Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[N-:8]=[C:9]=[O:10].[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16]N)[CH3:12]>C(#N)C>[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH:8][C:9](=[O:10])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: Nc1ccncc1
Reactant: [N-]=C=O
Reactant: CCOC(=O)CCN
Solvent: CC#N
Product: CCOC(=O)CCNC(=O)Nc1ccncc1
Yield: 99 %

Procedure:
A solution of 1 g (10.64 mmol) of 4-aminopyridine and 2.3 g (15.9 mmol) of beta-alanine ethyl ester isocyanate in 30 ml of anhydrous acetonitrile is agitated for 20 hr at room temperature. After concentration to dryness and trituration of the resulting oily residue in ether (4 × 20 ml), 2.5 g (yield 88%) of 4-pyridylcarbamoyl-beta-alanine ethyl ester is obtained in the form of a solid having a melting point of 95° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH:12]1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39][NH2:40].C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C:14](=[N:40][CH2:39][C:38]2[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:36]([C:35]([F:34])([F:48])[F:49])[CH:37]=2)[CH2:13][CH:12]1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC1CC(=O)c2cc(C(F)(F)F)ccc2N1C(=O)OCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CC(=NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(C(F)(F)F)ccc2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.6 %

Procedure:
2-Methyl-4-oxo-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (5.5 g, 15.1 mmol) was combined with triethylamine (15 mL, 106 mmol) and 3,5-bis-trifluoromethyl-benzylamine (5.5 g, 22.7 mmol) in anhydrous dichloromethane (80 mL). This solution was cooled in a room temperature water bath as 7.6 mL of 1M solution of titanium tetrachloride (TiCl4) in dichloromethane (7.6 mmol) was slowly added. The reaction was stirred at room temperature overnight before the mixture was poured into a stirred solution of water (125 mL) and potassium carbonate (15 g). After filtration of the resulting emulsion, the filtrate was extracted with ethyl acetate (1×200 mL, then 2×75 mL), the combined organic phases were washed with water (100 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title product (10.63 g, >theory). 1H NMR (CDCl3) δ 1.2 (d, 3H), 2.7-2.9 (m, 2H), 4.0-4.1 (m, 1H), 4.65 (d, 1H), 4.75 (d, 1H), 5.1-5.4 (m, 2H), 7.3-7.5 (m, 5H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[CH3:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[C:17]([CH3:19])[CH:18]=1>>[CH3:12][C:13]1[CH:14]=[C:15]([C:4]2([OH:5])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:1][C:2]2=[O:3])[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Cc1cc(C)cc([Mg]Br)c1
Product: Cc1cc(C)cc(C2(O)C(=O)Nc3ccccc32)c1
Yield: 81.3 %

