Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.C([O-])(=O)C.[Na+].[NH2:10][CH2:11][C:12]([OH:14])=[O:13].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1>C1(C)C=CC=CC=1>[N:10]1([CH2:11][C:12]([OH:14])=[O:13])[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: COC1CCC(OC)O1
Reactant: NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)Cn1cccc1
Reaction time: 0.03 h
Yield: 33.6 %

Procedure:
To a 1 liter flask fitted with a condenser, a magnetic stirrer and a nitrogen inlet tube is added acetic acid (glacial, 300 ml) and sodium acetate (32.8g; 0.4 mole). The system is purged with nitrogen and a positive nitrogen pressure is maintained. Then glycine (15.0g; 0.2 mole) is added and the solution is heated to reflux. To the refluxing, clear solution is added 2,5-dimethoxytetrahydrofuran (29 ml, 0.2 mole) over a period of 2 - 3 minutes; refluxing is continued an additional 2 minutes. The reaction mixture is cooled in an ice bath and most of the acetic acid is removed under vacuum. The residue is taken up in water and extracted with four portions of ether. The ether extracts are washed with water, dried over anhydrous magnesium sulfate, filtered and the ether is evaporated to yield a slurry. The slurry is taken up into toluene, filtered through celite and crystallized by cooling to give 8.41g. (33.6%) of the title compound. M.P. 88°-90° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[CH:38]=[CH2:39]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: C=CCOC(=O)Cl
Agent: Cl
Product: C=CCOC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and allyl chloroformate by using the same method as in Example 107.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([CH3:39])[CH:33]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[CH:33][C:34]=3[CH3:39])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: Cc1cc(F)ccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 95.4 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 81, step 2 and 4-fluoro-2-methylaniline (0.044 g, 0.35 mmol), the title compound (0.114 g, 96%) was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2)=[CH2:2].Br[CH:20]([C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([F:32])=[C:29]([Cl:31])[CH:30]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:31][C:29]1[CH:30]=[C:25]([CH:20]([C:21]([F:24])([F:23])[F:22])/[CH:2]=[CH:1]/[C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]3)[CH:26]=[C:27]([Cl:33])[C:28]=1[F:32]
Reactant: C=Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Reactant: Fc1c(Cl)cc(C(Br)C(F)(F)F)cc1Cl
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)OC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 150 °C

Procedure:
To a stirred solution of tert-butyl 5-vinyl-1H-indole-1-carboxylate (0.65 g, 2.67 mmol), in 1,2-dichlorobenzene (10.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (1.74 g, 5.37 mmol), CuCl (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg, 1.07 mmol). The resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% EtOAc/petroleum ether) to afford the title compound as a light brown gummy material (0.25 g, 10%): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 1.65 (s, 9H); ESIMS m/z 485.91 ([M−H]−); IR (thin film) 1165, 854 cm−1.
Reaction SMILES: [CH2:1]([CH:5]1[CH:9](O)[C:8]2[CH:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[CH:13]=[CH:14][C:7]=2[O:6]1)[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Oc2ccc(NC(C)=O)cc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCCCc1cc2cc(NC(C)=O)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of N-(2-butyl-3-hydroxy-2,3-dihydro-5-benzofuranyl)acetamide [9a] (2.50 g, 10.0 mmol), p-toluenesulfonic acid monohydrate (0.19 g, 1.0 mmol) and dichloromethane (30 mL) was stirred for 1 hour at room temperature and passed through short silica gel column. The column was washed with dichloromethane (300 mL). The solvent was evaporated under reduced pressure to give 2.11 g (91.3%) of N-(2-butyl-5-benzofuranyl)acetamide [10a] as off-white crystals with mp 71-73° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[N:13]=[C:14](Cl)[C:15]([CH3:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O-:21].[Na+]>>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[N:13]=[C:14]([O:21][CH3:20])[C:15]([CH3:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn2nc(SCc3ccccc3)nc2nc1Cl
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc2nc(SCc3ccccc3)nn2cc1C
Yield: 64 %

