Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:38])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][S:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[O:24][CH2:23]2)[CH:17]([CH:39]([OH:41])[CH3:40])[C:16]3=[O:42])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:47].O>[Pd].O1CCOCC1>[Na+:47].[F:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([CH2:27][CH:25]2[O:24][CH2:23][CH:22]([S:21][C:20]3[CH:19]([CH3:38])[CH:18]4[N:15]([C:16](=[O:42])[CH:17]4[CH:39]([OH:41])[CH3:40])[C:14]=3[C:12]([O-:13])=[O:11])[CH2:26]2)(=[O:30])=[O:29])=[CH:32][CH:33]=1
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CS(=O)(=O)c4ccc(F)cc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(CS(=O)(=O)c4ccc(F)cc4)C3)C(C)C12
Yield: 20.1 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.821 g of product from Example 33, 0.124 g of sodium bicarbonate, 8 ml of water, 20 ml of dioxane, and 0.380 g of 10% palladium/carbon to give 0.135 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[N:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Oc1ccc(Br)nc1
Product: Oc1ccc(-c2ccc(Cl)cc2)nc1
Yield: 73 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 4-chlorophenylboronic acid and 2-bromo-5-hydroxypyridine to afford the title compound as an off-white solid (1.3 g, 73%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22]Br>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([Br:22])[C:10](=[O:14])[CH:9]1[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1Cc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Br)C(=O)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 2-benzyl-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (25.9 g, 0.09 mol) in CHCl3 (200 mL) was added Br2 (15.8 g, 0.099 mol, dissolved into 80 mL of CHCl3) dropwise at 0° C. After the addition, the mixture was stirred at 25° C. for 2 hrs, and then it was filtered. The filtrate was washed with saturated NaHSO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude 2-benzyl-4-bromo-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (18 g) as brown oil, which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>C(COC)OC>[Cl:12][CH2:13][C:14]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]2[CH:16]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Product: FC(F)(F)c1ccc2nc(CCl)cn2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72.1 %

Procedure:
A mixture of 2-amino-5-trifluoromethylpyridine (Fluorochem; 3.19 g), 1,3-dichloroacetone (Aldrich; 3.00 g), and dimethoxyethane (Aldrich; 15 mL) is stirred at room temperature for 4 days. The resulting solid is collected and washed with several milliliters of dimethoxyethane. The solid is then taken up in ethanol (30 mL) and the mixture is heated at 80° C. for 2.5 h, at which time diisopropylethylamine (Aldrich; 3.5 mL) is added. After stirring with heating an additional 3.5 h, the mixture is cooled and the solvent is removed under reduced pressure. The residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are filtered through sodium sulfate and concentrated; the residue is chromatographed on silica gel using methanol/dichloromethane (1/99) to give 3.33 g of 2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine. 1H NMR (CDCl3) δ 4.78, 7.36, 7.69, 7.73, 8.48.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]3[CH2:19][NH:20][CH2:21][CH2:22][N:11]3[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>C(Cl)(Cl)Cl.O1CCCC1>[C:30]([N:20]1[CH2:21][CH2:22][N:11]2[CH2:10][C@@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:18]3[C:13]([C@@H:12]2[CH2:19]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)(=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: c1ccc([C@@H]2CN3CCNC[C@H]3c3ccccc32)cc1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(=O)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a stirred solution of cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride (7.8 g, 0.023 m) and triethylamine (9.4 g, 0.093 m) in chloroform (100 ml) maintained at 0° under nitrogen was added dropwise hexanoyl chloride (4.79 g, 0.0356 m). The mixture was allowed to warm to ambient temperature and stirred for 3 hours, then treated with 10% HCl (25 ml). The layers were separated and the organic phase washed with 10% HCl (2×25 ml), water and dried over MgSO4. Evaporation of the solvent gave an oily residue which was dissolved in tetrahydrofuran and a white solid crystallized which was collected by filtration to give 6.4 g of cis-1,3,4,6,7,11b-hexahydro-2-hexanoyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline, m.p. 163°-164.5°. An additional 3.1 g of good purity product was recovered from the tetrahydrofuran to give a total of 9.5 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:6](=[S:17])[NH:5][C:4](=[O:18])[C:3]=1[N:19]=O>C(O)(=O)C>[NH2:19][C:3]1[C:4](=[O:18])[NH:5][C:6](=[S:17])[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:2]=1[NH2:1]
