Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:8]=1)(=O)=O.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:6][C:7]2[N:8]=[C:9]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][CH:12]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COS(C)(=O)=O)n1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(Cc2cccc(NC(=O)OC(C)(C)C)n2)CC1
Reaction time: 16 h

Procedure:
To a solution {6-[(tert-butoxycarbonyl)amino]pyridin-2-yl}methyl methanesulfonate (156 mg, 0.518 mmol) in acetonitrile (2.5 mL) was added N-methyl piperazine (103 mg, 1.03 mmol) and potassium carbonate (214 mg, 1.55 mmol) at room temperature. After 16 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate, partially concentrated under reduced pressure, and then diluted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl {6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}carbamate that was used without further purification. MS ESI calc'd for C16H27N4O2 [M+H]+ 307. found 307.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1>CCO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)c1ccc(C=C2CCN(C)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1ccc(CC2CCN(C)CC2)cc1
Reaction time: 2 h
Yield: 105.2 %

Procedure:
1-[4-(1-methyl-piperidin-4-ylidenemethyl)-phenyl]-ethanone (401 mg, 1.75 mmol) was dissolved in EtOH (20 ml) and 5% Pd/C (40 mg) was added to the resulting solution. The mixture was hydrogenated in a Parr apparatus at 40 psi for 2 h. The catalyst was then filtered and the solvent was removed in vacuo. The residue was taken up with DCM and treated with HCl/Et2O until reaching a pH value of 1. The solvent was removed in vacuo to give an oil which was allowed to crystallize. The solid was triturated in Et2O and filtered to obtain 426 mg of 1-[4-(1-methyl-piperidin-4-ylmethyl)-phenyl]-ethanone as its hydrochloride salt.
Reaction SMILES: [C:1]([O:18][CH2:19][CH:20]([CH2:22][OH:23])[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>ClCCl>[C:1]([O:18][CH2:19][CH:20]([CH2:22][O:23][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
1-palmitoyl-glycerol (33.0 g), dichloromethane (330 ml) and imidazole (13.6 g) were added into 1 L reactor, and the reaction mixture was cooled to 0° C. Then, t-butyl-dimethylsilylchloride (18.0 g) was added, and the reaction mixture was stirred for 2 hours. After filtering the reaction mixture, the solvent was removed by distillation under reduced pressure, and purified water (165 ml) and heptane (150 ml) were added for an extraction. The separated organic layer was extracted with purified water (80 ml) again, and then the organic layer was dehydrated with anhydrous MgSO4, and filtered. Then, the solvent was removed by distillation under reduced pressure to obtain 1-palmitoyl-3-t-butyldimethylsilyl-glycerol (yield: 100%) {1H NMR (400 MHz, CDCl3): δ 0.78-0.83 (m, 18H), 1.18-1.31 (m, 24H), 1.50-1.56 (m, 2H), 2.24 (t, 2H), 3.51-3.60 (m, 2H), 3.76-3.79 (p, 1H), 4.01-4.10 (m, 2H)}.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32](/[C:37](/[C:45]2[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][CH:46]=2)=[CH:38]/[C@H:39]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40]2)=[N:33][C:34]=1[O:35][CH3:36]>C(Cl)(Cl)Cl.CN(C)C=O.C(N(CC)CC)C>[Cl:28][C:29]1[CH:30]=[CH:31][C:32](/[C:37](/[C:45]2[CH:46]=[CH:47][C:48]([C:49]([N:3]([CH3:4])[CH3:2])=[O:50])=[CH:52][CH:53]=2)=[CH:38]/[C@H:39]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40]2)=[N:33][C:34]=1[O:35][CH3:36]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(=O)O)cc2)ccc1Cl
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(=O)N(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
Dimethylamine hydrochloride (43 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (121 mg), 1-hydroxybenzotriazole monohydrate (97 mg) and triethylamine were added to a mixed solution of 4-{(E)-1-(5-chloro-6-methoxypyridin-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}benzoic acid (131 mg) in chloroform and N,N-dimethylformamide (4 mL, 3:1), and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated and the resulting residue was purified by silica gel chromatography (chloroform:methanol=100:0→80:20) to give 4-{(E)-1-(5-chloro-6-methoxypyridin-2-yl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-N,N-dimethylbenzamide as a brown oil (139 mg, 99%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].O1CCCC1>O>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cc2c(N3CCN(C)CC3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3[nH]c(C(=O)O)cc23)CC1
Yield: 48.6 %

