Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]1(OB(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-c2c(Br)sc3ccccc23)cc1
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
A mixture of 2-bromo-3-(4-(methanesulfonyl)phenyl) benzo-[b]thiophene (400 mg) from Step 3, phenylboric acid (590 mg), Pd (PPh3)4 (89 mg) and 1 molar NaOH in toluene (6 mL) and EtOH (8 mL) was refluxed for 24 hrs. After cooling to 25° C. a saturated NaHCO3 solution was added and the mixture was extracted with Et2O (2×), the organic portions were combined, washed with brine, dried over MgSO4, filtered and the solvent evaporated under vacuum. Purification by column chromatography using 2% isopropanol in hexane afforded the title compound. m.p. 172.9-173.9° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[F:13][C:14]([F:27])([F:26])[C:15](=O)[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.S(=O)(=O)(O)O>C(O)C(F)(F)F.O.C([O-])(O)=O.[Na+]>[CH3:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([N:1]2[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][C:15]([C:14]([F:13])([F:26])[F:27])=[N:2]2)=[N:4][CH:5]=1)(=[O:10])=[O:11]
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)nc1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a mixture of the 2-hydrazino-5-(methylsulfonyl)pyridine (456 mg, 2.04 mmol) and 4,4,4-trifluoro-1-phenyl-1,3-butanedione (441 mg, 2.04 mmol) in dry trifluoroethanol (30 ml) was added a catalytic amount of concentrated sulfuric acid (-0.5 ml) and the mixture was refluxed overnight. The reaction mixture was cooled to room temperature and diluted with water 50 ml and neutralized with saturated NaHCO3 to PH˜7 and then extracted with EtOAc (50 ml×3). The organic layer was washed with brine (25 ml), dried (MgSO4) and concentrated to give the crude solid. The crude solid was recrystallized in ethanol to provide a desired product as a crystalline white solid (337 mg, 45% yield).
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([C:10]([OH:12])=O)=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:22][C:23]1([CH3:30])[NH:28][CH2:27][CH2:26][NH:25][C:24]1=[O:29].CCN(C(C)C)C(C)C>ClCCl>[C:1]([C:5]1[NH:9][C:8]([C:10]([N:28]2[CH2:27][CH2:26][NH:25][C:24](=[O:29])[C:23]2([CH3:30])[CH3:22])=[O:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(C(=O)O)[nH]1
Reactant: CC1(C)NCCNC1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc([N+](=O)[O-])c(C(=O)N2CCNC(=O)C2(C)C)[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 53.1 %

Procedure:
The previously prepared 5-tert-butyl-3-nitro-1H-pyrrole-2-carboxylic acid (0.203 g, 1.11 mmol) and PCl5 (0.232 g, 1.11 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 5 minutes. The resulting solution was added in one portion to a solution of 3,3-dimethylpiperazin-2-one (0.214 g, 1.67 mmol) and DIEA (0.288 g, 2.23 mmol) in dichloromethane (3 mL) and stirred at room temperature for 5 minutes. The reaction mixture was diluted with dichloromethane and washed sequentially with 1N aqueous HCl, saturated sodium bicarbonate, dried and the solvent removed under vacuum. The crude product was purified by chromatographic column (silica gel, dichloromethane:methanol, 95:5) to afford 0.190 g of expected 4-(2-tert-butyl-4-nitro-1H-pyrrole-5-carbonyl)-3,3-dimethylpiperazin-2-one.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](Cl)[CH:4]=[C:3](NN=C(C#N)C#N)[CH:2]=1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:5]1([CH:15]([CH3:20])[CH3:16])[CH:4]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: N#CC(C#N)=NNc1cccc(Cl)c1
Solvent: Oc1ccccc1
Product: CC(C)c1ccccc1
Yield: 10 %

Procedure:
According to A.C. CCCP 1235860 (1986) before decomposition, the phenol tar is diluted by high-molecular weight aromatic compounds such as Baltic shale oil (grade kerogen -70) weight ratio of tar to shale oil 1.3/2.5. Process conditions are: pressure 3-7 MP, temperature 400°-430 ° C., time 5-20 min. Liquid products obtained are separated by distillation. This process takes place under relatively severe conditions and gives a poor yield of phenol (4-5% ) and cumene (10-15% ). In addition it requires the addition of shale oil.
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:6][CH:5]([CH2:7][NH2:8])[CH2:4][O:3]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN1CCOCC1>>[CH3:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:6][CH:5]([CH2:7][NH:8][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)C1(C)CC(CN)CO1
Reactant: O=C(Cl)c1ccccc1
Solvent: CN1CCOCC1
Product: CC1(C(=O)O)CC(CNC(=O)c2ccccc2)CO1

