Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9](=[O:12])[CH2:10][Cl:11])([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:9]([OH:12])[CH2:10][Cl:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the thus-prepared reducing agent was added 299 mg (1.0 mmol) of [1(S)-benzyl-2-oxo-3-chloropropyl]carbamic acid t-butyl ester, and the mixture was stirred at 25° C. for 16 hours. After hydrolysis with 1 N hydrochloric acid, the reaction mixture was extracted with ethyl acetate.
Reaction SMILES: CN(C=[N:5][N:6]=[CH:7][N:8]([CH3:10])[CH3:9])C.[CH2:11]([N:18]1[CH2:23][CH2:22]C(N)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:10]([N:8]2[CH:7]=[N:6][N:5]=[CH:9]2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CN(C)C=NN=CN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(n3cnnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,2-bis[(dimethylamino)methylene]hydrazine (660 mg) in toluene (10 ml) was added 1-benzylpiperidin-4-amine (0.8 ml) and p-toluenesulfonic acid (75 mg) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was refluxed for 8 hours and then evaporated to dryness. The residue was purified by chromatography on silica eluting with a gradient of methanol/ethyl acetate to give 1-benzyl-4-(4H-1,2,4-triazol-4-yl)piperidine. Yield 220 mgs. NMR (d6 DMSO): 2.0 (m, 4H), 2.1 (m, 2H), 2.9 (m, 2H), 3.5 (s, 2H), 4.2 9m, 1H), 7.35 (m, 5H), 8.65 (s, 2H).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[N+:14]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([O-:16])=[O:15]>CN(C)C=O.C(Cl)(Cl)Cl>[N+:14]([C:17]1[N:18]=[CH:19][N:20]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[OH:7])[CH:21]=1)([O-:16])=[O:15]
Reactant: C1CCC2OC2C1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(C2CCCCC2O)cn1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
40.0 ml (395 mmol) of cyclohexene oxide and 86.37 g (625 mmol) of potassium carbonate were added to a suspension of 50.08 g (443 mmol) of 4-nitroimidazole in 800 ml of N,N-dimethylformamide. The obtained mixture was stirred under heating at 100° C. for 3 days and 20 hours to give a yellowish-brown suspension. This suspension was cooled by allowing to stand, and filtered to remove insolubles. The filtrate was concentrated in a vacuum. Water was added to the obtained residue to form a crystalline precipitate. This crystalline precipitate was recovered by filtration and washed with water. The obtained crude crystal was dissolved in chloroform and the obtained solution was washed with a saturated aqueous solution of common salt. The organic phase was dried over anhydrous magnesium sulfate and concentrated in a vacuum. In the course of the concentration, a crystal began to precipitate. This crystal was recovered by filtration to give 53.26 g of the title compound as a colorless crystal. Further, the filtrate was recrystallized from dichloromethane/diisopropyl ether to give 5.14 g of the title compound as a light-brown crystal. Thus, 58.30 g of the title compound was obtained in total (yield: 70%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2)(=[O:5])=[O:4]>[Pd].CO>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CCN2
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)c1ccc2[nH]ccc2c1
Reaction time: 23 h
Yield: 94.7 %

