Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=[O:11])=O)(C)(C)C.Cl>ClCCl.CCOCC>[NH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=[O:16])=[O:11]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)CNC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)CN)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl 3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoate (4) (0.36 g; 0.61 mmol) in dichloromethane (5 ml) was treated with a 4.8M solution of hydrogen chloride in ether (1 ml). The mixture was stirred at ambient temperature for 1 hour. After dilution with ether, the resulting precipitate was filtered, washed with ether and dried to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl 3-[(2-aminoacetyl)amino]propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[CH:9]([C:11]([F:14])([F:13])[F:12])=O.S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[CH:9]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[Cl:8])[C:11]([F:14])([F:13])[F:12]
Reactant: O=CC(F)(F)F
Reactant: Clc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Product: FC(F)(F)C(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Yield: 76 %

Procedure:
1 mol (374 g) of α,α-bis-(2,4-dichlorophenyl)-β,β,β-trifluoroethane (obtained by condensation of m-dichlorobenzene with fluoral in the presence of concentrated sulfuric acid) is dissolved in 800 ml of "glyme". There is then added with stirring 80 g of 1,2,4-triazole, and at 80°-85° there is subsequently added dropwise 250 ml of 60% KOH. The reaction mixture is refluxed for about a further 3 hours. After cooling, the aqueous phase is separated and discarded. The organic phase is concentrated by evaporation, and the residue is subjected to molecular distillation under high vacuum. The substance distills over at 180° and 0.1 Torr as colourless oil, which solidifes on cooling to form a solid resin. The yield is about 76%. The compound can be crystallised from a mixture of cyclohexane and methanol: m.p. 84°-86°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1.CN(C)C(=O)C.[H-].[Na+].[ClH:29].[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O>[ClH:30].[ClH:29].[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)C1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Reaction time: 1 h

Procedure:
To a stirred mixture of 167 parts of ethyl 3-(1H-benzimidazol-2-ylamino)-1-pyrrolidinecarboxylate and 2790 parts of N,N-dimethylacetamide were added portionwise 61.0 parts of a sodium hydride dispersion 50% Upon completion, stirring was continued for 1 hour at 50° C. 127.2 Parts of 2-(chloromethyl)pyridine hydrochloride were added portionwise at 80° C. After complete addition, the whole was stirred for 2 hours at 80° C. After cooling, the reaction mixture was poured into 1000 parts of water. The product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 and 99:1 by volume) as eluents. The first and second fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane. The salt was filtered off and dried, yielding 69.5 (24%) parts of ethyl 3-[[1-(2-pyridinylmethyl)-1H-benzimidazol-2-yl]amino]-1-pyrrolidinecarboxylate dihydrochloride; mp. >140° C. (compound 23).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21]([O:26][CH3:27])([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][C:21]([O:26][CH3:27])([CH:24]=[O:25])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -65 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of oxalyl chloride (4.36 ml) in dichloromethane (220 ml) was added dropwise at −70% a solution of dimethylsulfoxide (5.32 ml) in dichloromethane (20 ml), and 30 minutes later, to the mixture was added dropwise a solution of 1-(tert-butoxycarbonyl)-4-methoxy-4-piperidinemethanol (6.13 g) in dichloromethane (60 ml). The mixture was stirred around −65° C. for 1 hour. To the mixture was added triethylamine (17.4 ml), and the mixture was stirred between the temperature ranging from −60° C. to 0° C. for 2 hours. The reaction solution was washed with water and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give colorless solid of the title compound (6.32 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([CH3:16])[CH:10]=1.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:16][C:11]1[CH:10]=[C:9]([Br:8])[CH:15]=[CH:14][C:12]=1[NH:13][C:5]([CH3:6])=[O:7]
Reactant: Cc1cc(Br)ccc1N
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Br)cc1C
Temperature: 85 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
Acetic anhydride (15.2 ml, 0.16 mol) was added dropwise to a stirred mixture of 4-bromo-2-methylaniline (10.0 g, 0.054 mol) and sodium acetate (2.52 g, 0.056 mol) in toluene (150 ml). Once the addition was complete the mixture was warmed to 85° C. and stirred for 40 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic solution was evaporated in vacuo, a further quantity of toluene was added and then the solvent was evaporated to give 4-bromo-2-methylacetanilide (12.3 g), as a colourless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34]([C:38]1[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](Cl)=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>O1CCCC1>[C:34]([C:38]1[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:45])=[CH:40][CH:39]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Reactant: CC(C)(C)c1ccc(OCC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(OCC(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.4 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL) was added dropwise 4-tert-butylphenoxyacetyl chloride (0.32 g, 1.41 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 21 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a colorless syrup that was triturated with diethyl ether to afford the title compound (0.280 g, 58%) as a white solid, m.p. 85° C.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C@@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH3:20].C1COCC1>>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:8][BH:20][N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Reactant: B
Solvent: C1CCOC1
Product: B1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Yield: 25.4 %

