Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:36][CH2:37][C:38]([NH:40][CH:41]([CH3:43])[CH3:42])=[O:39].C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][C:6]=1[C:7]([NH:36][CH2:37][C:38](=[O:39])[NH:40][CH:41]([CH3:43])[CH3:42])=[O:9]
Reactant: CC(C)NC(=O)CN
Reactant: Nc1ccc(O)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)CNC(=O)c1cc(O)ccc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-hydroxyanthranilic acid (7.6 g, 49.3 mmol) in DMF (100 mL) was added 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride (EDC) (10.4 g, 54.2 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (7.3 g, 54.2 mmol), 2-amino-N-isopropyl-acetamide hydrochloride (INTERMEDIATE I.1) (7.5 g, 49.3 mmol) and N,N-diisopropylethylamine (DIEA) (9.50 mL, 7.0 g, 54.2 mmol). The reaction mixture was stirred at room temperature for 24 h, concentrated in vacuo to half of its volume and partitioned between diethyl ether (100 mL) and 1N HCl (aq.) (400 mL). The aqueous layer was extracted with diethyl ether (5×100 mL), and ethyl acetate (5×100 mL). The aqueous layer was then concentrated under high vacuum to dryness. The red residue was dissolved in ethanol (20 mL) followed by addition of dichloromethane (1 L). The resulting brown precipitate was filtered under vacuum and washed with a minimum amount of methanol to give the desired product 2-amino-5-hydroxy-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE I.1) hydrochloride salt as a white solid (5.7 g, 19.8 mmol, 40%).
Reaction SMILES: C[N:2]([CH3:13])[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH3:11].[OH:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22]C#N)[CH2:16]1>>[OH:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][C:13]2[NH:2][C:3](=[O:12])[C:4]3[C:5]([CH:11]=2)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=3)[CH2:16]1
Reactant: N#CCCN1CCCC(O)C1
Reactant: Cc1cccc(C(=O)N(C)C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CCCC(O)C3)cc12
Yield: 6.6 %

Procedure:
By the reaction in the same manner a: in Example 1a, using N,N-dimethyl-2,3-dimethylbenzamide (5.1101 g) and 3-(3-hydroxypiperidin-1-yl)propionitrile (2.2 g), 3-[2-(3-hydroxypiperidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (269.6 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[C:21]([C:23]([OH:25])=O)[N:20]=[C:19]([C:26]([OH:28])=[O:27])[CH:18]=1.[C:29](Cl)(=O)C(Cl)=O.Cl.[CH3:36][OH:37]>C(Cl)Cl.CN(C=O)C.O>[CH3:36][O:37][C:23]([C:21]1[CH:22]=[C:17]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:3]=2[O:2][CH3:1])[CH:18]=[C:19]([C:26]([O:28][CH3:29])=[O:27])[N:20]=1)=[O:25]
Reactant: COc1cc(OCc2ccccc2)ccc1-c1cc(C(=O)O)nc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2OC)cc(C(=O)OC)n1
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of 10 g (0.026 mole) of the diacid 22 in 100 ml of CH2Cl2 and 7 drops of DMF was added, at 0° C., in a dropwise fashion 12 ml (0.138 mole) of oxalyl chloride. After addition the mixture was allowed to come to room temperature with vigorous evolution of HCl gas and stirred for 2 hours. The resulting homogeneous solution was then cooled in an ice bath and 20 ml of methanol in 40 ml of CH2Cl2 was slowly added. The resulting mixture was stirred for 30 minutes at room temperature and poured into 300 ml of water. The organic phase was removed, washed with 10% NaHCO3, water, dried (Na2SO4) and solvents removed. The crude diester (15 g) was purified via plug filtration with SiO2 /EtOAc/CH2Cl2 (20:80) yielding 7.0 g (65%) of the diester (23):NMR (CDCl3 ) 3.85 (s, 3,OCH3), 4.05 (s,6,CO2Me), 5.1 (s,2,OCH2O), 6.7 and 7.4 (m,3,--C6H3O2R2) 7.35 (s,5,--C6H5), 8.5 (s,2,--C5H2N'.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(Br)n[nH]c2c1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of 5.0 g of 6-nitro-1H-indazole in 50 ml dimethylformamide was added 5.73 g of N-bromosuccinimide at room temperature, and the mixture was stirred at the same temperature for 1 hour. After removing the solvent by distillation, the residue was added with 250 ml of ethyl acetate. The mixture was sequentially washed with half-saturated aqueous sodium hydrogencarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. After filtrating the organic layer through a silica gel pat, the solvent was evaporated and the resulting crystals were suspended in toluene, to give 6.59 g of the title compound as light brown crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)(O)[O-].[Na+].I[CH2:25][CH3:26]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH2:25][CH3:26])=[O:6]
Reactant: CCI
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of 3-methyl-4-nitrobenzoic acid (1) (362.3 g, 2.0 mol), N,N-dimethylformamide (2000 mL), sodium bicarbonate (200 g, 2.38 mol) and iodoethane (623.9 g, 4.0 mol) was stirred at 70° C. for 18 h. The mixture was allowed to cool to room temperature and poured into water (2000 mL. The resulting solid was collected by filtration, washed with water and dried. The solid was washed further with hexane and dried to provide the title product (382.1 g, 91%) as an off-white solid: mp 51°-52.5° C.; 1H NMR (CDCl3) δ 8.04-7.98 (m, 3H), 4.42 (q, 2H), 2.63 (s, 3H), 1.42 (t, 3H); Mass spectrum (NH3 --CI) m/z 210 (100%, M+H+).
