixture was acidified to pH 3-4 with 2 M aqueous hydrochloric acid and concentrated. The mixture was diluted with ethyl acetate (25 mL) and water (25 mL) and stirred vigorously. After 5 hours, the heterogeneous mixture was filtered and the solid was washed with water (until the pH of the filtrate was 5), ethyl acetate (3×10 mL), and air dried to afford the title compound as a white solid. MS m/z 424.74 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a suspension of 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (330 mg, 1.0 mmol) in THF (3 mL) and methanol (3 mL) was added a solution of lithium hydroxide monohydrate (85.1 mg, 2.0 mmol) in water (3 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (1 N, 30 mL) and the resulting mixture was filtered. The solid was dried to afford the title compound (284 mg, 90%) which was obtained as a white solid. MS: m/e=310.5 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:4]=2)=[CH:12][CH:11]=1)=[O:30]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1oc(-c2ccc(N)cc2)nc1-c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1oc(-c2ccc(NC(=O)c3ccc(Cl)cc3Cl)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
to a solution of 4-(5-methyl-4-phenyloxazol-2-yl)benzenamine (311 mg, 1243 μmol) and pyridine, anhydrous (1013 μl, 12425 μmol) in 4 mL dichloromethane at room temperature was added all at once by metered pipet 2,4-dichlorobenzoyl chloride (192 μl, 1367 μmol). The reaction was stirred at room temperature for 1 hour then concentrated under reduced pressure, triturated with heptane and concentrated under reduced pressure. The residue was triturated with ethyl acetate and the isolated solid (170 mg) was purified by reversed phase preparative HPLC. Fractions containing product were combined and concentrated under reduced pressure. The concentrate was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution and the organic separation dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a colorless solid (100 mg, 19%). ESI+ m/z=423.0 [MH]+.
Reaction SMILES: [C:1]1([P:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](=O)[CH3:22].[O:24]1[CH2:29][CH2:28][N:27]([S:30]([NH2:33])(=[O:32])=[O:31])[CH2:26][CH2:25]1>ClC1C=CC=CC=1>[C:15]1([P:7](=[O:8])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:21]([NH:33][S:30]([N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)(=[O:32])=[O:31])[CH3:22])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(OP(c2ccccc2)c2ccccc2)cc1
Reactant: CC=O
Reactant: NS(=O)(=O)N1CCOCC1
Solvent: Clc1ccccc1
Product: CC(NS(=O)(=O)N1CCOCC1)P(=O)(c1ccccc1)c1ccccc1

Procedure:
When a mixture of equimolar quantities of phenyl diphenylphosphinite, acetaldehyde, and morpholinosulfonylamine in chlorobenzene is treated by the procedure used in the preceding experiment, the product is a white solid, mp 215°-217°C., 31P nmr (DMSO-d6) -30.9 ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]([CH3:24])([CH3:23])[CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[F:22])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](=[O:38])=[N:34][C:35](Cl)=[O:36]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]([CH3:24])([CH3:23])[CH2:9][N:10]1[C:35](=[O:36])[NH:34][C:33](=[O:38])[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[F:22])[C:11]1=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(NC(=O)NCC(C)(C)NC(=O)OC(C)(C)C)c1F
Reactant: O=C=NC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(-n2c(=O)[nH]c(=O)n(CC(C)(C)NC(=O)OC(C)(C)C)c2=O)c1F
Reaction time: 1 h

