Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H:18]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1>CN(C=O)C.[Cu]I>[F:42][C:39]1[CH:40]=[CH:41][C:36](/[C:35](/[CH3:18])=[CH:34]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH:15]([CH3:16])[CH2:14][C:5]2=3)=[CH:37][CH:38]=1
Reactant: Fc1ccc(C=CBr)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)C(C)C2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,3,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (107 mg, 0.5 mmol) was dissolved in DMF. Copper (I) iodide (9.5 mg, 0.05 mmol), L-proline (11.5 mg, 0.1 mmol) and potassium phosphate (414 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(2-bromovinyl)-4-fluorobenzene (107.83 mg, 0.55 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 100° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-7% MeOH-DCM. Yield: 92 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.70 (m, 2H), 7.30 (s, 1H), 7.10 (m, 4H), 6.95 (s, 1H), 4.70 (m, 1H), 4.60 (m, 1H), 3.90 (m, 1H), 3.20 (m, 1H), 2.95 (m, 4H), 2.42 (s, 3H), 1.90 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)#[N:17].[OH-].[Ba+2].[OH-].COCCOC>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:22]2[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=2)[C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2cccc(OCc3ccccc3)c2)c1
Temperature: 80 °C
Yield: 59.9 %

Procedure:
A degassed mixture of 3-benzyloxy-phenyl bromide (28) (0.2 g, 0.76 mmol), 3-cyanophenylboronic acid (0.223 g, 1.52 mmol), barium hydroxide (0.285 g, 1.67 mmol), Pd(PPh3)4 (0.088 g, 0.076 mmol), DME (5 mL) and H2O (3 mL) was heated (80° C.) for 6 hours with vigorous stirring under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a plug of celite. The filtrate was diluted with brine; the organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue obtained was purified by flash column chromatography (20% diethyl ether-hexane) to give 75 (0.130 g, 60% yield) as a viscous liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]3[CH2:15][CH2:16][CH:10]2[CH2:11][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)=[N:7][CH:8]=1)#[N:2].Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:26][NH:25][C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:10]3[CH2:16][CH2:15][CH:14]2[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]3)=[N:7][CH:8]=1)=[NH:2]
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(C#N)cn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(C(=N)NO)cn1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
The product of step b) (7.6 g) is dissolved in 75 ml of ethanol, and a solution of 3.36 g of hydroxylamine hydrochloride dissolved in 38 ml of water is added, followed by addition of 5 g of sodium carbonate. The mixture is stirred at 90° C. for 4 hours. The resulting mixture is cooled and filtered. 8 g of the title compound are obtained in the form of a white solid.
Reaction SMILES: FC1(F)CC[N:5](C(C2C=CC(C(F)(F)F)=CC=2)CN)[CH2:4]C1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:4][NH2:5])=[CH:26][CH:25]=1
Reactant: C1COCCN1
Reactant: NCC(c1ccc(C(F)(F)F)cc1)N1CCC(F)(F)CC1
Reactant: COc1ccc(C=O)cn1
Product: COc1ccc(C(CN)N2CCOCC2)cn1

Procedure:
This compound was prepared using a method analogous to that of 2-(4,4-difluoropiperidin-1-yl)-2-(4-(trifluoromethyl)phenyl)-ethanamine (A.2.18), 6-methoxy-pyridine-3-carboxaldehyde replacing 4-(trifluoromethyl)benzaldehyde and morpholine replacing 4,4-difluoropiperidine HCl.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[F:31])[C:8]([NH:10][C:11]1[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[F:31])[C:8]([NH:10][C:11]1[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])#[N:2]
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(F)c(Br)c2)cc1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(F)c(C#N)c2)cc1
Temperature: 200 °C
Reaction time: 20 h
Yield: 30.7 %

Procedure:
CuCN (606 mg, 6.77 mmol) was dissolved in NMP (25 mL) and the solution was heated to 200° C. for 45 min. To this stirring solution was added N1-(3-bromo-4-fluorobenzoyl)-N2-(4-methoxybenzoyl)-1,2-benzenediamine (700 mg, 2.26 mmol) and stirring continued for 20 h. The solution was then cooled to room temperature, diluted with ethyl acetate and washed once with 1 N ammonium hydroxide, twice with 1 N HCl and once with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The residue was chromatographed with 10% ethyl acetate/dichloromethane to give 270 mg (44%) of off-white solid.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[O:39])=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[O:39])=[CH:34][C:33]=1[C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(Br)o2)c(C)cn1
Reactant: O=Cc1ccc(Cl)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(C=O)ccc3Cl)o2)c(C)cn1
Yield: 83.6 %

