Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([OH:18])=O)(=[O:10])=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.Cl.[CH3:38][NH:39][O:40][CH3:41].Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:19])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([N:39]([O:40][CH3:41])[CH3:38])=[O:18])(=[O:9])=[O:10]
Reactant: CNOC
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a mixture of 3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carboxylic acid (2.5 g, 7.8 mmol) described in Production Example 1-1 and tetrahydrofuran (25 mL) was added 1,1′-carbonyldiimidazole (2.0 g, 12 mmol) at room temperature, followed by stirring at that temperature for 30 minutes. Imidazole (1.1 g, 16 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.2 g, 12 mmol) were added successively at room temperature to the reaction mixture, followed by stirring at that temperature for 5 hours. A 1 N aqueous solution of hydrochloric acid (50 mL) was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the title compound (1.5 g, 53% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20]CC)=[O:19])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Temperature: 0 °C
Yield: 99.4 %

Procedure:
Ethyl 4-benzyloxyindol-2-carboxylate (10 g) was dissolved in a mixed solvent (200 ml) of dioxane-water (1:1) and potassium hydroxide (3.8 g) was added. The mixture was refluxed under heating for 2 hr. The reaction mixture was poured into ice water, made acidic with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-benzyloxyindol-2-carboxylic acid as pale-yellow crystals (9.0 g). The crystals were dissolved in dimethylformamide (100 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC, 7.6 g), 1-hydroxybenzotriazole hydrochloride (HOBt, 6.9 g), triethylamine (7.0 ml) and acetohydrazine (2.6 g) were added thereto. The mixture was stirred at room temperature for 6 hr. The reaction mixture was poured into ice water and the precipitated crystals were collected by filtration to give the title compound (10 g).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]([CH3:36])[CH2:34][NH2:35])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=3[C:16]([NH:35][CH2:34][CH:33]([C:28]3[CH:29]=[CH:30][C:31]([Cl:32])=[C:26]([Cl:25])[CH:27]=3)[CH3:36])=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CC(CNC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=11.97 min. MS (ESI−): mass calcd. for C22H17Cl3N4O3S2, 553.98; m/z found, 553/555/557 [M−H]. 1H NMR (400 MHz, CDCl3): 11.51 (s, 1H), 8.36 (dd, J=7.0, 1.1, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.74-7.70 (m, 2H), 7.40 (d, J=8.2, 1H), 7.29 (d, J=2.1, 1H), 7.04 (dd, J=8.3, 2.1, 1H), 7.01-6.99 (m, 1H), 6.89 (dd, J=8.4, 2.0, 1H), 5.81 (s, 1H), 3.74-3.67 (m, 1H), 3.34-3.28 (m, 1H), 3.06-2.98 (m, 1H), 1.30 (d, J=7.0, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C@@H:11]([C@@H:26]1[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@H:40]([CH2:41][CH2:42]2)[C@:38]2([CH3:39])[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:32][CH2:31]3)[CH2:28][CH2:27]1)[CH2:12][CH2:13][C:14]([F:25])([F:24])[C:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])([CH3:17])[CH3:16])C>O1CCCC1.CCOCC>[CH2:22]([O:21][CH:19]([O:18][C:15]([C:14]([F:24])([F:25])[CH2:13][CH2:12][C@H:11]([C@@H:26]1[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@H:40]([CH2:41][CH2:42]2)[C@:38]2([CH3:39])[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:32][CH2:31]3)[CH2:28][CH2:27]1)[CH2:10][OH:9])([CH3:16])[CH3:17])[CH3:20])[CH3:23]
Reactant: CCOC(=O)[C@H](CCC(F)(F)C(C)(C)OC(C)OCC)[C@H]1CC[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.20 g (0.0053 mol) of lithium aluminum hydride and 10 mL of tetrahydrofuran at 0° C. was added 2.55 g (0.0034 mol) of [1α,3β]-1,3-bis[tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-oic acid ethyl ester in 35 mL of tetrahydrofuran. The mixture was heated at 50° C. for 1.5 hr, recooled to 0° C., and diluted with 120 mL of ether. The mixture was then quenched with the dropwise addition of 0.40 ml of water and 0.32 mL of 10% aqueous sodium hydroxide. The mixture was stirred at 25° C. for 1 hr and was filtered. The solids were triturated with ether and filtered. Evaporation of solvent afforded [1α,3β]-1,3-bis[tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21ol, [α]D20 +4° (c 1, CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([NH:28][C:29]([NH2:31])=[S:30])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32](I)[CH3:33]>CC(C)=O>[C:12]([O:11][C:9]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([NH:28][C:29](=[NH:31])[S:30][CH2:32][CH3:33])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27]1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(NC(N)=S)ccc1-n1cccc1)C(=O)OC(C)(C)C
Reactant: CCI
Solvent: CC(C)=O
Product: CCSC(=N)Nc1ccc(-n2cccc2)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Yield: 77 %