Procedure:
To 20 mL of anhydrous CH2Cl2 was added 0.93 g of {2-[3-(2-Fluoro-3-methoxy-phenyl)-ureido]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester and triethylamine (1.0 eq, 0.36 mL). N-(chlorocarbonyl) isocyanate (1.0 eq, 0.11 mL) was added to the solution in one portion. The reaction stalled after one hour, so additional triethylamine (1.0 eq, 0.36 mL) and N-(chlorocarbonyl) isocyanate was added. The reaction was determined to be complete by LC/MS after two hours. Excess isocyanate was quenched with the dropwise addition of H2O (1 mL). The reaction was then diluted with 20 mL H2O, and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography and eluted with 60% EtOAc/hexanes to yield 0.65 g (59%). Rf=0.66 in 60% EtOAc/hexanes. 1H NMR (CDCl3) δ: 7.19 (dt,1H), 7.09 (dt,1H), 6.90 (dt,1H), 5.15 (ds,1H), 4.1 (q,2H), 3.92 (s,3H), 1.42 (s,9H), 1.38 (d,6H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15](F)[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CS(C)=O>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NCc1ccccc1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccccc1)C(F)CC(NCc1ccccc1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (4.0 g), benzylamine (20.0 g) and dimethylsulfoxide (100 ml) was stirred at 70° to 80°C for 8 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was sufficiently washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Treatment of the residue with ethanol afforded γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-4-benzylamino-2-fluorobutyrophenone. M.P. 158° - 165°C. IR νmaxNujol 3350, 1650 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[N+:12]([C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:18]=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C1Cc2cc(-c3cccc([N+](=O)[O-])c3)ccc2N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.5 %

Procedure:
5-bromo-2-indolinone (1.08 g, 5.09 mmol) and tetrakistriphenyl phosphine Pd(0) (0.273 g) were stirred under an atmosphere of nitrogen in ethylene glycol dimethyl ether (35 mL). After 15 minutes, 3-nitrophenyl boronic acid (1.70 g, 10.2 mmol) was added, followed by potassium carbonate (4.24 g, 30.7 mmol) in water (15 mL). The reaction was heated to reflux overnight, cooled to room temperature and then filtered. Saturated ammonium chloride was added. The water layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried with MgSO4, filtered, and solvent removed in vacuo. The product was purified by flash silica gel chromatography (3:2 hexane; ethyl acetate) to give 5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one (0.084 g, 65%), Mp=269° C.; 1H NMR (DMSO) δ 10.5 (s, 1H), 8.38-8.36 (m, 1H) 8.17-8.14 (m, 1H), 8.10-8.07 (m, 1H), 7.75-7.60 (m, 3H), 6.95 (d, 1H, J=8.1 Hz), 3.57 (s, 2H); IR (KBr) 3420, 3190, 1700 cm−1; MS (EI) m/z 253 (M−H)−; CHN calculated for C14H10N2O: C, 66.14; H, 3.96; N, 11.02; Found: C, 64.59; H, 4.16; N, 9.43.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5](=[O:17])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:2].[Se]=[O:22]>C(O)C>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:17])[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11]/[CH:12]=[C:13](\[CH3:15])/[CH2:14][OH:22])[CH3:20]
Reactant: O=[Se]
Reactant: CCOC(OCC)C(=O)CCC=C(C)CCC=C(C)C
Solvent: CCO
Product: CCOC(OCC)C(=O)CC/C=C(\C)CC/C=C(\C)CO
Yield: 56.2 %

Procedure:
In 70 ml of 95 % ethanol was dissolved 7.4 g of 1,1-diethoxy-6,10-dimethyl-2-oxo-5,9-undecadien, and the resulting solution was, after addition of 1.7 g of selenium oxide, refluxed for 15 minutes. The ethanol was removed by evaporation, and the residue was, after addition of water, extracted with ether. The ethereal extract was washed with an aqueous sodium hydrogencarbonate solution and dried. The solvent was then removed by evaporation to leave an oil, and the oil was purified by the silica gel column chromatography to yield 3.0 g of the desired product.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH2:27][CH3:28])=[C:14]2[C:29](=[O:33])[C:30]([NH2:32])=[O:31])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:32][C:30](=[O:31])[C:29]([C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][C:6]([OH:34])=[O:5])[CH:12]=2)[N:16]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]=1[CH2:27][CH3:28])=[O:33]
Reactant: CCc1c(C(=O)C(N)=O)c2cc(OCCCC(=O)OC(C)(C)C)ccc2n1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(C(=O)C(N)=O)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Yield: 63.1 %