Procedure:
(S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol (378.5 mg, 1.5 mmol) was dissolved in 4.09 mL (4.5 mmol) of BH3.THF (1.1M), and the resulting solution was refluxed for 48 h under argon atmosphere (1 bar). The solvent was removed under vacuum, and the residue was sublimed (150°-160° C./0.1 Torr) to give 258 mg of a crude product. This product (94.1 mg) was resublimed (145°-160° C./0.05 Torr) to give 36.7 mg (0.139 mmol), 25.4% yield) of (S)-5,5-diphenyl-3,4-propano-1,3,2-oxazaborolidine as colorless crystals, mp 107°-124° C.,
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][C:12]([OH:14])=[O:13])[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:23]=1>C(O)(C(F)(F)F)=O.O.CS(C)=O>[Cl:1][C:2]1[C:3]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][C:12]([OH:14])=[O:13])[NH:7][C:6]=2[CH:23]=1
Reactant: C[Si](C)(C)CCOCn1c(OCC(=O)O)nc2cc(C#Cc3ccccc3)c(Cl)cc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C(O)COc1nc2cc(C#Cc3ccccc3)c(Cl)cc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
In a 4 mL vial, [6-chloro-5-phenylethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxy]-acetic acid (compound 48-2, 79.0 mg, 0.173 mmol) was dissolved in 9:1 TFA/water (3 mL) and stirred at 65° C. for 10 min. The solution was then evaporated to dryness in vacuo to give brownish oil, which was dissolved in DMSO (1 mL), filtered and purified by reverse-phase HPLC to give the title compound as a yellowish solid. LR-MS (API-ES): calculated for C17H11ClN2O3 326.1, observed m/e 327.1 (M+H)+ (Rt 1.25 min).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([CH:41]([CH2:45][CH:46]=[CH2:47])[C:42](O)=[O:43])[CH:39]=[CH2:40]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:42](=[O:43])[CH:41]([CH2:45][CH:46]=[CH2:47])[CH2:38][CH:39]=[CH2:40])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=CCC(CC=C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C=CCC(CC=C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 75.8 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 560 mg (4.0 mmol) of 2-allyl-4-pentenoic acid, to provide 1.02 g of the title compound.
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[C:14](=[O:15])[C:13]2[C:12]([N+]#N)=[C:11]3[O:18]C[O:20][C:10]3=[CH:9][C:8]=2[N:7]([CH2:21][CH3:22])[CH:6]=1)([OH:4])=[O:3].O>OS(O)(=O)=O>[Cl:1][C:12]1[C:11]([OH:18])=[C:10]([OH:20])[CH:9]=[C:8]2[C:13]=1[C:14](=[O:15])[C:5]([C:2]([OH:4])=[O:3])=[CH:6][N:7]2[CH2:21][CH3:22]
Reactant: [Cl-]
Reactant: CCn1cc(C(=O)O)c(=O)c2c([N+]#N)c3c(cc21)OCO3
Agent: O=S(=O)(O)O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c(Cl)c(O)c(O)cc21
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 7-carboxy-5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-9-diazonium chloride (7.5 g, 23.17 mmol) (Mixture of 16c and 16d) in 50% H2SO4 (60 mL) was heated at 95° C. for 4 h. The reaction mixture was cooled down to r.t. and then poured into 450 mL of water. The precipitates were collected by filtration and dried to afford 5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6 g, 18.61 mmol, 80% yield) as a yellow brown solid. LCMS: (M+H)+: 284.1.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])O.[Na+]>>[C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH:15][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:14][C:7]=2[O:6]1)#[N:2]
Reactant: CCOC(=O)Cl
Reactant: N#CCCC1CCc2cc(N)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Nc1ccc2c(c1)CCC(CCC#N)O2