Reactant: COc1ccc(Cn2c(N)c(N=O)c(=O)[nH]c2=S)cc1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(N)c(N)c(=O)[nH]c2=S)cc1
Yield: 72.7 %

Procedure:
The title compound was prepared according to the general method of Example 14 (c) except that dilute acetic acid was used for neutralization of the reaction mixture. The desired product (0.83 g, 73%) was prepared as a yellow solid starting from 6-amino-1-(4-methoxybenzyl)-5-nitroso-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.2 g, 4.1 mmol).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:7]2.C(Cl)Cl.C1C=CC=CC=1.[Br-].[CH2:28]([O:30][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][Zn+])[CH3:29]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:13]([F:16])([F:15])[C:12]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH2:34][CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])[CH2:7]1)=[O:17]
Reactant: O=C(N1CCc2c(Br)cccc2C1)C(F)(F)F
Reactant: CCOC(=O)CCC[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1cccc2c1CCN(C(=O)C(F)(F)F)C2
Temperature: 25 °C

Procedure:
A mixture of 1-(5-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (4.0 g, 13 mmol) and Pd(dppf)Cl2.CH2Cl2 (530 mg, 0.65 mmol) was azeotroped with benzene and suspended in 50 mL of dry THF. At room temperature, 4-ethoxy-4-oxobutylzinc bromide (0.5M in THF, 52 mL, 26 mmol) was added dropwise with syringe. The orange suspension became a clear brown solution. The reaction mixture was then refluxed for 1 h. After cooling to room temperature, it was quenched with brine, extracted with EtOAc, washed with 10% HCl and brine, dried over Na2SO4, and evaporated to dryness. Flash chomatography (SiO2, EtOAc/hexane=15:100 to 20:100) gave ethyl 4-(2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)butanoate as a white solid.
Reaction SMILES: CS(I)(C)(C)=O.[CH3:7][C:8]([O-:11])([CH3:10])[CH3:9].[K+].[Br:13][C:14]1[CH:33]=[CH:32][C:17]2[O:18]CC(=O)C3[S:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:23][C:22]=3[C:16]=2[CH:15]=1>ClCCl>[Br:13][C:14]1[CH:33]=[CH:32][C:17]2[O:18][CH2:7][C:8]3([C:10]4[S:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:23][C:22]=4[C:16]=2[CH:15]=1)[CH2:9][O:11]3
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1nc2c(s1)C(=O)COc1ccc(Br)cc1-2
Agent: CS(C)(C)(=O)I
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)C1(COc3ccc(Br)cc3-2)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of S,S-dimethylmethanesulfinyl iodide (1.15 g, 5.23 mmol, 1.60 equiv), t-BuOK (4 mL, 1.20 equiv) in dichloromethane (5 mL) at room temperature After 30 minutes a solution of ethyl 9-bromo-4-oxo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (1.2 g, 3.26 mmol, 1.00 equiv) in dichloromethane (10 mL) was added slowly. The resulting solution was stirred for 5 h at room temperature, quenched with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:19) to give 600 mg (48%) of the titled compound as a off-white solid; LC-MS 382,384[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[Cl:7].[H-].[Na+].Br[CH2:12][C:13]1[S:28][C:16]2[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=2[C:14]=1[C:29]([O:31][CH3:32])=[O:30].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH2:12][C:13]2[S:28][C:16]3[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18](=[O:23])[N:19]([CH3:22])[C:20](=[O:21])[C:15]=3[C:14]=2[C:29]([O:31][CH3:32])=[O:30])[C:6]=1[Cl:7]
Reactant: COC(=O)c1c(CBr)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cn2c(C)nc(Cl)c2Cl)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4,5-Dichloro-2-methylimidazole (1.3 g) in dry tetrahydrofuran (20 ml) was added dropwise to a suspension of sodium hydride (0.34 g, 60%) in dry tetrahydrofuran (20 ml) at room temperature under nitrogen. After 15 min, a solution of the product of step b) (3.35 g) in dry tetrahydrofuran (20 ml) was added dropwise and the reaction was stirred for 3 h at room temperature. The solution was poured into water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica chromatography eluting with a gradient 50-100% ethyl acetate in isohexane to give the sub-title compound as a white solid (2.28 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:34](=[O:35])[CH2:33][O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)CCCCCOc1ccc(NC(=O)COCc2ccccc2)cc1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