Procedure:
A solution of 450 mg (0.97 mmol) of 4-[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid tert-butyl ester in 75 mL of methylene chloride and 1 mL of trifluoroacetic acid was stirred at room temperature for 2.25 hours and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with EtOAc to give 250 mg (63% yield) of 4-[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp 173°-175° C.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([CH3:38])[C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]2[CH:29]=[N:30]C(NC)=C[CH:33]=2)=[CH:19][CH:18]=[C:17]([Cl:39])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[CH2:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])C.C(Cl)(=[O:49])C.O>ClCCl>[Cl:1][C:2]1[C:20]([N:21]([CH3:38])[C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]2[CH:29]=[N:30][C:43]([N:42]([CH3:40])[C:45](=[O:49])[CH3:46])=[CH:44][CH:33]=2)=[CH:19][CH:18]=[C:17]([Cl:39])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CNc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N(C)c1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
To a mixture of 8-[2,6-dichloro-3-[N-methyl-N-[(E)-3-(6-methylaminopyridin-3-yl)acryloylglycyl]amino]benzyloxy]-2-methylquinoline (100 mg) and triethylamine (23.3 mg) in dichloromethane was added acetyl chloride (15.3 mg) under nitrogen in ice water bath, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=20:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N[(E)-3-[6-(N-methylacetamido)pyridin-3-yl]acryloylglycyl]amino]-benzyloxy]-2-methylquinoline (50 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4].[N:37]1([CH2:43][CH2:44][CH2:45][NH2:46])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:22])[NH:46][CH2:45][CH2:44][CH2:43][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4]
Reactant: NCCCN1CCOCC1
Reactant: COC(=O)c1c(-c2cccc(C(=O)O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(-c2cccc(C(=O)NCCCN3CCOCC3)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2 ml) of 4-(3-carboxyphenyl)-6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-morpholin-4-ylpropylamine (31 μl) in acetonitrile were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg) and 4-hydroxybenzotriazole monohydrate (38 mg) at room temperature with stirring and the mixture was stirred at room temperature for 12 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried and concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1) to give the title compound (93 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2[NH:8][C:9]([CH2:11][CH3:12])=[CH:10][C:5]=2[C:4](=O)[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[CH3:1][C:2]1[NH:7][C:6]2=[N:8][C:9]([CH2:11][CH3:12])=[CH:10][C:5]2=[C:4]([Cl:16])[N:3]=1
Reactant: CCc1cc2c(=O)nc(C)[nH]c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc2c(Cl)nc(C)[nH]c-2n1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 3.50 g (19.8 mmol) of 1,7-dihydro-2-methyl-6-ethyl-4H-pyrrolo[2,3-d]pyrimidin-4-one in 180 mL of phosphorous oxychloride was heated to reflux for 4 hours. The reaction was cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in 100 mL of methylene chloride and poured onto 100 g of ice. The mixture was neutralized to pH 7 by the addition of powdered potassium carbonate. After an additional 200 mL of methylene chloride and 200 mL of water were added, some solids remained and were removed by filtration. The solids were shown to be desired product by thin layer chromatography (silica, 19:1 methylene chloride-methanol). The solids were combined with the organic phase and concentrated to 4.0 g of brown residue. The residue was purified by flash chromatography (200 g of silica, 19:1 methylene chloride-methanol) to provide 3.32 g (86%) of 2-methyl-4-chloro-6-ethyl-1H-pyrrolo[2,3-d]pyrimidine as an off-white solid. nmr (500 MHz, dmso-d6) δ1.25 (t, J=7.5 Hz, 3H), 2.56 (s, 3H), 2.73 (q, J=-7.5 Hz, 2H), 6.21 (s, 1H), 12.15 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CC[C:17](OCC)=[S:18].[C:22]([O:26]Cl)(C)(C)[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18][CH:23]1[C:3]2[C:2](=[C:7]([CH3:8])[CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:1][C:22]1=[O:26]
Reactant: Cc1ccc(-c2ccccc2)cc1N
Reactant: CC(C)(C)OCl
Reactant: CCOC(=S)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2c(C)ccc(-c3ccccc3)c21
Temperature: -65 °C
Reaction time: 1.5 h

