Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:28])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:28])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)nn2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(-c1cnc3[nH]cc(C(=O)NC(C)(C)C)c3n1)nn2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 78.6 μmol) in dichloromethane (2 mL) was added TFA (2.96 g, 2000 μL, 26.0 mmol, Eq: 330), the reaction mixture turned bright orange and was stirred at 25° C. for 3 h, then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. overnight then evaporated to a light yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in a small amount of dichloromethane/MeOH, added cyclohexane and some solvents evaporated to allow solid formation, which was separated by filtration and dried to give N-tert-butyl-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (25 mg, 66.1 μmol, 84.0%) as an off-white solid. MS (M+H)+=379 (>90% purity); 1H NMR (CDCl3) δ: 9.11 (s, 1H), 8.31 (d, J=3.0 Hz, 1H), 8.22 (s, 1H), 7.86 (d, J=2.3 Hz, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.26 (br. s., 2H), 7.17-7.23 (m, 1H), 4.18 (s, 3H), 3.92 (s, 3H), 1.59 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1C2C(=CC=CC=2)C=C[CH:15]=1>Cl.O>[C:15]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])#[N:14]
Reactant: c1ccc2ncccc2c1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Yield: 48 %

Procedure:
4-Chloro-3-nitrobenzoic acid (5.84 g, 29 mM), cuprous cyanide (5.2 g, 58 mM), cuprous chloride (0.96 g, 9.7 mM), and quinoline (6.9 ml, 58 mM) were heated under an argon atmosphere at 180° for 3.5 hours. After cooling, the mixture was dissolved in concentrated hydrochloric acid (60 ml), diluted with water (80 ml), and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with aqueous NaH2PO4, brine, and dried over MgSO4. Crude product was purified by chromatography on silica, eluting with a mixture of dichloromethane/acetic acid (98:2), to give 4-cyano-3-nitrobenzoic acid (2.65 g, 48%). Nmr (DMSO-d6): δ 8.31 (d, 1H); 8.41 (dd, 1H); 8.68 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10].[CH3:12][C:13]#N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:3][CH2:2][CH2:7][CH2:6][CH2:5][CH2:4][CH2:13][CH3:12])=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)c1cc(O)ccc1Cl
Reactant: CC#N
Product: CCCCCCCCCOc1ccc(Cl)c(C(N)=O)c1
Yield: 80 %

Procedure:
Synthesised from 2-chloro-5-hydroxybenzenecarboxamide according to Method B, scheme 2. Yield 80%, HPLC-MS (method 1): m/z 339 [M+H+CH3CN]+, Rt=5.29 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[C:11](=[C:15](O)[CH2:16][O:17][CH3:18])[C:10](=[O:20])[CH2:9]1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]2[NH:23][N:22]=[C:15]([CH2:16][O:17][CH3:18])[C:11]=2[C:10](=[O:20])[CH2:9]1
Reactant: NN
Reactant: COCC(O)=C1C(=O)CC(c2ccccc2Cl)CC1=O
Solvent: CCO
Solvent: O
Product: COCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 25.3 %

Procedure:
A solution of 5-(2-chlorophenyl)-2-(1-hydroxy-2-methoxyethylidene)cyclohexane-1,3-dione (0.4 g) and hydrazine hydrate (0.072 g) in ethanol (15 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography to give 6-(2-chlorophenyl)-3-methoxymethyl-4,5,6,7-tetrahydroindazol-4-one (0.1 g) as oil.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[CH:16][C:15]([NH:22][C:23](=O)[CH3:24])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.C(OCC)(=O)C>O1CCOCC1>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][CH3:21])=[CH:16][C:15]([NH:22][C:23](=[S:35])[CH3:24])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(NC(C)=O)cc3c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(NC(C)=S)cc3c12
Yield: 53.7 %

Procedure:
2741 mg of 6-acetylamino-4-ethyl-β-carboline-3-carboxylic acid isopropyl ester is heated to 70° C. in 110 ml of dioxane with 3915 mg of Lawesson's reagent while being stirred. After cooling, it is mixed with 100 ml of ethyl acetate and washed with saturated sodium chloride solution. The organic phases are dried and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with toluene+methanol=8+2. 1541 mg of 4-ethyl-6-thioacetylamino-β-carboline-3-carboxylic acid isopropyl ester with a melting point of 158-160° C. is obtained from the desired fractions.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N+:5]([O-])=[C:4]2[CH2:9][CH2:10][C@@H:11]([CH3:12])[C:3]=12.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH:9]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[C@H:11]([CH3:12])[CH2:10]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CCc2c1c(Cl)nc[n+]2[O-]
Product: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Yield: 70 %

