Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19].Cl>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccccc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccccc1
Yield: 99.7 %

Procedure:
Method C. Reaction of benzoate 16 (290 mg, 0.78 mmol) and 6 M HCl (5 mL) gave acid 17 (278 mg, 100%) as a white solid: mp (H2O) 284-287° C.; 1H NMR δ 12.68 (br s, 1 H, CO2H), 8.04 (br d, J=8.4Hz, 2 H, H-2, H-6), 7.90 (br d, J=8.4 Hz, 2 H, H-3, H-5), 7.80 (br ddd, J=8.1, 1.9, 1.2Hz, 2 H, H-2′, H-6′), 7.75 (tt, J =7.5, 1.2Hz, 1 H, H-4′), 7.62 (br dd, J=8.1, 7.4Hz, 2 H, H-3′, H-5′), 4.68 (s, 2 H, CH2SO2), 2.13 (s, 3 H, CH3); MS m/z 358.8 (MH+, 100%).
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C[O:22][C:23]([C:25]1([CH:39]2[CH2:42][CH2:41][CH2:40]2)[CH2:29][C:28](=[O:30])[N:27]([C:31]2[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:38])[CH2:26]1)=O.[NH4+].[Cl-]>C1COCC1>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([NH:11][C:23]([C:25]2([CH:39]3[CH2:40][CH2:41][CH2:42]3)[CH2:29][C:28](=[O:30])[N:27]([C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH2:26]2)=[O:22])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: COC(=O)C1(C2CCC2)CC(=O)N(c2c(C)cccc2C)C1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1CC(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(C2CCC2)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.5 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 1.13 mL, 2.82 mmol) was added to a solution of 3,5-bis-trifluoromethylaniline (437 μL, 2.82 mmol) in THF (0.5 mL) at room temperature. The resulting dark brown colored solution was stirred for 10 min at room temperature. A solution of 3-cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 283 mg, 0.94 mmol) in THF (3 mL) was added and stirred for 30 min at 100° C. in a sealed vial. Saturated aqueous NH4Cl solution (10 mL) was added, extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (40 mL), brine (40 mL), dried (Na2SO4) and evaporated. The reaction mixture was then purified by automated flash chromatography (SiO2, 20→70% EtOAc/hexanes). Selected fractions were combined and concentrated under reduced pressure. The obtained product was further purified twice by preparative HPLC (5→90% gradient of MeCN—H2O with 0.1% TFA) to obtain the desired product 3-cyclobutyl-1-(2,6-dimethylphenyl)-5-oxo-pyrrolidine-3-carboxylic acid (3,5-bis-trifluoromethylphenyl)-amide (7 mg, 1.5% yield). LC-MS: Rt (retention time): 3.17 min, MS: (ES) m/z 499.1 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 3H), 7.63 (s, 1H), 7.12-7.16 (m, 1H), 7.04-7.09 (m, 2H), 4.18 (d, 1H, J=8.5 Hz), 3.58 (d, 1H, J=8.5 Hz), 3.18 (d, 1H, J=17 Hz), 2.8 (d, 1H, J=17 Hz), 2.2 (s, 3H), 2.17 (s, 3H), 1.85-2.0 (m, 2H), 0.68-0.8 (m, 1H), 0.5-0.62 (m, 2H), 0.15-0.2 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:5]2[C:6](=[O:10])[C:7]=1[CH2:8][CH3:9].[CH3:16]I.[BH4-].[Na+].[ClH:20]>C(O)C.O.CC(C)=O>[ClH:20].[CH3:16][N:3]1[CH:2]([CH3:1])[CH:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]2[CH:11]([CH3:15])[CH2:12][CH2:13][CH2:14][CH:4]12
Reactant: CCc1c(C)nc2cccc(C)n2c1=O
Reactant: CI
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: CCC1C(=O)N2C(C)CCCC2N(C)C1C
Reaction time: 24 h
Yield: 41 %

