Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1.[O:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[CH3:12][C:3]1[C:2]([NH:1][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)=[CH:7][N:6]=[CH:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cncc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cncc(NC2CCOCC2)c1C
Reaction time: 6 h
Yield: 91.6 %

Procedure:
To a stirred solution of methyl 5-amino-4-methylpyridine-3-carboxylate (805 mg, 4.84 mmol) in DCE (20 ml) under a nitrogen atmosphere was added oxan-4-one (537 μl, 5.80 mmol) followed by trifluoroacetic acid (742 μl, 9.69 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (1.54 g, 7.27 mmol). The reaction was stirred for 16 h at room temperature after which time more oxan-4-one (100 μl) and sodium triacetoxyborohydride (300 mg) were added and the reaction stirred for a further 6 h. Distilled water (20 ml) was added and solid NaHCO3 was added until pH8. The phases were separated and then the aqueous phase was washed with EtOAc (2×50 ml), the combined organics were washed with brine (50 ml), dried using Na2SO4, filtered and evaporated to afford the title compound as a pale yellow solid (1.11 g, 88%) which was used in the next stage without any further purification. LC-MS 96%, m/z=251.0, 1H NMR (500 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.10 (s, 1H), 4.03 (dt, J=11.9, 3.5 Hz, 2H), 3.92 (s, 3H), 3.68-3.58 (m, 1H), 3.54 (tt, J=8.1, 4.1 Hz, 3H), 2.35 (s, 3H), 2.12-2.05 (m, 2H), 1.53 (ddd, J=23.8, 11.0, 4.3 Hz, 2H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([CH3:22])=[CH:20][N:19]=[N:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[ClH:23].[H][H]>CO.[Pd]>[ClH:23].[CH3:22][C:21]1[N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:18]=[N:19][CH:20]=1
Reactant: [H][H]
Reactant: Cc1cnnn1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cnnn1C1CCNCC1

Procedure:
The compound of step (iii) was re-dissolved in methanol to the volume of 400 ml. Then to the solution were added 5% Pd/C and concentrated HCl (50 ml). The mixture was hydrogenated for 24 hr at hydrogen pressure of 100 atm and temperature 90° C. The mixture was cooled, filtered and evaporated. The resulting oily residue was dissolved at reflux in isopropanol (100 ml) and to the solution was added concentrated HCl (50 ml). The mixture was allowed to crystallise at 5° C. for 3 days and then filtered to give the title compound (135 g).
Reaction SMILES: [CH:1]([O:4][C:5]([O:7][CH2:8][N:9]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([C:19](=[O:33])[C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=2[N+:30]([O-])=O)=[N:10]1)=[O:6])([CH3:3])[CH3:2].C(OC(N1N=C(C(OCC)=O)C(C(=O)C2C=C(OC)C(OC)=CC=2[N+]([O-])=O)=N1)=O)(C)C>>[NH2:30][C:21]1[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[C:19]([C:11]1[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:13][N:9]([CH2:8][O:7][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:6])[N:10]=1)=[O:33]
Reactant: CCOC(=O)c1nn(COC(=O)OC(C)C)nc1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: CCOC(=O)c1nn(C(=O)OC(C)C)nc1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Product: CCOC(=O)c1nn(COC(=O)OC(C)C)nc1C(=O)c1cc(OC)c(OC)cc1N
Yield: 75.2 %

Procedure:
The 2:1 mixture (870 mg) of ethyl 2-(isopropoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate and ethyl 2-(isopropoxycarbonyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate prepared in step (7a) was reacted in the same manner as in Example 3 (3a). The reaction product was purified by column chromatography on silica gel (hexane/ethyl acetate) to give a 4:1 mixture (612 mg) of ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxycarbonyloxymethyl)-2H-1,2,3-triazole-4-carboxylate and ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(isopropoxycarbonyl)-2H-1,2,3-triazole-4-carboxylate as a light yellow foam.
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.C(OO)(=O)C>CN(C)C=O>[C:2]1([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+:14]=[N-:15])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(=O)OO
Agent: II
Solvent: CN(C)C=O
Product: [N-]=[N+]=C(c1ccccc1)c1ccccc1

Procedure:
To benzophenone hydrazone (4.9 g, 0.025 moles) in dimethylformamide (25 ml) containing iodine (1 ml, 1% w/v solution) and excess Dowex 1 × 2 quaternary ammonium hydroxide resin saturated with dimethyl formamide was added peracetic acid solution (5.7 ml, 1.27 × 0.025 m. moles) at 15° over 60 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12][Br:20])=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(C)cc1C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)cc1C#N
Yield: 21.9 %

