Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][C:5]([CH3:9])=[N:4]1)[CH3:2].[OH-].[Ca+2].[OH-].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O1CCOCC1.O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[C:5]([CH3:9])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)cc1O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCn1nc(C)c(C(=O)c2ccccc2)c1O
Temperature: 110 °C
Reaction time: 3.5 h

Procedure:
A suspension of 1.4 g of 2-ethyl-5-methyl-2H-pyrazol-3-ol, 1.6 g of calcium hydroxide and 1.3 ml of benzoyl chloride in 70 ml of 1,4-dioxane was stirred at 110° C. for 3.5 h. 1 ml of water was added and the mixture was stirred at 110° C. for 2 h. 25 ml of 2N hydrochloric acid was added. The mixture was stirred at room temperature for 16 h and extracted three times with 60 ml of ethyl acetate. The combined extracts were dried over magnesium sulphate, filtered and evaporated to give 3.1 g of (1-ethyl-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone as a yellow oil which was used without further purification. Mass spectrum (ES) m/z 231 [M+H]+, 272 [M+H+CH3CN]+.
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>N1C=CC=CC=1>[CH2:36]([O:35][C:33](=[O:34])[NH:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (400 mg, 874 μmol) was initially charged in abs. pyridine (15 ml). At 0° C., benzyl chloroformate was added in a plurality of portions (3×460 mg, 3×2621 μmol; 9 eq.), and the mixture was then stirred for 12 h with warming to RT. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (500 mg, quant.).
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:35])([CH:33]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([S:8][C:9]([CH3:35])([CH2:33][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(c1cccc2cc(C(=O)NCC(C)(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a mixture of N-[2-(benzylthio)-2-methyl-3-oxopropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.40 g), morpholine (0.13 ml) and 1,2-dichloroethane (4 ml) was added sodium triacetoxyborohydride (0.36 g) at 0° C., and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.25 g, yield 55%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). melting point 150-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:35])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([OH:35])([C:27]([F:28])([F:29])[F:30])[C:31]([F:32])([F:33])[F:34])=[CH:24][CH:25]=2)[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)c(Br)c1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
4-(2-Bromo-4-nitrophenoxy)piperidine (10.96 mmol, 3.3 g), 2-(4-(bromomethyl)-phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (10.96 mmol, 3.69 g) and potassium carbonate (32.9 mmol, 4.54 g) were combined in acetonitrile (40 mL) and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue dissolved in dichloromethane (150 mL). The organic phase was washed with water (2×50 mL) then brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with dichloromethane to 10% methanol/dichloromethane) to afford the title compound (5.25 g). MS (ESI) m/z 558.8 [M+H]+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[CH2:17]1[O:20][CH:18]1[CH3:19]>C1COCC1.CCCCCC>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:17][CH:18]([OH:20])[CH3:19]
Reactant: FC(F)(F)c1ccccc1I
Reactant: CC1CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
