Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].[K].[C:11]([NH:14][C:15]1[S:16][C:17](Cl)=[CH:18][N:19]=1)(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([NH:14][C:15]1[S:16][C:17]([S:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Fc1ccc(S)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ccc(F)cc2F)s1
Temperature: 130 °C
Reaction time: 7 h
Yield: 38.5 %

Procedure:
A mixture of salt of potassium 2,4-difluorothiophenol (20 g), 2-acetamido-5-chlorothiazole (21 g) and potassium carbonate anhydrous (29.8 g) in N,N-dimethylformamide (400 ml ) was stirred at 130° C. for 7 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with water and the precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel, 70-230 mesh; Merck: 750 g) and eluted with a mixture of chloroform and methanol (50:1). The fractions containing the objective compound were combined and evaporated to dryness in vacuo to give 2-acetamido-5-(2,4-difluorophenylthio)thiazole (11.91 g, yield: 38.5%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC1C=CC=C2C=1COC2=O>C(Cl)(Cl)(Cl)Cl>[C:12]([C:11]1[CH:16]=[CH:17][C:18]([CH2:20][Br:1])=[CH:19][C:10]=1[CH3:9])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(C)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1cccc2c1COC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1C

Procedure:
N-Bromosuccinimide (44.9 g) was added to a solution of methyl 2,4-dimethylbenzoate (41.36 g) in carbon tetrachloride containing a trace of dibenzoyl peroxide. The mixture was heated under reflux until no orange colour persisted then cooled, filtered and the filtrate evaporated to leave an oil. This was distilled until ~16 g distillate bp 98°-140°/0.8-5 mm (starting material ) had been collected. The residue was then heated at atmospheric pressure until no more methyl bromide was evolved, to give a mixture of the title compound and 4-methylphthalide. Addition of hot petrol and filtration from the phthalide gave after evaporation the title compound. τ (CDCl3) 7.48 (3H, s), 6.21 (3H, s), 5.65 (2H, s), 2.6-2.93 (2H, m), 2.18 (1H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:25]([OH:27])=[O:26])[CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:9]([CH3:28])[N:8]=[C:7]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:6]=2[CH:35]=1.[N+](=[CH2:38])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:25]([O:27][CH3:38])=[O:26])[CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[CH:9]([CH3:28])[N:8]=[C:7]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:6]=2[CH:35]=1
Reactant: C=[N+]=[N-]
Reactant: CC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NN=C(CCCN1CCN(C)CC1)C(=O)O
Product: COC(=O)C(CCCN1CCN(C)CC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1C

Procedure:
In the manner given in Example 14, a solution of 7-chloro-2-[[1-carboxy-4-(4-methylpiperazino)butylidene]-hydrazino]-3-methyl-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-4-(4-methylpiperazino)butylidene]-hydrazino]-3-methyl-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[C:36]([NH:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 28 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.83 (br s, 1H), 7.41–7.85 (m, 12H), 4.90 (s, 1H), 3.36 (dd, 2H, J=5.6, 12.0 Hz), 3.18 (d, 2H, J=11.6 Hz), 2.69 (t, 2H, J=6.4 Hz), 2.53 (m, 1H), 2.34 (m, 2H), 2.15 (s, 3H), 1.96–1.79 (m, 6H); ESMS m/e: 506.4 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:7](=[O:26])[O:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]1[CH2:22][CH2:23][C:24](=[O:25])[C:11]=1[CH:10]=2)C.Cl>C(O)(=O)C>[O:26]=[C:7]1[C:6]([CH2:5][C:4]([OH:27])=[O:3])=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]2[C:9](=[CH:10][C:11]3[C:24](=[O:25])[CH2:23][CH2:22][C:12]=3[CH:13]=2)[O:8]1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(=O)CC3
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(=O)CC3
Yield: 78.6 %