Procedure:
This material was prepared in 64% yield by reaction of 2-benzylthio-5-chloro-6-methyl-1,2,4-triazolo-[1,5-a]pyrimidine with sodium methoxide following the general procedure described in Example 22. The desired product was isolated as a solid, m.p. 145°-146° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Br.Cl[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)=[CH:7][CH:6]=1.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(OCC)(=O)C.CC(CC(C)C)=O>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:27][CH2:28][N:29]([CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([C:11]4[N:12]=[C:13]([NH2:16])[S:14][CH:15]=4)=[CH:7][CH:6]=3)[CH2:30][CH2:31]2)=[N:18]1
Reactant: Nc1nc(-c2ccc(CCCl)cc2)cs1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC(=O)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(-c2ccc(CCN3CCN(c4nsc5ccccc45)CC3)cc2)cs1

Procedure:
To a 50 ml round-bottomed flask equipped with condenser and N2 inlet were added 2.4 g (7.53 mmol) of 4-(4-(2-chloroethyl)phenyl)-2-aminothiazole hydrobromide, 1.65 g (7.53 mmol) of N-(3-benzisothiazolyl) piperazine (prepared according to the method of U.S. Pat. No. 4,411,901), 1.3 ml (7.53 mmol) of diisopropylethylamine, 1.6 g (15.1 mmol) of sodium carbonate, 2 mg of sodium iodide, and 25 ml of methylisobutylketone. The reaction was heated at reflux for 5 days, cooled, evaporated, and taken up in ethyl acetate/water. The ethyl acetate layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate as eluent to give a solid. The solid was taken up in hot ethyl acetate, precipitated by addition of hydrochloride gas, the precipitate filtered, washed with ether, and dried to give a beige solid, 1.536 g (38%), m.p. >300° C. (dec.). NMR (DMSO-d6): 3.2-3.8 (m, 10H), 4.1 (m, 2H), 7.25 (s, 1H), 7.4-8.2 (m, 8H), 11.5 (bs, 2H).
Reaction SMILES: [CH2:1]([NH:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][C:12]=1[C:21]([O:23]C)=[O:22])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C.O>[CH2:1]([NH:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[NH:13][C:12]=1[C:21]([OH:23])=[O:22])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)ccc12)c1ccccc1
Temperature: 60 °C

Procedure:
Dissolve 3-[(phenacyl)amino]-2-carbmethoxy-6-chloroindole (480 mg, 1.46 mmol) in tetrahydrofuran/water (20 mL, 1/1). Add lithium hydroxide monohydrate (316 mg, 2.92 mmol). Seal the flask and warm to 60° C. for 3 hours. Dilute with ethyl acetate/water (50 mL/50 mL) and separate the organic phase. Acidify the aqueous phase and extract with ethyl acetate. Dry (MgSO4) the combined organic phases and concentrate in vacuo. Precipitate with hexane to give the title compound; first crop (289 mg, 63%) and second crop (74 mg, 16%); mp 205°-210° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]#[N:14].[H-].[Na+].[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH3:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:22][CH3:23])[C:13]#[N:14]
Reactant: CCI
Reactant: Cc1ccc(C)c(OCc2ccccc2CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C#N)c1ccccc1COc1cc(C)ccc1C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A solution of 2-[2-(2,5-dimethylphenoxymethyl)phenyl]acetonitrile (2.00 g, 8.0 mmol) in N,N-dimethylformamide (20 ml) was stirred at 0° C. 60% oily sodium hydride (0.38 g, 9.5 mmol) was added thereto, and then ethyl iodide (1.37 g, 8.8 mmol) was added dropwise over 5 minutes. After 1 hour, water was added, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=19/1) to give the desired compound 2-[2-(2,5-dimethylphenoxymethyl)phenyl]butyronitrile (1.91 g, 86%) as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31](N3CCCC(C4CCCCC4)C3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([CH2:5][CH2:1][CH2:2][CH3:3])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N3CCCC(C4CCCCC4)C3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCCCc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-(3-cyclohexyl-piperidino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.65 (Silica gel: methylene chloride/ethanol=9:1)
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[C:8](=[O:24])[CH:7]=1.[Cl:30]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>CC(O)C>[Cl:30][C:7]1[C:8](=[O:24])[N:9]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(C)cn1
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1cc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(C)cn1
Temperature: 60 °C
Yield: 92 %