General Procedure HH: To a solution of 1-iodo-2-(trifluoromethyl)benzene (1.5 g, 5.5 mmol) in THF (10.0 mL) was added 2.5 M of n-BuLi in hexane (2.2 mL) at −78° C. and stirred for 10 min. Propylene oxide (370 mg, 6.4 mmol) was added to the reaction mixture at −78° C. and slowly warmed to rt. The reaction mixture was stirred for an additional 30 min. The reaction mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give a yellow oil. The material was purified by silica gel chromatography using Hexane/EtOAc (80:20) as eluent to yield the desired product as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ=1.30 (d, J=6.1 Hz, 3H), 1.46 (d, J=4.3 Hz, 1H), 2.82-3.06 (m, 2H), 4.03-4.12 (m, 1H), 7.32-7.38 (m, 1H), 7.41-7.45 (m, 1H), 7.48-7.53 (m, 1H), 7.67 (d, J=8.1 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[CH:7]=1)C.[OH-].[Na+]>O>[CH3:28][N:26]([CH3:27])[C:23]1[CH:22]=[CH:21][C:20]([C:17]2[O:16][C:15]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:29])=[O:3])[CH:11]=[CH:10][CH:9]=3)=[O:14])=[CH:19][CH:18]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(N(C)C)cc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc(-c2ccc(C(=O)Nc3cccc(CC(=O)O)c3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of (3-[(5-(4-dimethylamino-phenyl)-furan-2-carbonyl)-amino]-phenyl)-acetic acid ethyl ester (13) (0.33 g) in IMS (80 ml) was added a solution of sodium hydroxide (0.65 g) in water (21 ml). The resulting solution was stirred at room temperature for 1 hour then concentrated in vacuo below 40° C. to circa 15 ml volume. Water (50 ml) then acetic acid (1.5 ml) were added and the resulting precipitate filtered, washed with water and triturated with dichloromethane/pentane to yield the title compound (0.26 g; m.p. 187-190° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH:3]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[C:9]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH:15]=2)[N:8]=1)[CH:4]=[CH2:5].[N+](=[CH:38][C:39]([O:41]CC)=[O:40])=[N-].Cl.C(O)=O>ClCCl.O1CCOCC1.[Li+].[OH-].C([O-])(=O)C.[Rh+2].C([O-])(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)C>[F:13][C:12]1[C:7]([NH:6][CH:3]([CH:4]2[CH2:5][CH:38]2[C:39]([OH:41])=[O:40])[C:2]([CH3:34])([CH3:1])[CH3:35])=[N:8][C:9]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[NH:16][CH:15]=2)=[N:10][CH:11]=1
Reactant: C=CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Pd+2]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O=CO
Solvent: ClCCl
Product: CC(C)(C)C(Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C1CC1C(=O)O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To racemic N-(4,4-dimethylpent-1-en-3-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine, 89a, (0.105 g, 0.211 mmol) and rhodium(II) acetate (0.019 g, 0.042 mmol) in dichloromethane (6.2 mL) was added dropwise a solution of ethyl 2-diazoacetate (0.181 g, 0.166 mL, 1.582 mmol) in 2 mL dichloromethane over 30 minutes. Pd(OAc)2 (0.019 g, 0.042 mmol) in dichloromethane (2 mL) was added followed by ethyl 2-diazoacetate (0.181 g, 0.166 mL, 1.582 mmol) in dichloromethane (2 mL) dropwise. The reaction was stirred overnight and the solvent was concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0 to 100% EtOAc/Hexanes gradient) to afford a racemic mixture of diasteromeric esters, 90a. The mixture of esters was dissolved in dioxane (2 mL) and 2N LiOH (1 mL). After heating at 100° C. for 2 h and cooling to room temperature, the mixture was acidified pH 6.5 with 2N HCl. The aqueous phase was extracted twice with EtOAc and once with dichloromethane. The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography (0-20% MeOH/EtOAc gradient) to isolate the mixture of diastereomeric acids, which were further purified by preparatory HPLC (CH3CN/H2O—TFA modifier) to afford 3 diastereomers. Two of the diastereomers, 51 and 52, were isolated as a single diastereomer each. The third diastereomer, 50, was isolated as a mixture of diastereomers. All three diastereomers showed same LCMS: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 402.45.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])=[CH:7][C:6]=1[Br:31].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[Br:31][C:6]1[CH:7]=[C:8]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])[CH:9]=[C:10]([O:11][CH2:12][CH3:13])[C:5]=1[O:4][CH2:3][CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCN)c(OCC)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCNS(C)(=O)=O)c(OCC)c1