Procedure:
To a solution of N-{4-[5-bromo-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.45 g, 0.91 mmol) in 1,4-dioxane (5 mL) was added water (1.2 mL), tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.091 mmol), (2-chloro-5-formylphenyl)boronic acid (0.22 g, 1.19 mmol) and cesium carbonate (0.89 g, 2.74 mmol). The mixture was allowed to stir and subjected to microwave irradiation at 150° C. for 20 min. The mixture was diluted with water and extracted with EtOAc. The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-{4-[5-(2-chloro-5-formylphenyl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.42 g, 83%). LCMS (FA): m/z=552.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]3=[O:19])[CH2:9]2)=[CH:4][CH:3]=1.ClC1C=[CH:25][C:24]([C@H:27]2[C@@:29]3(C4C(=CC=CC=4)N[C:30]3=[O:38])[CH2:28]2)=CC=1.[H-].[Na+].BrCC1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:28][CH:27]4[CH2:29][CH2:30][O:38][CH2:25][CH2:24]4)[C:11]3=[O:19])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Reactant: O=C1Nc2ccccc2C12CC2c1ccc(Cl)cc1
Agent: BrCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CC2CCOCC2)c2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Racemic (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one and (1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one (270 mg, 1.0 mmol, 1.0 equiv.) were added to a stirred solution of sodium hydride (60%, 60 mg, 1.5 mmol) in 5 mL of DMF under argon atmosphere at 0° C. After stirring for 1 hour, 4-bromomethyl-tetrahydropyran (215 mg, 1.2 mmol) was added. The reaction mixture was stirred for 14 hours at room temperature. The crude product was purified by HPLC to give the title compound as a white solid (258 mg, 70%). LC/MS m/e calcd. for C22H22ClNO2: 367, observed (M+H)+: 368.2 1H NMR (400 MHz, MeOD-d4) δppm 1.39-1.55 (m, 2 H) 1.65 (dd, J=13.14, 1.77 Hz, 2 H) 2.11-2.25 (m, 3 H) 3.22 (t, J=8.46 Hz, 1 H) 3.37-3.47 (m, 2 H) 3.79 (d, J=7.33 Hz, 2 H) 3.94-4.04 (m, 2 H) 6.09 (d, J=7.58 Hz, 1 H) 6.76 (t, J=7.58 Hz, 1 H) 7.11 (d, J=7.83 Hz, 1 H) 7.17-7.25 (m, 3 H) 7.33 (d, J=8.34 Hz, 2 H). MS calcd. For C22H22ClNO2 367, obsd. (ESI+) [(M+H)+] 368.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]3[CH:25]([CH2:26][NH:27][CH2:28]3)[S:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:28][CH:29]2[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:23][S:24][CH:25]2[CH2:26]1)=[O:12]
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccccc1CC(=O)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
1.18 g of N,N'-carbonyldiimidazole are added to a solution of 1.16 g of 2-dimethylaminophenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 30 minutes at +5° C. and then a solution of 2.0 g of (4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride and 1.83 cm3 of triethylamine in 20 cm3 of dichloromethane is added. The reaction mixture is stirred for 1 hour at 20° C. and is then washed twice with 50 cm3 of water and dried over magnesium sulphate. The solution is filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2.8 cm, height 26 cm), eluting under a nitrogen pressure of 0.6 bar with a cyclohexane and ethyl acetate mixture of (60/40 by volume) and collecting fractions of 60 cm 3 . Fractions 6 to 20 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) and the residue is crystallized from an acetonitrile and diisopropyl oxide mixture. The crystals are drained and dried. 2.16 g of (4aRS,7aRS)-6-[(2-dimethylaminophenyl)acetyl]-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole are obtained in the form of a white solid; melting point 163° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-:9]>>[C:1]([NH2:2])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: [OH-]
Reactant: N#Cc1cccnc1
Product: NC(=O)c1cccnc1