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.Cl.[NH2:17][N:18]1[CH2:23][CH:22]=[CH:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:5]([NH:17][N:18]2[CH2:19][CH:20]=[CH:21][CH2:22][CH2:23]2)=[O:4])[CH:11]=1
Reactant: NN1CC=CCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1)NN1CC=CCC1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
To a solution of trichloromethyl chloroformate (2.76 ml) in methylene chloride (200 ml) was added a solution of 3-aminopyridine (2.165 g) in methylene chloride (50 ml) and stirred for 2 hours at -50° C. The mixture was added to a mixture of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (3.096 g) and triethylamine (2.327 g) in methylene chloride (100 ml) and the resultant mixture was stirred at the same temperature. After stirring for 1 hour, the reaction mixture was allowed to warm to ambient temperature and stirred for 17 hours. After evaporation of methylene chloride, the residue was dissolved in water (50 ml) and the resultant aqueous solution was adjusted to pH 8.0-8.5 with sodium bicarbonate. The precipitate was removed by filtration and the filtrate was extracted with ethyl acetate (300 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (40 g) using chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give N-[(3-pyridylcarbamoyl)amino]-1,2,3,6-tetrahydropyridine (1.62 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[C:9][CH3:10].CN(C)C=O.[CH2:17]([O:24][CH2:25][N:26]1[C:31](=[O:32])[C:30]2[NH:33][C:34]([N:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[N:35][C:29]=2[CH:28]=[N:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[CH2:17]([O:24][CH2:25][N:26]1[C:31](=[O:32])[C:30]2[N:33]([CH2:7][C:8]#[C:9][CH3:10])[C:34]([N:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)=[N:35][C:29]=2[CH:28]=[N:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3cnn(COCc4ccccc4)c(=O)c3[nH]2)CC1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(COCc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.5 %

Procedure:
0.74 g of potassium carbonate and 0.078 g of 2-butynyl bromide were added to a 20-ml N,N-dimethylformamide solution of 0.216 g of t-butyl 4-(6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine-1-carboxylate and the mixture was stirred at room temperature for 16 hours. Then, 50 ml of ethyl acetate was added to the solution. The organic layer was washed three times with 20 ml of water, and then with 10 ml of a saturated sodium chloride solution. The solution was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.139 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (3:2).
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[O:4].[Br:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)C(O)=O.Cl.[CH3:18][O:19]NOOC.C(N(CC)CC)C>C(Cl)(=O)C(Cl)=O.O.C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:15]=[CH:11][C:10]([Cl:16])=[C:9]([CH:8]=1)[C:3]([N:2]([O:19][CH3:18])[CH3:1])=[O:4]
Reactant: CONOOC
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
Oxalyl chloride (3.78 mL, 0.0441 mmol) and N,N-dimethylformamide (0.06 mL) were added to a chloroform (20 mL) solution of 5-bromo-2-chlorobenzoic acid (10.0 g, 0.0425 mol). After the reaction mixture was stirred at room temperature for one day, the reaction mixture was evaporated under reduced pressure. The obtained yellow oily substance was dissolved in chloroform (20 mL). This solution was added dropwise to a mixture of N,O-dimethoxyhydroxylamine hydrochloride (4.56 g, 0.0468 mol), triethylamine (12.3 mL, 0.0882 mol) and chloroform (50 mL) for 15 minutes, while maintaining the reaction temperature at 5° C. to 10° C. After stirred for 15 minutes, the reaction mixture was warmed to room temperature. After water (20 mL) was added to the reaction mixture, the organic layer was separated and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (11.8 g, 99.7%) as a colorless crystal. This was used in the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:25]([CH:26]=1)[C:8]1[N:9]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[C:10](=[O:17])[C:11]3[C:16]([C:7]=1[N:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>C(Cl)(Cl)Cl>[CH2:27]([NH:29][C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:25]([CH:26]=1)[C:8]1[N:9]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[C:10](=[O:17])[C:11]3[C:16]([C:7]=1[N:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:31])[CH3:28]
Reactant: Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Temperature: 25 °C
Reaction time: 216 h
Yield: 38.5 %

Procedure:
A mixture of compound 53 (1.0 equiv., 0.276 mmol, 0.100 g) and ethyl isocyanate (5.0 equiv., 1.382 mmol, 0.098 g) in chloroform (3 ml) was stirred at room temperature for 9 days. The resulting precipitate was filtered off and successively washed with methanol, isopropanol and isopropyl ether to give 1-ethyl-3-[6-(6-chloro-pyridin-3-yl)-5,6-dihydro-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-yl]-urea (60) (0.046 g, yield=38%, purity (LC)=90%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([S:14][C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[C:21]([NH:23][OH:24])=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25](Br)[CH:26]=[CH2:27].Cl>O.C1(C)C=CC=CC=1>[CH2:27]([O:24][NH:23][C:21]([C:16]1[CH:17]=[N:18][N:19]([CH3:20])[C:15]=1[S:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:22])[CH:26]=[CH2:25]
Reactant: Cn1ncc(C(=O)NO)c1SCc1ccccc1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCONC(=O)c1cnn(C)c1SCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
In a solution of potassium carbonate (1.3 g, 9.4 mmol) in water (10 ml), a solution of 5-benzylthio-1-methylpyrazole-4-carbohydroxamic acid (2.0 g, 7.6 mmol) and allyl bromide (1.1 g, 9.1 mmol) in toluene (10 ml) were added, and stirred at 50° C. for 4 hours. After cooling to room temperature, the mixture was adjusted to pH 1 by adding 35% hydrochloric acid and extracted with ethyl acetate. The resulting ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the aimed product (1.9 g). Oily substance. Proton nuclear magnetic resonance chemical shift values δ (ppm) (in CDCl3) 3.42 (s, 3H), 3.95 (s, 2H), 4.49 (d, J=6.3 Hz, 2H), 5.33-5.43 (m, 2H), 6.00-6.16 (m, 1H), 6.93-7.00 (m, 2H), 7.21-7.30 (m, 3H), 8.08 (s, 1H), 9.68 (brs, 1H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:36]([CH3:38])[CH3:37])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl.C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:36]([CH3:38])[CH3:37])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccccc3)CCC(=O)CC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)N1CCn2c(CC3(c4ccccc4)CCC(=O)CC3)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 71.9 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(4-oxo-1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (272) (200 mg, 0.39 mmol) in dichloromethane (25.0 mL) was added triphenyl phosphine (152 mg, 0.58 mmol) and diisopropyl azodicarboxylate (0.12 mL, 0.58 mmol) at room temperature and stirred for 30 min (silica TLC, 5% methanol in ethyl acetate, Rf=0.5). The reaction mixture was concentrated under reduced pressure and purified by normal silica gel (100-200 mesh) column chromatography using gradient polarity mobile phase (50% ethyl acetate in hexane to 5% methanol in dichloromethane) to get pure 9-benzyloxy-2-isopropyl-6-(4-oxo-1-phenyl-cyclohexylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (273) (140 mg, 72.53%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH3:11])#[N:2].S(=O)(=O)(O)[OH:22]>>[CH3:11][N:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1[S:6][N:5]=[C:4]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]=1[C:1]([NH2:2])=[O:22]
Reactant: CCCCCCSc1nsc(NC(=O)N(C)C)c1C#N
Reactant: O=S(=O)(O)O
Product: CCCCCCSc1nsc(NC(=O)N(C)C)c1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A mixture of 3-(4-cyano-3-hexylsulfanyl-isothiazol-5-yl)-1,1-dimethyl-urea (0.09 g, 0.29 mmol) and concentrated sulfuric acid (0.18 mL) was stirred at ambient temperature for 1.5 hours. The mixture was diluted with ice water, extracted three times into ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo affording 0.076 g (78%) of 5-(3,3-dimethyl-ureido)-3-hexylsulfanyl-isothiazole-4-carboxylic acid amide as a colorless solid: 1H NMR (300 MHz, acetone-d6) δ 7.08 (bs, 2H), 3.20 (t, 2H, J=7.2 Hz), 3.02 (s, 6H), 1.63 (p, 2H, J=7.2 Hz), 1.35 (m, 2H), 1.23 (m, 4H) 0.78 (t, 3H, J=6.9 Hz) ppm; MS (APCl, m/z): 331 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16].[Cl-].[Al+3].[Cl-].[Cl-].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>ClCCCl>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[C:29]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=2)(=[O:11])=[O:10])[CH:30]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1NC(=O)C(F)(F)F
Reactant: COc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(S(=O)(=O)c2cc(Br)ccc2OC)cc1NC(=O)C(F)(F)F

Procedure:
In a 500 mL 3-neck round bottom flask equipped with reflux condenser, N2 inlet, thermometer socket and magnetic bar inside was added 4-Methoxy-3-(2,2,2-trifluoroacetylamino)benzenesulfonyl chloride (17 grams, 53.5 mmol) in 1,2-dichloroethane (200 mL). To the stirred solution of above reactions mass, Aluminium chloride (7.86 grams, 58.89 mmol) and 4-bromo anisole (20 grams, 107 mmol) were added slowly. Then the reaction mass was stirred under reflux temperature for 20 hours. Reaction mass was quenched into ice cold water and acidified with 2N hydrochloric acid (50 mL) until the pH was ˜4 and extracted the product with ethyl acetate (3×200 mL). The combined organic layers were washed with brine solution (1×50 mL), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to obtain the technical product. It was further purified by column chromatography to obtain the title product, the eluent being 15% ethyl acetate in n-hexane. Yield: 18.4 grams
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:24](Br)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCl>[C:24]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:26])[CH3:25]
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Reactant: CC(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O/N=C1\CCc2ccccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Yield: 60.2 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (25 mg, 0.076 mmol) and acetylbromide (0.017 ml, 0.23 mmol) were added into dichloromethane (2.0 ml). Then, at room temperature triethylamine (0.032 ml, 0.23 mmol) was added, stirred for an hour so as to complete the reaction. Afterward, an organic layer was separated by blending water, washed again with water and saturated brine, and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and made to crystal by using a mixed organic solvent (diethylether/isopropanol/n-hexane=1/1/5, v/v/v). As a result, 16.9 mg of the present compound (productive yield 60%) was obtained as a white solid crystal.
Reaction SMILES: [C:1]12([C:8]3=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=[C:7]3[CH2:6][O:5][CH2:4]1)[CH2:3][CH2:2]2.CN(C)C=O.Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([O:13][C:9]2[C:8]3[C:1]4([CH2:4][O:5][CH2:6][C:7]=3[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]4)=[N:21][CH:22]=1)([O-:28])=[O:27]
Reactant: Oc1cccc2c1C1(CC1)COC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3c2C2(CC2)COC3)nc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 1H-spiro[2-benzopyran-4,1′-cyclopropan]-5-ol (Intermediate 136, 150 mg) in dry N,N-dimethylformamide (4 ml) potassium carbonate (176 mg, 1.277 mmol) and then 2-chloro-5-nitropyridine (148 mg, 0.936 mmol) were added and the reaction mixture was stirred for 1 h at 110° C. After cooling the reaction was quenched with brine (1 ml), diluted with water (5 ml) and extracted with ethyl acetate (3×15 ml). The organic layer was washed with ice cold brine (2×10 ml), dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane/ethyl acetate as eluents from 100:0 to 7:3. This afforded the title compound as a colourless gum (240 mg).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:30]#[N:31])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:30]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:16]=2)[C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:6]([OH:38])=[O:5])=[O:11])[N:13]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(C(=O)NCC(C(=O)O)c2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A mixture of 3-[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2-phenyl-propionic acid tert-butyl ester (60 mg) and TFA (2 mL) in DCM (2 mL) was stirred at rt for 3 h. The mixture was concentrated and resulting residue was treated with water; solids were collected via filtration and air dried to give desired product (50 mg). LC-MS ESI+: 454 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[O:30]1[C:34]([C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])=[CH:33][N:32]=[CH:31]1.Cl>O1CCOCC1.CC(O)C>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]4[CH:39]=[CH:40][CH:41]=[C:35]([C:34]5[O:30][CH:31]=[N:32][CH:33]=5)[CH:36]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1)C(F)(F)F
Temperature: 90 °C
Yield: 82.2 %

Procedure:
To a solution of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.0 g, 0.002 mol) (see Example 1, Step C) in 1,4-dioxane (25 mL) and i-PrOH (5 mL) was added 3-(1,3-oxazol-5-yl)aniline (1.15 g, 0.007 mols) followed by catalytic 12M HCl. After heating overnight at 90° C., the reaction was quenched with saturated NaHCO3 (25 mL), the solvent was removed by rotary evaporation, the aqueous layer extracted with DCM (25 mL), the organic layer concentrated, and purified by column chromatography (5-50% EtOAc in hexanes then 100% EtOAc) to provide the product (0.89 g, 69%) as an off-white solid. ES-LC/MS m/z=542 [M+H]+.