Procedure:
A mixture of the compound (55 mg) obtained in Example 1f, ethyl iodide (0.039 ml) and acetone (5 ml) was heated under reflux for 14 hours and then concentrated at reduced pressure. Saturated sodium hydrogencarbonate solution was added to the resulting residue and extraction with ethyl acetate was conducted. The organic layer was washed with brine, dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=4:6) to give the titled compound (yield, 77%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21](F)=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])CC1.[CH3:33]NC(C1C2C=C(C3C(C)=CN=C(Cl)N=3)SC=2C=CC=1)=O>>[CH3:1][NH:4][C:5]([C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[C:21]([CH3:33])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:17]=3)[S:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3F)cc12
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3C)cc12
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3C)cc12

Procedure:
Using the method of 2-[5-fluoro-2-(3-piperidin-4-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 424 [M+H].
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[CH:8]=[CH:7]2.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][C:2]([F:16])([F:15])[F:1])[CH:5]=2)[N:10]=1
Reactant: O=c1ccc2cc(OC(F)(F)F)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)Oc1ccc2nc(Cl)ccc2c1

Procedure:
The title compound may be prepared in a manner analogous to Example 3, Step C, from the 6-trifluoromethoxy-1H-quinolin-2-one of Step C, and phosphorous oxychloride.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.Cl.[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][NH:13]1)(=[O:11])[NH2:10].[OH-].[Na+]>O1CCOCC1>[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N:13]1[CH3:5])(=[O:11])[NH2:10]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Reaction time: 1 h

Procedure:
10.86 ml of dimethyl sulfate were added to a solution of 30 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine hydrochloride in a mixture of 36 ml of a 20% w/v aqueous solution of sodium hydroxide and 470 ml of dioxane, and the resulting mixture was stirred at a temperature of between 22° C. and 23° C. for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was extracted with 2 liters of ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solution was then concentrated by evaporation under reduced pressure, until crystals emerged, and then 400 ml of diisopropyl ether were added to the mixture and the crystals which precipitated were collected by filtration, to give 23 g of the title compound as crystals, melting at 113°-114° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c12
Reactant: c1nc[nH]n1
Product: Cc1csc2nc(-n3cncn3)nc(NCc3ccc4c(c3)OCCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[C:3](=[O:41])[N:4]([CH3:40])[C:5](=[O:39])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[C:30]1[C:31](=[O:38])[N:32]([CH3:37])[C:33](=[O:36])[C:34]=1Br)=[CH:27][CH:26]=[CH:25][CH:24]=2.[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH3:40][N:4]1[C:5](=[O:39])[C:6]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[NH:22][C:23]3[C:28]([C:29]=2[C:30]2[C:31](=[O:38])[N:32]([CH3:37])[C:33](=[O:36])[C:34]=2[N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:2]([N:4]2[CH2:5][CH2:6][CH2:2][CH2:3]2)[C:3]1=[O:41]
Reactant: CN1C(=O)C(Br)=C(c2c(CCCCCc3[nH]c4ccccc4c3C3=C(Br)C(=O)N(C)C3=O)[nH]c3ccccc23)C1=O
Reactant: C1CCNC1
Product: CN1C(=O)C(c2c(CCCCCc3[nH]c4ccccc4c3C3=C(N4CCCC4)C(=O)N(C)C3=O)[nH]c3ccccc23)=C(N2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g (1.5 mmol) of 3-bromo-4-(2-(5-(3-(4-bromo-1-methyl-2,5-dioxo-2,5-dihydro-1H-3-pyrrolyl)-1H-2-indolyl)pentyl)-1H-3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione is dissolved in 5 ml (60.6 mmol) of pyrrolidine and stirred overnight at room temp. Excess pyrrolidine is then distilled off. The residue is completely freed from solvent residues in an oil-pump vacuum and then purified by column chromatography (SiO2, CH2Cl2/ethyl acetate 95:5). Yield: 480 mg (49%).
Reaction SMILES: [CH:1]([O:12][CH:13]([CH2:15][CH3:16])[CH3:14])(OC(CC)C)OC(CC)C.[C:17]1(=O)[CH2:22][CH2:21]C[CH2:19][CH2:18]1.CC(O)CC>[Fe](Cl)(Cl)Cl>[CH3:14][CH:13]([O:12][C:1]1[CH2:21][CH2:22][CH2:17][CH2:18][CH:19]=1)[CH2:15][CH3:16]
Reactant: CCC(C)OC(OC(C)CC)OC(C)CC
Reactant: O=C1CCCCC1
Agent: Cl[Fe](Cl)Cl
Solvent: CCC(C)O
Product: CCC(C)OC1=CCCCC1
Temperature: 50 °C
Yield: 89.4 %

