Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].[CH:3]1([C@@H:9]2[NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]3[CH:34]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:21]3=[CH:35][C:17](=[CH:18][CH:19]=[CH:20]3)[CH2:16][O:15][C@H:14]3[CH2:36][N:11]([C@H:12]([C:37]([O:39]C)=[O:38])[CH2:13]3)[C:10]2=[O:41])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1.CCO.O>[CH:3]1([C@@H:9]2[NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]3[CH:34]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:21]3=[CH:35][C:17](=[CH:18][CH:19]=[CH:20]3)[CH2:16][O:15][C@H:14]3[CH2:36][N:11]([C@H:12]([C:37]([OH:39])=[O:38])[CH2:13]3)[C:10]2=[O:41])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NCCCCC=Cc1cccc(c1)-c1cccc(c1)CO2
Agent: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NCCCC/C=C/c1cccc(c1)-c1cccc(c1)CO2
Agent: O=C(O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NCCCC/C=C/c1cccc(c1)-c1cccc(c1)CO2
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCCC1)NCCCCC=Cc1cccc(c1)-c1cccc(c1)CO2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
LiOH (3.0 eq.) was added to a 0.04M solution of methyl (9R,11S,14S,20E)-14-cyclohexyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.19,12]octacosa-1(26),2(28),3,5,20,22,24-heptaene-11-carboxylate 110 in a mixture of THF:EtOH:H2O (2:1:1) and the reaction mixture was stirred at 40° C. for 2 h. The solvents were removed under reduced pressure, the residue was suspended in EtOAc/H2O, aqueous (1N) HCl was added to acidic pH and the phases separated. The collected organic layers were dried (Na2SO4) and evaporated under reduced pressure to afford a residue which was used without further purification. MS (ES+) m/z 517 (M+H)+
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.OS(O)(=O)=O.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[C:24]4[CH2:38][O:37][C:36](=[O:39])[C:25]=4[CH:26]=[C:27]4[C:35]=3[C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=[CH:28]4)=[CH:22][C:17]=2[O:16][CH2:15]1>C1COCC1.CCOC(C)=O>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[C:24]4[CH2:38][O:37][C:36](=[O:39])[C:25]=4[CH:26]=[C:27]4[C:35]=3[C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=[C:28]4[Br:1])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1OCc2c1cc1c(Br)cc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.8 %

Procedure:
N-bromosuccinimide (10.7 mg, 0.06 mmol) and concentrated H2SO4 (5 μL) were added to a solution of 2 (15.4 mg, 0.044 mmol) in THF (1 mL). The solution was stirred at room temperature for 20 h, and then diluted with EtOAc (30 μL). The same workup and purification procedure as described for the isolation of 37 gave 38 (12 mg, 64%) as a pale yellow powder. mp 256° C. (decomp.); 1H NMR (CDCl3) δ 8.89 (s, 1H, H4), 7.65 (s, 1H, H6), 6.76-6.91 (m, 3H, H2′+H5′+H6′), 6.08 (AB, 2H, 3′,4′-OCH2O—, Δδ=8.7 Hz, J=1.5 Hz), 5.97 (AB, 2H, 7,8-OCH2O—, Δδ=7.8 Hz, J=1.5 Hz), 5.22 (q, 2H, lactone-CH2—, J=8.4 Hz); MS (EI) m/z 428 [M+2]+, 426 [M]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7](=[O:9])[NH2:8])=[CH:5][N:4]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[C:23]#[N:24])[N:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1.CC([O-])=O.[K+].C(Cl)(Cl)Cl.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.N#N>C(O)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:7]([C:6]1[C:2]([NH:1][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[N:3][N:4]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH:11]2[C:23]#[N:24])[CH:5]=1)(=[O:9])[NH2:8]
Reactant: CC(C)(C)OC(=O)C1CCC(n2cc(C(N)=O)c(N)n2)C(C#N)C1
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CCC(n2cc(C(N)=O)c(Nc3ccc(Cl)cc3)n2)C(C#N)C1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A solution of (1S,3S,4S and 1R,3R,4R)-t-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-3-cyanocyclohexane-1-carboxylate (Intermediate #47-4, 11 g, 33 mmol), 1-bromo-4-chlorobenzene (9.2 g, 48 mmol), KOAc (9.4 g, 96 mmol), Pd2(dba)3.CHCl3 (4.9 g, 5.0 mmol) and t-Butyl X-Phos (4.1 g, 10 mmol) in iso-propanol (100 mL) was degassed with bubbling N2 gas for 15 minutes and then stirred at 85° C. under nitrogen for 16 hours, and then concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 1-2% MeOH/DCM). Desired fractions were identified, combined, and concentrated in vacuo. The residue was further purified by reverse-phase preparative HPLC (using a gradient elution of 40-60% MeCN/water with 0.5% ammonia in 20) to afford the title compound. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.54 (d, J=9.2 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 4.32-4.30 (m, 1H), 3.49-3.42 (m, 1H), 2.51-2.47 (m, 2H), 2.20-2.13 (m, 3H), 1.95-1.82 (m, 1H), 1.66-1.59 (m, 1H), 1.50 (s, 9H). MS ESI: [M+H]+ m/z 444.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][NH2:8])[C:4]([OH:6])=[O:5].Cl.[CH3:10]O>>[ClH:1].[ClH:1].[CH3:10][O:5][C:4](=[O:6])[CH:3]([NH2:2])[CH2:7][NH2:8]
Reactant: NCC(N)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)CN
Temperature: 0 °C
Reaction time: 48 h

