Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH3:44])[C@@H:11]2[CH2:16][CH2:15][N:14]([S:17]([CH:20]3[CH2:25][CH2:24][N:23](C(OCC4C=CC=CC=4)=O)[CH2:22][CH2:21]3)(=[O:19])=[O:18])[CH2:13][C@H:12]2[C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([C@@H:11]2[CH2:16][CH2:15][N:14]([S:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)(=[O:18])=[O:19])[CH2:13][C@H:12]2[C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH3:44])=[O:9])=[CH:6][CH:7]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(S(=O)(=O)C2CCN(C(=O)OCc3ccccc3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(S(=O)(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
A solution of the compound obtained in Example 496 (250 mg) and 6N hydrochloric acid (4 mL) in THF (4 mL) was stirred at 80° C. for 14 hr. The reaction mixture was made basic with 8N aqueous sodium hydroxide solution, and the resultant product was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure to give crude 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-(piperidin-4-ylsulfonyl)piperidin-4-yl]-N-methylbenzamide as a colorless oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH:34]4[CH2:37][O:36][CH2:35]4)[CH2:30][CH2:29]3)=[CH:24][N:23]=2)[C:15]2[N:16]([N:18]=[CH:19][N:20]=2)[CH:17]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][N:31]([CH:34]4[CH2:37][O:36][CH2:35]4)[CH2:32][CH2:33]3)=[CH:24][N:23]=2)[C:15]2[N:16]([N:18]=[CH:19][N:20]=2)[CH:17]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c3ncnn3c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=C1c2cc3c(n2CCN1c1nccc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4ncnn4c2)c1CO)CCCC3
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A mixture of 122a (200 mg, 0.29 mmol) and lithium hydroxide (42 mg, 1.0 mmol) in i-propanol/THF (1:1, 3.5 mL) and water (1 mL) was stirred at 40° C. for 0.5 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was extracted with ethyl acetate (2×5 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 122 (70 mg, 38%) as pale yellow solid. MS-ESI: [M+H]+ 647.3. 1H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.69 (s, 1H), 8.61 (s, 1H), 8.57-8.55 (m, 2H), 7.93 (d, J=2.5 Hz, 1H), 7.48-7.43 (m, 2H), 7.37-7.35 (m, 1H), 6.59 (s, 1H), 5.05 (t, J=5.0 Hz, 1H), 4.57-4.55 (m, 2H), 4.61-4.59 (m, 2H), 4.40-4.39 (m, 2H), 4.26-4.12 (m, 3H), 3.92-3.89 (m, 1H), 3.43 (t, J=6.0 Hz, 1H), 3.11-3.09 (m, 4H), 2.63-2.57 (m, 2H), 2.50-2.47 (m, 2H), 2.40-2.39 (m, 4H), 1.79-1.77 (m, 2H), 1.70-1.68 (m, 2H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:27])(=O)=O.C(OCC)C.C([O-])([O-])=O.[K+].[K+]>ClCCl.O>[C:1]1([C:7]2[CH:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]3[N:27]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: C(#Cc1ccccn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(-c2cc3ccccn3n2)cc1
Reaction time: 0.5 h

Procedure:
2-Phenylpyrazolo[1,5-a]pyridine was prepared by the following procedure. A solution of 2-(phenylethynyl)pyridine (3.2 g, 0.018 mol) in dichloromethane (20 mL) was cooled to 0° C. in an ice bath. A solution of O-mesitylenesulfonylhydroxylamine in dichloromethane was added dropwise, keeping the temperature below 5° C. The mixture was stirred for 30 minutes, then ethyl ether was added to precipitate a solid (5–7 g). The solid was filtered off, washed with ethyl ether and dried. The solid was re-dissolved in DMF and solid K2CO3 (4.5 g, 0.033 mol) was added in small portions. After stirring 2 h, water (100 mL) was added to the mixture, followed by extraction with dichloromethane. The organics were dried over magnesium sulfate, filtered, and evaporated to an orange oil (2.3 g). Chromatography on silica with dichloromethane eluent yielded the 2-(phenylethynyl)pyridine in 83% yield, mp 110° C. 1H NMR and mass spectra analysis confirmed the structure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:33]([NH:35][C@@H:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]4[C:42]([O:44]CC)=[O:43])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.[OH-].[Na+].Cl>O1CCOCC1>[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:33]([NH:35][C@@H:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]4[C:42]([OH:44])=[O:43])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1NC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)N[C@@H]4CCCC[C@H]4C(=O)O)CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (1R,2R)-ethyl 2-(1-(4′-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxamido)cyclohexanecarboxylate 2,2,2-trifluoroacetate (2.7 mg, 4.19 μmol) was added 5M sodium hydroxide (0.017 mL, 0.084 mmol). The reaction was stirred at room temperature overnight. The mixture was neutralized with 4M HCl in dioxane. The mixture was concentrated and triturated with acetonitrile to give the title compound. LCMS m/z=503.5 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[CH3:7])#[N:2].[OH-].[K+].C([OH:35])C>O>[O:17]1[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][N:6]([CH2:5][CH2:4][C:3]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:1]([NH2:2])=[O:35])[CH3:7])=[CH:18][C:14]=2[CH2:15][CH2:16]1
Reactant: CN(CCc1ccc2c(c1)CCO2)CCC(C#N)(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(CCc1ccc2c(c1)CCO2)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 140 °C