Procedure:
0.01 moles of 2,6-dimethyl-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine are dissolved in 20 ml. of acetone, 0.03 moles of methyl iodide are added and the mixture is kept in a bomb tube at 150° C. for 24 hours. The solution is evaporated to dryness, the residue is dissolved in 15 ml. of methanol and a solution of 0.05 moles of sodium tetrahydroborate (III) in 10 ml. of water is added. After 4 hours the methanol is distilled off and the aqueous phase is extracted with three 20-ml. portions of chloroform. The organic phase is dried, evaporated and added to the oily substance obtained are 10 ml. of ethanol saturated with hydrochloric acid. 1,2,6-trimethyl-3-ethyl-1,2,3,6,7,8,9,9a-octahydro-4-oxo-4H-pyrido[1,2-a]pyrimidine hydrochloride is obtained, which crystallizes when triturated with ether. The product obtained after recrystallization from a mixture of acetone and ether sublimates over 206° C. Yield: 41%.
Reaction SMILES: C([NH:11][C@H:12]([C:21]([OH:23])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.CN1CCOCC1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[NH:32][NH2:33]>O1CCCC1>[C:31]([NH:32][NH:33][C:21](=[O:23])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[NH2:11])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of CBZ-L-tyrosine (3.00 gm, 9.11 mmoles), N-methylmorpholine (0.92 gm, 1.00 ml, 9.11 mmoles) in 100 ml dry tetrahydrofuran (THF) was cooled to 0° C. under nitrogen. 2,2,2-Trichloro-1,1-dimethylethylchloroformate (2.18 gm, 9.11 mmoles) was added to the cold solution. After 5 minutes stirring, a solution of t-butyl carbazate (1.20 gm, 9.11 mmoles) in 20 ml dry THF was cooled to 0° C. and added to the reaction mixture. The mixture was allowed to warm slowly to room temperature and was stirred for about 18 hours. The solvent was removed by rotary evaporation and the residue was partitioned between chloroform and water and the layers separated. The organic layer was washed with saturated NaCl dried over Na2SO4, filtered, and solvent evaporated to yield the crude protected product. The CBZ-protected product, CBZ-tyrosine N'-Boc-hydrazide, was purified on silica gel via flash chromatography using a mixture of petroleum ether and ethyl acetate (1:1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:13]([NH:14][C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)=S)=[CH:12][N:11]=[CH:10][N:9]=1>[Hg]=O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][CH:12]=2
Reactant: CCOC(=O)N1CCC(NC(=S)Nc2cncnc2NCc2ccco2)CC1
Agent: O=[Hg]
Solvent: CCO
Product: CCOC(=O)N1CCC(Nc2nc3cncnc3n2Cc2ccco2)CC1
Reaction time: 2 h
Yield: 21.5 %

Procedure:
A mixture of 4 parts of ethyl 4-[[[[4-[(2-furanylmethyl)amino]-5-pyrimidinyl]amino]thioxomethyl]-amino]-1-piperidinecarboxylate, 6 parts of mercury(II)oxide and 80 parts of ethanol was stirred for 2 hours at reflux temperature. The whole was filtered while hot over Hyflo® and the filtrate was evaporated. The residue was crystallized from a mixture of acetonitrile and ethanol. The product was filtered off and dried, yielding 0.8 parts (21.5%) of ethyl 4-[[9-(2-furanylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate; mp. 171.9° C. (compound 7).
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=O)[CH:4]=1)[CH3:2].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:25]=1[NH2:26]>CN(C=O)C>[CH3:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:25]=1[NH:26][C:8]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[O:7][N:6]=1)=[O:10]
Reactant: Cc1cccc(C)c1N
Reactant: CCc1cc(C(=O)O)no1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2c(C)cccc2C)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
5.1 g (0.04 mole) of 5-ethyl isoxazole 3-carboxylic acid are dissolved in 100 ml of DMF under nitrogen, 13 g (0.08 mole) of carbonyl diimidazole are added and the mixture is stirred for 2 h at room temperature. 9.7 g (0.08 mole) of 2,6-dimethyl aniline are added and the mixture is stirred again for 48 h. After removal of the precipitate formed by filtration and evaporation of the solvent, the residue is crystallized from petroleum ether. M.p.=82°. The yield is 73%.
Reaction SMILES: [CH:1]([CH:4]1[C:9](CO)([C:10](OCC)=[O:11])[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[CH:24])=[C:7]([CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[C:6]([CH:30]([CH3:32])[CH3:31])=[N:5]1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]=[CH2:24])[C:7]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:6]([CH:30]([CH3:31])[CH3:32])[N:5]=1)([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1C1=C(C=CCCC)C(C(C)C)=NC(C(C)C)C1(CO)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=Cc1ccccc1-c1c(CO)c(C(C)C)nc(C(C)C)c1CCCCC