Procedure:
A solution of 1-(2-(ethoxycarbonyl)-1H-indol-4-yl)-4-methylpiperazine (0.91 g, 3.17 mmol), lithium hydroxide hydrate (0.136 g, 3.17 mmol, 1.0 equivalent), tetrahydrofuran (20 mL), and water (4 mL) was heated at reflux under nitrogen for 16 hours. The resulting reaction mixture was evaporated under reduced pressure, and the residue was chromatographed using silica gel (approximately 30 g) and elution with methylene chloride/methanol/ammonium hydroxide [3:2:0.2] to afford the title compound (0.40 g, 1.54 mmol, 49%) as a white solid: mp, 272-273° C.; R, =0.05 in methylene chloride/methanol/ammonium hydroxide [5:1:0.1]; 13C NMR (D2O) δ169.4, 145.0, 137.5, 132.9, 124.7, 120.7, 108.2, 107.3, 103.7, 58.7, 53.7, 51.0; LRMS (m/z, relative intensity) 260 (18), 259 (M+, 100), 244 (9), 215 (7), 170 (24); HRMS calculated for C14H17N3O2 259.1322, found 259.1325.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[F:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:18]#[N:19])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccc(C#N)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (69 mg, 86%), MS (ISP) m/z=320.5 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3-cyano-phenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].N1C=CC=C[CH:22]=1>>[CH3:22][S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1]
Reactant: c1ccncc1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Product: CSC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O

Procedure:
When glutathione was complexed with Cr(II), no measurable oxidation of the Cr(II) was observed until the appropriate pyridine derivative was added to the complex mixture. At this time, the 280 nm-340 nm charge transfer peak also appeared. At no time were the 450 nm and 585 nm peaks attributable to Cr--S observed. Replacing glutathione with S-methylglutathione gave identical results.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[Cl:17]Cl>C1C(Cl)=CC=C(Cl)C=1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([Cl:17])=[O:10]
Reactant: ClCl
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccc(Cl)cc1
Product: Cc1nn(C)c(Cl)c1C(=O)Cl
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of 48 g of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde in 195 ml of dichlorobenzene under protective gas are added 39.8 g of sodium carbonate. Subsequently, while illuminating with a mercury lamp, 24 g of chlorine gas are introduced at 20° C. within 3.5 hours. After the gas introduction has ended, the reaction solution is stirred with illumination at 20° C. for a further 20 minutes. The solid is filtered off and washed with a little dichlorobenzene. After the solvent has been removed, 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride is obtained in a yield of 87%.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([S:16]([O:9][C:3]2[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=c1cccccc1O
Solvent: c1ccncc1
Product: O=c1cccccc1OS(=O)(=O)c1ccccc1
Yield: 76 %

Procedure:
2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted with benzenesulfonyl chloride (0.63 mL, 4.9 mmol) in 5 mL of pyridine to afford PZBG-4a in 76% yield (0.33 g, 1.3 mmol). 1H NMR (400 MHz, DMSO) δ=7.95 (d, J=7.6 Hz, 2H), 7.80 (t, J=7.6 Hz, 1H), 7.67 (t, J=8 Hz, 2H), 7.43-7.37 (m, 2H), 7.25 (t, J=8.4 Hz, 1H), 7.14-7.09 (m, 2H). 13C NMR (100 MHz, CDCl3) δ=179.24, 154.79, 141.19, 138.21, 136.37, 136.33, 135.57, 131.96, 130.92, 130.27, 128.76. ESI-MS(+): m/z 262.97 [M+H]+, 279.72 [M+NH4]+, 284.99 [M+Na]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1.[OH-:38].[K+]>O1CCOCC1.[Cl-].[Na+].O.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].CC1C(C)=C(C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)C(P(C(C)(C)C)C(C)(C)C)=C(C)C=1C>[OH:38][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]([CH:27]([CH3:29])[CH3:28])[C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:14]=[N:15][CH:16]=3)=[CH:9][N:8]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Reactant: [OH-]
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 100 °C
Yield: 93.1 %

Procedure:
To a nitrogen gas purged microwave vial of 2-(5-(5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide 2-1a (800 mg, 1.439 mmol), 2-DI-T-BUTYLPHOSPHINO-3,4,5,6-TETRAMETHYL-2′,4′,6′-TRI-I-PROPYLBIPHENYL (55.3 mg, 0.115 mmol) and Pd2 dba3 (26.3 mg, 0.029 mmol) in Dioxane (6 ml) was added 1 M KOH (4.32 ml, 4.32 mmol). The reaction mixture was sealed and heated in an oil bath at 100° C. for 18 h. The reaction was cooled, diluted with brine and product extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered and concentrated to an oil. The oil was diluted with diethyl ether (18 ml) and sonicated. The resulting solid was filtered and washed with ether to give 720 mg white solid, 2-1b.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[F:16])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41]O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][O:15][C:8]2[CH:9]=[C:10]([O:12][CH2:13][CH3:14])[CH:11]=[C:6]([CH:5]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[C:4]([O:3][CH2:1][CH3:2])=[O:26])[C:7]=2[F:16])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1F

