Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.[CH3:10][N:11]([Si](C)(C)C)[C:12](=O)[CH3:13].[C:19](Cl)(=[O:37])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][S:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>N1C=CC=CC=1.ClCCl>[C:29]1([C:30]([N:11]2[CH2:12][CH2:13][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:10]2)=[O:31])[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][S:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:37]
Reactant: CC(=O)N(C)[Si](C)(C)C
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: O=C(O)C1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)C1CCN(C(=O)c2ccccc2SSc2ccccc2C(=O)N2CCC(C(=O)O)CC2)CC1
Reaction time: 24 h

Procedure:
Isonipecotic acid (4-piperidinecarboxylic acid) (0.76 g, 6 mmol), N-methyl-N-trimethylsilylacetamide and 3 drops of pyridine were stirred at room temperature for 2 hours. This suspension was added to a filtered solution of 2,2'-dithiobisbenzoyl chloride (1.0 g, 3.0 mmol) in 15 mL of dichloromethane. The solvent was removed after 18 hours and the residue was triturated with 1N HCl. The acid was decanted and the residue was dissolved in acetonitrile. After standing for 24 hours a precipitate formed. The solid was collected and dried to give 0.56 g of the title compound, mp>250° C.;
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:37])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[C:30](=[O:35])[C:29]2=[O:36])[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:8][C:9]1([CH3:37])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[C:30](=[O:35])[C:29]2=[O:36])[CH:23]=1
Reactant: CS(N)(=O)=O
Reactant: CN1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C(=O)C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(C3Nc4ccc(C(=O)NS(C)(=O)=O)cc4CC3(C)C)c2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a suspension of 60% sodium hydride (192 mg, 4.8 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (466 mg, 4.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (200 mg, 1.2 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (51 mg, 20%) as a white solid: LC/MS m/e calcd for C24H28N4O5S (M+H)+: 485.58, observed: 485.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][CH:4]=1.[C:13](Cl)(Cl)=[O:14].C(Cl)(Cl)=S.C1(C)C=CC=CC=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:8]([O:10][C:13](=[O:14])[NH:12][C:6]2=[CH:5][CH:4]=1)=[O:9]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)Cl
Agent: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a mixture of 10.0 g (60.0 mmol) of 5-methoxyanthranilic acid in 80 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene, or thiophosgene in an inert solvent, preferably a hydrocarbon solvent such as toluene, at room temperature. The mixture was stirred overnight at room temperature. This mixture was then concentrated in vacuo to a small volume. This concentrated reaction mixture was filtered through silica and the filter cake was washed with hexane to give 10.99 g (95.2%) of the 5-methoxyisatoic anhydride as an off white solid. MS (Cl mode) m/z 176 (M-18, 100%), 194 (M+H, 71%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][C:26]1[C:30]([NH2:31])=[C:29]([CH3:32])[O:28][N:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:31][C:30]3[C:26]([CH3:25])=[N:27][O:28][C:29]=3[CH3:32])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Cc1noc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1c(Nc2c(C)noc2C)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 740 mg, 2.0 mmol), 3,5-dimethylisoxazol-4-amine (672 mg, 6.0 mmol) and p-toluenesulfonic acid monohydrate (380 mg, 2.0 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was stirred at 130° C. for 16 hr. After cooling, the mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture followed by recrystallization from ethyl acetate/n-hexane to give the title compound (450 mg, 1.0 mmol, 50%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.CC1OC(C)O[CH:11]([CH3:16])O1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:19][CH:11]([N:3]1[C:2](=[O:1])[CH:6]=[C:5]([CH3:7])[O:4]1)[CH3:16]
Reactant: CC1OC(C)OC(C)O1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(O)no1
Solvent: c1ccccc1
Product: Cc1cc(=O)n(C(C)Cl)o1
Reaction time: 1 h

Procedure:
A mixture of 2.97 g of 3-hydroxy-5-methylisoxazole, 1.32 g of paraldehyde, 3 ml of thionyl chloride and 20 ml of benzene was stirred for 1 hour at 40°-50° C. On evaporating off the solvent and excess thionyl chloride, there were obtained 4.97 g of crude, crystalline 2-(1-chloroethyl)-5-methyl-4-isoxazolin-3-one.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(Cl)(Cl)Cl.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH2:29][CH2:30]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccccn2)CC1)CCC3
Yield: 68 %

Procedure:
Method B (75 h at 45° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-pyridinyl)piperazine; yield 68%; fusion point 152°-154° C. (from chloroform and ethanol). Fumarate: method E; yield 96%; fusion point 205°-207° C. (from acetone).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[N:14]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1)=[O:12]>O1CCCC1>[I:1][C:16]1[CH:17]=[C:13]([C:11]([O:10][CH3:9])=[O:12])[N:14]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:25]([CH3:27])[CH3:26])[CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cccn1[Si](C(C)C)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(I)cn1[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.4 %