Procedure:
A solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-oxide (1.45 g, 7.85 mmol) in acetic anhydride (20 mL) was heated to 110° C. for 2 hours. After cooling, excess solvent was removed under vacuum. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (3:1) to give (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.25 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 8.92 (m, 1H), 6.30-6.03 (m, 1H), 3.60-3.30 (m, 1H), 2.84 (m, 1H), 2.40-2.20 (m, 1H), 2.15 (d, J=6 Hz, 2H), 1.75 (m, 2H), 1.47 (d, J=6.8, 2H), 1.38 (d, J=7.2, 1H). MS (APCI+) [M+H]+227.
Reaction SMILES: [NH3:1].F[B-](F)(F)F.C(O[C:10](=[N+:20]1[CH2:28][CH:27]2[CH:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24][CH2:25][C:26]2=[O:29])[CH2:21]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:1]=[C:10]([N:20]1[CH2:28][CH:27]2[CH:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:24][CH2:25][C:26]2=[O:29])[CH2:21]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: CCOC(Cc1ccccc1OC)=[N+]1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reactant: N
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccccc1CC(=N)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 20 h

Procedure:
A 5.4N ethanolic solution (1.3 cc) of ammonia is added to a stirred suspension, cooled to -10° C., of (3aRS,7aRS)-2-[1-ethoxy-2-(2-methoxyphenyl)ethylidene]-4-oxo-7,7-diphenylperhydroisoindolium tetrafluoroborate (5.7 g) in anhydrous dichloromethane (15 cc). The reaction mixture is then allowed to return to room temperature and stirring is continued for 20 hours. The reaction mixture is diluted with dichloromethane (20 cc) and treated with 10% strength aqueous potassium carbonate solution (20 cc). The precipitate present is removed by filtration and the organic phase is then washed with distilled water (25 cc) and with saturated aqueous sodium chloride solution (25 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in acetonitrile (10 cc). The crystals obtained are drained, washed with acetonitrile (10 cc) and dried. and dried. (3aRS,7aRS)-2-[1-Imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenylperhydro-4-isoindolone (1 g), m.p. above 260° C. is obtained.
Reaction SMILES: C([O-])(O)=O.[Na+].I[CH2:7][CH2:8][F:9].[I:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=[O:19])=[CH:13][CH:12]=1>CN(C=O)C.O>[F:9][CH2:8][CH2:7][N:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[CH2:21][NH:20][C:18](=[O:19])[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([I:10])=[CH:16][CH:15]=1
Reactant: O=C(Cc1ccc(I)cc1)NC[C@H]1CCCN1
Reactant: FCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(I)cc1)NC[C@H]1CCCN1CCF
Temperature: 90 °C
Yield: 80.8 %

Procedure:
In a sealed tube, 0.53 g of NaHCO3 (6.4 mmol) and 0.49 g of 1-iodo-2-fluoroethane (2.8 mmol) are added to 0.88 g (2.6 mmol) of the compound obtained from step 1.10 dissolved in DMF (6 ml). The sealed tube is heated at 90° C. for 5 hours. The reaction mixture is cooled, the DMF is then evaporated off under reduced pressure, and the residue obtained is taken up in water (10 ml) and extracted with ethyl acetate (20 ml×2). The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol, 1% NH4OH), with a gradient of 0% to 10% methanol. 0.82 g of compound is obtained, in the form of a beige-coloured powder. Yield=85%. Melting point: 96° C. MH+: 391 (tr: 5.1 min., condition 1)
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1.NC(N)=[S:18]>C(O)C>[SH:18][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1
Reactant: Cc1ccc2c(n1)sc1c(Cl)nnnc12
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1ccc2c(n1)sc1c(S)nnnc12