Procedure:
In analogy to example 1.5, (RS)-(4-cyano-phenylamino)-(5-ethoxy-2-fluoro-3-hydroxy-phenyl)-acetic acid ethyl ester described in example 1.4 was reacted with 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester, diethyl azodicarboxylate and triphenylphosphine to give (RS)-4-(2-{3-[(4-cyano-phenylamino)-ethoxycarbonyl-methyl]-5-ethoxy-2-fluoro-phenoxy}-ethyl)-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid. MS: 570.2 ([M+H]+).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[CH2:9]([O:11][C:12](=[O:38])[CH2:13][C:14]1[CH:15]=[C:16]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)[CH3:10].ICCC.[Cl-].[NH4+]>C1COCC1>[CH2:9]([O:11][C:12](=[O:38])[CH:13]([C:14]1[CH:15]=[C:16]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=1)[CH2:2][CH2:3][CH3:4])[CH3:10]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCC(C(=O)OCC)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of LDA (4.5 mL of 1.8 M in THF, 8 mmol) was added dropwise to a stirred solution of (5-Benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (3 g, 7.3 mmol) in THF (50 mL) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C. before iodopropane (0.85 mL, 8.7 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. A saturated aqueous solution of ammonium chloride (10 mL) was carefully added and the residue was partitioned between EtOAc and water. The aqueous layers were extracted with EtOAc (×3). The combined organic layers were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 2-(5-Benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (2.2 g) as an oil in 66% yield.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.[CH3:29][N:30]([CH3:37])[CH2:31][CH2:32][CH2:33][C:34](O)=[O:35]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]([C:34](=[O:35])[CH2:33][CH2:32][CH2:31][N:30]([CH3:37])[CH3:29])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Reactant: CN(C)CCCC(=O)O
Product: CN(C)CCCC(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1