Procedure:
The title compound was prepared from ethyl 2,6-diisopropyl-3-hydroxymethyl-4-(2-ethynylphenyl)-5-(pent-1-enyl)pyridine-3-carboxylate by the procedure described in Example 125, Step F. 1H NMR (300 MHz, CDCl3) (reported as a mixture of olefin isomers): δ 0.60-0.90 (m, 3 H), 1.0-1.40 (m, 15 H), 1.60-1.90 (m, 2 H), 3.20-3.50 (m, 2 H), 4.20-4.40 (m, 2 H), 5.14 (dt, J=11.0, 1.0 Hz, 1 H), 5.40 (m, 1 H), 5.90 (m, 1 H), 6.30 (m, 1 H), 7.0-7.70 (m, 4 H). FAB-MS: calculated for C25H33NO 363.5; found 364 (M+H, 100%). Rf 0.28 (10% ethyl acetate/n-hexane).
Reaction SMILES: C([NH:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>CN(C=O)C>[NH2:18][C@H:19]([C:27]([OH:29])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.08 h

Procedure:
Wash Fmoc-phenylalanine on Sasrin resin (1.00 g, 0.69 mmol) with DMF (20 mL×2). Add 20% piperidine in DMF (20 mL), agitate for 5 minutes, and drain the solvent. Repeat two times for 15 minutes. Wash the residue with DMF (20 mL×5) and then CH2Cl2 (20 mL×5). Dry the resin in a vacuum oven at 40° C. for 20 hours to give title resin.
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[C:12]([O:14]CC)=[O:13])[C:3]([F:6])([CH3:5])[CH3:4].[OH-].[Na+].[CH3:31]O.O>O1CCCC1>[F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[C:12]([OH:14])=[O:13])[C:3]([F:6])([CH2:4][CH3:31])[CH3:5]
Reactant: CCOC(=O)C(Cc1cccc(C(F)C(C)(C)F)c1)C(O)c1ccc(F)cc1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(F)C(F)c1cccc(CC(C(=O)O)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-2-[3-(1,2-difluoro-2-methylpropyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate (2.849 g, 7.223 mmol), sodium hydroxide (0.58 g, 14.4 mmol), methanol (10 ml), water (10 ml) and tetrahydrofuran (10 ml) was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-2-[3-(1,2-difluoro-2-ethylpropyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionic acid as a liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[NH:14][C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]([CH3:31])[C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1N=C(C2CCCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCCC2)c2ccccc21