Procedure:
A solution of 30.6 grams (0.13 mole) of 3-amino-4-methylbiphenyl in 400 milliliters of methylene chloride is cooled to -65° C. and treated with 17.0 grams (0.13 mole) of ethyl 2-methylthioacetate and then 14.2 grams (0.132 mole) of t-butylhypochlorite while maintaining the temperature below -60° C. The reaction mixture is stirred at -65° C. for 1.5 hours, treated with 13.3 grams (0.132 mole) of triethyl amine and allowed to warm to ambient temperature. The solution is washed twice with water and concentrated. The residue is dissolved in 200 milliliters of methanol, 40 milliliters of 3 N hydrochloric acid are added, and the mixture refluxed overnight. The solution is concentrated until a solid begins to precipitate. The mixture is cooled, and the solid collected by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.Cl.C[C:22]1[NH:23]C=CN=1.O.NN.C([O-])([O-])OCC>C(O)C.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]3[CH:22]=[N:23][N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[CH:15]=1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: Cc1ncc[nH]1
Agent: CCOC([O-])[O-]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: CO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 8.1 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in 180 parts by volume of methanol are added 3.6 parts of 2-methylimidazole hydrochloride and 2.25 parts by volume of 80% hydrazine hydrate. The suspension is stirred at room temperature for 1.5 hours, and then 25 parts of ethyl orthoformate is added. To the mixture is added dropwise with stirring 60 parts by volume of ethanol containing 10% hydrogen chloride. After stirring for a further 1 hour, the mixture is warmed for a while so as to complete the reaction. After evaporation of the solvent, an aqueous solution of sodium bicarbonate is added to the residue to neutralize it. The mixture is then extracted with methylene chloride. The methylene chloride layer is washed with water and dried over sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from a mixture of acetone and n-hexane to give 8-chloro-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine as colorless flakes. Melting point; 226° C to 227° C.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[C:15]([F:35])=[CH:16][C:17]3[C:18]([CH:34]=2)=[N:19][C:20]2[N:21]([CH3:33])[CH:22]=[C:23]([C:28]([O:30]CC)=[O:29])[C:24](=[O:27])[C:25]=2[CH:26]=3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[OH-].[K+].C(O)C>[CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[C:15]([F:35])=[CH:16][C:17]3[C:18]([CH:34]=2)=[N:19][C:20]2[N:21]([CH3:33])[CH:22]=[C:23]([C:28]([OH:30])=[O:29])[C:24](=[O:27])[C:25]=2[CH:26]=3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(Cc5ccccc5)C4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(Cc5ccccc5)C4)cc3nc21
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
A suspension of (RS)-8-(3-benzyl-1-piperazinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4dihydrobenzo[b][1,8]naphthyridine (2.65 g) in N aqueous potassium hydroxide (14 cc) and ethanol (20 cc) is heated to a temperature in the region of 80° C. for 20 minutes, treated at the same temperature with 5% strength acetic acid (32 cc) and stirred for 20 minutes. The insoluble matter is drained at approximately 80° C. and washed with water (2×20 cc), ethanol (2×20 cc) and ethyl ether (2×20 cc). After 2 recrystallizations in dimethylformamide (50 cc each time), (RS)-8-(3-benzyl-1-piperazinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (2.05 g) is obtained in the form of a yellow solid, decomposing at 270°-275° C.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:36][C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc12

Procedure:
[8-(2-methoxy-5-trifloromethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 4-(4-methylpiperazin-1-yl)phenylamine (0.096 g, 0.5 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.1 g, 40%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.53 (d, J=7.1 Hz, 1H), 7.48 (d, J=7.1 Hz, 2H), 7.12 (d. J=8.2 Hz, 1H), 6.99-6.90 (m, 3H), 6.67 (s, 1H), 3.88 (s, 3H), 3.21-3.11 (m, 4H), 3.06 (s, 3H), 2.65-2.55 (m, 4H). MS=483 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ccc([N+](=O)[O-])cc2Cl)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of 2-chloro-1-fluoro-4-nitrobenzene (3.7 g) and 3-hydroxybenzonitrile (2.5 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.4 g), and the mixture was stirred at 60° C. for 4 hrs. After the completion of the reaction, water (50 mL) was added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (5.3 g) as pale-yellow crystals.