Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH:19]=4)[CH2:14][CH2:13]3)[C:6]=2[CH:27]=1.[CH3:28][CH2:29][CH2:30]CCC.C(Br)C=C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:13][CH:14]=[C:15]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH2:30][CH:29]=[CH2:28])[CH:19]=4)[CH2:16][CH2:17]3)[C:6]=2[CH:27]=1
Reactant: Clc1ccc2scc(CCN3CC=C(c4c[nH]c5ccccc45)CC3)c2c1
Reactant: CCCCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCn1cc(C2=CCN(CCc3csc4ccc(Cl)cc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(5-chloro-1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (392 mg, 1 mmol) (obtained from example 32, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and was washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and allyl bromide (183 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Yellow semi-solid. Yield: 156 mg (36%); 432 (M+H); 1H NMR: δ 7.90(1H, s, NH), 7.78(3H,m), 7.26(6H, m), 6.21(1H, s), 5.99(1H, m), 5.13(2H, m), 4.71(2H, m), 3.40(2H, s), 3.15(2H, m), 2.92(4H, m), 2.68(2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[NH:19][C:20]([C:22]1([CH3:25])[CH2:24][O:23]1)=[O:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:25][C:22]([OH:23])([CH3:24])[C:20]([NH:19][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:10]=2[CH3:9])=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1c(NC(=O)C2(C)CO2)cccc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1
Product: Cc1c(NC(=O)C(C)(O)COc2ccc(F)cc2)cccc1[N+](=O)[O-]

Procedure:
3-(4-Fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide was prepared as described in Example 1c starting from 4-fluorophenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.28 (3H, s), 3.96 (1H, d, J=9.5 Hz), 4.17 (1H, d, J=9.5 Hz), 6.14 (1H, s), 6.93-6.97 (2H, m), 7.08-7.13 (2H, m), 7.41-7.45 (1H, m), 7.66-7.68 (1H, m), 7.72-7.75 (1H, m), 9.72 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH:19]([CH3:21])[O:18][CH:17]([CH3:22])[CH2:16]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]#[N:10])([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH:17]([CH3:22])[O:18][CH:19]([CH3:21])[CH2:20]2)[CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)=[CH:4][CH:3]=1
Reactant: CC1CN(CCCCC(C#N)c2ccc(Cl)cc2)CC(C)O1
Reactant: ClCn1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCCCC(C#N)(Cn2cncn2)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This compound (400 mg.) was prepared using the procedure described in Example 2b except using 400 mg. (1.25 mmoles) of 2-(4-chlorophenyl)-6-(2,6-dimethyl-4-morpholinyl)capronitrile, 0.06 g. (1.38 mmoles) of sodium hydride, 0.15 g. (1.25 mmoles) of 1-(chloromethyl)-1,2,4-triazole, and 4 ml. of DMF and was isolated as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.F[C:20](F)(F)[C:21](O)=O>ClCCl>[O:1]=[C:2]1[N:6]([CH:7]([C:21]2[CH:20]=[CH:15][CH:5]=[CH:4][CH:18]=2)[C:8]([OH:10])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Solvent: ClCCl
Product: O=C(O)C(c1ccccc1)n1c(=O)[nH]c2ccccc21
Temperature: 25 °C

Procedure:
1.00 g (3.08 mmol) of tert-butyl (2-oxo-2,3-dihydrobenzimidazol-1-yl)acetate (XId) was dissolved in dichloromethane (10 ml) and, while stirring at room temperature, trifluoroacetic acid (6 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 827 mg (100%) of white solid
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[F:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:26][CH:25]=1>>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:32]4[CH2:31][CH2:30][N:29]([CH2:28][C:27]5[CH:35]=[CH:36][C:24]([F:23])=[CH:25][CH:26]=5)[CH2:34][CH2:33]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: Fc1ccc(CN2CCNCC2)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(Cc5ccc(F)cc5)CC4)cc3nc21
Yield: 58.6 %

Procedure:
1-Ethyl-7-fluoro-8-[4-(4-fluorobenzyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo-[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, LAW OFFICES but from 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 3.9 g of 4-(4-fluorobenzyl)piperazine. After recrystallizing twice from 20 cm3 of dimethylformamide on each occasion, 1.4 g of 1-ethyl-7-fluoro-8-[4-(4-fluorobenzyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 286-8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=2[C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]2[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[C:18](=[O:20])[CH3:19]
Reactant: COc1ccc(COc2cccc([N+](=O)[O-])c2C(C)=O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2cccc(N)c2C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 175.5 %

