Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[OH:21][C@@H:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23](O)=[O:24]>>[CH3:1][O:2][C:3](=[O:20])[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][C:23](=[O:24])[CH:22]([OH:21])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Product: CCCC(NC(=O)C(O)C(C)(C)C)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1

Procedure:
2-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-2-methyl-propionic acid methyl ester was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.1, 26.1, 26.2, 26.3, 35.3, 35.5, 52.6, 53.3, 61.1, 79.6, 106.1, 131.9, 137.5, 169.6, 172.7, 173.1; MS 397.23 m/z (M+1).
Reaction SMILES: B(F)(F)F.P(=O)(O)(O)O.[C:10]1([CH3:17])[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:18]1[CH2:22][CH2:21][CH2:20][CH:19]=1>CCCCC>[CH:18]1([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:17])[C:15]=2[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccccc1O
Reactant: C1=CCCC1
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: CCCCC
Product: Cc1cccc(C2CCCC2)c1O
Temperature: 0 °C
Yield: 29.2 %

Procedure:
170 ml of boron trifluoride/phosphoric acid adduct are added to 1.08 kg (10 moles) of o-cresol in 400 ml of pentane. 680 g (10 moles) of cyclopentene, dissolved in 1 l of pentane, are added dropwise at the reflux temperature in the course of 3 hours. The mixture is stirred for a further hour at the reflux temperature and then poured into ice water. The organic phase is separated off and is extracted with 4 times 600 ml of 10% strength sodium hydroxide solution. The organic phase is dried and evaporated down and the residue is distilled (84°-88° C./0.2 mbar). 515 g of 2-cyclopentyl-6-methylphenol (corresponding to 37% of theory, based on converted cresol) are obtained. 217 g of o-cresol and 282 g of 4-cyclopentyl-2-methylphenol are obtained from the alkaline wash solution after acidification, extraction and distillation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>C1COCC1>[F:12][C:13]([F:23])([F:24])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[O:18]
Reactant: Cc1ccc(N)cc1C(=O)O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a stirring solution of 5-amino-2-methylbenzoic acid (600 mg, 4.0 mmol) in anhydrous THF (25 mL), 3-(trifluoromethyl)benzoyl chloride (910 mg, 4.3 mmol) was added slowly. The mixture was stirred at room temperature under argon for overnight. The solvent was removed under reduced pressure and re-crystallized from acetone to afford the title compound as a white solid (600 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[C:28]([O:30][CH3:31])=[O:29])(=[O:17])=[O:16])=[S:13])[N:4]=1.O([CH3:34])[Na].CO.CI>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12](=[N:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[C:28]([O:30][CH3:31])=[O:29])(=[O:17])=[O:16])[S:13][CH3:34])[N:6]=1
Reactant: COC(=O)c1ccc2ccccc2c1S(=O)(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Reactant: CO[Na]
Solvent: CI
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccccc2c1S(=O)(=O)N=C(Nc1nc(OC)cc(OC)n1)SC

Procedure:
To a suspension of methyl 1-[[(4,6-dimethoxypyrimidin-2-yl)aminothiocarbonyl]aminosulfonyl]-2-naphthalenecarboxylate in 200 ml of anhydrous tetrahydrofuran can be added 16.7 ml of 3 M NaOCH3 /MeOH solution. The resulting reaction mixture can be heated to reflux, 3.1 ml of methyl iodide in 10 ml of anhydrous tetrahydrofuran can be added; and the reaction mixture can be refluxed for 3 hours. The reaction mixture can be cooled to cause the formation of a precipitate which can be filtered off and washed with tetrahydrofuran to afford the desired product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(F)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.148 g, 65%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.3 g, 0.70 mmol) and methylamine (0.22 g, 7.0 mmol). mp 175-178° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].[C:21]([O:25]CC)(=[O:24])[CH:22]=[CH2:23]>C(O)C>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:23][CH2:22][C:21]([OH:25])=[O:24])[CH2:19][CH2:20]2)=[CH:7]1)[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCOCCn1cc(C2CCNCC2)c2ccccc21
Solvent: CCO
Product: CCOCCn1cc(C2CCN(CCC(=O)O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of 0.5 g (1.84 mmol) of 4-[1-(2-ethoxy-ethyl)-indol-3-yl)-piperidine prepared as in Example 152 (part D) in 6 mL of ethyl alcohol, 0.240 g (2.4 mmol) of ethyl acrylate were added. The mixture was refluxed for 18 hours and the solvent was removed under reduced pressure. The residue was extracted between water and ethyl acetate. The crude product obtained after removing the solvent was dissolved with 3 mL of ethyl alcohol and 2 mL of a 2N aqueous sodium hydroxide solution were added. The mixture was stirred at room temperature for 18 hours and then neutralised with HCl 6N. After extraction with chloroform and removal of the solvent, 0.420 g (67%) of a yellow oil were isolated.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH2:28]([S:30]([O-:32])=[O:31])[CH3:29].[Br-].[Mg+2].C([Mg]Br)C.[Br-]>CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[Cu](I)I.CCOC(C)=O>[CH2:28]([S:30]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1)(=[O:32])=[O:31])[CH3:29]
Reactant: CCS(=O)[O-]
Reactant: O=C(NCc1ccc(Br)nc1)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: I[Cu]I
Agent: CC[Mg]Br
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 130 °C

