Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:13][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCCN
Solvent: CC#N
Product: CCCNCc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 100.8 %

Procedure:
In 15 ml of acetonitrile was dissolved 6.05 g (0.0373 mole) of 6-chloro-3-pyridylmethyl chloride, and under cooling with ice-water and stirring, the solution was added dropwise to a solution of 10.97 g of n-propylamine in 50 ml of acetonitrile. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour and at an external temperature of 50° C. for an additional 1 hour. The acetonitrile was distilled off and the residue was diluted with aqueous sodium hydrogen carbonate solution and extracted with CH2Cl2 (100 ml×3). The extract was dried over MgSO4 and distilled to remove CH2Cl2, whereby 6.94 g of N-(6-chloro-3-pyridylmethyl)-N-n-propylamine was obtained as a yellow-brown oil.
Reaction SMILES: N=[CH:2][C:3](=[O:21])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:6]1=[O:20].CC1(C)O[O:24]1>CC(C)=O>[O:21]=[C:3]([CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:6]1=[O:20])[CH:2]=[O:24]
Reactant: CC1(C)OO1
Reactant: N=CC(=O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Solvent: CC(C)=O
Product: O=CC(=O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-(3-imino-2-oxopropyl)-3-pyridin-2-yl-1,3-dihydro-2H-benzimidazol-2-one from Step A (54 mg, 0.19 mmol) in acetone (2 mL) at 0° C. was added a solution of dimethyldioxirane (0.02 M in acetone, 9.6 mL, 0.19 mmol). The reaction mixture was stirred for 90 min then concentrated in vacuo to give the title compound in sufficient purity for use in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH2:9])=[CH:4][N:3]=1.[BH4-].[Na+]>C1COCC1.O.C(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH3:17])=[CH:14][CH:15]=2)[CH3:9])=[CH:4][N:3]=1
Reactant: C=C(c1ccc(SC)cc1)c1ccc(F)nc1
Agent: Cl[Ru](Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CSc1ccc(C(C)c2ccc(F)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
2-Fluoro-5-(1-(4-(methylthio)phenyl)vinyl)pyridine (992 mg, 4.04 mmol) was dissolved in THF (12 mL) and water (4 mL) and the flask was cooled in an ice water bath under nitrogen. Then, ruthenium trichloride hydrate (212.4 mg, 0.9422 mmol) was added, and then sodium borohydride (393 mg, 10.4 mmol) was added portionwise over about 5 min. More THF (2 mL) was added, and the reaction was warmed to room temperature and stirred. After 2 hours and 15 minutes, more RuCl3*H2O (214 mg, 0.951 mmol) was added and the flask was again cooled in an ice water bath. Then, more sodium borohydride (384 mg, 10.2 mmol) was added, and the reaction was warmed to room temperature. The stirring was continued. Gas evolution was observed. After 50 min, more sodium borohydride (139 mg, 3.67 mmol) was added, and stirring was continued for 1 h. The reaction was diluted with water (20 mL) and DCM (30 mL). The suspension was filtered through a Celite® (diatomaceous earth) pad, which was washed repeatedly with DCM. The biphasic mixture was treated with saturated sodium bicarbonate (50 mL), and the layers were separated. The aqueous phase was extracted with DCM, and all the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted funnel with about 2 inches of silica gel; DCM) to give 2-fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridine (875 mg). 1H NMR (CDCl3, 400 MHz) δ 8.10 (d, J=1.96 Hz, 1H), 7.56 (td, J=8.07 Hz, 2.64 Hz, 1H), 7.24-7.19 (m, 2H), 7.15-7.09 (m, 2H), 6.84 (dd, J=8.41 Hz, 2.93 Hz, 1H), 4.15 (q, J=7.24 Hz, 1H), 2.47 (s, 3H), 1.64 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 248 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:19])[CH2:10][CH2:9]1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[Cl:31][C:28]1[CH:29]=[CH:30][C:16]([NH:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:17]([CH:27]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccn1)c1cc(Cl)ccc1NCC1CCNCC1
Reaction time: 24 h
Yield: 87 %