Procedure:
Using a method similar to Preparation 18 with isatin (1.47 g, 10 mmol) and 3,5-dimethylphenylmagnesium bromide (0.5M in THF, 42 mL, 21 mmol) gave 2.06 g (81%) of the title compound as a peach-color solid. MS (ES): m/z=236 (M+1−H2O), 252 (M−1); 1H NMR(DMSO-d6): δ10.34 (s, 1H), 7.23 (dt, J=1.3 Hz, J=7.6 Hz, 1H), 7.07 (d, J=6.7 Hz, 1H), 6.95 (dt, J=0.9 Hz, J=7.4 Hz, 1H), 6.88 (m, 4H), 6.51 (s, 1H), 2.21 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](Cl)=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([OH:17])C.C(N([CH2:23][CH3:24])CC)C>O1CCCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:13][CH2:23][CH3:24])=[O:17])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCO
Reactant: O=C(Cl)c1ccc2ccnc(Cl)c2c1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2ccnc(Cl)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
1-Chloroisoquinoline-7-carbonyl chloride (3.02 g, 13.4 mmol) was dissolved in tetrahydrofuran (135 mL) and was cooled to 0° C. Ethanol (6.1 mL, 94 mmol) and triethylamine (2.05 mL, 14.7 mmol) were added. The reaction was allowed to warm to room temperature and stir for 2 hours. The reaction mixture was partitioned between ethyl acetate (500 mL) and saturated aqueous sodium bicarbonate (250 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound (3.0 g, 96%) as a yellow solid. +ESI (M+H) 236.1; 1H NMR (400 MHz, CDCl3, δ): 9.06 (s, 1H), 8.30-8.39 (m, 2H), 7.89 (d, J=8.6 Hz, 1H), 7.63 (d, J=5.7 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]([Si:31]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[O:32][C:33]1[CH:34]=[C:35]2[CH:41]=[CH:40][NH:39][C:36]2=[N:37][CH:38]=1)([CH3:30])[CH3:29].[OH-].[K+].O>CO>[C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:41]2[C:35]3[C:36](=[N:37][CH:38]=[C:33]([O:32][Si:31]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:28]([CH3:29])[CH3:30])[CH:34]=3)[NH:39][CH:40]=2)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C=O)cn1
Reactant: CC(C)[Si](Oc1cnc2[nH]ccc2c1)(C(C)C)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)[Si](Oc1cnc2[nH]cc(C(O)c3ccc(N(Cc4ccc(C(F)(F)F)cc4)C(=O)OC(C)(C)C)nc3)c2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A mixture of (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (19, 41 mg, 0.11 mmol, prepared as described in Example 30), 5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridine (83, 34 mg, 0.12 mmol) and potassium hydroxide (9.8 mg, 0.17 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (84, 0.05 g, 70%). MS (ESI) [M+H+]+=671.38.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:22]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:30][CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NCCN1CCOCC1
Product: COc1ccc(N(C)c2nc(NCCN3CCOCC3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (10 mg, 0.033 mmol) and 2-morpholin-4-yl-ethylamine (30 μL) by a procedure similar to example 10 and was isolated as white powder (10 mg, 100%). 1H NMR (CDCl3): 7.42 (dd, J=8.7 and 1.2 Hz, 1H), 7.36 (ddd, J=8.1, 6.6 and 1.5 Hz, 1H), 7.10-7.09 (m, 2H), 6.92-6.86 (m, 3H), 6.67 (ddd, J=8.1, 6.6 and 1.4 Hz, 1H), 3.82 (s, 3H), 3.75-3.62 (m, 6H), 3.52 (s, 3H), 2.55-2.44 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC1C=CC(S(O[C@@H:31]2[CH2:35][CH2:34][O:33][CH2:32]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC>[C:14]1([CH2:13][O:12][C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C@H:31]3[CH2:35][CH2:34][O:33][CH2:32]3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCOC2)c1
Temperature: 130 °C
Yield: 84.1 %

Procedure:
A mixture of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (18.8 g, 72.75 mmol), (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (18.5 g, 76.4 mmol) and potassium carbonate (20.08 g, 145.5 mmol) in butyronitrile (250 mL) was heated to 130° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), 0.5M sodium hydroxide solution (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a colourless oil (20.1 g). 1H NMR δ (CDCl3): 2.08-2.26 (m, 2H), 3.78-4.01 (m, 4H), 3.90 (s, 3H), 4.92-4.96 (m, 1H), 5.08 (s, 2H), 6.69 (t, 1H), 7.15 (t, 1H), 7.29 (t, 1H), 7.34-7.44 (m, 5H); m/z 327 (M+H)+
Reaction SMILES: S(=O)(=O)(O)O.O[CH:7]([C:9]1[CH:10]=[C:11]([S:18]([NH2:21])(=[O:20])=[O:19])[S:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[CH3:8].C([O-])(O)=[O:23].[Na+].[C:27](#[N:29])[CH3:28]>>[C:27]([NH:29][CH:7]([C:9]1[CH:10]=[C:11]([S:18]([NH2:21])(=[O:20])=[O:19])[S:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[CH3:8])(=[O:23])[CH3:28]
Reactant: CC(O)c1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Reactant: O=C([O-])O
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC(C)c1cc(S(N)(=O)=O)sc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
To acetonitrile (30 ml) was added concentrated sulfuric acid (2.94 g, 0.03 mol) followed by 4-(1-hydroxyethyl)-5-methylsulfonylthiophene-2-sulfonamide (2.85 g, 0.01 mol). The resulting solution was stirred at room temperature for 24 hours. Only about 1/2 of the alcohol had reacted so additional sulfuric acid (2.94 g, 0.03 mol) was added. After another 16 hours at room temperature the reaction was complete. The mixture was basified with excess NaHCO3. Acetonitrile (100 ml) was added, the mixture was filtered and the acetonitrile was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The solid obtained was recrystallized from water to give 1.1 g (34%) of yellow solid, m.p. 114-117° C. HPLC and TLC confirmed the purity and NMR confirmed the structure.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:2][C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(S(=O)(=O)Nc2ccc3[nH]nc(-c4ccccc4)c3c2)c1
Temperature: 20 °C
Yield: 46.4 %

