Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH2:5]([O:7][C:8](=[O:24])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:22][OH:23])[CH3:6].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH2:5]([O:7][C:8](=[O:24])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH:22]=[O:23])[CH3:6]
Reactant: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1CO
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 4.25 h

Procedure:
1-(3-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 505 mg, 2.63 mmol) and DMSO (0.25 mL, 3.52 mmol) were added sequentially to a solution of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid ethyl ester (252 mg, 0.88 mmol) in benzene (5 mL). The mixture was cooled to 0° C. and pyridinium trifluoroacetate (187 mg, 0.97 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 4.25 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×5 mL). The combined benzene phases were concentrated in vacuo to afford crude 4-((R)-2-formyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid ethyl ester that was used without further purification.
Reaction SMILES: C[Al](C)C.[NH3:5].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[N:14]1[C:19]2[N:20]=[C:21]([NH:32][CH2:33][C:34](OC)=[O:35])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[C:18]=2[CH:17]=[CH:16][C:15]1=[O:38]>ClCCl.CCOC(C)=O>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[C:8]=1[N:14]1[C:19]2[N:20]=[C:21]([NH:32][CH2:33][C:34]([NH2:5])=[O:35])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])[C:18]=2[CH:17]=[CH:16][C:15]1=[O:38]
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: N
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1nc(NCC(N)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 16 h
Yield: 54 %

Procedure:
To a soln of trimethylaluminum (3.3 mL, 6.6 mmol) in dichloromethane was bubbled NH3 gas for 30 min, the product of Example 190 (500 mg, 1.1 mmol) was then added. The resulting mixture was stirred for 16 h. The mixture was diluted with EtOAc and washed with H2O to give the crude material. Purification by flash chromatography , eluting with EtOAc/triethylamine (100/2, v/v), gave the desired product (263 mg, 54%). LC-MS: 440.0 (MH+, m/z), 1.75 (Rt, min).
Reaction SMILES: Cl[S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:12][CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C(OCC)C>[CH3:12][CH:13]([N:17]1[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[S:2]1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C(Cl)c1ccccc1SCl
Reactant: CCCC(C)N
Solvent: CCOCC
Product: CCCC(C)n1sc2ccccc2c1=O
Reaction time: 16 h

Procedure:
2-Chlorosulphenylbenzoyl chloride (6 parts, 0.029M) dissolved in diethylether (30 ml) was added dropwise at 0 to 3° C. to a stirred solution of 1-methylbutylamine (7.36 parts, 0.84M ex Aldrich) in diethylether (30 ml). The reactants were stirred for 16 hours whilst allowing the temperature to rise to about 20° C. The ether solution was then screened, washed with water and dried over magnesium sulphate. After evaporation of the ether, the product was obtained as a pale yellow gum (5.5 parts, 86% theory) which gradually solidified on standing. This was recrystallised from hexane. mp=52-54° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:6][C:3]=1[CH:4]=O.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].C(OC)(OC)OC.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:6][C:3]=1[CH2:4][NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26]
Reactant: CN(C)CCN
Reactant: Cc1cccc(-c2nn3ccccc3c2-c2ccc(F)c(C=O)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccc(F)c(CNCCN(C)C)c2)n1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A solution of 2-fluoro-5-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-benzaldehyde (0.05 g, 0.15 mmol), N,N-dimethyl-ethylenediamine (0.013 g, 0.15 mmol), trimethyl orthoformate (2 mL) in MeOH (5 mL) is stirred for 2 hours at room temperature. The reaction is then treated with sodium borohydride (6.8 mg, 0.18 mmol) and stirred overnight. The reaction is then quenched with 2N NaOH and stirred for 30 minutes. The solution is diluted in CH2Cl2 and washed with saturated aqueous NaHCO3, brine, and dried over sodium sulfate. The solvent is removed in vacuo to afford 0.06 g (100%) of desired product. MS ES+ m/e 404.1 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH-].[Na+].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:12]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSCCC(N)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In accordance with the literature (J. Peptide Sci., 2001, 7, 619-625), 10 g of DL-methionine was added to 20 ml of water and 11.5 ml of 6 N NaOH, and dissolved therein. While keeping pH at 10.5 to 11.5, 8.6 ml of benzoyl chloride was added thereto, and the mixture was stirred at room temperature for two hours. The resulting reaction mixture was filtrated and then washed with diethyl ether. Concentrated hydrochloric acid was gradually added to adjust the pH to 1 to precipitate a crystal. The crystal was filtrated, washed with water, and dried under reduced pressure to obtain 16.2 g of N-benzoylmethionine. 24 ml of acetic anhydride was added to 4.9 g of obtained N-benzoylmethionine, the solution was heated at 100° C. for 4 hours, then cooled to room temperature, and the solvent was evaporated. The steps of adding 24 ml of toluene to the residue and evaporating the solvent were repeated twice. The, the residue was dissolved in 2.5 ml of pyridine, 10 ml of 35% formaldehyde solution was added, and the solution was stirred at room temperature for 17 hours. 40 ml of water was added to the resulting reaction solution, which was then extracted with 40 ml of ethyl acetate. The extract was washed with water and saturated brine, and dried on magnesium sulfate. Magnesium sulfate was removed and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 4/1 to 1/1). After evaporating the solvent, 2.56 g of 5-benzoylamino-5-methylthioethyl-4-oxo-1,3-dioxane was obtained. 7.5 ml of 6 N hydrochloric acid was added to 1.06 g of the obtained 5-benzoylamino-5-methylthioethyl-4-oxo-1,3-dioxane, which was then heated and refluxed for 7 hours. The reaction solution was filtrated, and then the solvent was evaporated. 5 ml of water was added to the residue, which was then purified using an ion exchange resin (Amberlite 120). After evaporating the solvent, the resulting crystal was recrystallized from water/ethanol, and dried under reduced pressure to obtain 129 mg of α-methylthioethyl-serine. NMR of this compound was measured, and almost agreed with the values described in the literature.