Procedure:
A mixture of 7 g. (0.03 M) of 4-chloro-7-methylpyrido[3',2':4,5]thieno[3,2-d]-1,2,3-triazine, and 7 g. (0.09 M) of thiourea in 350 ml. ethanol was refluxed for 2 hours. It was then cooled and filtered. The crude product was dissolved in 5% NaOH, and treated with charcoal and filtered. Acidification with HOAC followed by filtration yielded yellow solid, m.p. 205°-208° C.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CCCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenyl)butanamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature for 3 hours. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparatory HPLC. (0.031 g, 27% yield over 2 steps): 1H NMR (CD3OD) 8.75 (br s, 1H), 8.25 (br s, 1H), 8.1 (br s, 1H), 7.7–7.6 (m, 3H), 7.5 (t, 1H), 2.4 (t, 2H), 1.72 (sextet, 2H), 1.0 (t, 3H), ES-MS (m/z) 362 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]2[O:18][C:17](=S)[NH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:17]1[O:18][C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][N:16]=1
Reactant: S=c1[nH]cc(-c2ccccc2)o1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1ncc(-c2ccccc2)o1
Temperature: 0 °C

Procedure:
0.29 g (2.8 mmol) of triethylamine is added to a mixture of 0.5 g (2.8 mmol) of 5-phenyl-3H-oxazole-2-thione (FR 1,450,443) and 2.3 mL of phosphoryl chloride cooled to 0° C. The mixture is heated to 120° C. for 3 hours.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].I[CH:25]([CH3:27])[CH3:26].CC(C)=O>CCCCCC>[CH:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6](=[O:17])(=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:27])[CH3:26]
Reactant: CC(C)I
Reactant: O=S1(=O)c2ccccc2Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C)Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O
Reaction time: 8 h

Procedure:
A mixture of 1.00 gm (0.0043 mole) of 3-hydroxyphenoxathiin 10,10-dioxide (Example 7) 1.48 gm (0.0107 mole) of anhydrous granular potassium carbonate, 5.5 mL of 2-iodopropane (Aldrich Chemical Co.), and 60 mL of acetone were stirred overnight. The acetone was removed under water pump vacuum and the residue mixed with methylene chloride and filtered. The filtrate was washed with 2×200 mL of water and dried over magnesium sulfate. The solvent was removed under water pump vacuum to give an oil. Some hexane was added to the oil and the mixture heated on a steam bath. This gave a white solid which was recrystallized from ethyl acetate/hexane to yield 0.75 gm of 3-isopropoxyphenoxathiin 10,10-dioxide, m.p. 94-95°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH:9]=[CH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2>CO>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2
Reactant: O=C(C=Cc1cccc2[nH]ccc12)c1ccccc1O
Solvent: CO
Product: O=C(CCc1cccc2[nH]ccc12)c1ccccc1O
Yield: 71 %

Procedure:
A mixture of 200 mg of the product of Step A in 10 ml of methanol was hydrogenated in the presence of palladized activated charcoal at room temperature until absorption ceased and was then filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica. Elution with a 6-3-1 cyclohexane-dichloromethane-triethylamine mixture yielded 143 mg of 1-(2-hydroxyphenyl)-3-(1H-indol-4-yl)-1-propanone melting at ≃143° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](Cl)=[S:20])[CH:15]=[CH:16][CH:17]=1.Cl.CCOCC>[OH-].[Na+]>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[S:20])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(CC(=S)Cl)c1
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cccc(CC(=S)Nc2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 957.3 %