Procedure:
2,3-Diaminopropionic acid monohydrochloride (2.0 g, 14.3 mmol) is suspended in dry methanol (80 ml) and cooled on 0° C. Dry HCl gas is introduced into the solution for 30 min. Stirring is carried out at room temperature for 48 h, and the solvent is then removed in vacuo. The desired compound is obtained as a colorless solid and used directly for the next reaction.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10](=[O:15])[CH:9]=[CH:8]2.C(O[CH2:20][C:21](=[CH2:27])[CH2:22][Si](C)(C)C)(=O)C.P(OC(C)C)(OC(C)C)OC(C)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][C:10](=[O:15])[CH:9]3[CH2:22][C:21](=[CH2:20])[CH2:27][CH:8]3[C:7]=2[CH:6]=1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Reactant: COCOc1ccc2oc(=O)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: C=C1CC2C(=O)Oc3ccc(OCOC)cc3C2C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 6-methoxymethoxy coumarin 17a (21 g, 0.102 mol) and Pd(OAc)2 (2.75 g, 0.012 mol) in 500 mL THF add 2-(acetoxymethyl)allyl-trimethylsilane (26 mL, 0.122 mol) followed by triisopropyl phosphite (18.1 mL, 0.073 mol). After stirring at 60° C. overnight, cool the solution to RT, concentrate under reduced pressure, and dilute with EtOAc. Wash the solution with saturated aqueous sodium bicarbonate and brine. Dry over Na2SO4, and then concentrate to an oil. Purify the material by silica gel chromatography (Biotage 40M+65M columns, 10 to 30% EtOAc/Hex over 60 min at 50 mL/min followed by 30 to 50% EtOAc/Hex over 60 min at 50 mL/min) to give 18.3 g (0.070 mol, 69%) of cyclopentanoid 18 and 3.8 g (18.3 mmol, 18%) of recovered starting material. HRMS(ES+) calc for C15H17O4: 261.1127, found: 261.1122 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][CH:6](C(O)=O)[C:7]([OH:9])=[O:8].C(=O)=O>CCOCC>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([C:16]2[C:3]([O:2][CH3:1])=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:13]=[CH:14][CH:15]=2)=[O:25])=[CH:19][CH:20]=1
Reactant: COc1c(CC(C(=O)O)C(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: O=C=O
Solvent: CCOCC
Product: COc1c(CCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 67.2 %

Procedure:
96.2 g of 2-methoxy-3-(p-chlorobenzoyl)-benzylmalonic acid were heated at 170°-195° C under an argon atmosphere and after the evolution of carbon dioxide gas, the mixture was cooled and added to 1 liter of ether. The acid mixture was extracted several times with 600 ml of a solution of 10% potassium carbonate and 150 ml of water. The combined aqueous phases were acidified with concentrated hydrochloric acid and the acid precipitate formed was extracted with ether. The combined ether phases were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was crystallized from cyclohexane to obtain 56.8 g of 3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionic acid in the form of colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([O:24]CC)=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=[O:23])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2cccc(C#N)c2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.05 g (2.84 mmol) of the compound from Example 11A are provided in 30 ml of tetrahydrofuran, and 0.68 g (28.4 mmol) of lithium hydroxide and 10 ml of water are added at room temperature. The mixture is stirred at room temperature overnight, a 1N aqueous HCl solution is then added until an acidic pH is established, the mixture is extracted with ethyl acetate and the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 0.60 g (62% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[N:17]=[C:13]3[NH:12][C:11]([CH3:25])=[C:10]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:5][CH:4]=1)#[N:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[N:17]=[C:13]3[N:12]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=3)[C:11]([CH3:25])=[C:10]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7][CH:8]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C1=C(C)Nc2nc(NC(=O)C(F)(F)F)nn2C1c1ccc(C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)C(F)(F)F)nn2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
Ethyl 7-(4-cyanophenyl)-5-methyl-2-[(trifluoroacetyl)amino]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (45 mg, 107 μmol) and 3-(trifluoromethyl)phenylboronic acid (61 mg, 321 μmol, 3 eq.) were initially charged together with anhydrous copper(II) acetate (58 mg, 321 μmol, 3 eq.) and molecular sieve (0.1 g, 4 Å) and, under an atmosphere of argon protective gas, suspended in abs. dichloromethane (3 ml). Abs. pyridine (69 μl, 856 μmol, 8 eq.) and triethylamine (45 μl, 321 μmol, 3 eq.) were then added. After 12 h of stirring, more 3-(trifluoromethyl)phenylboronic acid (20 mg, 107 μmol, 1 eq.), anhydrous copper(II) acetate (19 mg, 321 μmol, 1 eq.) and pyridine (35 μl, 428 μmol, 4 eq.) were added, and the mixture was stirred for a further 24 h. The mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethan and methanol and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (10.3 mg, 17% of theory).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([CH2:15]O)[S:12][N:11]=2)=[CH:6][CH:5]=1.P(Br)(Br)[Br:20].O>C1(C)C=CC=CC=1>[Br:20][CH2:15][C:13]1[S:12][N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:18])([F:17])[F:1])=[CH:5][CH:6]=2)[N:14]=1
Reactant: OCc1nc(-c2ccc(OC(F)(F)F)cc2)ns1
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2nsc(CBr)n2)cc1
Temperature: 120 °C
Yield: 90.1 %