Procedure:
To a microwave tube charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (6-bromopyridin-3-ylmethyl)-amide (80 mg, 0.2 mmol) in DMSO (3 mL) was added magnesium bromide ethanesulfinate salt (122 mg, 0.618 mmol) (prepared by treating the Grignard reagent, ethylmagnesium bromide with SO2) followed by copper iodide (210 mg, 1.1 mmol). The mixture was warmed in a microwave at 130° C. for 1 hour. The reaction was monitored by TLC (EtOAc) indicating a major new more polar product than starting bromide. The reaction was diluted with first saturated aqueous potassium carbonate (5 mL) and then saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (5×10 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3×10 mL), brine (3×10 mL), dried over magnesium sulfate, treated with activated carbon, filtered through diatomaceous earth and concentrated. The solid was dissolved in dichloromethane and purified by silica gel chromatography eluting with EtOAc-dichloromethane (25:75, then 1:1, then 66:34, then 75:25). The material from the column was triturated with ether to afford the title compound as a white solid.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1(=[O:11])[CH2:10][CH2:9][CH:8]=[CH:7]1.[NH4+].[Cl-]>O>[CH2:2]([C:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: [Li]CCCC
Reactant: O=C1C=CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCCCC1(O)CCCC1
Reaction time: 0.03 h
Yield: 97.7 %

Procedure:
nBuLi (1.00 mL; 1.50 mmol; 1.00 equiv) was added to a solution of cyclopentenone (84 mg; 1.0 mmol) in the presence of LaCl3.2LiCl (0.33 M; 3.03 mL, 1.00 mmol, 1.00 equiv) at 0° C. After 2 min, sat. aq. NH4Cl (2 mL) and water (2 mL) was added and the aqueous layer was extracted with ether (4×10 mL). The combined extracts were dried (Na2SO4). Careful evaporation under reduced pressure afforded analytically clean 1-butylcyclopentanol (8) as colorless oil (139 mg, 98%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cccnc1Cl

Procedure:
A mixture of 2-chloronicotinic acid (2-chloro-3-pyridylcarboxylic acid, 4.0 g, 25.4 mmol), oxalyl chloride (2.28 ml, 26.65 mmol) and two drops of DMF are stirred in chloroform (60 ml) for 30 minutes and subsequently refluxed for 45 minutes. The volatiles are distilled under reduced pressure to give crude 2-chloronicotinoyl chloride. This crude product is added to a mixture of diethyl malonate (3.85 ml, 25.38 mmol), magnesium chloride (2.4 g, 25.38 mmol) and triethylamine (7 ml, 50.77 mmol) in acetonitrile (25 ml) with cooling, such that the temperature does not rise above 15° C. After stirring for 24 hours the reaction mixture is diluted with ether and washed repeatedly with 1 M hydrochloric acid and brine. Drying of the organic phase over magnesium sulfate, filtering and evaporation of the solvents gives crude diethyl 2-(2-chloronicotinoyl)-malonate. This crude product is dissolved in DMSO (40 ml) and water (3 ml), and is heated at 140-150° C. for four hours. The mixture is poured onto crushed ice and the product is extracted using ether. Filtering of the ether phase over a pad of silicagel gives 3-acetyl-2-chloropyridine as a yellow oil; 1H-NMR (CDCl3, 300 MHz): 8.50 (dd, 1H); 7.91 (dd, 1H); 7.34 (ddd, 1H); 2.71 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:9])[CH:3]=1.[NH2:25][CH:26]1[CH2:29][N:28]([C:30](=[O:32])[CH3:31])[CH2:27]1>CC(O)C>[C:30]([N:28]1[CH2:29][CH:26]([NH:25][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)=[O:9])[CH:3]=2)[CH2:27]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CC(N)C1
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Solvent: CC(C)O
Product: CC(=O)N1CC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ncn2)C1
Temperature: 60 °C
Yield: 112.7 %