Procedure:
A mixture of methyl 4-[(2,4-difluorobenzyl)oxy]-5′,6-dimethyl-2-oxo-2H-1,4′-bipyridine-2′-carboxylate (0.15 g, 0.375 mmol), N-chlorosuccinimide (0.06 g, 0.43 mmol) in 2-propanol (3.0 mL) containing dichloroacetic acid (0.05 mL) was heated at 60° C. under nitrogen for 2 h. The reaction mixture was concentrated, and the residue was purified by silica-gel flash chromatography using 4% methanol in ethyl acetate. Appropriate fractions were combined and concentrated under reduced pressure to give 0.15 g of the title compound. ES-MS, m/z=435 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24])[CH2:20][CH2:19]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:18]1([C:21]([C:22]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:3]3[C:4]4[CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:23]=2[CH3:24])=[O:26])[CH2:20][CH2:19]1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCC2
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1C(=O)C1CC1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To a stirred solution of 60 mg (0.24 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 3) in 2 ml acetic acid was added 41 mg (0.32 mmol) of 1-cyclopropyl-butane-1,3-dione (prep. described in the patent DE 94-4404059) and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 27 mg (33%) cyclopropyl-(2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-methanone as a light brown oil. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[C:7]2([CH3:15])[CH3:14])([O-])=O.NN>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[C:7]2([CH3:15])[CH3:14]
Reactant: CC1=Nc2ccc([N+](=O)[O-])cc2C1(C)C
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CC1=Nc2ccc(N)cc2C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To the solution of 5-nitro-2,3,3-trimethylindole (1) (10 g) in EtOH (50 mL), hydrazine (35% in water, 6.72 g) was slowly added. The mixture was allowed to stir at room temperature for 10 min followed by the addition of palladium on carbon (Pd/C) (20% Pd/C, 1.30 g). The resultant suspension was heated at 70° C. for 2 hours, filtered, and concentrated to provide the desired product 2 (8.52 g, 100% yield): ESI-MS, Calculated [M+H]+ 175.1, Found 175.1.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:20]2[O:30][C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[C:9]2[O:19][C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:3][CH:2]=1.[O:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[K]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[O:19]=[C:9]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[C:17]([O:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:18])[C:8](=[CH:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:20]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=1[C:28]([O:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])=[O:30]
Reactant: CC(C)(C)O[K]
Reactant: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1ccccc1NC(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)OC(C)(C)C
Yield: 59 %

Procedure:
The compound 52 (1.0 g, 2.5 mmol) obtained in the same manner as in Example 21 (b) was dissolved in dry benzene (80 ml), treated with KOC(CH3)3 (684 mg, 6.1 mmol), and heated under reflux for 1 hour. After completion of the reaction, the solvent was evaporated and the residue was dried and suspended by adding a small amount of water under ice cooling. The aqueous layer was made neutral with 0.5N.HCl, and the residue was dissolved by adding chloroform. The mixed layer was removed to a separating funnel. After the solid was completely dissolved, water was added to wash the solution so as to make the chloroform layer neutral or weak acidic. The chloroform layer was separated, washed with saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was evaporated to give a white solid. The product was dissolved in chloroform and purified by silica gel column chromatography (developing solvent: benzene:ethyl acetate=4:1) to give the desired compound as white solid (801 mg, crude yield 58%). Recrystallization from the mixed solvent of methanol and water gave white crystals (654 mg, yield, 47%). m.p., 117°-118° C.
Reaction SMILES: C(OCC)C.C([Li])CCC.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:21]([C:20]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:19]=2[Cl:18])[OH:22])[CH:13]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1ccc(Cl)cc1Cl
Temperature: -120 °C
Reaction time: 0.75 h