Reaction SMILES: C(O[N:9]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25]OCC1C=CC=CC=1)[CH2:10][C:11](=C=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:9][CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)C(=C=O)CN(CCCCNOCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CCNCCCCN
Yield: 99.8 %

Procedure:
2.49 g (5.14 mmol) of t-butyl 4,9-bisbenzyloxy-carbonyl-4,9-diazanonanoate was dissolved in 20 ml of methanol and 0.3 g of palladium black was added thereto. The obtained mixture was reduced at room temperature under atmospheric pressure in a hydrogen gas stream for three hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to thereby give 1.11 g of the aimed compound in the form of an oily product (yield: 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[N:9]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2c([nH]c3ccc(Cl)cc23)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2c(n(C(=O)c3ccc(Cl)cc3)c3ccc(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5.5 g. of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester in 40 ml. of dimethylformamide was added 0.9 g. of 54.5 percent sodium hydride in mineral oil. After the mixture had stirred 1 hour at room temperature, 3.5 g. of p-chlorobenzoyl chloride in 10 ml. of dimethylformamide was added dropwise over the course of 10 minutes. The mixture was then stirred for 5 hours between 60°-70° and then poured onto ice (500 g.). The mixture was extracted with ether (3 × 150 ml.) and the ether was in turn extracted with water (5 × 100 ml.). After drying the ether solution over sodium sulfate, the desiccant was removed by filtration and the ether was evaporated. Upon recrystallization of the residue with ethyl acetate, 3.8 g. of product was obtained, m.p. 129°-132° . Following two further recrystallizations from methanol, a yield of 2.3 g. of 6-chloro-9-(p-chlorobenzoyl)-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester was obtained, m.p. 136°-137°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([CH3:12])=[CH:4][C:3]=1[CH3:13].S(=O)(=O)(O)O.[Cl:19]Cl>>[Cl:19][C:4]1[C:3]([CH3:13])=[C:2]([Br:1])[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]=1[CH3:12]
Reactant: ClCl
Reactant: Cc1cc(C)c(S(C)(=O)=O)cc1Br
Agent: O=S(=O)(O)O
Product: Cc1c(Br)cc(S(C)(=O)=O)c(C)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g of the crude 4-bromo-6-methylsulfonyl-m-xylene obtained in Example 1 was added to 8 ml of 20% fuming sulfuric acid. A chlorine gas was flown little by little while stirring at room temperature in a reactor provided with a dry ice trap at the upper part. After one hour, the reaction liquor was added to ice, and was extracted twice with 30 ml of EDC. The EDC solution was washed with 50 ml of water and then with 20 ml of a saturated aqueous solution of common salt, and was dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried to a solid, thus obtaining 2.2 g of a crude product of the above-identified aimed compound (purity measured by gas chromatography: 81.6%). A part of the crude product was recrystallized from methanol to obtain the above-identified aimed compound.