Procedure:
A mixture of 3-Cyano-5-methyl-thiophene-2-carboxylic acid methyl ester (0.51 g, 2.81 mmol), NBS (1.05 g, 5.91 mmol), and ACHN (0.032 g, 0.14 mmol) in CCl4 (4 ml) was refluxed in a pressure tube 15 h. The reaction mixture was cooled and evaporated. The residue was purified by column (0-15% EtOAc in hexane) to give 0.16 g (22%) yellow solid.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:6]([O:8]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.Cl>C1(OC)C=CC=CC=1>[C:1]([S:4][CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(Cc1ccc(F)cc1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SC(Cc1ccc(F)cc1)C(=O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Diphenylmethyl 2-acetylthio-3-(4-fluorophenyl)propionate (3.38 g, 8.27 mmol) was dissolved in anisole (9.0 ml), followed by cooling to -10° C. Into this solution was further dropped trifluoroacetic acid (51.0 ml). Next, this solution was heated to 0° C. About 1 hour thereafter, it was concentrated under reduced pressure. To the concentrate was added diethyl ether (80 ml) and the resulting solution was extracted with a saturated aqueous solution of sodium hydrogencarbonate (100 ml×2). To the alkaline aqueous solution thus obtained was added a 2N aqueous solution of hydrochloric acid until the solution became acidic. Further, it was extracted with methylene chloride (100 ml×3). The organic phase was washed with a saturated aqueous sodium chloride (100 ml) and dried over magnesium sulfate. After drying, the filtrate obtained by filtering thereof was concentrated under reduced pressure. Thus, the title compound (1.96 g, 98%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[I:12]
Reactant: Cc1cc(Cl)cc(I)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1c(C)cc(Cl)cc1I
Temperature: 70 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
A solution of 4-chloro-2-iodo-6-methyl-benzoic acid (5.9 g, 20.0 mmol) in acetone (50 mL) was treated with anhydrous K2CO3 (4.14 g, 30 mmol) followed by methyl iodide (1.5 g, 24 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate was evaporated under reduced pressure. Silica gel column chromatography of the resulting material using 10% ethyl acetate in hexanes afforded 4-chloro-2-iodo-6-methyl-benzoic acid methyl ester (2.91 g, 47%). GC-MS: m/z 310 (M)+, 279 (M−31)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: ClCCCCc1ccc(Cl)cc1
Reactant: C1CNCCN1
Solvent: CCO
Product: Clc1ccc(CCCCN2CCNCC2)cc1
Yield: 46.3 %