Procedure:
Ethyl(2,8-dioxo-4-phenyl-2,6,7,8-tetrahydrocyclopenta[g]chromen-3-yl)acetate (1.2 g) was dissolved in acetic acid (20 ml) and concentrated hydrochloric acid (10 ml), and heated under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resultant residue was dissolved in a solvent mixture of THF (10 ml) and ethyl acetate (50 ml), and then washed with water followed by a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by recrystallization from ethyl acetate to obtain the title compound (0.87 g, yield: 79%).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3([CH3:24])[CH2:23][CH2:22]3)=[C:15]([CH:25]([CH3:27])[CH3:26])[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:25]([C:15]1[CH:14]=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:9]=2)[CH:18]=[CH:17][C:16]=1[CH2:19][O:20][C:21]1([CH3:24])[CH2:22][CH2:23]1)([CH3:27])[CH3:26]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(COC3(C)CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1COC1(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution methyl{4-[3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenylethynyl]-phenyl}-acetate (Compound 140. 70.0 mg, 0.19 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (240.0 mg, 6.0 mmols, 2.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded of the title compound as a colorless solid.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].[C:25]([C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=1)#[CH:26].C1(C(O)(C#C)C)C=CC=CC=1>>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:26]#[C:25][C:27]4[CH:28]=[N+:29]([O-:33])[CH:30]=[CH:31][CH:32]=4)[CH:19]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: C#Cc1ccc[n+]([O-])c1
Agent: C#CC(C)(O)c1ccccc1
Product: O=C(NC1CC1)c1cn(-c2cccc(C#Cc3ccc[n+]([O-])c3)c2)c2ncccc2c1=O