Procedure:
To a solution of [3-(4-trifluoromethoxyphenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.10 g, 0.36 mmol) in toluene (5 ml) was added PBr3 (0.050 ml, 0.54 mmol) and the resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.11 g, 89%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1F>>[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: O=C(O)c1ccc2sc(S)nc2c1
Product: O=C(O)c1ccc2sc(Sc3ccc([N+](=O)[O-])cc3Cl)nc2c1

Procedure:
2-(2-chloro-4-nitro-phenylsulfanyl)-benzothiazol-5-carboxylic acid was prepared (66%) from 2-mercapto-benzothiazol-5-carboxylic acid (240) and 2-chloro-1-fluoro-4-nitrobenzene, obtained from Aldrich, in a similar manner as described in example 251.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19]([O:23][C:24]([N:26]1[CH2:28][C@H:27]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:14]([O:13][C:12]([NH:11][C@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:1][CH2:28][C@H:27]([NH:26][C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C[C@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CNC[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1

Procedure:
The product from Example 70C and the product from Example 70A were processed as described in Example 1D to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([CH3:13])[CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([CH3:13])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(Br)c2c(c1)CC(CO)O2
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(Br)c3O2)cc1
Yield: 83.3 %

Procedure:
Treatment of 2-bromo-4-methylphenol (19.09 g, 102 mmol) with potassium carbonate (56.0 g, 400 mmol) and allyl bromide (15.96 g, 130 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-methylphenol. Treatment of 2-allyl-6-bromo-4-methylphenol (5.21 g, 23.0 mmol) with 3-chloroperoxybenzoic acid (9.13 g, 34.50 mmol, 77%) followed by potassium carbonate (7.9 g, 57.5 mmol) generally according to the procedure described for Intermediate 9 afforded 2.14 g (43%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (2.41 g, 10.0 mmol) with p-toluenesulfonyl chloride (2.1 g, 11.0 mol) generally according to the procedure described for Intermediate 10 gave 3.31 g (84%) of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-(7-bromo-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.25 g, 0.63 mmol) and phenylboronic acid (0.23 g, 1.89 mmol) generally according to the procedure described for Intermediate 154 afforded 0.23 g, (93%) of (±)-(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.19 g, 3.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.15 g (97%) of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-methyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.297 g, 1.13 mmol) according to the procedure described in Example 21 afforded 0.106 g (61%) of (±)-[(5-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 227-228° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([CH:17]=[CH2:18])[CH2:9][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1.C(NC1C=CC(S([N:32]=[N+:33]=[N-])(=O)=O)=CC=1)(=O)C.[N-]=[N+]=[N-].C(NC1C=CC(S([NH-])(=O)=O)=CC=1)(=O)C>C(N(CC)CC)C.ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([CH:17]=[CH2:18])[CH2:9][C:10](=[O:16])[C:11](=[N+:32]=[N-:33])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H](CC(=O)CC(=O)OC)c1cccc(F)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: CC(=O)Nc1ccc(S([NH-])(=O)=O)cc1
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C=C[C@H](CC(=O)C(=[N+]=[N-])C(=O)OC)c1cccc(F)c1
Temperature: 21 °C
Reaction time: 9 h