Procedure:
N-Iodosuccinimide (653 mg, 2.9 mmol) was added to a stirred solution of 2-methoxycarbonyl-1-triisopropylsilylpyrrole (815 g, 2.9 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for two days. The solvent was then removed in vacuo and the oily residue suspended in hexanes (50 mL) with vigorous stirring. The insoluble solid was removed by filtration and the filtrate concentrated in vacuo. Purification of the residue by column chromatography using hexanes gave 3-iodo-5-methoxycarbonyl-1-triisopropylsilylpyrrole (1.044 g, 88%) as a white crystalline solid, mp 81-83° C.: 1H NMR (CDCl3) δ 7.18 (d, 1H, J=1 5 Hz), 7.09 (d, 1H, J=1.5 Hz), 379 (s, 3H), 1.74 (sept, 3H, J=7.6 Hz), 1.11 (d, 18H, J=7.6 Hz).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[OH:27].[CH3:28][C:29]1([N:33]2[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]2)[CH2:32][O:31][CH2:30]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:15][C:16]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[O:27][CH:36]1[CH2:35][CH2:34][N:33]([C:29]2([CH3:28])[CH2:30][O:31][CH2:32]2)[CH2:38][CH2:37]1
Reactant: N#Cc1cc(O)c(Cl)c([N+](=O)[O-])c1
Reactant: CC1(N2CCC(O)CC2)COC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(N2CCC(Oc3cc(C#N)cc([N+](=O)[O-])c3Cl)CC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
DIAD (0.132 mL, 0.638 mmol) was added to a solution of 4-chloro-3-hydroxy-5-nitrobenzonitrile (95 mg, 0.478 mmol), 1-(3-methyloxetan-3-yl)piperidin-4-ol (78 mg, 0.456 mmol) and triphenylphosphine resin (3 mmol/g loading, 560 mg, 2.136 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 1-6% 2 N ammonia in methanol/dichloromethane). 4-chloro-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)-5-nitrobenzonitrile (106 mg) was obtained as a yellow solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH2:46][O:47][CH3:48])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:3][C:4](=[O:7])[O:5][N:41]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH2:46][O:47][CH3:48])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(COC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(COC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of hydroxylammonium chloride (2.6 g), sodium hydrogen carbonate (3.8 g) and dimethyl sulfoxide (18 mL) was stirred at 50° C. for 30 min, 4′-{[1-benzyl-4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.8 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (18 mL), N,N′-carbonyldiimidazole (0.92 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.85 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.4 g, 69%) as a solid.
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:31])[CH:19]=1)[C:12](OCC)=O)=[O:10].C(O)(C)C>CO.O>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:20](=[O:31])[CH:19]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)C(C=O)Cc1ccn(Cc2ccccc2)c(=O)c1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: [Na]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccn(Cc2ccccc2)c(=O)c1
Yield: 36.8 %

Procedure:
To a stirred solution of sodium (2.76 g) in methanol (50 ml) was added nitroguanidine (11.10 g. containing 25% water) and methanol (10 ml). The mixture was refluxed for 45 minutes and then ethyl α-formyl-β-(N-benzyl-2-oxo-4-pyridyl)propionate (25.07 g) in methanol (90 ml) was added over one hour. The reaction mixture was refluxed for 24 hours, cooled and evaporated under reduced pressure to afford an oily residue which was dissolved in water (100 ml). The solution was extracted with chloroform (3×50 ml) and the combined chloroform extracts were washed with water (3×25 ml). The combined aqueous layer and aqueous washings were taken to pH 5 with glacial acetic acid to give an oily solid. Isopropanol (35 ml) was added with warming to cause dissolution, on cooling a solid formed which was collected by filtration, washed with water, washed with isopropanol and recrystallised from water-acetic acid to give white crystals of 2-nitroamino-5-(1-benzyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (10.40 g), m.p. 200°-201° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.[NH2:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:3]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Fc1cc(Br)ccn1
Solvent: O
Solvent: CN(C)C=O
Product: OC(CNc1cc(Br)ccn1)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 82.3 %

Procedure:
A mixture of 4-bromo-2-fluoropyridine (100 mg, 0.57 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (117 mg, 0.57 mmol) and TEA (115 mg, 1.14 mmol) in DMF (5 mL) was stirred at 120° C. under microwave heating for 1 h. Water was added to the mixture which was extracted with DCM. The combined organic layers were concentrated to give the desired compound as a colorless oil (170 mg, Yield 82%) and used directly in the next step. LCMS (m/z): 362.08, 364.08 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]/[CH:12]=[CH:13]/[C:14](=[O:16])[CH3:15].C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@@H]23)C=CC=CC=1.CSC.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]/[CH:12]=[CH:13]/[C@H:14]([OH:16])[CH3:15]
Reactant: CC(=O)/C=C/Sc1ccc2ccccc2c1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: Cc1ccccc1
Product: C[C@@H](O)/C=C/Sc1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
(E)-4-(2-naphthylthio)-3-buten-2-one (228 mg, 1.0 mmol), (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2] oxazaborol (28 mg, 0.1 mmol) and MS4A (500 mg) were dried by a vacuum pump, followed by substituting with an argon gas. Dry toluene (5 ml) and dimethylsulfide (0.22 ml, 3.0 mmol) were added thereto and, after ice cooling, a solution of borane dimethylsulfide complex in toluene (1.07M, 0.65 ml, 0.7 mmol) was dropwise added. After stirring for two hours, an aqueous saturated ammonium chloride solution was added, followed by filtering through a cotton plug.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[C:10]#N)[CH2:3]1.[OH-:20].[Na+].[OH:22]O>C(O)C.O>[CH3:1][N:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[C:10]([OH:22])=[O:20])[CH2:3]1
Reactant: OO
Reactant: [OH-]
Reactant: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2C#N)C1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2C(=O)O)C1
Temperature: 40 °C
Yield: 72.6 %