Procedure:
At room temperature, to a solution of 2-methyl-4-aminomethyl-2-tetrahydrofuroic acid, tert-butyl ester (30 mg, 0.139 mmole) was added benzoyl chloride (0.167 mmol, 24 mg) and N-methylmorpholine (0.334 mmol, 34 mg). After being stirred at room temperature for 2.5d, volatiles were removed and the residue was flash chromatographed through silica gel. The title compound was obtained in quantitative yield (47 mg). TLC: Rf=0.45 (1:1 hexane:ethyl acetate); Mass Spectrum: ESI m/e 320 (M+1)+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate (1.8143 g, 4.66 mmol) and trifluoroacetic acid (14.36 ml, 186 mmol) in DCM (15.54 ml) was stirred at RT for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with DCM and washed with water. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to form an orange oil which was used in the next step without further purification;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:12]1([S:18]([N:1]2[C:9]3=[N:8][CH:7]=[CH:6][CH:5]=[C:4]3[CH:3]=[CH:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
A mixture of 7-azaindole (10 g, 84.6 mmol) and tetrabutylammonium bromide (0.81 g, 2.53 mmol) in dichloromethane (211 mL, 0.4 M) at 0° C. was treated with powdered sodium hydroxide (10.15 g, 253.9 mmol). This solution was stirred at 0° C. for 10 min, it was then slowly treated with benzenesulfonyl chloride (16.3 mL, 126.9 mmol). The reaction was allowed to gradually warm to 25° C. and was stirred for 16 h. At this time, the resulting solids were removed by filtration and were washed with dichloromethane (2×50 mL). The filtrate was concentrated in vacuo to afford a yellow solid which was dried under high vacuum for 30 min. At this time, the solids were triturated with hexanes (3×50 mL) to afford 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (19.5 g, 89.2%) as a light yellow solid: 1H NMR (400 MHz, d6-DMSO) δ ppm 8.38 (dd, 1H, J1=4.5 Hz, J2=1.2 Hz), 8.12 (d, 2H, J=7.8 Hz), 8.05 (dd, 1H, J1=7.8 Hz, J2=1.8 Hz), 7.93 (d, 1H, J=3.9 Hz), 7.74-7.59 (m, 3H), 7.32-7.28 (m, 1H), 6.84 (d, 1H, J=3.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([CH3:13])[C:10]([OH:12])=[O:11].[CH:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16](O)[CH:15]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CC=CN=1)C.ClCCl>[N+:20]([C:19]1[CH:14]=[CH:15][C:16]([O:11][C:10](=[O:12])[C:9]([CH3:13])=[CH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[CH:17][CH:18]=1)([O-:22])=[O:21]
Reactant: CC(=Cc1ccccc1N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(=Cc1ccccc1N)C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Into 20 ml of dichloromethane, 0.19 g (1.1 mmol) of (E) 3-(2-aminophenyl)-2-methyl-2-propenoic acid and 0.18 g of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved; and 10 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. Further, while the mixture was stirred under cooling with ice, 0.41 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC-HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto in portions. The mixture was returned to room temperature and then was stirred for 20 hours. After the end point of this reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. This solution was washed several times with a 5% aqueous sodium hydrogencarbon ate solution and then with a saturated aqueous sodium chloride solution, and was dried with magnesium sulfate anhydride. Thereafter, the solvent was evaporated, whereby a crude product was obtained. This product was recrystallized from ethanol, whereby 0.29 g of the aimed compound was obtained as a crystal (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:22]O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([O:16][CH3:22])=[O:15])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)s1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Cl)s1
Yield: 86 %

Procedure:
To a solution of 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionic acid (2.20 g) in methanol (50 ml) was added conc. sulfuric acid (1 ml) and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, iced water was poured on the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals (3.80 g, yield 86%) of methyl 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionate were obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from diethyl ether-isopropyl ether to give a colorless prism. melting point: 34–35° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:6]([CH:7]=[N:8][C@H:9]([CH2:15][F:16])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:5]([OH:18])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[CH2:7][NH:8][C@H:9]([CH2:15][F:16])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CC[C@@H](CF)N=Cc1cc(Cl)ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)CC[C@@H](CF)NCc1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
0.42 g of 18 dissolved in a small amount of ethyl alcohol was added drop-by-drop to a mixture of 0.06 g of sodium borohydride, 3.6 ml of ethyl alcohol and 0.9 ml of water, at 10° C. The resulting solution was stirred and allowed to warm to room temperature overnight. The resulting mixture was quenched with water, and the resulting mixture was extracted with ethyl acetate. The extract was dried (Na2SO4), filtered and the solvent was evaporated to give 19, as an oily solid.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:8]([CH3:16])=[N:9][C:10]([CH3:15])=[C:11]([Br:14])[C:12]=1[Cl:13].Cl[C:18](=[O:25])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]>C1COCC1>[Br:14][C:11]1[C:12]([Cl:13])=[C:7]([C:18](=[O:25])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:8]([CH3:16])=[N:9][C:10]=1[CH3:15]
Reactant: CC(C)OC(=O)C(=O)Cl
Reactant: Cc1nc(C)c(Br)c(Cl)c1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 75.4 %

