Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[CH:28]=[CH:27][S:26](=[O:30])(=[O:29])[C:25]=2[CH:31]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO.CCCCCC.CC(C)=O>[O:29]=[S:26]1(=[O:30])[CH:27]=[CH:28][C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])=[CH:31][C:25]1=2
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc2c(c1)S(=O)(=O)C=C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)S(=O)(=O)C=C4)c2cc1OCC
Temperature: 100 °C

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 230 mg (1.54 mM) of 6-Amino-1,1-dioxobenzo[b]thiophene and 161 mg of pyridine hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 6 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. The solid was dissolved in acetone and dried onto silica gel under high vacuum. Purification of the compound was obtained by chromatography using a gradient of 30% to 50% acetone in hexane. The first of the three components of the mixture isolated from the column was the desired product. Removal of the solvent by evaporation yielded 69 mg of 4-(1,1-Dioxo-1H-benzo[b]thiophen-6-ylamino)-6,7-diethoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 421.9, mp=155-160° C.
Reaction SMILES: [NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([F:19])[CH:17]=[C:16]([F:20])[CH:15]=3)[NH:1][C:22]2=[O:24])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(F)cc(F)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(=O)[nH]c2c(F)cc(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3,5-difluorobenzamide (760 mg, 2.23 mmol) in THF (10 mL) was treated portionwise with triphosgene (722 mg, 2.43 mmol). The solution was stirred at room temperature for 60 min, then was treated dropwise with saturated aqueous NaHCO3 and stirred until no more gas evolution was observed. The organic phase was separated, washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 0-100%), to give 3-(3-bromo-2-methylphenyl)-6,8-difluoroquinazoline-2,4(1H,3H)-dione (820 mg), used without further purification. Mass spectrum m/z 367, 369 (M+H)+, 389, 391 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9][CH3:10])=[C:4](Br)[N:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Br:8][C:6]1[C:5]([O:9][CH3:10])=[C:4]([C:13]#[C:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: COc1c(Br)cc(N)nc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1c(Br)cc(N)nc1C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (17 mg, 25 μmol) is added to a mixture of 2-amino-4,6-dibromo-5-methoxy-pyridine A1 (70 mg, 0.25 mmol), ethynylbenzene (55 μl, 0.50 mmol), copper(I) iodide (5 mg, 25 μmol) triethylamine (140 μl,1 mmol) and THF (1 ml) under argon atmosphere and is stirred at 50° C. for 1 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 35 mg (47%). HPLC-MS: tR=1.21 min (METHOD—1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:14]>C(O)C>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18][CH3:19])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCCCNCC
Solvent: CCO
Product: CCCCN(CC)c1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
Part A. A solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (prepared rising the methods of Albert, et al., J. Chem. Soc. 1954, p. 3832) (2.77 g, 13.3 mmol) in absolute ethanol (25 mL) was cooled to 0° C., and treated with triethylatine (2.00 mL, 14.3 mmol). Then, a solution of ethylbutylamine (1.80 mL, 13.2 mmol) in ethanol (3 mL) was added dropwise with stirring. The mixture was allowed to stir and warm to ambient temperature overnight, then was partitioned between water and ethyl acetate (100 mL each). The organic phase was separated, washed with satd. aq. brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, dichloromethane) to afford 4-chloro-6-(ethylbutylamino)-2-methyl-5-nitropyrimidine as an oil (3.34 g, 12.2 mmol, 92%). Spectral data: TLC RF 0.59 (dichloromethane). 1H NMR (300 MHz, CDCl3): δ3.45 (2H, q, J=7.0 Hz), 3.38 (2H, t, J=7.7 Hz), 2.50 (3H, s), 1.62-1.52 (2H, m), 1.38-1.26 (2H, m), 1.20 (3H, t, J=7.0 Hz), 0.94 (3H, t, J=7.3 Hz). MS (NH3 --CI): m/e 276 (4), 275 (40), 274 (16), 273 (100).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[N:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#N)[O:17][N:16]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:51])C>CCCCCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[N:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=[O:51])[O:17][N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2C#N)on1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2C=O)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
To a mixture of 2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile (2.60 g) and anhydrous toluene (100 mL) was dropwise added a solution (0.95 M, 15.5 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1.5 hrs. A saturated aqueous ammonium chloride solution (30 mL) was dropwise added to the mixture and the mixture was further stirred at room temperature for 30 min. Ethyl acetate was added to the mixture and the mixture was washed with saturated aqueous ammonium chloride solution and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.70 g, 65%) of 2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehyde from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 90-91° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].Cl.[NH2:30][OH:31].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:30][OH:31])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: NO
Reactant: COC(=O)C1=C(C=O)NC(C)=C(C(=O)OC(C)C)C1c1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C1=C(C=NO)NC(C)=C(C(=O)OC(C)C)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.88 g), hydroxylamine hydrochloride (0.7644 g) and sodium acetate (1.0664 g) in acetic acid (20 ml) was stirred at room temperature for an hour to form isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate. To the reaction mixture was added acetic anhydride (3.37 g) and the mixture was heated at 95° to 100° C. for 6 hours. After removal of the acetic acid, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, an aqueous sodium bicarbonate solution and water in turn, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residual oil (3.69 g) was chromatographed on a column of silica-gel (100 g), and eluted with a mixture of benzene and ethyl acetate (5:1, v/v) to give an oil of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-cyano-1,4-dihydropyridine-3-carboxylate (2.0 g), which was left in a refrigerator for several days to crystallize. Recrystallization from methanol gave pure crystals, m.p. 175.5°-176.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=3)[CH2:17][CH2:16]2)[C:4]=1[CH3:21]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: COc1c(C)c(N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 23.7 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference example 96 and 1-bromo-4-(trifluoromethoxy)benzene (542 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 160 mg (yield 16%). Melting point was 162 to 164° C. (hexane).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1.[O:18]1CC[CH2:20][CH2:19]1.C(Cl)(=O)C>CN(C)C=O.CCOCC>[C:19]([NH:1][C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1)(=[O:18])[CH3:20]
Reactant: C1CCOC1
Reactant: CCCN1CCC[C@H]2Cc3nc(N)sc3C[C@@H]21
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCN1CCC[C@H]2Cc3nc(NC(C)=O)sc3C[C@@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.3 %