Procedure:
A solution of 2-(1-Boc-piperidin-4-ylmethylamino)-5-chloro-N-(2-pyridyl)benzamide (6.1 g, 14 mmol) in trifluoroacetic acid (125 mL) was stirred at 70° C. for 2 h, then at room temperature for 24 h. The solution was concentrated in vacuo, and the residue was directly applied to a silica gel column. Elution with dichloromethane—2 M ammonia in methanol (9:1) afforded 4.2 g (89%) of the pure title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[NH:14][CH:13]=3)[N:9]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]=2[N:6]=[CH:7][N:8]=1.[H-].[Na+].[CH3:35]I>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]([CH3:35])[CH:13]=3)[N:9]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ccc2[nH]cc(-c3cc4c(OC)ncnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(OC)ncnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of 4-methoxy-6-(5-methoxy-1H-indol-3-yl)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [448 mg, Reference Example 5] in dimethylformamide (20 mL) was added the sodium hydride (44 mg, 60% dispersion in oil) and methyl iodide (156 mg) under inert atmosphere. The solution was stirred for 1 hour at room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (30:70, v/v) to give the title compound (260 mg) as an amorphous solid. MS: 464 [MH]+. LCMS (Method B) RT=4.39 minutes.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][CH:14]=1.[Br:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27]>O1CCCC1.O>[Br:22][C:23]1[CH:24]=[C:25]([CH:26]([C:14]2[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:13]=2[CH3:12])[OH:27])[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1csc2ccccc12
Reactant: O=Cc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C(O)c2cccc(Br)c2)sc2ccccc12
Yield: 91.8 %

Procedure:
A solution of 1.56 M hexane (23.7 ml) of n-butyl lithium was added dropwise to a solution of 3-methyl-1-benzothiophene (5.0 g) in tetrahydrofuran (50 ml) at −78° C. under an argon atmosphere, and the mixture was stirred for half an hour at the same temperature. Then, a solution of 3-bromobenzaldehyde (6.05 g) in tetrahydrofuran (6 ml) was added dropwise to the mixture, and the mixture was stirred for half an hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous solution of saturated ammonium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (3-bromophenyl)(3-methyl-1-benzothiene-2-yl) methanol (10.0 g) as achromatic oily matter. Borontrifluoride diethyl ether complex (4.42 ml) and triethylsilane (9.58 ml) were added to a solution of (3-bromophenyl)(3-methyl-1-benzothiene-2-yl) methanol in dichloromethane (100 ml) at −30° C., and the mixture was stirred for half an hours. After the reaction mixture was heated to −10° C. and stirred for 10 minutes, aqueous solution of saturated sodium carbonate was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 2-(3-bromobenzyl)-3-methyl-1-benzothiophene (6.68 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[CH3:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14].CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[CH3:7])=[O:6]
Reactant: O=C=NCCCl
Reactant: Cc1ccncc1N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1NC(=O)NCCCl
Temperature: 25 °C
Yield: 86.1 %

Procedure:
1-Chloro-2-isocyanato-ethane (5.91 ml, 69.35 mmol) was added dropwise to a stirred solution of 4-methyl-pyridin-3-ylamine (5 g, 46.23 mmol) in toluene (180 mL) at 0° C. The reaction temperature was maintained at room temperature for 5 hours. The reaction was monitored by TLC (5% MeOH in chloroform). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 8.5 g (86% yield) of 1-(2-chloro-ethyl)-3-(4-methyl-pyridin-3-yl)-urea.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Sn](CCCC)(CCCC)C=C)[CH2:20]CC>CN(C=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>[N+:16]([C:10]1[CH:11]=[C:12]([CH:19]=[CH2:20])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:18])=[O:17]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Yield: 93.5 %

Procedure:
A mixture of Example 68A (2.18 g, 7.08 mmol), Pd(PPh3)4 (1.23 g, 1.06 mmol) and tributyl-vinyl-stannane (2.48 mL, 8.49 mmol) in DMF (200 mL) was heated at 80° C. overnight. The solvent was removed by vacuum pump. The residue was dissolved in acetone (50 mL), and dried with silica gel powder (20 g). 10% ethyl acetate in hexanes (2 L) was used to run flash chromatography to give the title compound (1.69 g, 94%). MS (DCI) m/z 273.03 (M+NH4)+; 1H NMR (500 MHz, CD2Cl2) δ ppm 5.23 (s, 2 H) 5.72 (d, J=17.47 Hz, 1 H) 6.67 (dd, J=17.78, 10.92 Hz, 1 H) 7.12 (d, J=8.73 Hz, 1 H) 7.35 (m, 1 H) 7.38–7.43 (m, 2 H) 7.44–7.48 (m, 2 H) 7.56 (dd, J=8.73, 2.18 Hz, 1 H) 7.87 (d, J=2.18 Hz, 1 H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH:17]1([CH2:22][CH2:23]CS([O-])(=O)=O)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH2:23][CH2:22][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=S(=O)([O-])CCCC1CCCC1
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cc(I)c(OCCC2CCCC2)c(I)c1
Temperature: 65 °C
Yield: 72.2 %