Procedure:
A mixture containing 1-cyano-1,1-diphenyl-3-[N-{2-(2,3-dihydrobenzofur-5-yl)ethyl}-N-methylamino]propane (0.087 g), potassium hydroxide (0.074 g), ethanol (6 ml) and water (6 ml) was heated at 140° C. in a stainless steel pressure vessel for 48 hours. On cooling to room temperature the mixture was concentrated in vacuo. Water (20 ml) was added to the residue and the mixture was extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a glass, yield 0.056 g.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([CH3:37])[CH:28]=4)[CH:24]=[C:23]([C:38]([F:41])([F:40])[F:39])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:38]([F:39])([F:40])[F:41])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[C:33]([F:35])([F:34])[F:36]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4cccc(S(N)(=O)=O)c4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.6 %

Procedure:
To a cooled and stirred solution of 3′-[4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.52 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH) to yield the title compound as an white solid (0.29 g, 54%). MS (ISP) 536.2 [(M−H)−]; mp 205° C.
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Cl:16][CH2:17][C:18]#[C:19][CH2:20]Cl.[NH4+].[Cl-]>C1COCC1.[Cu]Cl>[Cl:16][CH2:17][C:18]#[C:19][CH2:20][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: ClCC#CCCl
Reactant: C#CCCCCCCCCC
Agent: Cl[Cu]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCCCCCCC#CCC#CCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
34.5 ml of a 1M solution of ethyl magnesium bromide in THF were added dropwise, at room temperature, to a solution of 5 grams of 1-undecyne in 15 ml of anhydrous THF, under an inert atmosphere with the addition complete, the mixture was maintained under stirring for 30 min at room temperature and then heated under reflux for 1 h 30 min. The mixture was cooled to room temperature and then 260 mg of copper(I) chloride were added and the mixture was again heated under reflux for 1 hour. The mixture was then cooled to room temperature and 11.3 g of 1,4-dichloro-2-butyne were added fairly rapidly. The mixture was refluxed for 1 h 30 min and then maintained under stirring for 15 h at room temperature before heating again under reflux for 3 h. The reaction medium was then cooled to 4° C. and hydrolyzed with care with a saturated aqueous solution of NH4Cl. The medium was then extracted 3 times with diethyl ether and the combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried over Na2SO4, filtered and concentrated under vacuum in a rotary evaporator. The oily residue containing 1,4-dichloro-2-butyne in excess was purified by distillation under reduced pressure to give 1-chloro-2,5-pentadecadiyne in the form of a colorless oil with a yield of 37.8%.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[CH2:22][C:23]3[CH:39]=[CH:38][C:26]4[N:27]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[CH3:37])[O:29][C:25]=4[CH:24]=3)=[CH:16][CH:15]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C(O)C>[C:32]1([CH3:37])[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:30][C:28]1[O:29][C:25]2[CH:24]=[C:23]([CH2:22][C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([C:5]4([CH2:4][C:3]([OH:41])=[O:2])[C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[CH2:7][CH2:6]4)=[CH:15][CH:16]=3)=[O:40])[CH:39]=[CH:38][C:26]=2[N:27]=1
Reactant: COC(=O)CC1(c2ccc(NC(=O)Cc3ccc4nc(Nc5ccccc5C)oc4c3)cc2)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C4(CC(=O)O)CCc5ccccc54)cc3)cc2o1
Yield: 62.3 %