Procedure:
3-Methylbenzenethiol and butyl bromoacetate were reacted by a conventional method and then hydrolyzed to obtain 3-methyl-α-phenylthioacetatic acid. 3-Methyl-α-phenylthioacetatic acid was reacted with thionyl chloride by a conventional method to obtain 3-methyl-α-phenylthioacetyl chloride. Anthranilic acid 5.6 g (4.1 mmol) was dissolved in 10% aqueous sodium hydroxide solution 32 ml and to this solution, 3-methyl-α-phenylthioacetyl chloride (99° C./3.3 mmHg) 8.9 g was added dropwise at 0° C. The resulting solution was stirred at room temperature for 20 minutes and neutralized with 10% hydrochloric acid solution. To this solution, ether was added, and deposited crystals were collected by filtration and washed with hot water to obtain N-(3-methylphenylthioacetyl)anthranilic acid (melting point: 148° to 150° C.) 11.2 g (yield: 25%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:55][CH2:56][C:57]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][C:58]=1[C:59]([NH:61][CH3:62])=[O:60]>CN(C=O)C.CN(C)C1C=CN=CC=1>[F:67][C:64]1[CH:65]=[CH:66][C:57]([CH2:56][NH:55][C:21]([C:10]2[N:11]=[C:12]3[C:18]([CH3:19])([CH3:20])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:22])=[C:58]([C:59](=[O:60])[NH:61][CH3:62])[CH:63]=1
Reactant: CC1(C)CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CNC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC2(C)C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Intermediate 6, 3-(benzyloxy)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxylic acid, (79 mg, 0.25 mmol) was placed together with O-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, HATU, (114 mg, 0.3 mmol) in 2 mL DMF under N2 and stirred for 20 min. 4-(Dimethylamino)pyridine, DMAP, (100 mg, 0.8 mmol) and intermediate 3, 2-aminomethyl-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (89 mg, 0.3 mmol) in 1 mL DMF were added and stirring continued for 20 min. The reaction mixture was concentrated, the residue dissolved in CH2Cl2 and washed with H2O. The CH2Cl2 layer was separated, dried (MgSO4), filtered and concentrated to give 118 mg of a the title compound as a solid (Yield=95%). 1H NMR (300 MHz, CDCl3) δ ppm: 8.31–8.46 (1 H, m) 7.24–7.46 (5 H, m) 6.95–7.15 (3 H, m) 6.88 (1 H, s) 5.23 (2 H, s) 4.48 (2 H, d, J=6.6 Hz) 3.95–4.10 (2 H, m) 2.93 (3 H, t, J=5.1 Hz) 2.00–2.16 (2 H, m) 1.34 (6 H, s); LC/MS m/z 479 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23]Cl>CN(C=O)C>[CH3:13][C:10]1([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=[C:2]([O:1][CH2:23][CH2:22][O:21][CH3:20])[C:11]1=2
Reactant: COCCCl
Reactant: CC1(C)CCC(C)(C)c2c(O)cc(C=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C=O)cc2c1C(C)(C)CCC2(C)C
Reaction time: 1 h
Yield: 95 %

Procedure:
34 g (148 mmol) of 4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde are dissolved in 400 mL of anhydrous DMF. 7.2 g (178 mmol) of 60% sodium hydride are then added portionwise, and the reaction medium is stirred for 1 hour. 16.5 mL (178 mmol) of 2-methoxyethyl chloride are added dropwise, and the medium is stirred at room temperature for 2 hours and then hydrolysed and extracted with ethyl ether. The organic phase is washed with 1N sodium hydroxide solution and then three times with water. The residue obtained is purified by chromatography (eluent: heptane). A yellow oil is obtained (m=42.7 g; yield=95%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1)=[O:13].[NH2:23][C:24]1[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:28][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:8])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[CH:15]=1)=[O:13]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1cc2nccnc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1cc2nccnc2s1
Yield: 52 %

Procedure:
A solution of 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)benzoic acid 50 (25 mg, 0.080 mmol), 3-aminobenzotrifluoride (9.87 μl, 12.86 mg, 0.080 mmol), TBTU (38.4 mg, 0.120 mmol) and DIPEA (0.039 mL, 0.239 mmol) in DMF (1 mL) under a nitrogen atmosphere was stirred overnight at 40° C. The reaction mixture was poured into 3% citric acid solution. The resulting precipitation was collected and washed with water to give the title compound N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 51 (19 mg, 53%). NMR (400 MHz, DMSO-d6) 2.38 (s, 3H), 7.46 (d, J=7.4 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.90 (dd, J=7.8 and 1.6 Hz, 1H), 8.04 (d, J=1.6 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.25 (s, 1H), 8.57 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 10.55 (s, 1H), 10.66 (s, 1H). (m/z)=457 (M+H)+.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([OH:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(O)cc3)CC2)c(OC)nc1C
Yield: 58 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31].O>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH2:30][CH3:31])[CH:20]=2)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:23])[CH:3]=1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (354 mg) in N,N-dimethylacetamide (4.7 ml) were added powdered potassium carbonate (131 mg) and ethyl iodide (141 mg). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with water and dried (MgSO4). The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (324 mg) as a light yellow oil. MS (m/e)=438.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:27]([C:26]5[CH:29]=[CH:30][C:23]([N:17]6[CH2:22][CH2:21][O:20][CH2:19][CH2:18]6)=[CH:24][CH:25]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:27]1[C:26]1[CH:25]=[CH:24][C:23]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: c1cc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2cc1-c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1

Procedure:
Compound 286 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 4-morpholinylbenzaldehyde. [M+H]+ calcd for C34H32N6O2: 557.26; found: 557.58.