Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[C:9](=[CH:20]\[CH2:21][CH2:22][C@H:23]([O:42][CH2:43][CH2:44][CH3:45])[C@H:24]([C@@H:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH3:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])/[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][CH2:22][C@H:23]([O:42][CH2:43][CH2:44][CH3:45])[C@H:24]([C@@H:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH3:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCO[C@@H](CC/C=C(\NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Solvent: CO
Product: CCCO[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)[C@@H](CCC(C)C)[C@H](C)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A solution of (6S,7S,Z)-benzyl 2-((tert-butoxycarbonyl)amino)-7-((S)-1-((4-methoxybenzyl)oxy)ethyl)-10-methyl-6-propoxyundec-2-enoate (1.50 g, 2.40 mmol) in MeOH (9.59 mL) was added to a 45 mL pressure reactor. The system was purged with N2 for 5 min and then (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium (I) trifluoromethanesulfonate (0.0170 g, 0.0240 mmol) was added. The system was purged with hydrogen gas (200 psi) 3 times, charged to 200 psi with hydrogen gas, and stirred at room temperature for 24 h. The hydrogen was evacuated and the solution was transferred to a round bottom flask rinsing with EtOAc (10 mL), and the solvent was removed under reduced pressure. The residue was dissolved in DCM (10 mL) and the resulting solution was treated with Celite® (3 scoopula tip-fulls). The solvent was removed under reduced pressure and the resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (40 g SiO2, 0→40% EtOAc/hexanes) to afford the title compound (1.10 g, 1.752 mmol, 73%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (m, 5H), 7.29-7.21 (m, 2H), 6.90-6.83 (m, 2H), 5.21-5.09 (m, 2H), 5.04 (d, J=8.4 Hz, 1H), 4.47 (d, J=11.3 Hz, 1H), 4.41-4.27 (m, 2H), 3.78 (s, 3H), 3.63-3.52 (m, 1H), 3.38-3.26 (m, 3H), 1.87-1.74 (m, 1H), 1.70-1.17 (m, 22H), 1.16 (d, J=6.2 Hz, 3H), 0.92-0.83 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 172.75, 158.98, 155.35, 135.47, 131.30, 129.09, 128.57, 128.35, 128.20, 113.70, 79.78, 75.02, 71.89, 69.98, 66.92, 55.24, 53.59, 46.51, 38.66, 32.83, 31.98, 28.69, 28.33, 23.83, 23.54, 22.66, 22.64, 22.22, 17.13, 10.84; ESIMS m/z 650 ([M+Na]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].O>C(OCC)C>[CH3:1][O:2][CH2:3][C:4]1([CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH2:5]1)[CH:21]=[O:22]
Reactant: COCc1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COCC1(C=O)C=CC=C(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.0 g of 1-(methoxymethyl)-3-(trifluoromethyl)benzene was dissolved in 300 ml anhydrous diethyl ether, and 19 ml n-butyl lithium (2.5 M solution in hexane) was added dropwise at −78° C. The reaction mixture was stirred at room temperature for 3 hours and cooled again at −78° C., and 10 ml N,N-dimethylformamide was added. The reaction solution was returned to room temperature, poured into water, extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (9:1), 5.0 g of 1-(methoxymethyl)-3-(trifluoromethyl)benzaldehyde was obtained as a reddish orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]=[N+:12]=[N-:13])[CH3:10].[C:14]([C:17]([OH:19])=[O:18])#[C:15]C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([N:11]1[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[N:13]=[N:12]1)[CH3:10]
Reactant: CC#CC(=O)O
Reactant: CC(N=[N+]=[N-])c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: CC(c1c(F)cccc1F)n1cc(C(=O)O)nn1

Procedure:
6.5 g (35 millimoles) of 1-(2,6-difluorophenyl)ethyl azide and 2.45 g (35 millimoles) of propinecarboxylic acid in 50 ml of toluene are heated for 24 hours to 60°-70° C. The cooled reaction mixture is extracted with 100 ml of 1N sodium hydroxide solution and the extract is acidified with hydrochloric acid to give 1-[1-(2,6-difluorophenyl)ethyl-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 135°-138° C. (dec.). 7.1 g (26.6 millimoles) of 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylic acid, 150 ml of ethanol and 1 ml of sulfuric acid are heated for 10 hours to reflux. Working up gives ethyl 1-[1-(2,6-difluorophenyl)ethyl]-1H-1,2,3-triazole-4-carboxylate with a melting point of 118°-121° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][O:14][C:15](=[O:36])[CH2:16][O:17][CH2:18][C:19]#[C:20][CH2:21][N:22]1[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:29][O:30]C(OCC)C>CO>[CH3:13][O:14][C:15](=[O:36])[CH2:16][O:17][CH2:18][C:19]#[C:20][CH2:21][N:22]1[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:29][OH:30]