Procedure:
3-Amino-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 0.06 ml of an aqueous hydrochloric acid solution is added to a solution of 0.28 g of 3-nitro-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide in 15 ml of absolute ethanol and 0.3 ml of water. The reaction mixture is refluxed, then 0.12 g of powdered iron is added in small portions. The reaction mixture is refluxed for 2 hours and is then cooled to a temperature in the region of 20° C. 30 ml of water are added to the mixture, which is filtered through Celite®, and the solid is washed with water then ethyl acetate. The filtrate is basified with an aqueous 32% ammonium hydroxide solution to a pH in the region of 12, and is then extracted with 3 times 20 ml of ethyl acetate. The organic extracts are pooled, washed with 3 times 10 ml of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The solid residue is washed successively with diisopropyl ether then dichloromethane, partially dried and dried. 0.12 g of 3-amino-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide is thus obtained in the form of an off-white powder melting at 205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:4]2[N:3]=1.[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCCC1>C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:4]2[N:3]=1
Reactant: O=C1CNC(=O)N1
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Solvent: C1CCNCC1
Solvent: CCO
Product: Nc1cc(NC2CC2)n2ncc(C=C3NC(=O)NC3=O)c2n1
Temperature: 80 °C
Yield: 44 %

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (75 mg, 0.34 mmol) in 1.0 mL ethanol was added hydantoin (34 mg, 0.34 mmol) and piperidine (33 ul). The reaction was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and yellow precipitate was filtered, washed with ethanol to yield 45 mg (44% yield) Z)-5-((5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=300)
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[N+:30]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])([O-:32])=[O:31]>ClCCl>[N+:30]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[N:6][CH:5]=1)[CH3:3])=[O:36])([O-:32])=[O:31]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To a stirred solution of 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.30 g, 1.0 mmol) in dichloromethane (10 mL) cooled to −78° C. was added triethylamine (0.42 mL, 3.0 mmol) and 2-nitrobenzoyl chloride (0.35 mL, 1.5 mmol). After stirring for one hour, the solution was quenched with water and allowed to warm to room temperature. The solution was diluted with dichloromethane (50 mL) and washed with 0.1N HCl (2×50 mL) and brine (50 mL). The solution was dried with magnesium sulfate and filtered, and silica gel (5 g) was added to the solution, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (20:80) to ethyl acetate:hexanes (100:0) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 2-nitro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.12 g) as a white solid. MS m/z455 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([NH:15][C:16]([NH:18]C(=O)C3C=CC=CC=3)=[S:17])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1)[CH3:2].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([NH:15][C:16]([NH2:18])=[S:17])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1)[CH3:38]
Reactant: CCOc1ccc(Cc2nc3cc(NC(=S)NC(=O)c4ccccc4)ccc3n2CCN(CC)CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2nc3cc(NC(N)=S)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C