Procedure:
A mixture containing 116.2 g (0.5 mol) of tri(2-butyl) orthoformate, 49.10 g (0.5 mol) of cyclohexanone and 3.7 g (0.05 mol) of 2-butanol was stirred at room temperature (25° C.) and 0.2 g (1 mmol) of reagent grade iron (III) chloride was added. The temperature of the reaction mixture rose to about 35° C. due to the exotherm and was heated and maintained at about at 50° C. until gas-chromatographic analysis indicated that the reaction was complete. After removing the by-products 2-butyl formate and 2-butanol by distillation under reduced pressure, the resulting residue was subsequently distilled to provide 1-(2-butoxy)-1-cyclohexene (bp 86° C. @2 mm Hg) as a colorless liquid; the yield was 89.4% with a purity exceeding 99%.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]=[C:15]([F:17])[C:14]([C:18]([C:20]4[C:28]5[C:23](=[N:24][CH:25]=[C:26]([CH3:29])[CH:27]=5)[N:22]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([C:4]2[N:9]=[CH:8][C:7]([NH:10][C:11]3[N:16]=[C:15]([F:17])[C:14]([C:18]([C:20]4[C:28]5[C:23](=[N:24][CH:25]=[C:26]([CH3:29])[CH:27]=5)[NH:22][CH:21]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cnc2c(c1)c(C(=O)c1ccc(Nc3ccc(C4CC4)nc3)nc1F)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc2[nH]cc(C(=O)c3ccc(Nc4ccc(C5CC5)nc4)nc3F)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To [6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (74, 134 mg, 0.25 mmol) in 10 mL of tetrahydrofuran, tetrabutylammonium fluoride, trihydrate (85.53 mg, 0.27 mmol) is added and the reaction stirred at room temperature for 30 minutes. Water is added and the mixture is extracted with ethyl acetate. The organic layer is washed with water and brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-3051, 82 mg). MS (ESI) [M+H+]+=388.0.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[NH:7][CH2:6][CH:5]([OH:13])[C:4]=2[CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18]Br.O>CN(C=O)C>[Br:16][CH2:17][CH2:18][N:7]1[CH2:6][CH:5]([OH:13])[C:4]2[CH:3]=[C:2]([Cl:1])[S:10][C:9]=2[S:8]1(=[O:11])=[O:12]
Reactant: BrCCBr
Reactant: O=S1(=O)NCC(O)c2cc(Cl)sc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)c2sc(Cl)cc2C(O)CN1CCBr
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.4 %

Procedure:
To a solution of 6-chloro-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (2.0 g, 8.37 mmol) in DMF (50 mL) was added sodium hydride (0.37 g, 9.2 mmol), after stirring for 30 min 1,2-dibromoethane (2.36 g, 16.7 mmol) was added and this mixture was stirred at room temperature for 72 hr. The reaction mixture was poured into water and the aqueous mixture was extracted with ether. The combined extracts were dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 30% ethyl acetate/hexane) to give 1.52 g (53%) of the desired product as a viscous syrup which was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=1.[CH3:16][C:17]1[C:18]([O:20][C:21](=O)[C:22]=1[CH3:23])=[O:19]>C(O)(=O)C>[NH2:15][S:12]([C:4]1[CH:3]=[C:2]([N:1]2[C:18](=[O:19])[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]2=[O:20])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=[O:13])=[O:14]
Reactant: COC(=O)c1ccc(N)cc1S(N)(=O)=O
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(N2C(=O)C(C)=C(C)C2=O)cc1S(N)(=O)=O
Reaction time: 2 h
Yield: 43 %

Procedure:
In 3 ml of acetic acid, 1 mmol of methyl 4-amino-2-(aminosulfonyl)benzoate and 1.05 mmol of 2,3-dimethylmaleic anhydride were stirred at 80° C. for 40 hours. Acetic acid was then distilled off from the reaction mixture, followed by the addition of 20 ml of ice water to the oily residue. After the mixture thus formed was stirred for 2 hours, the resulting precipitate was collected by filtration and then dried in air. Yield: 43%. Its physiocochemical properties are shown in Table 8.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[CH2:26]([S:27]([NH:30][C:12]1[C:13]2[C:14](=[O:16])[C:15]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH2:1])[C:7](=[O:18])[C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:29])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCS(N)(=O)=O
Reactant: Nc1cccc2c1C(=O)c1c(Cl)cccc1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1c(N)cccc1C2=O