Reactant: CCOC(C)OC[C@H]1CCCC(=O)N1CC#CCOCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CO
Reaction time: 20 h
Yield: 25.6 %

Procedure:
p-Toluenesulfonic acid hydrate (289 mg, 1.52 mmol) was added to a solution of (4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester (494 mg, 1.45 mmol) in MeOH (5.0 mL) at rt. After 20 h at rt, the mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2 →3% MeOH/CH2Cl2, gradient) afforded 100 mg (26%) of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][C@@:14]1([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[O:19][C:18](=[O:20])[N:17]([C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32](=[O:35])[NH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH3:22])[CH2:16][CH2:15]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:43]I>C1COCC1>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][C@@:14]1([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[O:19][C:18](=[O:20])[N:17]([C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][C:32](=[O:35])[N:31]([CH3:43])[CH:30]=3)=[CH:27][CH:28]=2)[CH3:22])[CH2:16][CH2:15]1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a suspension of NaH (18 mg, 0.72 mmol) in THF (0.5 mL) was added a solution of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.18 mmol) in THF (10 mL) at 0° C. The resulting mixture was stirred for 1 h. Then CH3I (613 mg, 43.2 mmol) was added, and the mixture was stirred for 3 h. The reaction was quenched with aq NH4Cl solution. The organic phase was separated, and concentrated to give (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (104 mg, 100%), which was used for the next step without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([NH:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][CH:19]=2)[NH:15][N:14]=1)=[O:11]>C(O)C.[C].[Pd]>[CH2:24]([C:21]1[CH:20]=[CH:19][C:18]([C:16]2[NH:15][N:14]=[C:13]([NH:12][C:10]([CH:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:1]3)=[O:11])[CH:17]=2)=[CH:23][CH:22]=1)[CH3:25]
Reactant: C=Cc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(-c2cc(NC(=O)C3Cc4ccccc4C3)n[nH]2)cc1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
3-(2-Indanyl)carbonylamino-5-(4-vinylphenyl)pyrazole (25.0 mg) was dissolved in ethanol (5.0 ml) to which was subsequently added 10% palladium-carbon (22 mg), and then the mixture was stirred under hydrogen atmosphere of 1 atmospheric pressure overnight. The catalyst was filtered off and then, the filtrate was concentrated under a reduced pressure to obtain the title compound (24.8 mg) as colorless crystals (melting point: 196-198° C.).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45][CH2:46][C@@H:47]([C:49]([OH:51])=[O:50])[NH2:48])=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:48][C@H:47]([C:49]([OH:51])=[O:50])[CH2:46][CH2:45][CH2:44][NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:42])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
3.00 g (6.16 mmol) of the compound from example 1A was dissolved in 60 ml dichloromethane. 1.43 g (6.16 mmol) N5-(tert-Butoxycarbonyl)-L-ornithine was added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 75° C. in a microwave synthesizer. The combined reaction mixture was extracted with approx. 500 ml saturated ammonium chloride solution. The aqueous phase was twice back extracted with approx. 30 ml dichloromethane each. The combined organic phases were extracted with approx. 50 ml brine and dried over sodium sulfate. The solvent was removed under reduced pressure. The raw product was dissolved in dichloromethane and chromatographed over approx. 500 ml silica gel. Solvents used were dichloromethane, dichloromethane/methanol 20/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.29 g (3.50 mmol, 57% of theory, 89% purity) of the desired product.