Procedure:
N-(1-(2-(diethylamino)ethyl)-2-(4-ethoxybenzyl)-1H-benzo[d]-imidazol-5-ylcarbamothioyl)benzamide 20 (272 mg, 0.513 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. 2M NaOH (0.513 mL, 1.026 mmol) added and the solution was heated to reflux for 6 hours and cooled to room temperature overnight. The solution was concentrated and the residue was partitioned between H2O and ethyl acetate, transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford an off white solid which was slurried in hot ethyl acetate to yield white solid 21 [1-(2-Diethylamino-ethyl)-2-(4-ethoxy-benzyl)-1H-benzoimidazol-5-yl]-thiourea. Yield: 110 mg (50.3%). 1H NMR (DMSO) δ: 0.80 (t, 6H, J=7.1), 1.29 (t, 3H, J=7.0), 2.41 (q, 4H, J=7.0), 2.45-2.50 (m, 2H), 3.96 (q, 2H, J=6.9), 4.12 (t, 2H, J=6.7), 4.24 (s, 2H), 6.86 (d, 2H, J=8.6), 7.09 (dd, 1H, J=8.4, 1.5), 7.16 (d, 2H, J=8.7), 7.24 (br, 1-2H), 7.40 (d, 1H, J=8.5), 7.51 (s, 1H), 9.56 (s, 1H). MS (ESI): 426 (MH+, 100%)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>O>[CH:22]([NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
To a mixture of 1.05 g of 4-fluoro-3-nitro-benzo trifluoride and 10 ml of N-methylpyrrolidone was added 1.10 g of sec-butylamine under ice cool, and the mixture was heated up to room temperature and stirred for 1.5 hours. Into the reaction mixture was poured water, and the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 1.16 g of N-sec-butyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [CH3:1]N(C)CCN.C[Al](C)C.C(O[C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[CH:20]=1)=[O:15])C>C1(C)C=CC=CC=1>[Br:27][C:23]1[CH:22]=[C:21]([N:19]2[CH:20]=[C:16]([C:14](=[O:15])[CH3:1])[CH:17]=[N:18]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(Br)c2)c1
Reactant: CN(C)CCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1cnn(-c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A solution of N,N-dimethylethylenediamine (1.8 ml, 16.76 mmol) in toluene (30 ml) was treated dropwise at 0° C. under an argon atmosphere with trimethylaluminum (2M in toluene, 22.86 ml, 45.7 mmol). The reaction mixture was stirred at 25° C. for 1 hour before adding 1-(3-bromo-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (3.8 g, 12.8 mmol) (CAS 784142-89-8; WO2004092140). The resulting mixture was heated to reflux for 12 hours. For the workup, the mixture was cooled to 25° C., quenched with hydrochloric acid (1N) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (50 ml), dried over sodium sulphate and evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a 9:1-mixture of hexane and ethyl acetate as the eluent to give the 1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]ethanone (2.4 g, 83.5%) as an off-white solid. MS (ISP): m/z=310 [M+CH3CN]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([CH:16]=1)[NH2:15].[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([NH:15][C:18](=[O:20])[CH3:19])[CH:16]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of triethylamine (2.9 g, 14.4 mmol) and 5-methoxy-2-methylaniline (1.0 g, 7.2 mmol) in DCM (30 mL) at 0° C., was added acetyl chloride (0.57 g, 7.2 mmol) dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution, and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to give N-(5-methoxy-2-methylphenyl)acetamide as needle-shaped crystals. The crude product was used in the next step without further purification.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[C:32](=O)(O)[O-].[Na+].O[O:38][S:39]([O-:41])=O.[K+]>CC(C)=O.O>[CH3:32][S:39]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:10]=2[O:19][CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:5]([C:28]([F:29])([F:30])[F:31])[CH:4]=1)(=[O:41])=[O:38]
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Reactant: CSc1ccc(-c2cc(C(F)(F)F)ccc2OCC(=O)OC(C)(C)C)c(C(F)(F)F)c1
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(C(F)(F)F)cc1-c1ccc(S(C)(=O)=O)cc1C(F)(F)F
Reaction time: 3 h

Procedure:
The product from step (iv) (0.564 g) was dissolved in 50% aqueous acetone (10 ml), sodium bicarbonate (0.94 g) added, followed by a solution of oxone (1.5 g) in water (ml) and stirred for 3 h. The reaction was quenched with aqueous sodium metabisulfite, extracted with EtOAc, washed with aqueous potassium carbonate, dried (Na2SO4) and evaporated to give the subtitle compound. Yield 0.32 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([N:6]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:23])[CH2:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[C:14]([C:20](=[O:23])[C:21]=1[CH3:22])=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[O:24]
Reactant: CCC(=O)c1ccc(Cl)cc1N(C(=O)C(=O)OC)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1c(C)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
To a stirred suspension of N-(5-chloro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester (15.0 g, 43.5 mmol) in methanol (200 mL) was added potassium carbonate (35.0 g, 253 mmol) at room temperature. The mixture was heated at 80° C. for 1 hr. Completion of the reaction was monitored by silica TLC (mobile phase; hexane:ethyl acetate=7:3; Rf=0.6). The reaction mixture was cooled to room temperature. The reaction mixture was filtered through a sintered glass funnel and the solids were washed with MeOH (2×50 mL). The combined filtrates were concentrated under reduced pressure. The residue obtained was taken up in ethyl acetate (500 mL), washed with water (2×200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by washing with a mixture of hexane-ether to afford 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (10.5 g, 73.4% yield). 1H NMR (DMSO-d6) δ 8.24 (d, J=8.7 Hz, 1H) 7.28-7.78 (m, 6H) 6.69 (d, J=1.7 Hz, 1H) 3.49 (s, 3H) 1.97 (s, 3H); MS calcd. for C18H14ClNO3 [(M+H)+] 328.0, obsd. 327.9.