Reaction SMILES: O1CCCCC1[N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25]C3CCCCO3)=[CH:20][CH:19]=2)=[N:8]1.C(O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[NH:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[N:8][N:7]=[N:11]1
Reactant: c1ccc(-c2nnn(C3CCCCO3)n2)c(-c2ccc(COC3CCCCO3)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To 2-(tetrahydro-pyran-2-yl)-5-[4′-(tetrahydro-pyran-2-yloxymethyl)-biphenyl-2-yl]-2H-tetrazole (3.36 g; 8.00 mmol) are added 94% ethanol (12 mL) and a 2 M aqueous solution of sulfuric acid (1.0 mL; 2.0 mmol). The resulting mixture is heated to 45° C. for 3.5 hours. Water (16 mL) is slowly added and the mixture is allowed to cool down to room temperature. The pH of the reaction mixture is adjusted to pH 2 to 3 by adding a 2M aqueous sodium hydroxide solution (0.6 mL). The mixture is concentrated under reduced pressure, diluted with isopropyl acetate (15 mL) and washed three times with water (3 mL). The organic extract is concentrated under reduced pressure to a volume of about 4 mL and tert-butyl methyl ether (8 mL in total) is slowly added. The mixture is stirred overnight, diluted with a small amount of isopropyl acetate and further stirred for 4.5 hours. The suspended, white solid is filtered, washed with a small amount of isopropyl acetate and dried under reduced pressure to afford [2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-methanol. The filtrate is concentrated under reduced pressure, and tert-butyl methyl ether (3 mL) and heptane (0.5 mL) are slowly added. The mixture is stirred at room temperature overnight and at 0 to 5° C. for 1 hour. The suspended, white solid is filtered, washed with a small amount of isopropyl acetate and dried under reduced pressure to afford a second crop of [2′-(1H-tetrazol-5-yl)-biphenyl4-yl]-methanol.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][N:26]=[N:27][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][N:26]=[N:27][C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=NCN12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=NCN12
Temperature: 70 °C
Yield: 87.5 %

Procedure:
To a solution of methyl 10-cyclohexyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylate (66 mg, 0.16 mmol) in THF (6 mL) and MeOH (3 mL), was added aq NaOH (1.0N, 1.5 mL, 1.5 mmol), and the mixture was heated at 70° C. for 2 h. The solvents were removed, and the white solid residue was washed with water and EtOAc, isolated by centrifuge and dried under vacuum to yield crude 10-cyclohexyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylic acid (54 mg, 0.14 mmol, 85%) as a white solid, which was used without further purification. 1H NMR (500 MHz, d6-DMSO) δ 1.07-1.19 (m, 1H), 1.34-1.46 (m, 3H), 1.65-1.75 (m, 2H), 1.86-2.12 (m, 4H), 2.73-2.84 (m, 1H), 5.04 (d, J=15.9 Hz, 1H), 5.93 (d, J=15.9 Hz, 1H), 7.63-7.74 (m, 5H), 7.79-7.85 (m, 1H), 8.18 (s, 1H), 9.08 (s, 1H). LCMS: m/e 399 (M+H)+, ret time 2.02 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:6]([CH:8]=1)[NH2:7].[N:18]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[N:18][NH:7]2)=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccc(F)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Fc1ccc(-c2n[nH]c3cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
To solution of 5-chloro-2-(4-fluorobenzoyl)aniline (5 g) in 6M aqueous HCl (25 ml) was added a solution of NaNO2 (2.5 g) in water (5 ml) at 0°-5° C. under stirring during 15 min. After stirring for further 0.5 h at 0° C. a solution of SnCl2 (20 g) in conc. aqueous HCl (25 ml) was added. The reaction mixture was allowed to heat to room temperature and after 0.5 h the precipitate was filtered off and suspended in 2 N aqueous NaOH. The suspension was filtered and dichloromethane was added to the precipitate. The thus obtained solution was washed with brine and dried (MgSO4). Evaporation of the solvents afforded the title compound (2.5 g) as an oil which was used without further purification. In a corresponding manner the following indazole derivative was prepared: 3-(4-Fluorophenyl)-5-trifluoromethyl-1H-indazole 25b, (oil)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].[Cl:18][CH2:19][C:20](=O)[CH2:21]Cl>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:21]=[C:20]([CH2:19][Cl:18])[N:8]=2)[CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1
Reactant: NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(CCl)CCl
Product: FC(F)(F)c1cc(-c2nc(CCl)co2)cc(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 353A using 3,5-bis-(trifluoromethyl)benzamide and 1,3-dichloro-2-propanone: 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2H), 7.96 (s, 1H), 7.80 (s, 1H), 4.59 (s, 2H).