Procedure:
A 50 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, addition funnel, nitrogen inlet, and steam pot, was charged with a solution of methyl (5S)-5-(3-fluorophenyl)-3-oxohept-6-enoate 8 (8823 g of solution, 1300 g of ketoester in 1,2-dichloroethane). Additional 1,2-dichloroethane (7 L) was charged to the flask, followed by 4-acetamidobenzenesulfonyl azide (1.25 kg). The solution was heated from about 18° C. to 21° C. with steam. (Note: the dissolution of azide was endothermic.) Triethylamine (2.17 L) was added over 40 min with water bath cooling to maintain a temperature of 19-23° C. The reaction was stirred at 18-23° C. for approximately 9 h. The reaction was mildly exothermic. The reagent product, 4-acetamidobenzenesulfonyl amide, began to precipitate from the reaction during the addition of triethylamine and eventually formed a thick slurry. The reaction was followed by HPLC and was judged complete when the amount of starting material was <0.5%. When completed, the reaction mixture was filtered, and the cake was washed four times with 1,2-dichloroethane (3×2 L displacement washes, 1×1 L slurry wash). The filtrate and washes were combined and extracted with cold (5-10 C) 2N HCl (7.4 L). The extraction was exothermic and was done in a 50 L extractor with cooling to maintain a temperature of 20-22° C. The pH of the aqueous phase was 1.0. The organic layer was extracted twice with water (2×7 L). The organic extract was charged to a 50 L, 4-necked round bottom flask, equipped with mechanical stirrer, thermocouple, nitrogen inlet, and stopper. The solution was dried for 4 h with sodium sulfate (1 kg). The organic solution was passed through a 5 μ inline filter. The final weight of organic solution was 25.6 kg. Final yield of 9 was >95%.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSC.[C:26]([O:30][C:31](=[O:53])[NH:32][C@H:33]1[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][C:40](=[O:51])[CH:41]=[CH:42][C:43]2[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[C:34]1=[O:52])([CH3:29])([CH3:28])[CH3:27].CO>ClCCl.C1COCC1>[C:26]([O:30][C:31](=[O:53])[NH:32][C@H:33]1[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][C@H:40]([OH:51])[CH:41]=[CH:42][C:43]2[CH:44]=[N:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[C:34]1=[O:52])([CH3:27])([CH3:28])[CH3:29]
Reactant: COc1ccc(C=CC(=O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C=C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of (S)-2-methyl-CBS-oxazaborolidine (4.47 mL, 1M in toluene) in dichloromethane (10 mL) was added a solution of borane-dimethylsulfide (0.45 mL, 10M) and the resulting solution was stirred at ambient temperature for 40 minutes. This solution was added to a stirred solution of 4-4 (580 mg, 1.49 mmol) in THF (15 mL) at −40° C. and the reaction mixture was stirred for 3 hours. Methanol (2 mL) was added and the reaction mixture was concentrated at reduced pressure. The residue was purified by flash column chromatography (silica gel, 2:1 ethyl acetate/hexanes) to give 4-5 as a colorless oil.
Reaction SMILES: C(#N)CC.[OH:5][CH2:6][CH2:7]C#N.[OH:10][CH2:11][CH:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:13]#[N:14]>>[C:6]([O:10][CH2:11][CH:12]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:13]#[N:14])(=[O:5])[CH3:7]
Reactant: N#CC(CO)c1ccc(Cl)cc1
Reactant: N#CCCO
Solvent: CCC#N
Product: CC(=O)OCC(C#N)c1ccc(Cl)cc1

Procedure:
This ester was prepared using the procedure described in Example 5, except 3-hydroxy-2-4-chlorophenyl)propanenitrile was used in place of 2-2-chloro-5-difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 3-hydroxy-2-(4-chlorophenyl)propanenitrile is described in Example 15. The recovered ester product was a colorless oil (79% yield).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[C:19]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][S:31]([CH3:33])=[O:32])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:54])C=1.S([O-])(O)=O.[Na+]>ClCCl>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:42])([CH3:43])[C:14]([N:16]([C:18]2[C:19]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][CH:27]([CH2:30][S:31]([CH3:33])(=[O:54])=[O:32])[CH2:28][CH2:29]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(CS(C)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CCC(CS(C)(=O)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
To a solution of 0.22 g (0.33 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-methanesulfinylmethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 5 ml dichloromethane were added 142 mg (70%, 0.58 mmol) 3-chloroperbenzoic acid at 0° C. After completed addition, the reaction mixture was allowed to warm to room temperature and stirred over night. An aqueous solution of sodium hydrogensulfite was added and the mixture was stirred for 10 min. Basification with 1 N aqueous sodium hydroxide solution was followed by extraction with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.13 g (55%) of the title compound as a white solid.