Procedure:
A mixture of 26.4 g of 4-(4-chlorophenyl)butyl chloride, 86.1 g of anhydrous piperazine and 250 ml of reagent ethanol was refluxed overnight. Solvent was evaporated from the product and the residue was chromatographed twice on silica with the eluant being CH2Cl2 /CH3OH/ammonium hydroxide (45:5:1). The first chromatography removed the bulk of the excess piperazine, the second provided 15.2 g of 1-[4-(4-chlorophenyl)butyl]piperazine as a colorless oil which solidified on standing (m.p. 139°-145° C.).
Reaction SMILES: ClC1C([CH:8]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:23]3)[N:9]2[C:17](=O)C3C(=CC=CC=3)C2=O)=NC=CN=1.NN.[CH2:38]([Cl:40])Cl>CCO>[Cl:40][C:38]1[C:17]([NH:9][CH2:8][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][C:24]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:23]3)=[N:23][CH:22]=[CH:27][N:26]=1
Reactant: O=C1c2ccccc2C(=O)N1C(c1ccc2ncc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: ClCCl
Agent: NN
Solvent: CCO
Product: Clc1nccnc1NCc1ccc2ncc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A flask containing crude (3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methanol (153 mg, ˜0.44 mmol) was flashed with Ar and charged with phthalimide (71 mg, 0.48 mmol) and triphenylphosphine (130 mg, 0.48 mmol) and anh. THF (10 mL). DIAD (0.1 mL, 0.48 mmol) was added slowly dropwise at rt and then the reaction was stirred at rt for 16 h. The reaction was concentrated under reduced pressure and purified by flash chromatography (silica gel, 5% EtOAc in DCM to 10%) affording 2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione compound as a creamy solid. To stirred solution of the crude 2-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione (147 mg, 0.31 mmol) in anh. EtOH (12 mL) and anh. DCM (2 mL) under Ar was added anh. hydrazine (0.03 mL, 0.9 mmol). The reaction mixture was stirred at rt for 22 h. The 1:1 mixture of the product and a partially cleaved phthalimide was concentrated under reduced pressure at rt and dried under high vacuum overnight. The light yellow, solid residue was dissolved in anh. i-PrOH (6 mL) and anh. CHCl3 (3 mL) and heated under Ar at 50° C. for 16 h. Later the reaction was cooled to rt, evaporated to dryness and triturated with DCM. The DCM aliquots were filtered through a pad of Celite affording the title compound as a light yellow solid; 1H NMR (400 MHz, CD3OD/CDCl3) δ 9.37 (s, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.23 (d, J=6.8 Hz, 2H), 8.12 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.88 (dd, J=0.8 Hz, 8.8 Hz, 1H), 7.62-7.52 (m, 3H), 5.81 (s, 1H). MS (ES+): m/z 348.0 (40) [MH+]; HPLC: tR=2.08 min (OpenLynx, polar—5 min).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[CH3:6][C:7]1[C:11]2[C:12](=[O:24])[N:13]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH2:14][CH2:15][C:10]=2[NH:9][C:8]=1[CH:30]=[O:31]
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
N,N-dimethylformamide (1.68 ml) was added dropwise slowly with phosphorus oxychloride (0.9 ml, 9.65 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature and cooled down to 0˜5° C. in an ice-water bath. A mixture of 3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (2.31 g, 8.77 mmol) in 10.5 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (5 ml) and stirred for 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (15 ml×6). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane:methanol (10:1) as eluents to give 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (550 mg, 17.5%) as a red oil.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:37])([CH2:35][CH3:36])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:34])([CH3:33])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:32])=[O:31])=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:37])([CH2:35][CH3:36])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:34])([CH3:33])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([CH3:32])=[O:31])=[CH:20][CH:19]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(-c3ccccc3S(C)=O)cc2)n1
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]c(C(C)(O)Cc2ccc(-c3ccccc3S(C)=O)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (2 mL, 8 mmol) was added to a solution of 4-(2,2-dimethylbutyl)-2-{1-hydroxy-1-methyl-2-[2′-(methylsulfinyl)biphenyl-4-yl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (274 mg, 0.52 mmol) in methanol (4 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded the title compound. (M+H) found: 425.
Reaction SMILES: [C:1](=[O:17])([O:14][CH2:15][CH3:16])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH:12]=[O:13])[CH:4]=1.[Mn]([O-])(=O)(=O)=[O:19].[K+].S(=O)(=O)(O)O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.CC(C)=O.C(O)(=O)C>[C:1](=[O:17])([O:14][CH2:15][CH3:16])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([C:12]([OH:19])=[O:13])[CH:4]=1
Reactant: CCOC(=O)Oc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Yield: 84.5 %

Procedure:
A stirred mixture of 3-formyl-4-nitrophenyl ethyl carbonate (33.1 g, prepared as described in J. Chem. Soc., 1925, 1195), potassium permanganate (17.0 g), acetic acid (33 ml) and acetone (330 ml) was cooled to keep the temperature below 50°, then allowed to stand at room temperature for a further forty-five minutes. Dilute sulphuric acid and chloroform were added and the mixture decolorised with sodium metabisulphite. The organic layer was extracted with sodium bicarbonate solution and the extracts acidified with dilute hydrochloric acid to give 3-carboxy-4-nitrophenyl ethyl carbonate (23.2 g, m.p. 132-7°).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31](S(C)=O)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31]([O:9][CH2:8][CH2:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1
Reactant: OCCc1ccncc1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCc2ccncc2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To a solution of 4-pyridineethanol (0.862 g, 7.0 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. in a sealed tube for 1.5 hours, cooled to room temperature, and then quenched by the addition of water (10 ml). The reaction mixture is transferred to an erlenmeyer flask and diluted to 75 ml with water. The mixture is cooled to 0° C. and stirred. During this time, a yellow precipitate is formed. This solid is collected by filtration and slurried in a 2:1 EtOAc:hexane mixture. This slurry is stirred for 10 minutes, filtered, and the collected solid is placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.231 g, 57%). Mass (m/z): 403.1 (M++1), 401.1 (M+−1).
Reaction SMILES: C([NH:4][C:5]1[C:10]2[O:11][C:12]([CH3:18])=[C:13]([C:14]([OH:17])([CH3:16])[CH3:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>C(O)C.O>[NH2:4][C:5]1[C:10]2[O:11][C:12]([CH3:18])=[C:13]([C:14]([OH:17])([CH3:15])[CH3:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1cccc2c(C(C)(C)O)c(C)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc2c(N)cccc2c1C(C)(C)O
Yield: 94 %