Procedure:
A solution was prepared from 0.15 g. of trans-(±)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline (from Example 1) in 3 ml. of tetrahydrofuran (THF) to which has been added two drops of dimethylformamide (DMF). Five hundredths milliliters of acetyl chloride were added and the solution stirred at room temperature for 15 minutes. In time, the reaction mixture became a solid colorless mass. The solid was suspended in ether and the ethereal suspension filtered. The solid was then recrystallized from a methanol/ether solvent mixture to give purified trans-(±)-2-acetylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline hydrochloride; yield=30.3%; melting point above 200° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C1(=O)O[CH2:16][CH2:15][O:14]1>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:16][CH2:15][OH:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1OCCO1
Reactant: CCCCOc1cccc(O)c1
Product: CCCCOc1cccc(OCCO)c1
Yield: 85 %

Procedure:
The title compund was prepared according to the procedure of Example 114, Step 1 starting from 3-n-butoxyphenol (2.0 g, 12 mmol) and ethylene carbonate (0.88 g, 10 mmol). Oil; yield 85%. MS m/z 210 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]([C:18]1[N:22]([CH3:23])[C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:16]([C:18]1[N:22]([CH3:23])[C:21]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CC(C)CNS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)CNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 16 h
Yield: 8.7 %

Procedure:
According to general procedure B, 4-bromo-N-isobutylbenzenesulfonamide (117 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-isobutylbenzenesulfonamide (11 mg, 9%) was provided after purification. MS (ESI) m/z 317. HPLC purity 100.0% at 210-370 nm, 10.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]([OH:14])[C:4]([O:6][CH2:7]C1C=CC=CC=1)=[O:5].C(Br)C1C=CC=CC=1.CI>>[NH2:1][C@@H:2]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]([OH:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCC[C@H](N)C(O)C(=O)OCc1ccccc1
Agent: BrCc1ccccc1
Solvent: CI
Product: CCCC[C@H](N)C(O)C(=O)OC
Yield: 91 %

Procedure:
The same reaction procedure for synthesizing of phenylmethyl (2RS,3S)-3-amino-2-hydroxyheptanoate as in Reference Example 17 was repeated except that benzyl bromide used in Reference Example 17 was replaced by 579 mg of methyl iodide, whereby 683 mg of the captioned methyl (2RS,3S)-3-amino-2-hydroxyheptanoate was obtained in a yield of 91%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23](F)[CH:22]=2)[N:3]=1.O.[NH2:31][NH2:32]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:9]2)[CH:5]=[C:4]([C:21]2[CH:22]=[C:23]3[C:24]([C:27]([NH2:28])=[N:31][NH:32]3)=[CH:25][CH:26]=2)[N:3]=1
Reactant: C[C@@H]1CO[C@H](CNS(C)(=O)=O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CO[C@H](CNS(C)(=O)=O)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 26.8 %