Procedure:
N-methyl-indoline-5-sulfonamide (225 mg, 1.06 mmol), as prepared supra, was mixed with 10% palladium on carbon (84 mg) in methanol (8 ml) and these were refluxed for 23 hours. Additional 10% palladium on carbon (100 mg) and methanol (5 ml) were added, and refluxing continued for an additional 23 hours. The cooled reaction mixture was filtered through a Celite® pad, evaporated, and the crude solid redissolved in tetrahydrofuran and again filtered through a Celite® pad. Evaporation of the filtrate gave 211 mg (95%) of N-methyl-1H-indole-5-sulfonamide. This intermediate could also be produced from the reaction of N-methyl-indoline-5-sulfonamide and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in refluxing ethylene glycol monomethyl ether in 35% yield using known procedures. See, e.g. H. Breuer and H. H ohn, Chimie Therapeutique, 6:659 (1973 ).
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:26](=[O:30])[CH2:27][CH2:28][CH3:29]>C1CCCCC1.C1COCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Reactant: CCCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 50 mL (65 mmol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (7.7 g, 32.5 mmol) in 100 mL of THF keeping the temperature below −40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to −10° C. and then the bath replaced. After the temperature said cooled to −60° C., 4.3 g (32.5 mmol) of N-methoxy-N-methylbutanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 22 hours. It was then poured into a mixture of 200 mL of ether and 200 mL of 0.5N HCl. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated at reduced pressure to give 9.9 g of crude 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-pentanone. This material was dissolved in 100 mL of methylene chloride and 20 mL of trifluoroacetic acid and stirred for a total of 23 hours. The mixture was washed with water, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 2.19 g of 4-methoxy-2-propyl-1H-indole as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[NH:16][C:15](=[O:17])[NH:14][C:13]1=[O:18].[Na].Cl.[CH2:21]([N:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26]Cl)[CH3:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[NH:16][C:15](=[O:17])[N:14]([CH2:26][CH2:25][CH2:24][N:23]([CH2:28][CH3:29])[CH2:21][CH3:22])[C:13]1=[O:18]
Reactant: CCN(CC)CCCCl
Reactant: O=C1NC(=O)C(Cc2c[nH]c3ccc(Cl)cc23)N1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCN(CC)CCCN1C(=O)NC(Cc2c[nH]c3ccc(Cl)cc23)C1=O
Reaction time: 18 h

Procedure:
5-(5-Chloroindol-3-ylmethyl)hydantoin (5 g, 0.019 mole) was added to a solution of sodium (0.88 g) in 200 ml of anhydrous C2H5OH. After heating to reflux for 30 minutes, 3-diethylaminopropyl chloride hydrochloride (3.54 g, 0.019 mole) was added and the mixture was heated to reflux with stirring for 18 hours. The mixture was filtered and diluted with H2O to form a solid. The solid was recrystallized from aqueous 2-propanol, twice from acetone-petroleum ether and again from 2-propanol, yield 1.8 g, mp 186°.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:18]COCC.C([Li])CCC.CI>O>[CH3:18][C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[S:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: Brc1ccc(C=Cc2csc3ccccc23)s1
Agent: [Li]CCCC
Solvent: CI
Solvent: O
Product: Cc1ccc(C=Cc2csc3ccccc23)s1
Temperature: -70 °C
Reaction time: 0.03 h
Yield: 88 %

Procedure:
To a chilled (-70° C.), stirred solution of 3-[2-(5-bromo-2-thienyl)ethenyl]-benzo[b]thiophene (5.00 g) and ether (250 ml) was added n-butyllithium (6.8 ml of a 2.5M solution in hexanes), under nitrogen, over 2 mins. The mixture was stirred and chilled for 1.5 hrs. Methyl iodide (8.83 g) was added, and the mixture was allowed to warm to ambient temperature, with stirring, overnight. Water (200 ml) was added. The mixture was agitated, and the organic phase was separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with 10% dichloromethane in hexane). The appropriate fractions were combined and evaporated to yield 3.53 g (88%) of product, mp 62°-64° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1F

Procedure:
4-Fluoro-3-nitrobiphenyl (1e) was prepared analogously from 1g and phenylboronic acid.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:29](=[O:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:3]1.N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1>[C:42]([NH:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)=[O:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:29](=[O:35])[C:30]([N:32]([CH3:33])[CH3:34])=[O:31])=[CH:3]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1C(=O)N1CCC(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(=O)N1CCC(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2NC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.3 %