Procedure:
By a process analogous to that of step 6 of Example 1, starting from 2.4 g (12 mmol) of 2-cyanoethyl-6-amino-3,4-dihydro-2H-1-benzopyran, 1.24 ml (13.0 mmol) of ethyl chloroformate and 1.5 g (18 mmol) of sodium hydrogencarbonate, 2.0 g of product are obtained.
Reaction SMILES: CC1C=CC(CP(=O)OCC2C=CC=CC=2)=CC=1.[H-].[Na+].C([O:28][C:29]([CH:31]([CH2:45][CH2:46][C:47]([O:49]CC1C=CC=CC=1)=[O:48])[CH2:32][P:33]([CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:35])[OH:34])=[O:30])C1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:39]1([CH2:38][CH2:37][CH2:36][P:33]([CH2:32][CH:31]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:29]([OH:30])=[O:28])([OH:35])=[O:34])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: Cc1ccc(C[PH](=O)OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCC(CP(=O)(O)CCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 163 %

Procedure:
To a solution of 4-methylbenzyl-O-benzylphosphinic acid (2, R=4-methylbenzyl) (2.16 g, 8.3 mmol) in THF (15 Ml) was added sodium hydride (0.10 g, 60% dispersion in oil) followed by dibenzyl 2-methylenepentanedioate (3) (3.24 g) at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with EtOAc (50 Ml) and poured into 1 N Hcl (50 Ml). The organic layer was separated, dried over Na2SO4, and concentrated. This material was purified by silica gel chromatography (hexanes: EtOAc, 4:1 to 1:1) to give 3.41 g of 2,4-di(benzyloxycarbonyl)-butyl(4-methylbenzyl)-o-benzylphosphinic acid (4, R=4-methylbenzyl) as colorless oil (70% yield). Rf 0.61 (EtOAc).
Reaction SMILES: [Si]([O:18][C@@H:19]([CH3:46])[C:20]([N:22]1[N:26]=[C:25]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[S:24][C@@:23]1([CH2:41][O:42][CH2:43][O:44][CH3:45])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:25]1[S:24][C@@:23]([CH2:41][O:42][CH2:43][O:44][CH3:45])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:22]([C:20](=[O:21])[C@@H:19]([OH:18])[CH3:46])[N:26]=1
Reactant: COCOC[C@@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COCOC[C@@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(tert-butyldiphenylsilyloxy)-1-((R)-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)propan-1-one (110 mg, 0.17 mmol) in THF (10 mL) was added TBAF (0.28 mL, 1.0 M, 0.28 mmol). After slowly warming to room temperature and stirring for 16 hours, the mixture was treated with 0.5 N HCl (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organics were washed with NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The pale yellow residue was chromatographed (9:1 to 4:1 hexanes/ethyl acetate) to provide the product as a white solid (0.045 g, 64%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:50])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)[C:14]3[CH:41]=[C:42]([CH3:49])[C:43]([C:45]([F:48])([F:47])[F:46])=[CH:44][C:13]2=3)=[CH:8][CH:7]=1.Cl>CO>[F:35][C:33]([F:34])([F:36])[C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=1)[CH2:26][N:19]([C:20]1[N:21]=[N:22][N:23]([CH3:25])[N:24]=1)[C@H:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:5]([OH:50])=[O:4])=[CH:11][CH:10]=2)[C:13]2[CH:44]=[C:43]([C:45]([F:46])([F:47])[F:48])[C:42]([CH3:49])=[CH:41][C:14]1=2
Reactant: COC(=O)c1ccc(N2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(c1ccc(C(=O)O)cc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C
Yield: 51.3 %