To a mixture of 6-(4-aminophenoxy)-hexanoic acid methyl ester 17 (25 g, 105 mmol) and triethylamine (21.4 g, 211.6 mmol) in acetone (200 ml) at 0° C. was added drop-wise benzyloxy acetyl chloride (25 g, 135.5 mmol) followed by stirring at room temp. for 12 hrs. The solids were filtered off, acetone distilled off and water (100 ml) added. Crude 53 was extracted into chloroform, washed with 5% sodium bicarbonate solution (2×100 ml), then water (100 ml), dried over sodium sulphate and distilled. Crude 53 was purified by column chromatography on silica gel using benzene as eluant to get pure 53 (9 g, 22.2%), an off-white powder with a m.p. between 46-49° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:16][CH2:15][C:14]3[C:13]([C:17](=[O:30])[CH:18]([C:28]#[N:29])[C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:20])=[N:12][N:11]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:10]=3[C:8]=2[CH:9]=1)([OH:3])=[O:2].CI.[C:39](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:28]([CH:18]([C:17]([C:13]1[C:14]2[CH2:15][S:16][C:7]3[CH:6]=[CH:5][C:4]([C:1]([O:3][CH3:39])=[O:2])=[CH:9][C:8]=3[C:10]=2[N:11]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:12]=1)=[O:30])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])#[N:29]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccc(C(=O)O)cc1-2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2c(c1)-c1c(c(C(=O)C(C#N)C(=O)Nc3ccccc3)nn1-c1ccccc1)CS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
3-(8-Carboxy-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (0.65 g) dissolved in dimethylformamide (50 ml) is reacted with methyl iodide (0.37 g) in the presence of anhydrous potassium carbonate (0.36 g) under stirring at room temperature for 2 hours. The reaction mixture is diluted with ice water and the precipitate is filtered, dissolved in chloroform and washed with 1N HCl and then with water. Evaporation of the solvent in vacuo gives a residue which is crystallized from CH2Cl2 /methanol to yield 0.48 g of 2-cyano-3-(1,4-dihydro-8-methoxycarbonyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 228°-230° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=1.[H-].[Na+].CI.[C:20](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:20][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2cccnc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, a dimethylformamide (30 ml) solution of 2-(3-pyridyl)indole (3.07 g) was added to dimethylformamide (20 ml) in which 60% sodium hydride (0.76 g) was suspended and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (1.2 ml) was added at 0° C. and the mixture was stirred at room temperature for one hour. The mixture was reacted at 0° C., then a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain 1-methyl-2-(3-pyridyl)indole (1.72 g).
Reaction SMILES: [BH4-].[Na+].CSC.B(F)(F)F.CCOCC.[CH:15]1([CH2:20][CH2:21][C:22](O)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[CH:15]1([CH2:20][CH2:21][CH2:22][OH:23])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)CCC1CCCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CSC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCCC1CCCC1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A 12-liter, 4-necked glass reaction vessel equipped as described in Example 1 was charged with 180 grams (4.75 moles) of sodium borohydride, 4 liters of tetrahydrofuran, 0.485 liter (6.6 moles) of dimethyl sulfide, and 0.74 liter (6.0 moles) of boron trifluoride diethyl etherate at 0°-5°C using essentially the same procedure as described in Example 1. After stirring for a additional 0.5 hour at 20°-25°C, 780 grams (5.5 moles) of 3-cyclopentylpropionic acid was added dropwise over a 3 hour period while maintaining a temperature of 35°-40°C. After standing overnight at room temperature, hydrolysis of the reaction mixture followed by distillation of the crude product gave 613 grams (87.5% yield) of 3-cyclopentyl-1-propanol, bp 93°-95°C at 8 mm, n20D 1.4595.
Reaction SMILES: C1(C)C=CC=CC=1.C([Li])CCC.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[O:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>CCCCCC.O1CCCC1>[OH:26][C:23]1([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Brc1cccnc1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cccnc2)CCOCC1
Yield: 29.9 %

Procedure:
According to Reference Example 8-23, by use of toluene (3.3+1.1 mL), n-butyllithium (a 2.77 mol/L solution in hexane, 1.24 mL, 2.28 mmol), 3-bromopyridine (300 μL, 3.12 mmol), tetrahydrofuran (1.1 mL) and tetrahydropyran-4-one (345 μL, 3.74 mmol), the mixture was stirred and reacted at 0° C. for 2 hours. Then, purification by silica gel column chromatography (chloroform/methanol=19/1) was performed to give 4-hydroxy-4-(pyridin-3-yl)tetrahydropyran (Compound DF) (167 mg, yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([Mg]Cl)[CH2:12][CH2:11][CH2:10]1>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cl[Mg]C1CCC1
Solvent: C1CCOC1
Product: Clc1nccc(C2CCC2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
2,4-Dichloropyrimidine (250 mg, 1.68 mmol) and ferric acetylacetonate (30 mg, 0.08 mmol) were taken up in tetrahydrofuran (3.4 mL) and the reaction was cooled to −78° C. Cyclobutylmagnesium chloride (0.5 M, 3.4 mL, 1.68 mmol) was added dropwise and the mixture was stirred at −78° C. for 30 min. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate. The combined organic fractions were washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-5% ethyl acetate in hexanes) to provide 121 mg (0.72 mmol, 43%) of 2-chloro-4-cyclobutylpyrimidine as a colorless oil. MS ESI: [M+H]+ m/z 169.1.