Procedure:
To the suspension of 2-{1-Amino-5-[4-(4-fluoro-benzyl)-piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamide (100 mg, 0.21 mmol) in anhydrous THF (3 mL) was added pyridine (60 uL, 0.63 mmol) and acetyl chloride (45 uL, 0.63 mmol) at 0° C. The mixture became clear and was stirred continually at RT for 72 h. The reaction mixture was evaporated in vacuo. The crude material was added water and it was extracted with CH2Cl2. The organic extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by radial chromatography with 0-3% MeOH/CHCl3 to give 30 mg (28% ) of the desired product. M+H+ (523).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][CH:4]=1.[Li][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.CO.[NH4+].[Cl-]>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][N+:11]([O-:13])=[O:12])=[CH:7][CH:8]=1
Reactant: [Li]c1ccccc1
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(C(C[N+](=O)[O-])c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a cold (−78° C.), stirred solution of (E)-1-methoxy-4-(2-nitrovinyl)benzene (153 mg, 0.86 mmol) in THF (20 mL) was added PhLi (0.64 mL, 1.6M) under Ar. After 1.5 h, the reaction was treated with MeOH, sat. NH4Cl and brine, and allowed to warm to room temperature. The reaction was extracted with EtOAc (3×), dried (MgSO4), filtered, concentrated then purified on Biotage Horizon to provide the product (150 mg, 68%) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm: 7.32 (2H, t, J=7.20 Hz), 7.19-7.25 (3H, m), 7.14 (2H, d, J=8.84 Hz), 6.84 (2H, d, J=8.84 Hz), 4.90-4.96 (2H, m), 4.81-4.87 (1H, m), 3.77 (3H, s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[NH:17]2)[C:13]([NH2:15])=[O:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:28](=O)([O-])[O-].[Na+].[Na+].CI>C(#N)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12](=[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]([CH3:27])([CH3:26])[N:17]2[CH3:28])[C:13]([NH2:15])=[O:14])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(N=NC(C(N)=O)=C2NC(C)(C)Cc3ccccc32)cc1
Agent: [Na+]
Solvent: CI
Solvent: CC#N
Product: CC(=O)c1ccc(N=NC(C(N)=O)=C2c3ccccc3CC(C)(C)N2C)cc1
Temperature: 25 °C

Procedure:
2-(4-acetyl-phenylazo)-2-(3,3-dimethyl-3,4-dihydro-2H-isoquinoline-1-ylidene) acetamide (Asinex Corp., Russia) and sodium carbonate are added to acetonitrile, and an acetonitrile solution of methyl iodide is slowly dropped and refluxed. The refluxed product is cooled to room temperature and, then, the solvent is removed by reducing a pressure; the residue is dissolved in dichloromethane and washed with distilled water. Thereafter, the product is dried with anhydrous sodium sulfate and filtered and, then, the solvent is removed by reducing the pressure. The residue containing the reaction product is purified by column chromatography to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([O:24]C)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: COC(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.15 g of 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-methoxycarbonylbenzamide is dissolved in 50 mL of isopropanol, and 50 mL of 1 molar sodium hydroxide solution is added and the mixture is stirred for 3 hours at ambient temperature. Then it is poured into 250 mL ice water and extracted twice with ethyl acetate. The aqueous phase is adjusted to pH 4 with 1 molar hydrochloric acid and the precipitate formed is separated off by filtration. The solid is washed with a little demineralized water and dried at 40° C. Then the solid obtained is treated with 150 mL of solvent mixture comprising petroleum ether/diethyl ether/ethyl acetate and dried again. Yield: quantitative; C16H11Cl2N3O3 (364.19); mass spectrum: (M+H)+=364/66/68 (chlorine isotope).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][NH2:10])=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]2[C:23]([C:24]([O-])=[O:25])=[C:22]([CH3:27])[NH:21][C:20]([CH3:28])=[C:19]2[C:29]([O:31][CH2:32][CH2:33][C:34]#[N:35])=[O:30])[CH:15]=[CH:16][CH:17]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]2[C:23]([C:24](=[O:25])[NH:10][CH2:9][CH:8]=[CH:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:22]([CH3:27])[NH:21][C:20]([CH3:28])=[C:19]2[C:29]([O:31][CH2:32][CH2:33][C:34]#[N:35])=[O:30])[CH:15]=[CH:16][CH:17]=1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: NCC=Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCC=Cc2ccncc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
221 mg (0.610 mmol) of 3-pyridine-4-yl-allylamine and 200 mg (0.554 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate were dissolved in 10 ml of DMF. 159 mg (0.831 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 123 mg (1.22 mmol) of triethylamine were added to the obtained solution under cooling with ice, and they were stirred at room temperature for 2 days. DMF was evaporated under reduced pressure. After the extraction with a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>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.O1CCOCC1>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][N:7]2[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(CCC)n1ccc(=O)c2c(Br)cccc21
Reactant: Cc1ccc(B(O)O)c(C)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CCC)n1ccc(=O)c2c(-c3ccc(C)cc3C)cccc21
Temperature: 90 °C
Yield: 84.4 %