Procedure:
To a stirred suspension of 1-{2-[(4-methoxybenzyl)oxy]-6-nitrophenyl}ethanone (0.50 g, 1.659 mmol) in ethanol was added a solution of ammonium chloride (0.10 g, 1.825 mmol) in water (5 mL) followed by iron powder (0.75 g). The mixture was stirred at 100° C. for 1 hr. The reaction mixture was filtrated on Celite®. The filtrate was diluted with ethyl acetate and washed with water. The separated organic phase was washed with brine and dried over Na2SO4, filtrated and concentrated under reduced pressure to give 1-{2-amino-6-[(4-methoxybenzyl)oxy]phenyl}ethanone as a yellow solid (0.790 g, yield; 108%). The residue was used for the next step without further purification. [Starting Compound 1I]
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH3-]C#N.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(F)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(F)cc2)n1

Procedure:
119 mg (65.0%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-fluorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (112.3 mg, 0.431 mmol), 1-(2-fluorophenyl)piperazine (102.22 mL, 0.647 mmol), and NaCNBH3 (274.29 mg, 1.294 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13]>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:18]3[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=3)[C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc3c(c2)CCC3=O)c1

Procedure:
The title compound was prepared from 5-bromo-1-indanone and 3-cyanophenyl boronic acid according to the coupling procedure as described in example 6. MS m/z 234; HRMS: calcd for C16H11NO+H+, 234.09134; found (ESI, [M+H]+), 234.0905;
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12]CC)=[O:11].C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1cccc(C(=O)O)c1

Procedure:
The reaction of butyl bromide and ethyl 3-hydroxybenzoate in the presence of potassium carbonate was performed as described for Compound 24 to give 3-butoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.93 (s, COOH); 7.48 (m, 1 arom. H); 7.40 (m, 2 arom. H); 7.12 (m, 1 arom. H); 3.97 (t, CH3CH2CH2CH2O); 1.69 (m, CH3CH2CH2CH2O); 1.42 (m, CH3CH2CH2CH2O); 0.91 (t, CH3CH2CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.12 (—C═O); 158.63; 132.13; 129.67; 121.40; 119.31; 114.41; 67.30; 30.64; 18.68; 13.65.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C1COCC1.CCN(CC)CC>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)=[C:3]([C:4](=[O:5])[NH2:6])[CH:7]=1
Reactant: Cc1cc(Br)cc(C(N)=O)c1N
Reactant: O=C(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cc(C(N)=O)c1NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-5-bromo-3-methylbenzamide (820 mg, 3.55 mmol, 1.0 eq.) in THF (15 mL) and Et3N (0.7 nit) was added nicotinoyl chloride (551 mg, 3.91 mmol, 1.1 eq.) in anhydrous THF (15 mL) dropwise. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the resultant precipitate was filtered and dried in vacuo to give 1.74 g of crude iii-e as a yellow solid. LCMS m/z=333.8, 335.8 (M+1) (Method B) (retention time=1.42 min).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: ON=C(Cl)Cc1ccc(CCC2CCCO2)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(CCC3CCCO3)cc2)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To an anhydrous tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (43.7 mg, 0.37 mmol) was added (4-(2-tetrahydrofuran-2-yl-ethyl)phenyl)-acetohydroximoyl chloride (300 mg, 1.12 mmol) described in Manufacturing Example 82-1-6 under nitrogen atmosphere at room temperature. Triethylamine (0.31 mL, 2.24 mmol) was then added dropwise and stirred for 2 hours at 60° C. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:9 then 3:7) to obtain the title compound (68 mg, 53%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Mg]Br.BrC1C=CC=CC=1CO.C([Li])CCC>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: Clc1ccccc1[Mg]Br
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: OCc1ccccc1Br
Agent: [Li]CCCC
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2Cl)CC1