Procedure:
1-(n-octylsulfonylamino)-8-aminoanthraquinone was prepared as follows. 1-amino-8-chloroanthraquinone (1.0g), n-octanesulfonamide (1.0g), potassium carbonate (1.0g), cupric acetate monohydrate (0.85g) and chlorobenzene (16.0g) were refluxed for 5.5 hours. The cooled mixture was filtered and aqueous methanol was added to the filtrate. The supernatant liquid was decanted and the remaining oil was dissolved in dichloromethane. On addition of methanol and partial evaporation of the solvent, the product separated as a red solid.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([O:7][C:8]1[CH:30]=[CH:29][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:26]([CH3:28])[CH3:27])[N:22]=[C:23]([CH3:25])[N:24]=1)[N:13]=3)([CH3:6])[CH3:5].[OH-].[Na+]>CO>[CH:26]([N:21]1[C:20]([C:14]2[N:13]=[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]4[CH:9]=[C:8]([O:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:31])=[O:2])[CH:30]=[CH:29][C:11]=43)[CH:15]=2)=[N:24][C:23]([CH3:25])=[N:22]1)([CH3:28])[CH3:27]
Reactant: COC(=O)C(C)(C)Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(C)C(=O)O)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Yield: 100.2 %

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropionic acid methyl ester (39.2 mg, 0.0922 mmol) in MeOH (1.5 mL) was added 1M NaOH (0.46 mL) and the mixture was heated at 100° C. for 1 h using microwave irradiation. After cooling to RT, the organic solvent was removed in vacuo and the pH of the resulting mixture was adjusted to 8 by addition of 1M HCl. The mixture was then subjected to column chromatography (C18, gradient 25-40% MeOH in H2O followed by C18, gradient 1-20% MeOH in H2O) affording 2-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropionic acid (38 mg, quantitative). LCMS: RT 2.82 min [M+H]+ 412.0
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)Cl>[C:8]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N+:5]=1[O-:18])#[N:9]
Reactant: Cc1ccnc(C#N)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution of 4-methylpicolinonitrile (5 g, 42.3 mmol) in DCM (25 mL) was cooled in an ice/brine bath. To this solution was added mCPBA (14.61 g, 85 mmol). The reaction mixture was allowed to warm to RT and was stirred overnight. The mixture was subsequently diluted with DCM until all solids were dissolved and was washed with 1N NaOH (2×200 mL) and with brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a white solid (4.03 g, 71%). ESI-MS m/z [M+H]+ 135.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([O:30][C:31]1[CH:64]=[CH:63][C:34]([C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][N:45]([CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C:46](=[O:54])[C:47]3[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=3)=[CH:40][CH:39]=2)=[O:36])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.CN(C=O)C>[CH2:23]([O:30][C:31]1[CH:64]=[CH:63][C:34]([C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][N:45]([CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C:46](=[O:54])[C:47]3[CH:48]=[CH:49][C:50]([NH:53][C:10](=[O:12])[CH2:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:13]([F:16])([F:15])[F:14])=[CH:51][CH:52]=3)=[CH:40][CH:39]=2)=[O:36])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(N)cc3)cc2)cc1
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Prepared using General Procedure 7: To 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (299 mg, 1.28 mmol) in DCM (5 mL) and DMF (20 μL) was added oxalyl chloride (0.117 mL, 1.34 mmol). After stirring at room temperature for 30 min, 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4 (700 mg, 1.22 mmol) and TEA (0.424 mL, 3.05 mmol) in DCM (10 mL) were added. The reaction was stirred for 1 h then diluted with DCM (100 mL) and washed with NaHCO3 (100 mL). The crude product was purified by chromatography to provide 555 mg (58%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-6. LCMS-ESI (m/z) calculated for C44H49F3N2O8: 791; no m/z observed, tR=3.28 min (Method 4).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Nitro-indole-1-carboxylic acid t-butyl ester (1 eq) was dissolved in methanol (0.1M), to this solution was added palladium on carbon (0.1 eq) in methanol under nitrogen. A hydrogen atmosphere was then inserted and resulting mixture allowed to stir for 3 hours at room temperature. The reaction mixture was then filtered through celite and solvent removed in vacuo to afford 6-Amino-2,3-dihydro-indole-1-carboxylic acid t-butyl ester as a white solid. MS: MH+ 235