Procedure:
Following the procedure of PREPARATIVE EXAMPLE 4, but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 1 of PREPARATIVE EXAMPLE 3 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, and 3-ethynylpyridine N-oxide from Step 1 for 2-phenyl-3-butyn-2-ol, the N-cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][CH:14]([CH3:20])[CH2:15][CH:16]([NH2:19])[CH2:17][CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:19][CH:16]([CH2:15][CH:14]([CH3:20])[CH3:13])[CH2:17][CH3:18])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: CCC(N)CC(C)C
Reactant: COc1ccc(C(=O)O)cc1C
Product: CCC(CC(C)C)NC(=O)c1ccc(OC)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and 5-methylhexan-3-amine (example 5a). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 9H); 1.38 (m, 2H); 1.47 (m, 1H); 1.65 (m, 2H); 2.24 (s, 3H); 3.86 (s, 3H); 4.16 (m, 1H); 5.65 (d, 1H); 6.83 (d, 1H); 7.54 (s, 1H); 7.61 (d, 1H). MS (264, M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C1(N=C=NC2CCCCC2)CCCCC1.[C:25](=S)=[S:26]>CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:6]=[C:25]=[S:26]
Reactant: NCc1cccc(F)c1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: Fc1cccc(CN=C=S)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 3-fluorobenzylamine (6.26 g., 0.05 mole) in ether (10 ml.) was added dropwise to a solution of dicyclohexylcarbodiimide (10.3 g., 0.05 mole) and carbon disulfide (20 ml., 0.333 mole) in ether (60 ml.) at -5 °to -10° C. and the mixture was stirred for 17 hours at 25° C. The mixture was filtered, and the solvent was removed under vacuum. The resulting oil was dissolved in hexane-ethyl acetate (19:1), filtered and the solvent removed under vacuum. The oil was then dissolved in hexane-ethyl acetate (9:1) and purified by flash chromatography (silica) to give 3-fluorobenzylisothiocyanate as an oil (8.14 g., 97%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[C:46]([CH3:49])[C:45]([F:50])=[C:44]([NH:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[C:46]([CH3:49])[C:45]([F:50])=[C:44]([NH:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=3)[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: COc1ccc(CNc2nc(N)c(F)c(C)c2F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)c(C)c2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 3 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.78 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.90 g of 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)-4-methylpyridine. The solution was concentrated under reduced pressure, and to the residue were added 1.3 g of anhydrous potassium carbonate and 3 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as a brown crude oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][CH:8]=2)[C:5]([C:25]2[CH:44]=[CH:43][C:28]([O:29][C@H:30]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]([O:33]CC)=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][CH:12]=2)[C:5]([C:25]2[CH:26]=[CH:27][C:28]([O:29][C@H:30]([CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]([OH:33])=[O:32])=[CH:43][CH:44]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(C)n2-c2ccc(OCCCCCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)n1-c1ccc(OCCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a mixed solution of ethyl (2R)-2-(4-{5-methyl-1-[4-(5-phenylpentyloxy)phenyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate (520 mg, 0.884 mmol) in THF (20 ml) and methanol (20 ml) was added 1N aqueous potassium hydroxide solution (5 ml, 5 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 336 mg (yield: 67.9%)
Reaction SMILES: CO[CH:3]([O:15]C)[C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl.CCOCC>[CH:3]([C:4]1[CH:5]=[C:6]([NH:7][C:24](=[O:26])[CH3:25])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)=[O:15]
Reactant: COC(OC)c1cc(N)cc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(C=O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-(dimethoxymethyl)-5-(trifluoromethyl)aniline in dichloromethane (5 ml) at 0° C., triethyl amine (0.2 ml) was added followed by acetyl chloride. Reaction mixture was stirred at rt for 2 h. Then dichloromethane was removed under reduced pressure. Reaction mixture was diluted with ether, washed with water, brine and dried. Crude residue was column chromatographed to yield 170 mg of the amide. Then solvent was removed and the crude residue was column purified (40% ethylacetate/60% hexanes) to yield 100 mg of N-(3-(dimethoxymethyl)-5-(trifluoromethyl)phenyl)acetamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21]3)[CH:17]=[CH:16][C:15]=2[N+:31]([O-])=O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C1COCC1.O.[Fe].CC(O)=O>[O:12]=[C:11]1[CH2:10][C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[N:31][C:15]2[CH:16]=[CH:17][C:18]([N:20]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21]3)=[CH:19][C:14]=2[NH:13]1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3ccc(-c4ccccc4)c3)ccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(C2=Nc3ccc(-n4ccc(-c5ccccc5)c4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 3-(3-cyano-phenyl)-N-[2-nitro-5-(3-phenyl-pyrrol-1-yl)-phenyl]-3-oxo-propionamide (Example M12) by reductive cyclization with Fe/HOAc in THF/H2O at 80° C. according to the general procedure J (method d). Obtained as a yellow solid (11 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>CN(C)C(=O)C.C(OCC)(=O)C>[F:16][C:17]([F:25])([F:26])[C:18]1[CH:19]=[CH:20][C:21]([NH:22][S:2]([C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3])=[CH:23][CH:24]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To ethyl 3-(chlorosulfonyl)benzoate (4.0 g, 16.08 mmol) in N,N-dimethylacetamide (20 mL) was added 4-(trifluoromethyl)aniline (10.37 g, 64.3 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 2.5 hours, and then it was diluted with ethyl acetate (130 mL). The organic solution was washed with 1 N HCl (2×60 mL) and saturated NaCl (60 mL). The organic layer was concentrated, ethanol (40 mL) was added, and the mixture was concentrated to give ethyl 3-({[4-(trifluoromethyl)phenyl]amino}sulfonyl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([C:32]2[C:33]([CH3:42])=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[N+:37]=2[O-:38])[CH:29]=[CH:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:36]5[N+:37]([O-:38])=[C:32]([C:28]6[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=6)[C:33]([CH3:42])=[CH:34][CH:35]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)O)[n+]([O-])c1-c1cccc(F)c1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)[n+]([O-])c1-c1cccc(F)c1
Yield: 75 %