Procedure:
9.74 g of the entitled compound was obtained as a pale yellow oily substance in the same manner as in Production Example 8-3, for which, however, benzyl 4-oxopiperidine-1-carboxylate was used in place of tert-butyl 3-oxo-8-aza-bicyclo-[3.2.1]octane-8-carboxylate used in Production Example 8-3, and 2-chlorophenylmagnesium bromide was used in place of the lithium reagent prepared from 2-bromobenzyl alcohol and n-butyllithium.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)(=[O:3])[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:18][CH:19]=2)=[O:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(NC(=O)OC(C)(C)C)cc2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
A mixture of 2-(acetylamino)-1,3-thiazole-4-carboxylic acid (500 mg), tert-butyl 4-aminophenylcarbamate (615 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (566 mg), 1-hydroxybenzotriazole (399 mg) and dichloromethane (5 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen bicarbonate, and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 3% methanol/chloroform as an eluent. The crystalline residue was collected and washed with ethyl acetate to give tert-butyl 4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}amino)phenylcarbamate (580 mg).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)/[C:6](=[O:8])[N:7]=1.Cl.[O:28]1CCCC1>>[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2/[CH:9]=[C:5]2/[C:6](=[O:8])[NH:7][C:3](=[O:28])[S:4]/2)[CH:22]=[CH:21][CH:20]=1
Reactant: C1CCOC1
Reactant: CSC1=NC(=O)/C(=C/c2ccccc2Nc2cccc(C(F)(F)F)c2)S1
Agent: Cl
Product: O=C1NC(=O)/C(=C/c2ccccc2Nc2cccc(C(F)(F)F)c2)S1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a room temperature solution of (Z)-2-methylthio-5-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylene]-4(5 H)-thiazolone (507 mg, 1.28 mmols) in 14 mL of tetrahydrofuran is added 14 mL of 10% aqueous hydrochloric acid. The mixture is heated at reflux for 30 minutes, then allowed to cool to room temperature. The mixture is partitioned between water and ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate followed by brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 390 mg (83%) of (Z)-5-[[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]methylene]-2,4-thiazolidinedione. An analytical sample is obtained by recrystallization from ethyl acetate and hexane; mp 213°-214° C. dec.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:17][CH2:16][C:3]1[C:2]([Cl:1])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:15])[CH:4]=1
Reactant: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(CBr)cc1F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-2-fluoro-4-methyl-N-(methylsulfonyl)benzamide (0.8 g, 3.0 mmol), N-bromosuccinimide (1.6 g, 9.0 mmol) and azodiisobutyronitrile (16 mg, 0.09 mmol) in 1,2-dichloroethane (20 mL) was stirred at 90° C. for 16 hrs. The reaction was quenched with Na2SO3 (10 mL, 10%), extracted with 1,2-dichloroethane (20 mL×3), dried over anhydrous Na2SO4, concentrated and the residue was used in next step without further purification (1.1 g, crude). LCMS (ESI) m/z: 342.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[N:6][C:5]=2[O:4][N:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:15]([N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[N:6]=[C:7]1[CH2:12][CH2:13][CH3:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1nc2onc(C)c2c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A suspension of 3-methyl-6-propyl-5H-isoxazolo[5,4-d]pyrimidin-4-one (method 17) (1.698 g, 8.8 mmol), benzylbromide (1.5 g, 8.8 mmol), potassium carbonate (2.43 g, 17.6 mmol) in 10 ml DMF was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc (50 ml×3), the combined organic phases were dried, concentrated, purified by flash column chromatography (elute: hexane-EtOAc=5:1). 1.69 g (68%) of the title compound was obtained as white solid. 1H NMR (DMSO-d6): 0.80 (t, 3H), 1.61 (m, 2H), 2.43 (s, 3H), 2.73 (t, 2H), 5.35 (s, 2H), 7.12-7.35 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]([CH3:13])[CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[F:14][C:15]([F:25])([F:24])[C:16](=O)[CH2:17][C:18](OCC)=[O:19]>>[O:19]=[C:18]1[NH:1][C:2]2=[N:11][C:10]3[N:9]([CH3:12])[CH2:8][CH2:7][CH:6]([CH3:13])[C:5]=3[CH:4]=[C:3]2[C:16]([C:15]([F:25])([F:24])[F:14])=[CH:17]1
Reactant: CC1CCN(C)c2nc(N)ccc21
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: CC1CCN(C)c2nc3[nH]c(=O)cc(C(F)(F)F)c3cc21