Procedure:
Add 5 N sodium hydroxide solution (0.5 mL) to a solution of (S)-4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-benzoic acid methyl ester (40 mg, 0.058 mmol) in methanol (1 mL) and heat at 60° C. for 4 h. After the reaction cools to room temperature, acidify to pH 4 with 2 N hydrochloric acid solution and extract the aqueous mixture with ethyl acetate (3×10 mL). Wash the organic layer with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as an off-white solid (20 mg, 51%). mp 101-105° C.; 1H NMR (CDCl3, 300 MHz) δ 1.75-1.91 (m, 1H), 2.05-2.36 (m, 3H), 2.29 (s, 3H), 3.35-3.43 (m, 1H) 3.99-4.09 (m, 1H), 4.19 (s, 3H), 4.70-5.35 (m, 3H), 6.70-6.75 (m, 2H), 7.20 (s, 1H), 7.47 (s, 1H), 7.63-7.72 (m, 2H), 7.80 (s, 1H), 7.96-8.10 (m, 2H); ESI MS m/z 673 [C30H25F9N6O2+H]+.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C@H:11]([OH:15])[C:12]([OH:14])=[O:13])[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO[C:18](OC)([CH3:20])[CH3:19]>CC(C)=O.[Cu](Cl)Cl>[CH:1]1([CH2:6][C@H:7]([C@H:11]2[C:12](=[O:14])[O:13][C:18]([CH3:20])([CH3:19])[O:15]2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@@H](O)[C@@H](CC1CCCC1)C(=O)O
Reactant: COC(C)(C)OC
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CC1(C)OC(=O)[C@H]([C@@H](CC2CCCC2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2R,3S)-2-(cyclopentylmethyl)-3-hydroxysuccinic acid (18.97 g, 87.73 mmol; 1.0 eq.) in acetone (300 mL) was added 2,2-dimethoxypropane (21.6 mL, 175.46 mmol, 2.0 eq.) and copper (II) chloride (1.18 g; 8.77 mmol, 0.1 eq.). The resulting reaction mixture was stirred for 16 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3 (200 mL). Activated charcoal (10 g) was added and the resulting mixture was stirred at RT for 30 minutes. Filtration on a pad of celite gave the title product as yellowish oil. Purification by flash chromatography (Si60; 40-60 microns) eluting with Heptane/MTBE 60/40 gave the title product (16.30 g; 72.5%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([OH:16])[C@H:6]([NH2:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH3:2].[ClH:18].[CH2:19](O)[CH2:20]CC>>[CH2:1]([O:3][C:4](=[O:17])[C@H:5]([OH:16])[C@H:6]([NH2:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH2:2][CH2:19][CH3:20].[ClH:18]
Reactant: CCCCO
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Agent: Cl
Product: CCCCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Temperature: 70 °C

Procedure:
(2R,3R)-3-Amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (100 mg, 0.4 mmol) was combined with 1-butanol (5 mL) and concentrated HCl (1 mL) and heated at 70° C. for 24 hours. Excess solvent was removed to yield the title compound as an HCl salt.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.CCN(C(C)C)C(C)C.[Br:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C@H:33]([NH:37][C:38]([C:40]3[S:41][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:43][CH:44]=3)=[O:39])[C:34](O)=[O:35])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:19][C:20]1[CH:25]=[N:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C@H:33]([NH:37][C:38]([C:40]3[S:41][C:42]([C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:43][CH:44]=3)=[O:39])[C:34]([N:1]3[CH2:5][CH2:4][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]3)=[O:35])=[CH:30][CH:31]=2)=[N:22][CH:21]=1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)s1
Reactant: COC(=O)[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CCN(C(=O)[C@H](Cc2ccc(-c3ncc(Br)cn3)cc2)NC(=O)c2ccc(C(C)(C)C)s2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirring solution of methyl (S)-pyrrolidine-3-carboxylate (357.0 mg, 2.16 mmol) in DMF (10 mL) were added DIEA (465.26 mg, 3.60 mmol) and (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic acid (700.0 mg, 1.44 mmol). The solution was cooled to 0° C. at ice bath and then HATU (677.55 mg, 2.88 mmol) in 2 mL DMF solution was slowly added. The reaction was stirred 1 hour at 0° C. and then warmed to RT with stirring for 2 hours. The reaction solution was extracted with DCM (3×20 mL) and aqueous NaHCO3 (3×10 mL). The combined organics were dried over MgSO4 and evaporated. The final compound was purified by column chromatography (40% DCM in hexane) to afford 501.0 mg (58%) of methyl (S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate INT-35 as a powder. LCMS-ESI (m/z calculated for C28H31BrN4O4S: 598.1. found 599.3 [M+H]+, tR=3.553 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.05 (d, J=1.1 Hz, 2H), 8.77 (dd, J=11.5, 8.3 Hz, 1H), 8.25 (d, J=7.7 Hz, 2H), 7.72 (d, J=3.5 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 6.92 (d, J=3.8 Hz, 1H), 4.98-4.73 (m, 1H), 3.88 (dd, J=10.3, 8.0 Hz, 1H), 3.71 (dd, J=15.5, 7.5 Hz, 1H), 3.50 (ddd, J=18.3, 12.2, 5.4 Hz, 2H), 3.38 (dd, J=17.3, 7.6 Hz, 1H), 3.23 (ddd, J=28.0, 15.0, 8.7 Hz, 1H), 3.18-2.85 (m, 3H), 2.17-1.96 (m, 2H), 1.87 (td, J=15.2, 7.4 Hz, 1H), 1.32 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[C:37](Cl)[CH:36]=1>>[CH2:2]1[C:37]2[C:38](=[CH:39][CH:40]=[C:35]([NH:34][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:5][CH2:4][NH:3]1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-amino-2-chlorophenol in a manner analogous to Example 27, Step D. MS (ESI): 569 (M+Na)+.