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][C:19]=1[CH3:28]>>[NH2:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:14]([C:10]2[CH:9]=[C:8]([O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[C:19]([CH3:28])[CH:20]=1)(=[O:25])=[O:26]
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Reactant: O=C(O)c1cc(OC2CCCCC2)ncn1
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(OC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting 6-(cyclohexyloxy)pyrimidine-4-carboxylic acid (Intermediate 32) and 4-amino-3-methylbenzenesulfonamide (Biofine), the title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-])=O.O.O.[Sn](Cl)[Cl:15].O>Cl>[Cl:15][C:5]1[C:4]([NH2:9])=[C:3]([NH:2][CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: Cl[Sn]Cl
Reactant: CNc1ccncc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: CNc1ccnc(Cl)c1N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A solution of methyl-(3-nitro-pyridin-4-yl)amine (7.00 g) in concentrated hydrochloric acid (150 mL) was heated to 90° C. Tin(II) chloride dihydrate (52.2 g) was then added, and this was heated at 90° C. for 30 minutes. The reaction solution was cooled to 0° C., iced water (700 mL) was added, and this was stirred for 30 minutes. The solution was concentrated under reduced pressure, and then ammonia-saturated methanol solution (700 mL) was added to the residue, and this was stirred at 5° C. for 15 hours. The solvent was removed by concentration under reduced pressure. The residue was suspended in ethyl acetate (500 mL), and this was filtered through celite. The celite and the suspended material were washed five times with 250 mL of ethyl acetate, then the organic layers were combined, and this was concentrated under reduced pressure to give the title compound (7.22 g).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=O)[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](P(=O)(OCC)OCC)#[N:22].[C-]#N.[Li+].O>O1CCCC1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([C:21]#[N:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: O=C1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [C-]#N
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
7-Benzenesulfonyl-chroman-4-one from Preparation 1 above (500 mg, 1.73 mmol) was dissolved in 10 mL of tetrahydrofuran (THF). Diethyl cyanophosphonate (789 uL, 5.21 mmol) and lithium cyanide (10.42 mL, 5.21 mmol) were added, and the reaction mixture was stirred for 10 minutes at room temperature. Water (150 (mL) was added, and the aqueous mixture was extracted twice with 200 mL of EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was dissolved in 5 mL THF, and 70 mL of MeOH was added. SmI2 (52 mL, 5.21 mmol) was then added over five minutes, and the reaction mixture was stirred for 10 minutes at room temperature. The reaction was quenched by addition of 20 mL 1 N HCl, and the resulting aqueous mixture was extracted with EtOAc and 1 N Na2S2O3. The organic phase was dried over MgSO4, and solvent was removed under reduced pressure. The residue eluted through silica gel using 40% EtOAc in hexanes, and solvent was removed under reduced pressure to yield 300 mg (1 mmol, 58%) of 7-benzenesulfonyl-chroman-4-carbonitrile. MS: 300 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH2:8][NH:9][CH:10]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH:26]3[CH2:31][CH2:30][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]3)[CH:21]=2)[CH:16]=1)[C:11]([F:14])([F:13])[F:12])(C)(C)C.O1CCOCC1>Cl>[CH3:1][O:5][C:6](=[O:36])[CH2:7][CH2:8][NH:9][CH:10]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH:26]3[CH2:27][CH2:28][CH:29]([C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:30][CH2:31]3)[CH:21]=2)[CH:16]=1)[C:11]([F:14])([F:13])[F:12]
Reactant: CC(C)(C)OC(=O)CCNC(c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCNC(c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-{1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-2,2,2-trifluoro-ethylamino}-propionic acid tert-butyl ester (0.174 g, 0.343 mmol) was dissolved in 4 M of Hydrogen chloride in 1,4-Dioxane (3 mL, 10 mmol) and stirred at RT for 2.5 hrs. ALL solvent is removed after purification of the previous step. Reaction was then concentrated to dryness under reduced pressure to give the title compound which was taken directly to the next step.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[Br:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:9][C:8]1[CH:11]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:13][CH3:14])=[CH:6][C:7]=1[CH3:12]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Product: COc1cc(C)c(C=C2C(=O)Nc3ccc(Br)cc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>ClCCl>[OH:15][C:14](=[C:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])[CH2:13][C:12](=[O:16])[CH3:11]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Product: CC(=O)CC(O)=C1C(=O)OC(C)(C)OC1=O
Yield: 80 %

Procedure:
The above procedure is a modification of the procedure described in the literature at Kang, J; Kim, Y; Park, M; Lee, C.; Kim, W. Synthetic Communications (1984), 14(3), 265-9. In essence Meldrum's acid was reacted with diketene in dichloromethane in the presence of TEA at 20-25° C. for 2 hours to give 80% of 5-(1-hydroxy-3-oxobutylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH2:9][OH:10])[CH:8]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:8]=1)[CH:9]=[O:10]
Reactant: COc1ccc([N+](=O)[O-])c(CO)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
To the solution of (5-methoxy-2-nitrophenyl)methanol (18 g, 0.098 mol) in anhydrous DCM (0.2 L) was added PDC (11.5 g, 0.147 mol, 1.5 eq) and 4 A MS (120 g) in portions. The mixture was stirred at room temperature for 16 h, filtered through a Celite pad. The filtrate was evaporated to dryness in vacuum to afford 5-methoxy-2-nitrobenzaldehyde (10 g, yield: 57%) as a light yellow solid. 1HNMR (400 MHz, DMSO-d6) δ: 10.24 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.31 (dd, J=8.8, 3.2 Hz, 1H), 7.20 (d, J=3.2 Hz, 1H), 3.89 (s, 3H); ESI-MS: m/z 182.0 ([M+1]+).