Reaction time: 17 h

Procedure:
A mixture of the product of step c (130.7 mg), triethylamine (93 μl) and methanesulfonyl chloride 21 μl in dichloromethane (3 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with 0.5N aqueous HCl. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 57.1 mg. MS-ESI: [M+H]+=566.0/568.0; HPLC: Rt=12.49 min. (method 1). Diast. ratio: 4:1
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([O:21][C:22]1[O:26][CH:25]=[C:24]([C:27]([CH:29](C(C)=O)[C:30]([O:32][CH3:33])=[O:31])=[O:28])[CH:23]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O>[CH3:33][O:32][C:30](=[O:31])[CH2:29][C:27]([C:24]1[CH:23]=[C:22]([O:21][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:26][CH:25]=1)=[O:28]
Reactant: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)C(C(C)=O)C(=O)OC)co1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)CC(=O)OC)co1

Procedure:
To a cooled mixture of 40.0 g (0.106 mole) of 5-(cis-9-octadecen-1-yloxy)-3-furoic acid in methylene chloride is added 30 ml of thionyl chloride. The mixture is stirred for 5 hours. Then the solvent and excess thionyl chloride is removed under reduced pressure affording the crude 5-(cis-9-octadecen-1-yloxy)-3-furoyl chloride. A mixture of 11.6 g (0.100 moles) of methyl acetoacetate and 2.3 g of sodium in 1 liter of benzene is refluxed for 20 hours, then cooled, and the crude 5-(cis-9-octadecen-1-yloxy)-3-furoyl chloride is added over a two hour period. The mixture is refluxed for 6 hours, cooled by the addition of ice and mixed well. The benzene layer is separated, washed with 5% sodium bicarbonate solution and dried. The benzene is distilled off under reduced pressure yielding 2-[5-(cis-9-octadecen-1-yloxy)-3-furoyl]acetoacetic acid, methyl ester. To a solution of 3.3 g of ammonium chloride in 15 ml of water at 40° C is added 10 g of the above ester maintaining the temperature at 40° C for 15 minutes followed by rapid cooling. The solution is extracted with ether, the extract dried, and evaporated to dryness affording 2-[5-(cis-9-octadecen-1-yloxy)-3-furoyl]acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.7 %

Procedure:
To a solution of 4(3-fluoro-phenyl)1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (56.4 mg, 48%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)[CH2:29][C@@H:28]3[CH3:42])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.O>C1COCC1.CO>[F:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][N:30]1[C@H:31]([CH3:33])[CH2:32][N:27]([C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:43])[C@@H:28]([CH3:42])[CH2:29]1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H]1CN([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(C(=O)O)CC3)c2)[C@@H](C)CN1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a solution of 1-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-hydroxy-phenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid ethyl ester (463 mg, Example 124) in THF (4 mL) was added 1N NaOH solution (3 mL). The reaction was stirred at room temperature overnight. The reaction solution was neutralized by the addition of 1 N HCl solution (3 mL). The resulting solution was concentrated under vacuum to give crude product, which was subjected to reverse phase C-18 column chromatography conducted on CombiFlash™ Sq 16×(gradient: 100% H2O to 100% MeOH) to give 1-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxyphenyl)-methyl]-benzoyl}-piperidine-4-carboxylic acid (183 mg; 41%). 1H NMR (300 MHz, CD3OD) δ 7.48 (m, 2H), 7.37 (m, 2H), 7.27 (m, 1H), 7.16 (m, 3H), 7.04 (m, 1H), 6.71 (m, 3H), 5.21 (s, 1H), 4.47 (m, 1H), 4.13 (d, J=13.5 Hz, 1H), 3.66 (m, 1H), 3.51 (d, J=13.5 Hz, 1H), 3.09 (m, 2H), 2.81 (m, 3H), 2.68 (m, 1H), 2.55 (m, 1H), 2.30 (m, 1H), 2.06 (m, 2H), 1.83 (m, 1H), 1.65 (m, 2H), 1.21 (d, J=6.0 Hz, 3H), 1.15 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:10])[CH:5]=1.[F:12][C:13]([F:17])([F:16])[CH2:14]I>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:5]=1