Procedure:
A mixture of 5-Bromo-1-(1-propylbutyl)quinolin-4(1H)-one (0.096 g, 0.30 mmol), 2,4-dimethylbenzeneboronic acid (0.067 g, 0.45 mmol), potassium carbonate (0.124 g, 0.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.15 mmol) were put under nitrogen gas. Dioxane (4 mL) was added followed by water (27 μL 1.5 mmol). The reaction was heated at 90° C. overnight. The solution was cooled and concentrated. Flash chromatography (60% ethyl acetate/hexanes) gave 0.088 g (85% yield) of the desired product.
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>O1CCCC1.CO>[CH3:3][O:4][C@@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: C1CCOC1
Solvent: CO
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In a glove box (O2 content≦2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 4.48 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BARF (0.0023 mmol, S/C 2,000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run under 30 bar of hydrogen at 60° C. for 20 h and subsequently at 80° C. for 2 h. Then the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (5)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.0% (>99.9% conversion) and an enantiomeric purity of 99.8%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[N:11]2[CH2:15][C@H:16]([OH:18])[CH2:17][C@H:10]2[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:15][C@H:16]([OH:18])[CH2:17][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@@H]2C[C@@H](O)CN2C(=O)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Temperature: 65 °C
Reaction time: 78 h

Procedure:
To a suspension of Example 19C (60 g, 0.23 mol, 1 equivalent) in tetrahydrofuran (900 mL), lithium aluminum hydride (2 M in tetrahydrofuran, 460 mL, 0.92 mol, 4 equivalents) was added slowly at about 15° C. Then, the mixture was stirred at about 65° C. for 78 hours. The reaction mixture was cooled to 0-5° C., quenched using ethyl acetate (300 mL), water (60 mL), 10% NaOH solution (60 mL), followed by water (60 mL), and the mixture was stirred at 20-25° C. for 30 minutes. The suspension was filtered through diatomaceous earth, and the filtrate was concentrated. This crude material was purified by column chromatography on silica gel using a gradient of 0-10% methanol-ethyl acetate to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.46-1.49 (m, 2H), 1.68, (t, 1H, J=9.9 Hz), 1.91 (dd, 1H, J=5.4 Hz, J=8.9 Hz), 2.04-2.13 (m, 1H), 2.15-2.49 (m, 2H), 2.67 (d, 1H, J=10.3 Hz), 2.78 (d, 2H, J=5.4 Hz), 3.25 (dd, 1H, J=4.5 Hz, J=8.9 Hz), 3.47 (dd, 2H, J=4.5 Hz, J=17.4 Hz), 4.15-4.22 (m, 1H), 4.73 (bs, 1H), 7.23-7.318 (m, 5H); 13C NMR (75 MHz, DMSO-d6) δ ppm 39.74, 51.34, 52.64, 57.61, 60.72, 62.56, 63.16, 68.46, 127.26, 128.54, 129.2, 138.84; MS (ESI) m/z 233 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[C:4]([CH3:11])=[N:3]1.[C:12]([O:16][C@@H:17]([C:23]1[C:38]([CH3:39])=[CH:37][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=3)[S:29][C:25]=2[C:24]=1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:15])([CH3:14])[CH3:13]>CN1C(=O)CCC1>[C:12]([O:16][C@@H:17]([C:23]1[C:38]([CH3:39])=[CH:37][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([N:7]4[CH2:8][CH2:9][C:10]5[N:2]([CH3:1])[N:3]=[C:4]([CH3:11])[C:5]=5[CH2:6]4)[CH:31]=3)[S:29][C:25]=2[C:24]=1[C:40]1[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:13])([CH3:14])[CH3:15]
Reactant: Cc1nn(C)c2c1CNCC2
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCc5c(c(C)nn5C)C4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (47.6 mg, 0.315 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (32 mg, 0.060 mmol) in anhydrous NMP (1.0 mL) was heated at 90-110° C. for 40 h. Reaction mixture was cooled to room temperature, filtered through a syringe filter and purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). Product-containing fractions were diluted with ethyl acetate, washed with saturated sodium bicarbonate solution. Aqueous layer was back-extracted with ethyl acetate and the combined organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give product. LCMS-ESI+: calc'd for C35H39ClN5O3S: 644.2 (M+H+); Found: 644.3 (M+H+).