Procedure:
A solution of 2M isopropyl magnesium chloride (84 mL, 168 mmol) was added drop wise over 20 min to a cold (−70° C.), nitrogen purged solution of 3,5-dibromo-4-chloro-2,6-dimethylpyridine (48 g, 160 mmol) and copper(I)bromide-dimethyl sulfide complex (1.65 g, 8.02 mmol) in THF (240 mL), which was then allowed to warm to −10° C. over 60 min. The reaction mixture was transferred via cannula into a 1 L RB-flask containing isopropyl 2-chloro-2-oxoacetate (26.6 g, 176 mmol) in THF (160 mL) maintained at −60° C., and the reaction stirred an additional 2.5 h while being allowed to warm to −10° C. The reaction was quenched upon diluted with a mixture of 10% NH4Cl solution (80 mL) in ether (320 mL). The organic layer was washed with 160 mL of sat'd NaHCO3/10% NH4Cl solution (1:1), brine, and dried (Na2SO4). The crude product was charged (DCM solution) to a 330 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate 40.38 g (76%). 1H NMR (500 MHz, CDCl3) δ 5.28-5.21 (m, 1H), 2.77 (s, 3H), 2.47 (s, 3H), 1.40 (d, J=6.3 Hz, 6H). LCMS (M+H)=336.04.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][C:8]([C:18]([F:21])([F:20])[F:19])=[C:7]([Br:22])[N:6]=1)=[O:4].[OH-].[Na+].O.Cl>C1COCC1>[Br:22][C:7]1[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]([N:11]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:17])=[CH:9][C:8]=1[C:18]([F:20])([F:19])[F:21]
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1-n1c(C)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C(F)(F)F)c(Br)nc1C(=O)O

Procedure:
6-Bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (1.9 g, 5.04 mmol) and 2M NaOH (2.52 ml, 5.04 mmol) in THF (10 ml) was stirred at RT for 1 hour. The reaction mixture was poured into water (50 ml) and the pH was adjusted to pH 4 by addition of 1M HCl. The mixture was extracted with EtOAc (2×50 ml) and the organic portion was washed with brine (30 ml), dried over MgSO4 (5 g), filtered and concentrated to give the title compound as a crystalline orange solid; LC_MS Rt=1.21 min [M+H]+ 363.1 (Method 2 minLC_v003).
Reaction SMILES: BrC1SC2C(O)=CC(C)=CC=2N=1.C(N(CC)CC)C.[Cl-:20].C(OCC)(=O)C=O.Br[C:29]1[S:30][C:31]2[C:37]([OH:38])=[C:36]([CH:39]([OH:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([CH3:46])=[CH:34][C:32]=2[N:33]=1>ClCCl>[Cl:20][C:29]1[S:30][C:31]2[C:37]([OH:38])=[C:36]([CH:39]([OH:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([CH3:46])=[CH:34][C:32]=2[N:33]=1
Reactant: [Cl-]
Reactant: CCOC(=O)C(O)c1c(C)cc2nc(Br)sc2c1O
Agent: CCOC(=O)C=O
Agent: Cc1cc(O)c2sc(Br)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)cc2nc(Cl)sc2c1O
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-methylbenzo[d]thiazol-7-ol (2.48 g, 10.16 mmol) in dichloromethane (100 mL) at 0° C. was added triethylamine (1.42 mL, 10.16 mmol) to give a clear solution. Titaniuim(IV) chloride (1.0M in CH2Cl2, 10.67 mL, 10.67 mmol) was added slowly to give an orange reaction mixture that was stirred for 30 minutes. A solution of cracked ethyl glyoxalate (1.04 g, 10.16 mmol) in CH2Cl2 (1 mL) was added over 2 minutes and reaction mixture was stirred at room temperature for 2.5 h. Reaction mixture was quenched with Rochelle's salt and stirred at room temperature for 2 h, diluted with CH2Cl2, and aqueous layer extracted with CH2Cl2 (2×). The combined organic layer was dried (MgSO4), filtered and concentrated. Purification by CombiFlash (40 g, 0 to 30% EtOAc/Hex) gave product contaminated with ethyl 2-(2-bromo-7-hydroxy-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate. LCMS-ESI+: calc'd for C12H13ClNO3S: 302.8 (M+H+); Found: 302.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[C:25](=S)=[S:26].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:25]([SH:26])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: S=C=S
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)CCCCCOc1ccc2nc(S)n(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
0.4 g of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was dissolved in 5 ml of pyridine, mixed with 75 μl of carbon disulfide, and the mixture was stirred for 12 hours at 20° C. It was mixed with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 368 mg was obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([O:49][CH3:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([O:49][CH3:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:51]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OC)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OC)c2)CCN3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.4 g) was dissolved in ethanol (300 ml), and to the solution, sodium borohydride (0.11 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 3) (0.35 g) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][C:36]([F:39])([F:38])[F:37])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][C:36]([F:39])([F:37])[F:38])[CH:29]=3)[O:23][C:22](=[O:24])[C:21]([CH2:11][C:9]3[N:10]=[C:5]4[N:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[N:8]=3)=[C:20]([OH:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CC(=O)OC(CCc2ccc(O)c(CC(F)(F)F)c2)(C2CCCC2)C1
Reactant: Cc1cnc2nc(C=O)nn2c1
Solvent: CO
Product: Cc1cnc2nc(CC3=C(O)CC(CCc4ccc(O)c(CC(F)(F)F)c4)(C4CCCC4)OC3=O)nn2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.7 %