Procedure:
To a stirred mixture of 2,4,6-triiodophenol (20.36 g, 43.2 mmol) and milled anhydrous potassium carbonate (7.2 g, 52.2 mmol) in 75 ml of dry dimethylformamide was added dropwise over 10 minutes, a solution of 2-cyclopentylethylmethanesulfonate (8.2 g, 42.7 mmol) in 10 ml of dimethylformamide. The mixture was heated at 65° C. under argon overnight and the solvent was then removed under vacuum. The resulting amber residue was partitioned between ethyl acetate (200 ml) and water (30 ml). The aqueous layer was further extracted with ethyl acetate (2×250 ml) and the combined ethyl acetate extracts were treated with decolorizing carbon, dried over magnesium sulfate and passed through a short pad of basic alumina. The filtrate was evaporated under vacuum to give 17.5 g (73%) of the desired product as an amber oil. Title Compound: 1H (300 MHz) and 13C (75 MHz) NMR spectra were consistent with the desired structure. FAB/MS: M+ 568; Calculated for C13H15I3O: C, 27.49; H, 2.66; I, 67.03. Found: C, 27.42; H, 2.62; I, 66.74.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([F:13])[C:11]=1[OH:12])[CH:7]=O)[CH3:2].[C:14]1([C:20](=O)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:29][C:30]([NH2:32])=[O:31].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:32][C:30](=[O:31])[NH:29]2)[CH:9]=[C:10]([F:13])[C:11]=1[OH:12])[CH3:2]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc(F)c1O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(F)c1O
Yield: 8.5 %

Procedure:
The mixture of 3-ethoxy-5-fluoro-4-hydroxybenzaldehyde (Intermediate 32) (160 mg, 0.87 mmol), 1,2-diphenyl-ethanone (170 mg, 0.87 mmol), urea (157 mg, 2.61 mmol), and concentrated HCl solution (0.2 mL) in ethanol (20 mL) was degassed and refluxed for 3 days under N2 protection. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to give Compound 64 (30 mg, 10.6%). 1H NMR (DMSO-d6 300 MHz) δ 9.08 (s, br, 1H), 8.63 (s, 1H), 7.42 (s, 1H), 7.19-7.26 (m, 5H), 7.01-7.03 (m, 3H), 6.72-6.81 (m, 4H), 5.04 (d, J=2.7 Hz, 1H), 3.99 (q, J1=6.9 Hz, J2=9.0 Hz, 2H), 1.33 (t, J=6.9 Hz, 3H); MS (ESI): m/z 405.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([O:13][CH:14]([C:16]#[C:17][CH3:18])[CH3:15])[CH:3]=1.O.Cl>CO.[OH-].[Na+]>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:13][CH:14]([C:16]#[C:17][CH3:18])[CH3:15])[CH:3]=1
Reactant: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)O
Yield: 97 %

Procedure:
To the suspension of methyl 4-amino-5-chloro-2-{(3-pentyn-2-yl)oxy}benzoate (56.0 g) in methanol (1.3 l), aqueous sodium hydroxide (5N) solution (140 ml) was added. The resultant mixture was stirred for 6 hours at 50° C., and then 3 days at room temperature. To the obtained mixture, water (1 l) was added, followed by acidification with 2N hydrochloric acid. Crystal thus precipitated was recovered by filtration, washed with water and dried to obtain 51.5 g of the title compound as colorless crystal.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@@H:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1.[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(SCC(C)C(O)=O)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:16]([S:24][CH2:25][CH:26]([CH3:30])[C:27]([N:3]1[C@H:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Reactant: COC(=O)[C@@H]1Cc2ccccc2CN1
Agent: CC(CSC(=O)c1ccccc1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1Cc2ccccc2CN1C(=O)C(C)CSC(=O)c1ccccc1
Yield: 80.5 %