Procedure:
3(R,S)-[(Benzyloxycarbonyl)amino]-5-cycloheptyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Example 1, Step 3, 500 mg) in anhydrous toluene (40 ml) was heated to reflux. A solution of dimethylformamide dimethyl acetal (786 μl) in anhydrous toluene (10 ml) was added dropwise and the mixture was heated at reflux for a further hour. The solvent was evaporated and the residue triturated with diethyl ether to afford the title compound (441 mg) as a colourless solid. 1H NMR (360 MHz, CDCl3) δ 1.24-1.90 (11H, m), 2.00-2.14 (1H, m), 2.90-3.00 (1H, m), 3.40 (3H, s), 5.04-5.18 (3H, m), 6.52 (1H, d, J=7.5 Hz), 7.24-7.60 (9H, m). TLC (silica, petrol (60/80): ethyl acetate 2:1). Rf=0.30.
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]([OH:11])=[O:24])=[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:20]=1
Reactant: OO
Reactant: COc1c(C)c(Cc2ccc(C=O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC#N
Solvent: O
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
An aqueous solution (2 ml) of sodium dihydrogenphosphate (157 mg, 1.31 mmol), an aqueous solution (7 ml) of sodium chlorite (795 mg, 80%, 7.07 mmol) and aqueous hydrogen peroxide (0.5 ml, 30%) were added to an acetonitrile solution (5 ml) of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (735 mg, 1.69 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous 10% sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (603 mg, 1.33 mmol, 79%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[C:13]([O:17][C:18]([NH:20][C@@H:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CN1CCOCC1.C(Cl)CCl>CCOC(C)=O>[F:1][C:2]1[C:7]([O:8][C:22](=[O:23])[C@@H:21]([NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Pentafluorophenol (8.75 g, 47.5 mmol) dissolved in EtOAc (5 mL) was added to a solution of 2(S)-tert-butoxycarbonylamino-3,3-dimethyl-butyric acid (10 g, 43 mmol) in EtOAC (35 mL) and the mixture cooled to 0° C. NMM (4.75 mL, 43 mmol) followed by EDC (9.12 g, 47.6 mmol) were added to this cooled solution and the reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with EtOAc (200 mL) and washed with 1M HCl (2×200 mL), 1M Na2CO3 (3×200 mL) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 10% EtOAc in hexanes) to give the title compound as a white solid (12.03 g, 70%).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]1([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CO>O.C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[OH2:1].[C:7]1([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:1])[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)CSCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CS(=O)CCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 141.9 %

Procedure:
Oxone (potassium monopersulfate compound) (3.30 g, 5 mmol) was added in one portion to a stirred mixture of methyl [[6-(3,4,5-triphenyl-1H-pyrazol-1-yl)hexyl]thio]acetate (2.08 g, 4.3 mmol), methanol (100 mL) and water (50 mL) maintained at -10° C. The mixture was allowed to warm slowly to 0° C. and stirred for 45 minutes before being diluted with water and chloroform. The organic phase was separated and the aqueous layer extracted with CHCl3. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give an oil. Chromatography on a column of silica gel using a mixture of ethyl acetate and hexane (7:3) as eluent furnished methyl [[6-(3,4,5-triphenyl-1H-pyrazol-1- yl)hexyl]sulfinyl]acetate hydrate (1.84 g, 85%) that slowly crystallized; m.p.=70.5°-71.5° C. MS(CI): m/e=501 (MH+).
Reaction SMILES: [OH:1][C@@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1O>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:1][C@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: COC(=O)[C@@H](O)C(C)C
Product: COC(=O)[C@H](Oc1cc(C)ccc1Cl)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (S)-methyl 2-hydroxy-3-methylbutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenol instead of the m-cresol.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13]2([CH2:33][O:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH2:18][CH2:17][C:16](O)(C3C=CC=C(OC4C=CC=CC=4)C=3)[CH2:15][CH2:14]2)(=O)=O)=CC=1.[OH-:45].[Na+]>C1COCC1.O>[CH3:44][C:41]1[CH:42]=[CH:43][C:38]([S:35]([O:34][CH2:33][C:13]23[CH2:18][CH2:17][C:16]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:45][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:14]=4)([CH2:15][CH2:14]2)[O:11][CH2:12]3)(=[O:37])=[O:36])=[CH:39][CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCC(O)(c3cccc(Oc4ccccc4)c3)CC2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC23CCC(c4cccc(Oc5ccccc5)c4)(CC2)OC3)cc1
Temperature: 25 °C
Yield: 171.6 %