Procedure:
The title compound was prepared from N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide and 4-(dimethylamino)butanoic acid following the procedure of Example 110 Step 1. LC-MS Method 1 tR=2.4 min, m/z=493.38; 1HNMR (CD3OD) δ=1.55-1.73 (m, 4H), 1.80-1.94 (m, 8H), 1.95-2.10 (m, 8H), 2.66-2.72 (m, 2H), 2.82-2.92 (s, 6H), 3.05-3.19 (m, 2H), 3.19-3.28 (m, 2H), 3.80-3.92 (m, 1H), 3.92 (s, 3H), 3.93-4.04 (m, 1H), 4.72-4.80 (m, 2H), 5.78-5.95 (m, 1H), 7.15-7.30 (m, 3H), 7.40-7.47 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a DMF solution of 4-bromo-2-ethylphenol were added potassium carbonate and benzyl bromide, and the whole was stirred at an oil bath temperature of 60° C. for 30 minutes to obtain benzyl (4-bromo-2-ethylphenyl) ether, which was then treated in a similar manner to the first half of Reference Example 2 to obtain methyl 6-(4-benzyloxy-3-ethylphenyl)pyridine-2-carboxylate. The obtained compound was stirred in a mixed solution of methanol and THF in the presence of 10% palladium/carbon under a hydrogen atmosphere of normal pressure at room temperature for 24 hours and then thus obtained product was dissolved in trifluoroacetic acid. Pentamethylbenzene was added thereto under ice cooling and the whole was stirred at an oil bath temperature of 50° C. for 1 hour and further at room temperature for 4.5 days to obtain methyl 6-(3-ethyl-4-hydroxyphenyl)pyridine-2-carboxylate. The obtained compound was treated with trifluoromethanesulfonic anhydride in pyridine to obtain methyl 6-(3-ethyl-4-trifluoromethanesulfonyloxyphenyl)pyridine-2-carboxylate. Further, to a 1,4-dioxane solution of the ester compound obtained above were added tributylvinyltin, lithium chloride, tetrakis(triphenylphosphine)palladium(0), and 2,6-di-t-butyl-4-methylphenol, and the whole was heated to reflux for 18 hours. Thereafter, tetrakis(triphenylphosphine)palladium(0) was further added thereto, followed by 2 days of heating under reflux. Then, potassium fluoride was added thereto at room temperature and the whole was stirred at room temperature for 2 days to obtain methyl 6-(3-ethyl-4-vinylphenyl)pyridine-2-carboxylate. The compound was treated with a 1M aqueous sodium hydroxide solution in methanol to obtain an objective compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.C([Li])CCC.[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]I>C1COCC1>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: ClCCCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCCCCCCc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a stirred solution of 2,2′-bithiophene (10.0 g, 60.24 mmol) in anhydrous THF (150 ml) was added n-butyllithium (2.5 M in hexanes, 20.0 ml, 50.0 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 1-chloro-6-iodohexane (14.55 g, 50.0 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with sat. aq. NH4Cl, and the reaction mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water, brine, and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica, eluting with petroleum ether, to give 5-(6-chlorohexyl)-2,2′-bithiophene as a white solid (7.73 g, 54%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.14 (d, J=5.3 Hz, 1.3 Hz, 1H, Ar—H), 7.08 (dd, J=3.5 Hz, 1.1 Hz, 1H, Ar—H), 6.97 (m, 2H, Ar—H), 6.66 (d, J=3.5 Hz, 1H, Ar—H), 3.51 (d, J=6.6 Hz, 2H, ClCH2), 2.78 (t, J=7.1 Hz 2H, ArCH2), 1.61-1.81 (m, 4H, CH2), 1.35-1.51 (m, 4H, CH2); MS (m/e): 282 (M+, 2%), 166 (8), 123 (39), 110 (22), 97 (100).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:34])[C:13]2[O:19][C:18]3[C:20]([Cl:30])=[CH:21][C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:32])(=[O:31])[C:14]=2[CH:33]=1)=[O:9].N1C=CC=CC=1>ClCCl>[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]([CH3:34])[C:13]2[O:19][C:18]3[C:20]([Cl:30])=[CH:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([S:1]([CH3:4])(=[O:3])=[O:2])[CH2:28][CH2:29]4)=[CH:23][C:17]=3[CH2:16][S:15](=[O:31])(=[O:32])[C:14]=2[CH:33]=1)=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(S(C)(=O)=O)CC3)cc(Cl)c1O2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Mesyl chloride (0.16 mL, 2.059 mmol) was added to a solution of 4-Chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.687 mmol) in dichloromethane (20 mL) and stirred at 20° C. for 10 min. To this pyridine (0.3 mL, 4.12 mmol) was added and the reaction mixture was stirred further for 5 h. The reaction mixture was washed using aqueous hydrochloric acid 10% (15 mL), water and then brine solution. Solvent was removed and the crude product obtained was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 0.14 g, (38.45%); 1H NMR (DMSO-d6, 300 MHz): δ 2.63 (s, 3H, CH3), 2.90 (s, 3H, CH3), 3.22 (s, 4H, 2CH2); 3.31 (s, 4H, CH2); 3.85 (s, 3H, OCH3); 5.16 (s, 2H, CH2), 7.13 (d, 1H, Ar), 7.18 (s, 1H, Ar), 8.09 (t, 1H, Ar), 8.15 (d, 1H, Ar); MS: m/e (ES+) 515 (M+1); analysis: C21H23ClN2O7S2.H2O requires C, 47.32; H, 4.73; N, 5.26; Cl, 6.65; S, 12.03. found: C, 46.86; H, 4.18; N, 4.96; Cl, 7.11; S, 12.57%.
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:10]1[CH:11]=[CH:12][CH2:13][CH2:14][CH:15]1[O:1][C:2]([CH3:9])([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: C1=COCCC1
Reactant: COC(=O)CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: COC(=O)CC(C)(C)OC1CCC=CO1

Procedure:
In 50 ml of 7 wt. % hydrochloric acid methanol solution was dissolved 1.18 g of β-hydroxyisovaleric acid, and an reaction was allowed to proceed at room temperature overnight. The solvent was removed from the solution as reacted by distillation under a reduced pressure to obtain 1.30 g of crude methyl β-hydroxyisovalerate. The crude methyl β-hydroxyisovalerate was dissolved in diethyl ether, and 0.91 g of 3,4-dihydro-2H-pyran and a catalytic amount of p-toluenesulfonic acid were added thereto. Stirring was continued at room temperature overnight for reaction. The resultant reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water and dried over magnesium sulfate. The solvent was removed from the dried reaction mixture by distillation under a reduced pressure to obtain 1.98 g of crude methyl β-dihydropyranyloxyisovalerate.