Procedure:
6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.88 g, 0.546 mmol) was added to a solution of example A(228) 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (0.175 g, 0.455 mmol) and borane-dimethylamine complex (53 mg, 0.9 mmoL) in MeOH (10 mL). The reaction was stirred at room temperature for 15 hours, after which time the mixture was concentrated to a residual oil, and purified by preparatory HPLC to afford the title compound as a white solid (50 mg). 1H NMR (DMSO): δ 1.35–1.85 (brm, 8H), 2.00–2.20 (brm, 3H), 2.50 (s, 3H), 2.74 (s, 2H), 2.99(m, 2H); 3.04 (m, 2H), 3.54 (m, 3H), 6.81 (m, 2H), 7.00(s, 1H), 8.55 (s, 1H), 8.72 (s, 1H). Anal. Calcd. For C27H29O4N4F3: C, 61.14; H, 5.51; N, 9.06. Found: C, 61.21; H, 5.60; N, 9.14.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]2[C:20]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:19][CH:18]=[C:17]([C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)=[N:31][CH:32]=3)[N:16]2[CH:46]=1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[N:33]1([C:30]2[N:31]=[CH:32][C:27]([C:17]3[N:16]4[CH:46]=[C:13]([CH2:12][O:11][C:2]5[CH:3]=[CH:4][C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[N:1]=5)[N:14]=[C:15]4[C:20]([CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:19][CH:18]=3)=[CH:28][CH:29]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(C4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2nc(OCc3cn4c(-c5ccc(N6CCNCC6)nc5)cnc(C5CCOCC5)c4n3)ccc2c1
Yield: 55 %

Procedure:
Compound 91a (130 mg, 0.210 mmol) was treated with TFA as described in Example 87, Step F to obtain the title compound 83 as a light yellow solid (61.7 mg, 55% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.84 (s, 1H), 8.51 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.13 (s, 1H), 8.03 (dd, J=2.4 Hz, 8.7 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.86 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.72-7.67 (m, 1H), 7.49-7.44 (m, 1H), 7.12 (d, J=9.0 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 5.65 (s, 2H), 4.03-4.00 (m, 2H), 3.87-3.78 (m, 5H), 3.61-3.54 (m, 2H), 3.28-3.20 (m, 4H), 2.01-1.87 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C30H31N7O2: 522.3 (M+H). Found 522.3.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=O)=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]>S(=O)(=O)(O)O.O.[Zn]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([SH:12])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Product: CCCCCc1ccc(S)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Zinc dust (39 g) was added to a mixture of 4-n-pentylbenzenesulfonyl chloride (27 g, 0.11 ml) in concentrated sulfuric acid (43 ml) and water (270 ml) at less than 0° C. Thereafter, stirring was continued at a temperature less than 0° C. for about one hour followed by refluxing for approximately three hours. The reaction mixture was cooled and then poured into ice water (350 ml) and the reaction product was extracted with ether (2×400 ml). The extract was washed with water and dried over anhydrous sodium sulfate. The solvent (ether) was evaporated and the reaction product was vacuum-distilled to yield 4-n-pentylbenzenethiol (14 g, 71%, boiling point 90°-94° C./0.6 mm).