Procedure:
To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (240 g, 0.69 mol) in i-PrOH (2.5 L) was added 1-(3-amino azetidin-1-yl)ethanone (120 g) and TEA (100 g). After addition, the solution was heated at 60° C. for 16 h, at which time LCMS showed completion of the reaction. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 420 g, 90% purity. This crude was further purified on preparative HPLC to give the title compound (330 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 8.27 (s, 1H), 7.12-6.98 (m, 5H), 4.71 (s, 1H), 4.54 (m, 1H), 4.32 (m, 1H), 4.06 (m, 2H), 3.88 (m, 1H), 3.70 (s, 2H), 3.53-3.50 (m, 2H), 2.91-2.83 (m, 4H), 2.65 (m, 2H), 1.88 (s, 3H); LCMS (m/z): 425.2 [M+H]+
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])(=[O:27])=[O:26])[C:15]=1[C:16]([O:18][CH3:19])=[O:17])C1C=CC=CC=1.[Li+].[OH-]>CO.[OH-].[OH-].[Pd+2]>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:25]([NH:24][C:20]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:35])=[O:8])[CH:23]=[CH:22][CH:21]=1)(=[O:27])=[O:26]
Reactant: COC(=O)c1c(/C=C/CCC(=O)OCc2ccccc2)cccc1NS(=O)(=O)c1ccccc1F
Agent: [Pd+2]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1c(CCCCC(=O)O)cccc1NS(=O)(=O)c1ccccc1F
Reaction time: 24 h
Yield: 96.4 %

Procedure:
A solution of Example 510D (9.84 g, 19.77 mmol) in methanol (150 mL) was added to Pd(OH)2 (1.97 g). The suspension was shaken in a reactor pressurized with 60 psi of H2 at 25° C. for 24 hours, filtered, and concentrated. The concentrate was dissolved in 4:1 methanol/H2O (200 mL), treated with LiOH (1.38 g, 57.66 mmol), stirred for 18 hours, quenched with 1N HCl (100 mL), and concentrated. The remaining solution was extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated to provide desired product (7.80 g, 96%). MS (ESI(+)) m/e 427 (M+NH4)+, 432 (M+Na)+; MS (ESI(−)) m/e 408 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 11.97 (br s, 1H), 10.05 (br s, 1H), 7.68 (m, 2H), 7.41 (dd, 1H), 7.31 (t, 2H), 7.15 (d, 1H), 7.02 (d, 1H), 3.66 (s, 3H), 2.53 (m, 2H), 2.17 (m, 2H), 1.44 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1cccs1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4cccs4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.080 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:14][C:15]1([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:18]1[CH2:19][CH2:20][C:15]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)([F:14])[CH2:16][CH2:17]1)=[O:9]
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: CCc1cc(C)c(N)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(C)c(N)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.5 %

Procedure:
A mixture of 5-amino-2-ethyl-4-methylbenzoic acid (compound 48.4, 100 mg, 0.56 mmol, 1.00 equiv), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 140 mg, 0.69 mmol, 1.23 equiv), HBTU (320 mg, 0.84 mmol, 1.51 equiv), and DIEA (150 mg, 1.16 mmol, 2.08 equiv) in DMF (20 mL) was stirred for 48 h at room temperature. Water (30 mL) was added and the resulting mixture was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with PE:EtOAc (1:1) to yield 130 mg (38%) of the title compound as a light yellow solid.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:10]([C:28]1[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:30]([CH3:37])[CH:29]=1)([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:15]([CH3:27])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]>>[CH2:8]([C:10]([C:28]1[S:32][C:31]([S:33]([NH:36][CH2:6][C:5]([OH:4])=[O:7])(=[O:35])=[O:34])=[C:30]([CH3:37])[CH:29]=1)([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([OH:26])[C:22]([CH3:24])([CH3:25])[CH3:23])=[C:15]([CH3:27])[CH:14]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: COC(C)=O
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: [Li+]
Agent: [OH-]
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(=O)(=O)NCC(=O)O)s1

Procedure:
Using LiOH hydrolysis as described in Example 136, (5-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid methyl ester gives the title compound (quant).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[NH4+]>CO.C1COCC1.[Ni]>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCSCC2)nc1
Agent: [Ni]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(N2CCSCC2)nc1
Temperature: 35 °C
Reaction time: 4 h