Procedure:
A mixture of crude N-({(2S,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)methanesulfonamide (0.25 mmol theoretical) and hydrazine monohydrate (0.24 mL, 4.95 mmol) in 1,4-dioxane (3 mL) was stirred at 100° C. in a sealed tube for 17 hours. The mixture was concentrated in vacuo and the residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were concentrated in vacuo, taken up in EtOAc (25 mL), washed with saturated aqueous NaHCO3 (2×15 mL) and brine (15 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (29 mg) as a pale yellow solid. LC-MS (ES) m/z=433 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.18 (d, J=6.6 Hz, 3H), 2.72-2.88 (m, 1H), 2.96 (s, 3H), 3.09-3.22 (m, 2H), 3.45-3.55 (m, 1H), 3.67 (dd, J=11.4, 2.5 Hz, 1H), 3.79 (d, J=11.1 Hz, 1H), 4.04-4.75 (bs, 2H), 5.39 (s, 2H), 6.14 (s, 2H), 6.56 (s, 1H), 7.23 (t, J=6.1 Hz, 1H), 7.57 (dd, J=8.6, 1.0 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([CH3:31])([S:22]([C:25]1[CH:29]=[CH:28][O:27][C:26]=1[CH3:30])(=[O:24])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)C>C(O)C.[OH-].[Na+]>[CH3:31][C:5]([S:22]([C:25]1[CH:29]=[CH:28][O:27][C:26]=1[CH3:30])(=[O:24])=[O:23])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:8]=1)[C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCN2CCCCC2)cc1)S(=O)(=O)c1ccoc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1occc1S(=O)(=O)C(C)(Cc1ccc(OCCN2CCCCC2)cc1)C(=O)O
Yield: 32 %

Procedure:
2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid was prepared according to the general method as outlined in example 1. Starting from 2-methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-propionic acid ethyl ester (2.01 g, 4.5 mmol), dissolved in ethanol (20 mL) and 10 N sodium hydroxide (10 mL). The resulting mixture was worked up as outline in example 9. Yield 2.03g; amber crystals mp 66-68° C.; MS 434 (M−H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:30])([CH3:29])[C@@H:14]([O:21]CC1C=CC=CC=1)[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:30])[C@@H:14]([OH:21])[C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OC(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OC(C)C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of isopropyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (25c) (0.20 g, 0.45 mmol) and 200 mg of 10 wt-% of palladium on activated carbon in 10 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC after lyophilization of the solvents, 100 mg (63% yield) of the title compound (25) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=0.95 (s, 3H), 1.13 (s, 3H), 1.32 (d, J=6.0 Hz, 3H), 1.34 (d, J=6.4 Hz, 3H), 1.99 (s, 3H), 2.02-2.16 (m, 2H), 3.12-3.26 (m, 2H), 3.29 (br. d, J=6.0 Hz, 1H), 3.32-3.47 (m, 2H), 3.95 (d, J=9.6 Hz, 1H), 3.99 (br. d, J=4.8 Hz, 1H), 4.17 (d, J=9.2 Hz, 1H), 5.14 (septet, J=6.4 Hz, 1H), 6.00-6.06 (br. m, 1H) ppm. MS (ESI) m/z: 354.13 (M+H)+, 352.16 (M−H)−. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH:12]=[C:13]([O:15][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(F)(F)F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from 2-(3′-fluoro-5-hydroxy-5′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example B) and 3-trifluoromethylbenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [CH:1](OCC)=[O:2].[CH:6]1([C@H:12]([NH2:14])[CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:6]1([C@H:12]([NH:14][CH:1]=[O:2])[CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C[C@@H](N)C1CCCCC1
Reactant: CCOC=O
Product: C[C@@H](NC=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl formate (1.2 mL, 15.0 mMol) was added to a round bottom flask containing (1R)-1-cyclohexyl-ethylamine Compound 17a (1.27 g, 10 mMol) at 0° C. and the mixture was stirred at r.t. for 15 hrs. Excess ethyl formate was removed in vacuo to obtain N-[(1R)-1-cyclohexyl-ethyl]-formamide Compound 17b (1.55 g) as a white solid, which was used in the next step without purification. MS m/z 156 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:8]=[C:9]([N:11]([CH2:17][CH3:18])[C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:10]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH2:17]([N:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH:8]=1)[CH3:18]
Reactant: CCN(C(=O)C(C)C)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(C(=O)C(C)C)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
5-(Ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (0.461 g, 1.36 mmol) was dissolved in THF (10 mL). To this THF solution was added a solution of LiOH (0.342 g) in water (8 mL). The mixture was stirred at 50° C. for three hours, then cooled to room temperature. The mixture was acidified by addition of 1N aqueous HCl and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 0.46 g of 5-(ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3-carboxylic acid as a clear foam.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[O:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([S:21]([N:24]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[C:16]([F:42])[CH:15]=2)=[CH:5][N:4]([CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[N:3]=1.[C:49](OC(=O)C)(=[O:51])[CH3:50].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:41][O:40][C:33]1[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:32]=1[CH2:31][N:24]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][N:26]=1)[S:21]([C:17]1[C:16]([F:42])=[CH:15][C:14]([O:13][C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[C:6]2[C:2]([NH:1][C:49](=[O:51])[CH3:50])=[N:3][N:4]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH:5]=2)=[C:19]([CH3:20])[CH:18]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3N)cc2F)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3NC(C)=O)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.8 %

Procedure:
To a solution of the 4-({(1S*,2R*)-2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (78 mg, 0.115 mmol) prepared in Example 96a in pyridine (0.50 mL), acetic anhydride (0.021 mL, 0.229 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. To the reaction solution, water (10 mL) and ethyl acetate (10 mL) were added, and the organic layer was washed with water (10 mL) and then saturated saline (10 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography to yield the title compound (37.2 mg, 45%) as a colorless amorphous solid.