Procedure:
To a solution of Example 97A (10.9 g, 40.5 mmol) in ethanol (50 mL) and water (15 mL) at 40° C. was added sodium hydroxide (7.5 mL, 142 mmol, 50% aqueous solution), followed by hydrogen peroxide (7.0 mL, 122 mmol, 50% aqueous solution), which was added in 4 portions, each portion one hour apart. The reaction was stirred at 40° C. for 4 more hours. The reaction was monitored by LC/MS. After almost all the nitrile was converted to the amide, sodium hydroxide (6.4 mL, 122 mmol, 50% aqueous solution) was added followed by 10 mL of water. Then the reaction mixture was stirred at 80° C., cooled, concentrated and dissolved in 100 mL of water. The resultant solution was washed with diethyl ether (2×25 mL). The aqueous solution was neutralized to pH 7 with 6N HCl. and then concentrated to dryness. The precipitate was suspended in ethanol/dichloromethane (100 mL, 1:1), heated to 60° C. and filtered. This process was repeated 3 times. The combined filtrates were concentrated and azeotroped with toluene to obtain 8.5 g (80%) of the title compound. MS (ESI+) m/z 290 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:3]([NH:5][C@@H:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15]CC)=[O:14])=[O:8])=[O:4].O[C@H](C(C)(C1C=CC=CC=1)C)C(N[C@@H](C(C)(C)C)C(N(C)[C@@H](C(C)C)/C=C(\C)/C(OCC)=O)=O)=O.O.O.[OH-].[Li+]>CO.O1CCCC1>[OH:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:28])[C:3]([NH:5][C@H:6]([C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([OH:15])=[O:14])=[O:8])[C:23]([CH3:24])([CH3:25])[CH3:26])=[O:4]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](O)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](O)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](O)C(C)(C)c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A 1:1 mixture of ethyl (E,4S)-4-[((2S)-2-{[(2S)-2-hydroxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate and ethyl (E,4S)-4-[((2S)-2-{[(2R)-2-hydroxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (0.34 g, 0.70 mmol, from Reference Example 41) is dissolved in methanol (3.2 mL) and tetrahydrofuran (3.2 mL). To this solution is added water (1.6 mL) and lithium hydroxide monohydrate (64 mg, 1.5 mmol), and the resulting mixture is stirred at 65° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white foam. A sample of this crude material (200 mg) is subjected to HPLC purification (Prodigy OS3 column, acetonitrile/water/TFA) to give (E,4S)-4-[{N-[(2S)-2-hydroxy-3-methyl-3-phenylbutanoyl]-3-methyl-L-valyl}(methyl)amino]-2,5-dimethyl-2-hexenoic acid as a hard white foam, which is crushed into a powder (50 mg). MS (ES+): (M+H)=461.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:17]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:10]([CH3:17])[C:11](=[O:13])[CH3:12])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: CC(=O)N[C@H](C)c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N(C)[C@H](C)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a vial is added N-[(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-acetamide (111 mg, 0.46 mmol) in 3 ml of THF, followed by the addition of 60% NaH (35 mg, 0.92 mmol). Then iodomethane (130 mg, 0.91 mmol) is added. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with DCM, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 103 mg of N-[(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-N-methyl-acetamide.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(OCCc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(OCCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.30 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 2 mL of methanol and 2 mL of tetrahydrofuran containing 0.19 g of methyl 2-(benzamido)-4-(phenethyloxy)benzoate while ice-cooled, and stirred at room temperature for 14 hours and 30 minutes. The solvent was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated, the solvent was evaporated under reduced pressure and the residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=2:1] to obtain 85 mg of 2-(benzamido)-4-(phenethyloxy)benzoic acid as white solid.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:37])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:38][O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46](Br)[CH:47]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:58]N(C)C=O>>[CH2:38]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:4][CH3:5])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:1][CH3:2])=[CH:7][C:8]=2[CH3:21])[CH:47]=1)[CH3:58]
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CN(C)C=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cncc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C4(O)CCCCC4)c(C)c3)cc2C)c1
Temperature: 140 °C
Yield: 91 %

Procedure:
A solution of 1-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-cyclohexanol (Example 36-(3); 0.05 g, 0.0994 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 34.3 mg, 0.14 mmol), tetrakistriphenylphosphine palladium (16.0 mg, 0.0139 mmol) and potassium phosphate (31.7 mg, 0.14 mmol) in N,N-dimethylformamide (0.27 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (47.8 mg, 91%).