Procedure:
To the solution of 6-thiomorpholinonicotinonitrile 8-3 (1.0 g, 4.8 mmol) in methanol (15 ml) and THF (9 ml) was added Raney-Nickel (0.7 g) and aqueous ammonium (3 mL). The reaction was stirred under hydrogen balloon at 35° C. for 4 hours. After removing the Raney-Nickel by filtering through celite pad, the filtrate was concentrated to give (6-thiomorpholinopyridin-3-yl)methanamine 8-4 as a light green solid. MS m/z 210.1 (M+1).
Reaction SMILES: CC([O-])(C)C.[Na+].[C:7]1(Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[SH:14][C:15]([CH3:18])([CH3:17])[CH3:16]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:7]1([S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1ccccc1
Reactant: CC(C)(C)S
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
In the drybox, 51.0 mg (0.226 mmol) of (Me2CH)PH(O)(1-NMe2-4-Me—C6H3) from Example 32, 34.0 mg (0.151 mmol) of Pd(OAc)2 and 4.0 ml of toluene were loaded into a reactor (20 ml) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature for 1 h. Next, 216.0 mg (2.25 mmol) of NaOtBu, 314.0 mg (2.0 mmol) of PhBr and 135 mg (1.5 mmol) of HS-t-Bu were added into the mixture above, The resulting mixture was refluxed for 18 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 126 mg (51% yield) of t-butyl phenyl sulfide. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.43-7.42 (m, 2H), 7.22-7.19 (m, 3H), 1.17 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3): δ137.4, 132.7, 128.5, 128.3, 30.9 ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:4]=2[O:3]1.[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[N:6]([CH:21]([CH3:23])[CH3:22])[C:5]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:4]=2[O:3]1
Reactant: CC(C)I
Reactant: COC(=O)c1ccc2c(c1)OC(C)(C)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)OC(C)(C)C(=O)N2C(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 47.9 %

Procedure:
To a solution of 2,2-dimethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (10.8 g) in dimethylformamide (200 ml) were added 60% sodium hydride (in oil) (1.9 g) and 2-iodopropane (7.8 g) and the mixture was stirred at 60° C. for 5 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:5 (v/v)] to give 2,2-dimethyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (6.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:24]=[C:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[C:7]2[C:12]=1[N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:23])[CH2:9][CH2:8]2.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[C:7]2[C:12]=1[N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:23])[CH2:9][CH2:8]2
Reactant: COc1ccc(C=C2SC(=O)NC2=O)c2c1N(Cc1ccc([N+](=O)[O-])cc1)C(=O)CC2
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: Cc1ccccc1
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc([N+](=O)[O-])cc1)C(=O)CC2
Yield: 97.1 %

Procedure:
600 mg of 5-[8-methoxy-1-(4-nitrobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethylidene]thiazolidine-2,4-dione, 415 mg of diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate, and 600 mg of silica gel were added to 20 ml of toluene, followed by heating and refluxing for 14 hours. The solvent was distilled off, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1→1:1). The purified product was recrystallized from an ethyl acetate-ether mixed solvent, giving 585 mg (97% yield) of 5-[8-methoxy-1-(4-nitrobenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [CH2:1]([CH:5]([CH:9]=[CH2:10])[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:19])C=1.O>ClCCl>[CH2:1]([CH:5]([CH:9]1[O:19][CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(CCCC)C(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCCC(C(C)=O)C1CO1
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of 3-butyl-4-penten-2-one (14.0 g) in dichloromethane (100 ml) was added m-chloroperbenzoic acid (26.0 g) at 0° to 5° C., and the mixture was stirred at the same temperature for 1 hour and then at 20° C. for 12 hours. The reaction solution was then poured into water, followed by phase separation. The dichloromethane layer was washed with an aqueous sodium hydrogen carbonate solution and then with an aqueous sodium sulfite solution, followed by concentrating. The residue was distilled to obtain 13.3 g of 3-butyl-4,5-epoxy-pentan-2-one.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[OH:17].[NH3:19]>>[OH:17][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:9][C:4]=1[C:3]([NH2:19])=[O:2]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)ccc1O
Reactant: N
Product: NC(=O)c1cc(-c2ccc(F)cc2)ccc1O

Procedure:
A mixture of 5.3 grams of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate and 20 ml. of liquid ammonia is reacted in a bomb at 100° C. for 4 hours. After cooling the bomb is opened and the ammonia allowed to evaporate. The residue is then recrystallized from benzene to yield 2-hydroxy-5-(4'-fluorophenyl)-benzamide (m.p. 206° - 207° C.).