Procedure:
A suspension of 7-acetylamino-3-(1-hydroxy-1-methylethyl)-2-methylbenzo[b]furan (1.82 g) in a mixture of ethanol (15 ml) and 3N-aqueous sodium hydroxide (10 ml) was refluxed for 20 hours. The reaction mixture was cooled, diluted with water (20 ml) and evaporated in vacuo until the ethanol of the solution was removed. The separated solid was collected, washed with water and dried to give 7-amino-3-(1-hydroxy-1-methylethyl)-2-methylbenzo[b]furan (1.42 g).
Reaction SMILES: [NH2:1][NH2:2].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[N:19][NH2:20])[S:15][CH:16]=2)[CH:7]=1.[ClH:22]>C(O)C>[ClH:22].[NH2:20][N:19]=[CH:18][NH:17][C:14]1[S:15][CH:16]=[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([NH:1][NH2:2])=[O:4])[N:13]=1
Reactant: COC(=O)c1cccc(-c2csc(NC=NN)n2)c1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: NN=CNc1nc(-c2cccc(C(=O)NN)c2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 10 ml. of 95% hydrazine is added 3-[2-[(aminoiminomethyl)amino]-4-thiazolyl]benzoic acid methyl ester (1.1 g., 0.004 mole). This is stirred for 1 hour at room temperature. The product precipitates out and is filtered off and rinsed with ethanol. The filtrate is reduced to dryness and ethanol is added to the residue, and the insoluble material is filtered off and combined with previously filtered solid to give a crude yield of about 1 g. of the carboxhydrazide. This crude solid is added to 40 ml. ethanol and to this is added 10 ml. of ethanolic HCl solution and the mixture is heated briefly at reflux temperature. The suspension that forms is filtered off and recrystallized from 90% aqueous ethanol to give 0.65 g. of the desired product, m.p. 275° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:30])([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=[O:24])[C:15]3[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(F)cc1)N2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1C(=O)C(C)(c1nccn1C)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.38 mmol) and cesium carbonate (268 mg, 0.76 mmol) in DMF (10 mL) was added iodomethane (0.2 mL, 2.28 mmol) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 4 h and then at room temperature overnight. The resulting solution was added 50 mL of water, and then extracted with ethyl acetate (100 mL×3). The extracts were concentrated to give the crude product as a yellow solid (145 mg, yield 90%), which was used in the next step without further purification. LC-MS (ESI) m/z: 408 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2nccs2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2nccs2)cc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
A stirred solution of 2-[(4-nitrophenyl)sulfonyl]thiazole (1.50 g, 5.6 mmol) and stannous chloride dihydrate (6.26 g, 27.7 mmol) in absolute ethanol (25 mL) was heated at reflux for 1 hour. The reaction mixture was poured into ice water, and the aqueous solution basified with 15% NaOH and extracted with ethyl acetate (2×200 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed to yield a solid which on trituration with diethyl ether and filtration yielded the title thiazole (1.21 g, 89%) as a pale yellow solid, mp 148°-150° C. 1H-NMR (250 MHz, d6 -DMSO): 6.44 (br s, 2H, NH2), 6.66 (d, 2H, J=8.8 Hz, aromatic), 7.61 (d, 2H, J=8.7 Hz, aromatic), 8.03 (d, 1H, J=3.2 Hz, aromatic), 8.14 (d, 1H, J=3.2 Hz, aromatic). MS (CI, CH4): 241(M+1).
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([CH:16]=[CH:17][C:18]([OH:20])=O)=[CH:3]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:46]([O:50][C:51]([NH:53][NH2:54])=[O:52])([CH3:49])([CH3:48])[CH3:47]>CN(C)C=O>[CH3:47][C:46]([CH3:49])([O:50][C:51]([NH:53][NH:54][C:18](=[O:20])[CH:17]=[CH:16][C:4]1[NH:5][CH:6]=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:2](=[O:1])[CH:3]=1)=[O:52])[CH3:48]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Reaction time: 8 h

Procedure:
3-[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2pyridinyl]-2-propenoic acid (1.36 g), 0.75 g of N-hydroxybenzotriazole, 0.01 g of N,N-dimethylaminopyridine and 1.06 g of dicyclohexylcarbodiimide were stirred in 20 ml of dimethylformamide at 0° C. for 20 minutes. 0.66 g of N-(t-butoxycarbonyl)hydrazine was added. After stirring overnight, the formed dicyclohexylurea was filtered off and the filtrate was washed with 10 ml of dimethylformamide. The filtrate was evaporated to dryness and the residue was suspended in 30 ml of water, 1 g of sodium bicarbonate was added, and after stirring, the title compound was isolated by filtration. Recrystallization from dimethylformamide/water gave white crystals. Yield: 1.47 g, melting point 141° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Nc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 44 %

Procedure:
To a 50 mL flask was added 10 (221 mg, 1 mmol) and 10 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug, Column chromatography of the plug with hexane:acetyl acetate=20:1 as eluent afford 105 mg (44%) of 11 as a yellow solid.