Procedure:
This is a representative procedure for making azaquinolones. 7-Amino-1,4-dimethyl-1,2,3,4-tetrahydro-1,8-naphthyridine (0.9 g.) and 1.0 g. of ethyl trifluoroacetoacetate were heated at 145°-165° for 18 hours. The cooled, semisolid mass was slurried with 5 ml. of ether, filtered and washed with more ether, 1.3 g., m.p. 225°-230°, wet 200°. Other data are found in the table. 1H nmr (deuteriochloroform, 100 MHz): δ1.30 (d,3H, CH3CH, J=7 Hz), 1.74 (m, 1H, H7a or H7b), 1.89 (m, H, H7a or H7b), 2.92 (m, 1H, H6), 3.20 (s, 3H, NCH3), 3.49 (t, 2H, H8, H8, J=6 Hz), 6.62 (s, 1H, H3), 7.46 (q, 1H, H5, JH5 --CF3 =~1.5 Hz), 9.40 (broad s, 1H,NH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:23][C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:26])[F:27])=[O:25])[CH2:11][CH2:12]1
Reactant: O=C(CCl)Nc1ccccc1C(F)(F)F
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2-trifluoromethylphenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 41 mg (75%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.65 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.65 (t, J=5 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.55 (t, J=6 Hz, 1H), 7.73 (m, 2H), 8.15 (d, J=5 Hz, 1H), 8.22 (d, J=6 Hz, 1H), 9.95 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([NH2:26])[N:23]([CH2:27][CH3:28])[C:22](=[S:29])[N:21]=1.CO.N>O1CCOCC1>[NH2:17][CH:16]1[C:15](=[O:18])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][S:29][C:22]3[N:21]=[C:20]([NH2:19])[CH:25]=[C:24]([NH2:26])[N+:23]=3[CH2:27][CH3:28])[CH2:7][S:8][C@H:9]12
Reactant: CCn1c(N)cc(N)nc1=S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CC[n+]1c(N)cc(N)nc1SCC1=C(C(=O)[O-])N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Under an anhydrous condition, a solution containing 2.72 g of 3-acetoxymethyl-7-amino-3cephem-4-carboxylic acid and 1.8 g of 4,6-diamino-1-ethyl-2-(1H)-pyrimidinethione suspended in 20 ml of dry dioxane was cooled to 0° C.; and 3 ml of boron trifluoride diethylether was added. The temperature of the reaction solution was increased to 40° C.; the solution was stirred for one hour; and then 10 ml of methyl alcohol was added. The resultant solution was stirred for 10 minutes and was added with 30 ml of ice water. The pH of the solution was adjusted to 7.1 by adding aqueous ammonia solution After concentration under a reduced pressure, e.g., about 20 mmHg, the solution was adjusted to pH 3.6 with 2N-aqueous hydrochloric acid; and allowed to stand at a room temperature for 24 hrs. The precipitates resulted from the reaction solution were filtered, washed with 10 ml of distilled water and with 10 ml of methyl alcohol, and dried to give 2.87 g of the title compound as a solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([OH:19])[N:9]=1.Br[CH2:21][CH:22]([F:24])[F:23]>O>[Cl:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([O:19][CH2:21][CH:22]([F:24])[F:23])[N:9]=1
Reactant: FC(F)CBr
Reactant: Oc1cc2c(Cl)cccc2c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: FC(F)COc1cc2c(Cl)cccc2c(Cl)n1
Temperature: 50 °C
Yield: 90.8 %

Procedure:
Potassium carbonate (646 mg, 4.67 mmol) was added to a solution of 1,5-dichloroisoquinolin-3-ol (500 mg, 2.336 mmol) and 2-bromo-1,1-difluoroethane (677 mg, 4.67 mmol) and heated to 50° C. for 18 hrs. The reaction was diluted with water and extracted with EtOAc. The organic layer was washed with water (2×) followed by brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude product 1,5-dichloro-3-(2,2-difluoroethoxy)isoquinoline (590 mg, 90% yield) which was used as is in the next step. MS: MS m/z 278.1(M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]([C:10](Cl)=[O:11])[CH2:3]1.[NH2:14]C(C)(C)CO>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]([C:10]([NH2:14])=[O:11])[CH2:3]1
Reactant: CC1CCCC(C)(C)CC1C(=O)Cl
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC1CCCC(C)(C)CC1C(N)=O

Procedure:
3,3,7-Trimethylcycloheptanecarbonyl chloride, prepared from the product of Part A by the method of Example 26 Part B, (0.5 g. 0.0025 mole) in 10 ml methylene dichloride was added to a stirred solution of 2-amino-2,2-dimethylethanol (0.5 g) in 50 ml methylene dichloride. After 3 hours the solution was washed with 2 N HCl, then with NaHCO3 solution and then dried (MgSO4). Removal of the solvent left an oil which was distilled to yield N-1',1'-dimethyl-2'-hydroxyethyl)-3,3,7-trimethylcycloheptanecarboxamide, bp. 135°/0.015 mm.