Reaction SMILES: C(Cl)CCl.C1C=C[C:8]2N(O)N=[N:11][C:9]=2[CH:10]=1.CCN(CC)CC.[C:22]([O:26][C:27]([NH:29][CH:30]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:31]([OH:35])[C:32]([OH:34])=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1(N)CC1>C(Cl)Cl>[CH:9]1([NH:11][C:32](=[O:34])[CH:31]([OH:35])[CH:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:10][CH2:8]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)O
Agent: NC1CC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
EDC (8.3 g, 43.3 mmol), HOBT (6.6 g, 43.1 mmol) and Et3N (7 ml, 50.2 mmol) were added to a mixture of 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutanoic acid (10.6 g, 35.9 mmol) and cyclopropylamine (3.3 ml, 47.6 mmol) in DCM (300 mL) at 5° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. After cooling to 5° C. more cyclopropylamine (2 ml, 28.5 mmol), EDC (5 g, 26.1 mmol), HOBT (4 g, 26.1 mmol) and Et3N (3.5 ml, 25.1 mmol) were added, the mixture was allowed to warm to room temperature and the stirring was continued overnight. DCM (300 mL) was added, followed by washing with 0.5 M aqueous HCl solution, brine and drying with MgSO4. The crude product was recrystallized from methyl-tert-butylether, the crystals obtained were washed with n-pentane and dried providing the title compound (10.2 g, 85%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]([OH:27])([CH3:26])[CH3:25])[N:18]=[C:17]2[CH2:28][CH2:29][CH3:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:27][C:24]([C:19]1[N:18]=[C:17]([CH2:28][CH2:29][CH3:30])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:20]=1[C:21]([OH:23])=[O:22])([CH3:25])[CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 60 %

Procedure:
Into the same device as used in Example 34 were placed 43.5 g (0.10 mole) of ethyl ester of 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid, 13.1 g (0.20 mole) of sodium azide, 31.9 g (0.23 mole) of triethylamine hydrochloride and 206 ml of toluene. Thereafter, the mixture was reacted and treated in the same manner as in Example 34, giving 27.0 g (0.06 mole) of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid (yield 60.0% based on ethyl ester of 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid).
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:26])[C@H:18]([CH:19]=[C:20]([CH3:22])[CH3:21])[C@H:17]1[C:23](Cl)=[O:24].Cl.CCOCC>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:15][C:16]1([CH3:26])[C@H:18]([CH:19]=[C:20]([CH3:21])[CH3:22])[C@H:17]1[C:23]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:24]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2cnc(Oc3ccccc3)s2)C1(C)C
Temperature: 20 °C
Reaction time: 17 h

Procedure:
2.07 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of (1R,3R) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylic acid chloride prepared from 1.68 g of the corresponding acid in 30 ml of benzene and 1.7 ml of pyridine were slowly added thereto at 10° C. The mixture was stirred at 20° C. for 17 hours and was poured into dilute aqueous hydrochloric acid. The decanted aqueous phase was extractedwith ether and the combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 1.9 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3R) 2,2-dimethyl-3-(2-methyl-1-propenyl)-cyclopropane-1-carboxylate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O.Cl>CN(C)C=O.C(OCC)(=O)C>[S:12]1[CH:13]=[CH:14][C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])[CH:16]=[CH:15][C:11]1=2
Reactant: CCNCC
Reactant: ClCCCOCCc1ccc2sccc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)CCCOCCc1ccc2sccc2c1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
In 6 mL of N,N-dimethylformamide is dissolved 0.80 g of 5-[2-(3-chloropropyloxy)ethyl]benzo[b]-thiophene, to which is added 3.2 mL of diethylamine. The mixture is stirred in an ampoule at 100° C. for 10 hours. After cooling, the reaction mixture is introduced into a mixture of water and ethyl acetate, pH is adjusted to 1.0 with 6 mol/L hydrochloric acid, and the aqueous layer is separated. Ethyl acetate is added to the aqueous layer, pH is adjusted to 10.0 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1 to 4:1). Thus, 0.48 g of N-[3-(2-benzo[b]thiophen-5-ylethoxy)propyl]-N,N-diethylamine is obtained as an oily product.