Reaction SMILES: O1CCOCC1.[CH:7]1([CH2:10][O:11][C:12]2[C:17]([O:18]COC)=[CH:16][CH:15]=[CH:14][C:13]=2[I:22])[CH2:9][CH2:8]1.Cl>O>[CH:7]1([CH2:10][O:11][C:12]2[C:13]([I:22])=[CH:14][CH:15]=[CH:16][C:17]=2[OH:18])[CH2:8][CH2:9]1
Reactant: COCOc1cccc(I)c1OCC1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Oc1cccc(I)c1OCC1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.9 %

Procedure:
To 100 ml of 1,4-dioxane solution containing 33.9 g (0.10 mol) of 2-cyclopropylmethoxy-1-iodo-3-methoxymethoxybenzene obtained in Reference example 12-(b) was added 150 ml of 1,4-dioxane solution containing 4N hydrogen chloride, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, 100 ml of water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 22.3 g of the title compound as a colorless oil. (Yield: 77%)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:17]([OH:19])=O)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C([O-])(O)=O.[Na+].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:47]([O:51][NH2:52])([CH3:50])([CH3:49])[CH3:48]>CN(C=O)C>[C:47]([O:51][NH:52][C:17](=[O:19])[CH:16]([NH:15][S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)ON
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)O)c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)NOC(C)(C)C)c2ccc(O)cc2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
To a solution of 12.18 g (32.48 mmol) of product of ({[4-(2-butynyloxy)phenyl]sulfonyl}amino)(4-hydroxyphenyl)acetic acid in 5 ml of DMF at room temperature was added 165.65 g (1.95 mol) of NaHCO3, 17.4 g (90.9 mmol) of EDC, 10.53 g (77.95 mmol) of HOBT and 61.2 g (487.2 mmol) of O-t-butylhydroxylamine hydrochloride. The reaction was stirred at 50° C. for 6 h, then at room temperature overnight. DMF was removed. The resulting light brown solid was diluted with ethyl acetate/water, extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was washed with 3-5 ml dichloromethane, The product, ′N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]-sulfonyl}amino)-2-(4-hydroxyphenyl)acetamide, (12 g, 83%) was obtained as a light yellow solid. Electrospray Mass Spec 447.4 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10](=[O:18])[CH2:9]2)=[CH:4][CH:3]=1.[OH:19][C:20]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:21]=1>>[C:20]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:10]2=[O:18])(=[O:19])[CH3:21]
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Reactant: O=C1CC(c2ccc(Cl)cc2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 99 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(4-chlorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one and being stirred for 1.5 h to obtain the title compound (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](O)[C@@H:9]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=2)[CH2:10][C@:11]([CH3:23])([CH2:20][CH:21]=[CH2:22])[C:12]([NH:14][C@@H:15]([CH2:18][CH3:19])[CH2:16][OH:17])=[O:13])=[CH:4][CH:3]=1.ClC1C=CC([C@@H](O)[C@H](C2C=NC=C(Cl)C=2)C[C@@](C)(CC=C)C(N[C@@H](CC)CO)=O)=CC=1.C(N(CC)CC)C.Cl.CN(C)C.CC1C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>C(Cl)Cl.CC#N>[CH2:20]([C@@:11]1([CH3:23])[CH2:10][C@H:9]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=2)[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:14]([C@@H:15]([CH2:18][CH3:19])[CH2:16][OH:17])[C:12]1=[O:13])[CH:21]=[CH2:22]
Reactant: C=CC[C@@](C)(C[C@H](c1cncc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@@H](CC)CO
Agent: C=CC[C@](C)(C[C@@H](c1cncc(Cl)c1)[C@H](O)c1ccc(Cl)cc1)C(=O)N[C@@H](CC)CO
Agent: CN(C)C
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CC[C@@]1(C)C[C@H](c2cncc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
The mixture of diastereomers of (S)-2-((2R,3R)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropyl)-N-((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide and (R)-2-((2S,3S)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropyl)-N-((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide (Example 400, Step G, 6.34 g,) was combined in DCM (68 ml) and triethylamine (13.3 ml, 95 mmol). After cooling in an ice bath, trimethylamine hydrochloride (1.953 g, 20.43 mmol) was added. 4-Methylbenzenesulfonic anhydride (17.78 g, 54.5 mmol) was added slowly as a solid, keeping the temperature below 10° C. The brownish colored solution was allowed to slowly warm to room temperature, and then stirred over night. The next day more trimethyl amine hydrochloride (0.271 mg, 2.91 mmol) was added and the solution was stirred for another day. The reaction was quenched with ice water. The layers were partitioned and the aqueous layer was washed with DCM. The combined organics were dried over MgSO4, filtered, and concentrated to provide a brown oil. The oil was dissolved in MeCN (100 ml) and then heated to 60° C. for 4 hours. The solution was concentrated and the residue dissolved in 100 ml of DCM. To this was added 100 ml of sat. NaHCO3 and the biphasic solution was stirred at rt. for 5 days. The solution was partitioned and the aqueous layer was washed with DCM. The organics were dried over MgSO4, filtered and concentrated. The product was purified by silica gel chromatography to give (3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one as the second eluting diastereomer.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17]>CC(O)C>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:10][CH2:9][N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]1=[NH:2]