Procedure:
As to preparative methods for these compounds, cyanopyridines have frequently been hydrolyzed in batch and continuous processes with catalytic to stoichiometric excesses of a base. A majority of the methods reported have been batch processes. For example, 4-cyanopyridine in the presence of sodium hydroxide at a molar ratio of 1:(0.03-0.075) and at 120°-170° C. is reported to give isonicotinamide. See U.S.S.R. SU 1,553,531 (1990); CA:113:78174f (1990). Similarly, 2-cyanopyridine is reported to react with sodium hydroxide at a molar ratio of 1:(0.03-0.20) and at temperatures ranging from 100°-130° C. to give 2-picolinamide. See U.S.S.R. SU 1,553,530 (1990); CA:113:78173e (1990). With a molar ratio of 4-cyanopyridine:sodium hydroxide of 1:(1.5-1.75) and a hydrolysis temperature of 50°-80° C., the reported hydrolysis product was isonicotinic acid. See U.S.S.R. SU 1,288,183; CA:106:176187n (1987). The hydrolysis of 3-cyanopyridine with excess ammonia at 107°-109° C. for 12 hours was reported to give mixtures of nicotinamide and niacin. See J. Am Chem. Soc. 65, at pages 2256-7 (1943). In still another variation, the hydrolysis of 3-cyanopyridine has been reported with a polymeric base, Dowex 1X4 (in the hydroxide form), to yield nicotinamide. See Dutch Patent Application No. 7706612-A; CA:90:186814e. U.S. Pat. No. 4,314,064 describes the continuous hydrolysis of 3-cyanopyridine with 0.3 to 3.0 moles of an alkali metal hydroxide for each 100 moles of cyanopyridine at pressures of between 3 to 20 bars and with heating or cooling to maintain the prescribed reaction temperature. Similarly, 3-cyanopyridine is reported to react in a continuous process with aqueous ammonia at a molar ratio of 1:0.5 and a contact time of 40-50 minutes at 200°-260° C. to give nicotinamide. See Journal of Applied Chemistry of the USSR (English Translation: 45:2716-2718 (1972).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.C[Mg+].[Br-].[Li]CCCC.CCCCCC.[CH:41](=[O:44])[CH2:42][CH3:43]>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][C:4]2[C:3]3[C:2]([CH:41]([OH:44])[CH2:42][CH3:43])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[N:6]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[C:5]=23)=[CH:21][CH:22]=1
Reactant: CCC=O
Reactant: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Agent: C[Mg+]
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
To a solution of (+)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 7A, 700 mg, 1.5 mmol) in THF (15 mL) at −78° C. was added 3M MeMgBr in THF (1.9 mmol) followed by the addition of 1.6M nBuLi in hexane (3.1 mmol). The reaction mixture was stirred at −78° C. for 2 minutes and an excess of propionaldehyde was added. The reaction mixture was stirred at −78° C. for 15 minutes, warmed to r.t and quenched with saturated aqueous NH4Cl The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with EtOAc/hexanes/AcOH (20:30:1) to provide the title compound as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH2:14]Br>>[ClH:11].[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH2:14][N:8]1[CH2:9][CH2:10][C:4]2[CH:3]=[CH:2][S:1][C:5]=2[CH2:6][CH2:7]1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: c1cc2c(s1)CCNCC2
Product: Cl
Product: Clc1cccc(Cl)c1CN1CCc2ccsc2CC1

Procedure:
This compound was prepared analogous to Example 17 from 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine and 2,6-dichlorobenzyl bromide.
Reaction SMILES: [CH2:1]([CH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:9]=2[O:8][C:7]1=[O:23])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-:24].[K+]>CO>[OH:8][C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([OH:23])=[O:24]
Reactant: CCCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: CCCCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1O

Procedure:
3-(n-Pentyl)-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in methanol in a similar manner to that of Example 21-(10) to give 2-[2-hydroxy-3-(o-tolyloxy)phenyl]n-heptanoic acid, mp. 113°-114° C.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([CH2:23][OH:24])([CH2:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])(=[O:5])[CH2:2][CH2:3][CH3:4].OCC(CO)(CO)CO.[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>N1C=CC=CC=1>[C:1]([O:6][CH2:7][C:8]([CH2:23][OH:24])([CH2:16][OH:17])[CH2:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:11]([O:10][CH2:9][C:8]([CH2:23][O:24][C:34](=[O:38])[CH2:35][CH2:36][CH3:37])([CH2:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)OCC(CO)(COC(=O)CCC)COC(=O)CCC
Reactant: CCCC(=O)Cl
Agent: OCC(CO)(CO)CO
Solvent: c1ccncc1
Product: CCCC(=O)OCC(CO)(CO)COC(=O)CCC
Product: CCCC(=O)OCC(COC(=O)CCC)(COC(=O)CCC)COC(=O)CCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 26 %
Yield: 14 %