Procedure:
A solution of (1-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-indan-1-yl)-acetic acid methyl ester [0.028 g, Reference Example 9(b)] in ethanol (5 mL) was treated with aqueous sodium hydroxide (0.3 mL, 1N) and the mixture was heated at reflux temperature for 2.5 hours. The mixture was then treated with a further aliquot of aqueous sodium hydroxide (0.15 mL, 1N) and heating at reflux temperature for continued for a further hour. The reaction mixture was concentrated to about 2 mL and then treated with water (12 mL). The resulting solution was acidified to pH 1 by addition of hydrochloric acid (1.75 mL, 1N) with stirring when a solid was deposited. The mixture was ice-cooled and then filtered. The solid was washed three times with water (3 mL) and then dried at 60° C. under vacuum to give the title compound (0.017 g) as a fawn coloured solid. LC-MS: RT=3.69 minutes, MS(ES+): 532(M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25](Br)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: CC(C)(C)OC(=O)N(Cc1cc(-c2ccccn2)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
From cis-3-[(5-bromobenzofuran-7-ylmethyl)tert-butoxycarbonyl-amino]-2-phenyl-piperidine-1-carboxylic acid tert-butyl ester (409 mg) and 2-tributylstannanyl-pyridine (339 mg).
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2].C(N[C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2C[C@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=O)C1=O)(=O)C.C(N[C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(O)=O)C1=O)(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N[C@]1([C@@H](CC)C)CCN([C@@H](CCC2C=CC=CC=2)C(N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=O)C1=O)(=O)C.CN1CCOCC1>CN(C=O)C>[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:21][C@H:20]([OH:22])[CH2:19][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@@H](O)CN2C(c2ccccc2)c2ccccc2)C1=O
Agent: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Agent: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)C1=O
Agent: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](O)CN2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Step 15 (B): (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin 1-yl)-N-((1S,2S)-1-((2R,4S)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamide. To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation A, 38.9 mg, 0.108 mmol) in DMF (2 mL) was added HATU (49.43 mg, 0.130 mmol). A solution of (3S,5R)-5-((1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl)-1-benzhydrylpyrrolidin-3-ol (Step 15 (A), 47.3 mg, 0.108 mmol) in DMF (2 mL) was then added, followed by N-methylmorpholine (42 μl, 0.378 mmol). The reaction mixture was stirred at rt for 3 h. pH 4 buffer was then added to quench. The mixture was extracted with ethyl acetate. The organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. The crude mixture was purified by reverse phase Prep HPLC to give the title compound (60.5 mg, 72% yield) as a clear oil:
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)[CH2:2][CH3:3].[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCCc1csc(N)n1
Product: CCCc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Yield: 39 %

Procedure:
The title compound was prepared from 4-propyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 90 mg (39% yield): mp 169° C.; HRMS Calcd (found) for C13H15ClN2O2S2 M/Z 330.0263 (330.0251).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC([O-])(C)C.[K+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=2)[N:27]=[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:25]=1>CS(C)=O.O>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH:14]([O:16][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH:25]=2)[CH2:13][CH:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Reactant: COc1ccc2c(Cl)cc(-c3ccccn3)nc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3ccccn3)nc2c1
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
To a solution of N—Boc-4-hydroxyproline (1.6 g, 6.7 mmol) in DMSO (20 mL) was added t-BuOK (1.9 g, 16.8 mmol). The generated mixture was stirred for 1.5 h and 4-Chloro-7-methoxy-2-pyridin-2-yl-quinoline (2.0 g, 7.4 mmol) and DMSO (10 mL) were added. The reaction mixture was stirred for 38 h, diluted with cold water and extracted with EtOAc/ether (1/4, 2×). the aqueous layer was acidified to pH 4 and extracted with EtOAc/THF (5×). the combined extract was dried (Na2SO4/MgSO4), removed the solvent in vacuo and the residue was purified by preparative HPLC (0-80% solvent B) to provide the product (1.6 g, 50%): LC-MS (retention time: 1.23, Method I), MS m/z 466 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([CH:25]=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][N:12]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Solvent: CCO
Product: CCOC(=O)c1cnc2c(OCc3c(F)cccc3F)cccn12

Procedure:
1.93 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 4A; 8.2 mmol, 1 equivalent) were initially charged in 50 ml of ethanol, and 8.2 g of ethyl 2-chloro-3-oxopropanoate (75% pure, crude product from Example 29A, 40.8 mmol, 5 equivalents) were added. The resulting reaction mixture was heated at reflux overnight. The reaction solution was concentrated and the crude product obtained was chromatographed on 340 g of silica gel (Biotage Isolera) (mobile phase: cyclohexane:ethyl acetate gradient; Rf value of the product in cyclohexane:ethyl acetate 2:1=0.36). The product fractions were combined and concentrated and the residue obtained was triturated with diisopropyl ether. The solid was filtered off and dried under high vacuum. This gave 2.02 g of the title compound (71% of theory).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[N:8]O)[C:3]1([CH3:11])[CH3:10].N>[Ni].CO>[NH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[C:3]1([CH3:11])[CH3:10]
Reactant: CC1(C)C(=NO)CCCC1O
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC1(C)C(N)CCCC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 3-hydroxy-2,2-dimethylcyclohexanone oxime (1.8 g, crude) and Raney nickel (1.5 g) in a MeOH (50 mL) and ammonia (5 mL) was stirred at 25° C. under hydrogen atmosphere overnight. The reaction mixture was filtered through celite and the filter cake was rinsed with MeOH (50 mL). The filtrate was concentrated to afford the title compound (1.30 g, crude). MS (ESI) m/z 144.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[Cl:29][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33](=[O:36])[CH2:34]Br.C(=O)([O-])O.[K+]>CC(C)=O>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:17][CH:18]([C:19]3[N:20]=[C:21]([C:24]([F:26])([F:27])[F:25])[S:22][CH:23]=3)[O:28][C:33]([OH:36])([C:32]3[CH:37]=[CH:38][CH:39]=[C:30]([Cl:29])[CH:31]=3)[CH2:34]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC(O)(c3cccc(Cl)c3)C2)cc1

Procedure:
from N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine (pair of diastereomers A) with 3-chloro-phenacyl bromide and potassium hydrogen carbonate in acetone.