Procedure:
A solution (5 mL) of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (196 mg, 0.60 mmol), 6-(3-fluorophenyl)-5-methylpyridine-2-carboxylic acid 1-oxide (178 mg, 0.72 mmol), HATU (273 mg, 0.72 mmol) and N,N-diisopropylethylamine (155 mg, 1.20 mmol) in N,N-dimethylformamide was stirred at room temperature for 5 hr. The reaction solution was divided into two layers with tetrahydrofuran and sodium hydrogen carbonate saturated aqueous solution and the aqueous layer was subjected to extraction (3 times) with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica) and recrystallized from ethanol/water to give the title compound (250 mg, 75%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([NH2:30])=[S:29])=[CH:24][CH:23]=1>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:30]=[C:28]([CH2:27][O:26][C:25]3[CH:31]=[CH:32][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[S:29][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(OCC(N)=S)cc1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CC#N
Product: COc1ccc(OCc2nc(-c3ccc(F)cc3)c(-c3ccc(SC)cc3)s2)cc1
Yield: 54 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromo-ethanone, (Example 1, Step 3) (2.30 g, 6.8 mmol) and 4-methoxyphenoxy thioacetamide (1.35 g, 6.8 mmol) in 20 mL of acetonitrile was heated to reflux for 1.1 hours. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford a solid that was recrystallized from a mixture of ethyl acetate and isooctane to provide pure 4- (4-fluorophenyl) -5- (4-methylthiophenyl)-2-((4-methoxyphenoxy) methyl) thiazole (1.60 g; 54%): mp 89°-92° C., 1H NMR (CDCl3) 300 MHz 7.47 (dd, J=3.2, 8.7Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5Hz, 2H), 6.98 (m, 4H), 6.86 (d, J=9.1 Hz, 2H), 5.33 (s, 2H), 3.78 (s, 3H), 2.49 (s,3H). 19F NMR (CDCl3) -114.07 (m). Mass spectrum M+H+=438.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])C(=O)C(F)(F)F)[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:41][CH2:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CS(=O)(=O)CCN(CCCCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)CCNCCCCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 34.9 %

Procedure:
In 2.6 ml of a mixture (1:1) of tetrahydrofuran and methanol was dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(4 (N-(2-(methanesulfonyl)ethyl)-2,2,2-trifluoroacetamido)butyloxyimino)quinazoline (V-14, 40 mg), and 86 μl of 1 mol/L aqueous sodium hydroxide solution was added, followed by stirring at room temperature for 14 hours, and at 40° C. for 2 hour. After the reaction, the reaction mixture was extracted with ethyl acetate, the organic layer was dried, and filtrate was concentrated. The concentrated residue was purified by chromatography (eluting with 0 to 3% methanol-contenting ethyl acetated) using an amino column, and the resulting pale yellow oil was powdered with a mixture of hexane and ethyl acetate to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(4-(2-(methanesulfonyl)ethylamino)butyloxyimino)quinazoline (V-15, 12 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NCc2cccnc2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(N(Cc2cccnc2)S(C)(=O)=O)c(C)c1

Procedure:
A 4.2 g. portion of 3-(2,4-dimethylphenylaminomethyl)pyridine was dissolved in 20 ml. of dichloromethane and 4.1 g. of potassium carbonate and 2.5 ml. of methanesulfonyl chloride were added. The mixture was stirred over the week-end under reflux, and was then extracted with 20 ml. of aqueous sodium bicarbonate. The organic phase was dried and evaporated under vacuum. The residue was dissolved in diethyl ether and the solution was separated from insolubles and evaporated under vacuum. The oil was dissolved in chloroform and chromatographed over silica gel, eluting with chloroform:ethyl acetate to obtain 2.5 g. of the desired product, m.p. 62°-65°.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:17][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:20]>>[ClH:20].[CH2:18]([S:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2)[CH3:19]
Reactant: CCSc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: CCSc1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A3 (e) from 5-Ethylsulfanyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCl. Light Brown solid. MS (m/e): 216.3 ([M+H+, 100%).