Procedure:
A mixture of (4-hydroxy-4-(3-phenoxyphenyl)cyclohexane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (390 mg, 0.612 mmol) and powdered NaOH (320 mg, 8.00 mmol) in THF (5 mL) was refluxed for 24 h. The reaction was cooled to rt, diluted with water, and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (244 mg, 86% yield) as a white solid. LCMS, [M+H]+=465.2. 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J=8.3 Hz, 2H), 7.42-7.36 (m, 2H), 7.37-7.31 (m, 2H), 7.28 (dd, J=9.6, 6.3 Hz, 1H), 7.15-7.08 (m, 3H), 7.03-6.98 (m, 2H), 6.87 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 3.83 (d, J=1.3 Hz, 2H), 3.77 (s, 2H), 2.49 (s, 3H), 2.09-1.97 (m, 4H), 1.75 (tt, J=9.6, 2.8 Hz, 2H), 1.69-1.60 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH:15]([NH:17][C:18](=O)[CH3:19])[CH3:16])=[N:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:16])[N:17]=[C:18]([CH3:19])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)c1nnc(-c2ccc(Br)cc2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1nc(C)n2nc(-c3ccc(Br)cc3)[nH]c(=O)c12
Reaction time: 0.5 h

Procedure:
A solution of 10.0 g (29.66 mmol) of N-{1-[3-(4-bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl} from example 7A in 340 ml of 1,2-dichloroethane is treated with 13.64 g (8.30 ml, 88.98 mmol) of phosphoryl chloride. The mixture is boiled under reflux for 15 h. After cooling, the solvent is removed. The residue is stirred with diethyl ether and filtered off with suction. The crystals are stirred for 1 h with 150 ml of saturated aqueous sodium hydrogencarbonate solution, and subsequently diluted with 100 ml of water. After 30 min, the solid is filtered off with suction, washed well with water and rewashed with petroleum ether.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:5]([S:12][CH2:13][CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].[Li+]>N1C=CC=CC=1>[CH2:13]([S:12][C@H:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C@@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:3]([OH:32])=[O:2])[CH3:14]
Reactant: CCS[C@H](c1ccccc1)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1)C(=O)OC
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCS[C@H](c1ccccc1)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
(2S,3R)-3-Ethylsulfanyl-2-(4′-fuoro-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid. A mixture of (2S, 3R)-3-ethylsulfanyl-2-(4′-fluoro-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid methyl ester 4b (28 mg, 0.059 mmol) and lithium iodide (105 mg, 0.785 mmol) in pyridine (3 mL) is refluxed under argon overnight. The mixture is cooled to room temperature and partitioned between ethyl acetate and 1.0 N aq. HCl. The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by reverse phase preparative HPLC (gradient elution, 0.1% aq. trifluoroacetic acid/acetonitrile) to give the desired product as a pale orange solid.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.O=C1CCC(=O)N1[O:29][C:30]([NH:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[N:36][N:37]2[C:42]([O:44][CH3:45])=[O:43])=O>CN(C=O)C.O>[C:1]1([CH2:11][NH:12][C:30]([NH:32][C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][N:37]3[C:42]([O:44][CH3:45])=[O:43])=[O:29])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: NCc1cccc2ccccc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)n1ncc2c(NC(=O)NCc3cccc4ccccc34)cccc21
Reaction time: 0.5 h

Procedure:
1-Naphthylmethylamine (2.1 mmol) and diisopropylethylamine (2 mmol, 0.26 g) were combined in DMF (6 mL) and treated with methyl 4-({[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}amino)-1H-indazole-1-carboxylate (6.6 g, 2 mmol) at ambient temperature. After stirring for 30 minutes, the reaction mixture was diluted with water (6 ml) and filtered. The filter cake was washed with water:acetonitrile (1:1) and dried to provide the title compound. 1H NMR (DMSO-d6) δ 4.02 (s, 3H); 4.81 (d, 2H); 6.85 (m, 1H); 7.42-7.64 (m, 5H); 7.67 (d, 1H); 7.87 (m, 2H); 7.97 (d, 1H); 8.15 (d, 1H); 8.38 (s, 1H); 8.99 (s, 1H).