Procedure:
To a 500 ml 3-neck round bottom flask equipped with an addition funnel, septum, thermometer and an argon inlet was added 150 ml of anhydrous diethyl ether and 94 ml of 1.6 molar butyllithium solution (in hexane). The system was cooled to -120° C. and 14.5 ml of 3-bromopyridine in 75 ml of tetrahydrofuran was added over 1 hour. After addition of the 3-bromopyridine, the system was stirred for an additional 45 minutes. At this time, 26.25 gm of 2,4-dichlorobenzaldehyde in 75 ml of tetrahydrofuran was added to the system while still maintaining at temperatures of -120° C. The system was kept at -120° C. for an additional 6 hours after addition of the 2,4-dichlorobenzaldehyde and afterwards allowed to come to room temperature. After 10 hours at room temperature, the system was quenched with saturated ammonium chloride (in water). The system was then adjusted to a pH 2 with concentrated HCl solution. The solution was extracted with diethyl ether. The aqueous solution was made basic with a 50% NaOH solution. The product was extracted with methylene chloride and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 25.75 gm of the 3-pyridyl-2,4-dichlorophenyl-carbinol as tan solid, m.p. 108°-111° C., and listed as compound number 2 in Table I.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Br:13][C:14]1[C:15]([Cl:21])=[C:16](F)[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[C:15]([Cl:21])=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:17]=[CH:18][CH:19]=1
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: Fc1cccc(Br)c1Cl
Product: CN1CCC(Oc2cccc(Br)c2Cl)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:23]([CH2:24][N:25]([C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH2:26][CH3:27])=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:7]=1)C.[OH-].[Li+]>C1COCC1.O.CCOC(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:30]1([C:28]([N:25]([CH2:24][C:23]2[C:14]([C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:33])=[O:3])[CH:11]=[CH:10][C:9]=3[O:12][CH3:13])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:26][CH3:27])=[O:29])[CH2:32][CH2:31]1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(=O)C2CC2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1cc2ccccc2nc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1
Temperature: 25 °C

Procedure:
(3-{3-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-quinolin-2-yl}-4-methoxy-phenyl)-acetic acid ethyl ester (0.272 g, 0.61 mmol) in THF (5 mL) and H2O (2 mL) was treated with lithium hydroxide (0.090 g, 2.1 mmol) and stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was diluted with EtOAc and H2O, and citric acid was added to acidify the solution. The mixture was extracted with EtOAc, and the combined organic layers were washed with H2O, dried over MgSO4, filtered and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([N:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:29])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][Mg]Br>O1CCCC1.C(OCCCC)CCC>[C:25]([C:23]1[N:24]=[C:19]([CH2:18][N:15]2[CH2:16][CH2:17][N:13]([C@@H:8]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:14]2=[O:29])[CH:20]=[CH:21][CH:22]=1)(=[O:27])[CH3:30]
Reactant: C[Mg]Br
Reactant: COC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of the product from Example 17D (1.95 g, 4.815 mmol) in tetrahydrofuran (50 mL) at −78° C. was treated methylmagnesium bromide in butyl ether (5.7 mL, 1 M). The mixture was stirred 0.5 hours at −78° C., quenched with acetone (3 mL) and 10% citric acid. The reaction mixture was partitioned between ethyl acetate and 1 N NaHCO3, and the organic phase layer was decanted and concentrated. The residue was purified by flash chromatography on silica gel eluting with 25%-50% ethyl acetate in hexane give the title compound (1.6 g, 85% yield).
Reaction SMILES: C1([Li])C=CC=CC=1.[C:8]1([S:14][CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]I)=[CH:23][CH:22]=1>O.O1CCCC1>[C:8]1([S:14][CH2:15][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1ccccc1
Reactant: COc1ccc(CCCCCCI)cc1
Agent: O=C=O
Agent: [Li]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCCCCCCSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenyllithium (378 ml., 0.755 mole) was added over a period of 2-5 minutes to a solution of 94.5 g. of thioanisole in 600 ml. of tetrahydrofuran, stirred under nitrogen. The mixture was stirred at room temperature for about 16 hours, then cooled to -70° C. (solid CO2), and 141 g. of 6-(4-methoxyphenyl)hexyl iodide in 210 ml. of tetrahydrofuran was added slowly. The reaction mixture was stirred at -65° C. for two hours and then allowed to warm to room temperature. Water was added and the mixture extracted with pentane. The pentane extracts were washed with water, dried and concentrated to remove the solvent. The residue was distilled in vacuo, b.p. 171°-174° C. (0.15 mm.). The distillate crystallized and was recrystallized from pentane, to give 7-(4-methoxyphenyl)heptyl phenyl sulfide, m.p. 58°-59° C.