Procedure:
5.69 g of methyl (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride are suspended in 50 ml of chloroform, and 5.6 g of triethylamine are added thereto under ice-cooling and stirring. 3-benzoylthio-2-methylpropionyl chloride (which is prepared by heating a mixture of 5.6 g of 3-benzoylthio-2-methyl-propionic acid and 6 ml of thionyl chloride at 60° C. for 2 hours, followed by distillation thereof to remove the excess of thionyl chloride) is dissolved in 10 ml of tetrahydrofuran, and said tetrahydrofuran solution is added dropwise to the suspension obtained above. After the mixture is stirred at room temperature overnight, the chloroform layer is collected therefrom and washed with water, an aqueous sodium bicarbonate solution, diluted hydrochloric acid and water, successively. The chloroform solution is dried and then distilled to remove solvent. The residue thus obtained is purified by silica gel column chromatography (Solvent, toluene-ethyl acetate (4:1)). 8.0 g of methyl (3S)-2-(3-benzoylthio-2-methylpropionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate are obtained as colorless oil. Yield: 80.5 %
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH3:7][O:8][CH2:9][CH2:10]Cl.C(N(CC)CC)C>>[CH3:7][O:8][CH2:9][CH2:10][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: COCCCl
Reactant: Cc1ncc[nH]1
Solvent: CCN(CC)CC
Product: COCCn1ccnc1C
Reaction time: 72 h

Procedure:
In an autoclave of 100 mL, 2-methylimidazole (19.2 g, 200 mmol) was made reacted with chloroethyl methyl ether (22.7 g, 240 mmol) at 140 deg C. for 72 hours. Brown liquid that was obtained was washed with 120 mL of a compound liquid of ethanol and ether (volume ratio thereof is 1:5), and then made reacted with triethylamine (20.2 g, 200 mmol) in the autoclave of 100 mL at 130 deg C. for 24 hours. Solid salts that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 20 cm. The obtained product was a transparent liquid which has a boiling point of 160-163 deg C. when a pressure is 10 Pa. 1H-NMR measurement of obtained amine was performed, and it was confirmed that chemical shifts, δ (ppm), are 6.95 (d, 1H), 6.72 (d, 1H), 4.07-4.04 (t, 2H), 3.62-3.60 (t, 2H), 3.27(s, 3H), and 2.29 (s, 3H), and 1-(2-methoxyethyl)-2-methyl imidazole was synthesized.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].[Cl:19][C:20]1[S:21][C:22]([Cl:28])=[CH:23][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1.CCOCC>[C:1]([N:5]([C:25]([C:24]1[CH:23]=[C:22]([Cl:28])[S:21][C:20]=1[Cl:19])=[O:26])[NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Reactant: Cc1ccc(C(=O)NNC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(C(=O)NN(C(=O)c2cc(Cl)sc2Cl)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N'-t-butyl-N-4-methylbenzoylhydrazine (0.7 g) was dissolved in 35 ml toluene. Water (5 ml) and 50% aqueous sodium hydroxide (0.8 g) were added followed by 2,5-dichlorothiophene-3-carbonylchloride (2.0 g). After stirring for 3 hours at room temperature, ether was added and the organic layer separated. Evaporation afforded a solid which was triturated with 10% ether-hexane to afford N'-t-butyl-N-(4-methylbenzoyl)-N'-(2,5-dichlorothiophene-3carbonyl)hydrazine. m.p. 163°-165° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Br:19])=[CH:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][C:14]=3[Br:24])[C:5]2=[N:4][C:3]=1[CH3:25].CO.[OH-].[Na+].Cl>O.O1CCCC1>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Br:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=3[Br:24])[C:5]2=[N:4][C:3]=1[CH3:25]
Reactant: COC(=O)c1cc(Br)c(COc2cccn3c(Br)c(C)nc23)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(Br)cc(C(=O)O)cc3Br)cccn2c1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a mixture of 3-bromo-8-(2,6-dibromo-4-methoxycarbonylbenzyloxy)-2-methylimidazo[1,2-a]pyridine (550 mg), methanol (10 ml) and tetrahydrofuran (5 ml) was added 1N aqueous solution of sodium hydroxide (1.135 ml), and the mixture was stirred for 1 hour at 60° C. The reaction mixture was adjusted pH 4 with 1N hydrochloric acid, and water was added thereto. The precipitate was collected by filtration to give 3-bromo-8-(2,6-dibromo-4-carboxybenzyloxy)-2-methylimidazo[1,2-a]pyridine (518 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:33][CH:34]([CH3:36])[CH3:35])[CH3:32]>>[CH2:31]([N:33]([CH:34]([CH3:36])[CH3:35])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH3:32]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CCNC(C)C
Product: CCN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)C(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and ethyl-isopropyl-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 428.4 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:41]=[CH:40][C:29]([O:30][C:31]([CH3:39])([CH3:38])[CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:28][CH:27]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:27]=[CH:28][C:29]([O:30][C:31]([CH3:39])([CH3:38])[CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:40][CH:41]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CC(C)(CN1CCCC1)Oc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(CN1CCCC1)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 1-(2-(4-bromophenoxy)-2-methylpropyl)pyrrolidine.