Reactant: Nc1cccc[n+]1CSc1ccccc1Br
Agent: [Cl-]
Solvent: CC(C)O
Product: N=c1ccccn1CSc1ccccc1Br

Procedure:
To a suspension of 2.05 g of sodium 2-propoxide in 200 ml of 2-propanol is added 8.3 g of 2-amino-1-[[(o-bromophenyl)thio]methyl]pyridinium chloride, and the mixture is stirred and heated under reflux for about 5 hours. During this time the flocculent sodium 2-propoxide is replaced by a granular precipitate. The mixture is filtered hot, the insoluble solid is washed repeatedly with warm 2-propanol, and the combined filtrate and washings are concentrated to a volume of about 25 ml in vacuo. The solution is cooled, the solid that separates is filtered, and then is recrystallized from cyclohexane to give 1-[(o-bromophenylthio)methyl] -2-iminopyridine.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:34][C:20]3=[N:21][CH:22]=[CH:23][C:24]([C:25]4[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=4[O:32][CH3:33])=[C:19]3[CH:18]=2)[CH2:12]1)(C(C)(C)C)(C)C.CO.Cl>ClCCl>[F:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:24]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:34][C:17]([CH:13]4[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][CH2:9][OH:8])[CH2:12]4)=[CH:18][C:19]=23)[CH:30]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCO[Si](C)(C)C(C)(C)C)C3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCCN(CCO)C3)cc12

Procedure:
A solution of Example 128A (80 mg, 0.16 mmol)) in dichloromethane (2 mL) and methanol (2 mL) was treated with 37% hydrochloric acid (0.1 mL) for 10 minutes and concentrated. The residue was purified by reverse phase HPLC, and was eluted with 10-70% acetonitrile in 0.1% trifluoroacetic acid/water to afford the title compound. LCMS: 370.20 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 1.56-1.69 (m, 1H) 1.83-2.01 (m, 2H) 2.16 (d, 1H) 2.85-2.99 (m, 1H) 3.14-3.23 (m, 3H) 3.26-3.40 (m, 2H) 3.74 (s, 3H) 3.75-3.80 (m, 2H) 6.11 (d, 1H) 7.09 (d, 1H) 7.18-7.24 (m, 2H) 7.25-7.32 (m, 1H) 8.22 (d, 1H) 9.55 (s, 1H) 11.88 (s, 1H).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9](/[CH:30]=[CH:31]/[C:32]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])[CH:10]=[C:11]([CH3:29])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:16][N:15]=1.[CH:40]([C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Cl)=[CH:44][CH:43]=1)=[CH2:41].C([O-])([O-])=O.[K+].[K+]>O>[Cl:6][C:7]1[CH:8]=[C:9](/[CH:30]=[CH:31]/[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:46][C:45]3[CH:48]=[CH:49][C:42]([CH:40]=[CH2:41])=[CH:43][CH:44]=3)[CH2:36][CH2:35]2)=[O:33])[CH:10]=[C:11]([CH3:29])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:16][N:15]=1
Reactant: Cc1cc(/C=C/C(=O)N2CCNCC2)cc(Cl)c1Oc1ccc(OCc2ccccc2Cl)cn1
Reactant: C=Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(CN2CCN(C(=O)/C=C/c3cc(C)c(Oc4ccc(OCc5ccccc5Cl)cn4)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a DMF (7 mL) solution of (E)-3-[3-chloro-4-({5-[(2-chlorobenzyl)oxy]-pyridin-2-yl}oxy)-5-methylphenyl]-1-(piperazin-1-yl)prop-2-en-1-one (0.70 g) and 4-vinylbenzyl chloride (240 μL) was added K2CO3 (291 mg) at room temperature. After stirring at room temperature for 36 hours, to the reaction mixture was added water, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 0/1 and then AcOEt/MeOH=19/1) to give (E)-3-[3-chloro-4-({5-[(2-chlorobenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-[4-(4-ethenylbenzyl)-piperazin-1-yl]prop-2-en-1-one as a colorless powder (0.73 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18](=[O:20])[NH:24][C:23]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:22]=1[Cl:21])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)O
Reactant: Nc1c(F)cccc1Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To the solution of (S)-3,4-dihydro-1H-isoquinoline-1,2-dicarboxylic acid 2-tert-butyl ester (100 mg, 361 μmol, Eq: 1) and 2-chloro-6-fluoroaniline (63.0 mg, 433 μmol, Eq: 1.2) in pyridine (2.00 mL) at 0° C. was added POCL3 (82.9 mg, 50.4 μL, 541 μmol, Eq: 1.5). Reaction was warmed to RT and stirred for 2 h. The mixture was evaporated and water was added to the residue. The mixture was extracted with EtOAc, the combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-1-(2-chloro-6-fluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (79 mg) as a white solid.
Reaction SMILES: Br.Br.C([O:5][C:6]([C@@H:8]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[S:20][CH2:19]1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+]>[C:6]([C@@H:8]([NH:17][C@@H:18]1[C:24](=[O:25])[N:23]([CH2:26][C:27]([OH:29])=[O:28])[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[S:20][CH2:19]1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 2 h
Yield: 58 %

Procedure:
In 4 ml of 0.1N aqueous sodium hydroxide solution is dissolved 0.15 g of 3(R)-[1(S)-ethoxycarbonyl-3(4-piperidyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide as obtained in Example 72, and the solution is allowed to stand at room temperature for 2 hours. The solution is made weakly acidified with 1 ml of acetic acid, and purified by Amberlite XAD-2 column chromatography (methanol:water=1:1). The eluate is concentrated under reduced pressure, and the residue is lyophilized to give 0.06 g of 3(R)-[1(S)-carboxy-3-(4-piperidyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.