Reactant: FC(F)(F)CI
Reactant: COC(=O)c1cccc(S)c1
Product: COC(=O)c1cccc(SCC(F)(F)F)c1
Reaction time: 8 h
Yield: 82 %

Procedure:
3-(2,2,2-Trifluoroethylthio)benzoic acid methyl ester was prepared 3-mercaptobenzoic acid methyl ester and trifluoroethyl iodide by following Method C. The reaction was conducted at room temperature overnight. The crude residue was chromatographed in 10-20% EtOAc/hexanes to afford 3-(2,2,2-trifluoroethylthio)benzoic acid methyl ester (82% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>C(Cl)Cl>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)C(C)C)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.40 mmol) in CH2Cl2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol) and isobutyryl chloride (0.03 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 1 hour. The solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 2% to 10% of MeOH/CH2Cl2. The solid was further purified by flash chromatography on silica gel, eluting with 0% to 5% of MeOH/EtOAc, to afford the title compound (0.080 g, 50%): 1H NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.11 (d, J=9.0 Hz, 2H), 7.03 (d, J=9.1 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.76-3.92 (m, 6H), 3.52-3.71 (m, 4H), 3.16-3.44 (m, 4H), 2.83-3.00 (m, 1H), 1.02 (d, J=6.8 Hz, 6H); APCI MS m/z 437 [M+H]+.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[O:29]>>[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C@@H:28]([OH:29])[CH:17]=[CH:16][C:15]([CH3:19])([CH3:18])[CH3:14]
Reactant: O=Cc1ccccc1Br
Reactant: C#CC(C)(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C=C[C@H](O)c1ccccc1Br
Yield: 76 %

Procedure:
The product was prepared by General procedure S using 50 mg (0.28 mmol) Cy2BH, 35 μL (0.28 mmol) 3,3-dimethyl-1-butyne, 0.26 mL (0.53 mmol, 2.0 M in hexanes) Et2Zn, 2.4 mg (0.01 mmol) (−)-MIB, and 29 μL (0.25 mmol) o-bromobenzaldehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a colorless oil in 76% yield (51 mg, 0.19 mmol). [α]D20=−31.8 (c=0.33, CHCl3, 93% ee); 1H NMR (CDCl3, 500 MHz): δ 1.02 (s, 9H), 2.03 (s, 1H), 5.46-5.53 (m, 2H), 5.86 (d, 1H, J=15.0 Hz), 7.13 (t, 1H, J=7.6 Hz), 7.33 (t, 1H, J=7.5 Hz), 7.52 (d, 1H, J=8.9 Hz), and 7.54 (d, 1H, J=8.2 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 29.4, 33.0, 73.8, 122.6, 125.0, 127.7, 127.8, 128.9, 132.8, 142.3, and 144.3 ppm; IR (neat): 3353, 3064, 3013, 2958, 2865, 1721, 1661, 1590, 1568, 1465, 1439, 1363, and 1267 cm−1; HRMS-CI m/z 251.0432 [(M−OH)+; calcd for C13H16Br: 251.0435].
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:35]([NH:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]([O:26][CH3:25])=[O:37])=[O:36])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added methyl-2-isocyanatobenzoate (216 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 239 mg (69.5%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][C:33]1[C:34](B(O)O)=[N:35][CH:36]=[CH:37][CH:38]=1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:33]([CH3:32])=[CH:38][CH:37]=[CH:36][N:35]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: Cc1cccnc1B(O)O
Product: Cc1cccnc1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@H](F)CO2)cs1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-methylpyridin-2-yl)boronic acid gave 231. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.53 (dd, J=4.7, 1.5 Hz, 1H), 8.47 (s, 1H), 7.91-7.83 (m, 1H), 7.81 (s, 1H), 7.45 (dd, J=7.7, 4.6 Hz, 1H), 4.84 (dd, J=10.7, 3.6 Hz, 1H), 4.53-4.30 (m, 1H), 4.25-3.94 (m, 2H), 3.79 (s, 3H), 3.29-3.12 (m, 1H), 2.85 (s, 3H), 2.51 (s, 1H), 2.13-2.02 (m, 1H), 1.94-1.79 (m, 1H), 1.76-1.62 (m, 4H). LCMS (ES+) m/z 431 (M+1).