Procedure:
In this example, pentaerythritol tributyrate, the tributyl ester of pentaerythritol, was synthesized from pentaerythritol and butyryl chloride as follows. To a solution of pentaerythritol (0.99 g, 7.28mmol) in dry pyridine (50 mL, under argon) at 0° C. was added butyryl chloride (2.3 mL, 22 mmol, 3 equiv) dropwise over one hour. The ice bath was removed after one hour, and the reaction stirred 24 hours at room temperature. Water (7 mL) was added and the bulk of pyridine was removed on the rotary evaporator at 2 Torr. The residue was dissolved in 1N HCL (12 mL) and the pentaerythritol esters extracted with CHCl3 (3×20 mL). The combined organic extracts were dried (MGSO4) and concentrated under vacuum to an oil (2.73 g). Purification by flash column chromatography using silica gel afforded the desired triester pentaerythritol tributyrate (1.34 g; 53%) as well as pentaerythritol dibutyrate (0.51 g; 26%) and pentaerythritol tetrabutyrate (0.42 g; 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4](I)[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](B(O)O)[CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:11][C:12]1[CH:17]=[C:16]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH:15]=[CH:14][N:13]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: COc1ccc(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1ccnc(Cl)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 4-chloro-2-iodo-1-methoxybenzene (542 mg, 2.02 mmol), (2-chloropyridin-4-yl)boronic acid (400 mg, 2 mmol), and sodium carbonate (860.2 mg, 8.116 mmol) in 1,4-dioxane (8.4 mL, 110 mmol) and water (2.8 mL, 160 mmol) was sparged 5 minutes with argon. Tetrakis(triphenylphosphine)palladium(0) (139.9 mg, 0.1210 mmol) was added and the reaction vial was capped. The reaction mixture was heated at 90° C. After 3 hours, the reaction mixture was cooled to ambient temperature and poured into water. The mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash chromatography (24 g SiO2, hexanes to 3:1 hexanes-ethyl acetate) to afford the product as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH3:14][C@@H:15]([CH2:18][CH3:19])[CH2:16][NH2:17].Cl[CH2:21][C:22](O)=[O:23]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:17]([CH2:16][C@@H:15]([CH3:14])[CH2:18][CH3:19])[C:22](=[O:23])[CH2:21][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC[C@H](C)CN
Reactant: O=C(O)CCl
Product: CC[C@H](C)CN1C(=O)CSC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with (2S)-2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-((2S)-2-methyl-1-butyl)-l ,3-thiazolidin4-one.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=4[F:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS([C:40]1[CH:45]=CC(N2C=CC(OC3CCN(C(OC4C=CC(Br)=CC=4C)=O)CC3)=CC2=O)=C[CH:41]=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:41][CH2:40][CH3:45])=[CH:29][C:28]=4[F:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1cc(Br)ccc1OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(C(=O)Oc4ccc(Br)cc4F)CC3)cc2=O)cc1
Product: CCCc1ccc(OC(=O)N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)c(F)c1

Procedure:
Example 149 was prepared according to procedures described in Example 148 substituting 4-bromo-2-fluorophenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate for 4-bromo-2-methylphenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate at Step A. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=8.80 Hz, 2H), 7.62 (d, J=8.25 Hz, 2H), 7.32 (d, J=7.70 Hz, 1H), 7.07 (t, J=8.25 Hz, 1H), 6.91-7.00 (m, 2H), 6.31 (d, J=2.47 Hz, 2H), 6.22 (dd, J=7.70, 2.20 Hz, 1H), 4.60-4.72 (m, 1 H), 3.88-3.99 (m, 1H), 3.83 (app brs, 1H), 3.68 (app brs, 1H), 3.57 (app brs, 1H), 3.11 (s, 3H), 2.50-2.61 (m, 2H), 2.11 (app brs, 2H), 1.94 (app brs, 2H), 1.57-1.69 (m, 2H), 0.94 (t, J=7.15 Hz, 3H). MS (EST) 529 (M+H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C(N([Sn:14]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])C(=O)OC)C.[CH2:27]([N:34]=[N+:35]=[N-:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[C:2]([C:1]([O:5][CH3:6])=[O:4])=[C:3]([Sn:14]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH2:25][CH3:26])[N:36]=[N:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N(CC)C(=O)OC
Reactant: C#CC(=O)OC
Reactant: [N-]=[N+]=NCc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2ccccc2)c1C(=O)OC
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Methyl propiolate (5.75 g, 68.4 mmol) was added to methyl ethyl(tributylstannyl)carbamate (26.9 g, 68.6 mmol) in a large sealed tube. The mixture was heated to 70° C. overnight. The mixture was cooled to ambient temperature and the vial was stirred unsealed for 10 minutes. Benzyl azide (10.2 mL, 81.6 mmol) was added, and the vial was resealed and heated to 130° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 508.3 (M+H)+.