Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH2:20]([O:27][CH2:28][CH2:29]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:11]([O:10][C:8](=[O:9])[C:7]([CH2:29][CH2:28][O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:19])[CH3:12]
Reactant: BrCCOCc1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCOCc1ccccc1)(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.3 %

Procedure:
Sodium hydride (406 mg) was dissolved in dimethylformamide (20 mL) and the solution was cooled to 0° C. To this solution was added phenylmalonic acid diethyl ester (2.0 g), and the mixture was stirred at room temperature for 30 minutes. Bromoethyl benzyl ether (2.0 g) was further added thereto, stirred at 60° C. for 4 hours, and water was added thereto. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water, dried over sodium sulfate and purified by column chromatography on silica gel with ethyl acetate:hexane=1:9 to give the title compound (1.2 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>O.CN(C=O)C>[Br:1][C:2]1[C:3]([C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ncccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ncccc1Br)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round-bottomed flask that had been purged with nitrogen, were added 3-bromopicolinic acid (500 mg, 2.50 mmol), morpholine (259 mg, 3.00 mmol), EDCI (712 mg, 3.70 mmol), HOBT (501 mg, 3.70 mmol), triethylamine (1.0 mL, 7.4 mmol) and DMF (12 mL). The mixture was stirred at rt for 24 h, before diluting with water (100 mL) and extracting with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated bicarbonate (1×50 mL), water (2×50 mL), dried with sodium sulfate, and concentrated to dryness. The crude product was purified by FCC to provide the title compound. MS (ESI): mass calcd. for C10H11BrN2O2, 270.00; m/z found, 271.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.57 (dd, J=4.7, 1.4, 1H), 7.93 (dd, J=8.2, 1.4, 1H), 7.23 (dd, J=8.2, 4.7, 1H), 3.90-3.77 (m, 4H), 3.74-3.62 (m, 2H), 3.30-3.15 (m, 2H).
Reaction SMILES: [C:1]12([O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12]1)[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2.C([N-]C(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:38])(=O)=O)=CC=1.[NH4+].[Cl-]>O1CCCC1>[F:38][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][C:1]2([O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[O:15]2)[CH2:6][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C1CCC2(CC1)Oc1ccccc1O2
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CCC2(CC1)Oc1ccccc1O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 350A (5.25 g) in tetrahydrofuran (40 mL) was added dropwise to a solution of lithium diisopropylamide (12 mL, 2.0M in tetrahydrofuran/heptane/ethylbenzene) at 0° C. The solution was stirred at 0° C. for 30 minutes, and then was transferred by cannula to a pre-cooled (0° C.) stirring solution of N-fluorobenzenesulfonimide (7.89 g) in dry tetrahydrofuran (20 mL). The reaction mixture was stirred at 0° C. for 30 minutes, and then at 20° C. for 18 hours. The reaction mixture was poured over aqueous NH4Cl and extracted with diethyl ether (3×200 mL). The combined organic layers were washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([C:32](Cl)=[O:33])=[CH:24]1.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25]([C:32]([NH:1][C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)=[O:33])=[CH:24]1
Reactant: O=C(Cl)c1csc2ccccc12
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1Nc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)c2csc3ccccc23)cc1Nc1ccc(F)cc1
Reaction time: 2 h

Procedure:
To dichloromethane 3.0 mL solution of tert-butyl 4-amino-2-(4-fluoroanilino)benzoate 40 mg were added triethylamine 0.064 mL, benzothiophene-3-carbonyl chloride 55 mg and dichloromethane 1.5 mL at room temperature, and it was stirred at same temperature for 2 hours. Aminomethylated-polystyrene 250 mg was added to the reaction mixture, and it was stirred at room temperature for 4 hours. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and insoluble matter was filtrated. The organic layer was separated and collected, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 4-(benzothiophene-3-carboxamido)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([N:52]([CH2:61][CH2:62][CH3:63])[CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1)[CH2:50][CH3:51]>CN(C=O)C>[NH:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:58]2[CH2:59][CH2:60][N:55]([CH2:54][CH2:53][N:52]([CH2:61][CH2:62][CH3:63])[CH2:49][CH2:50][CH3:51])[CH2:56][CH2:57]2)=[O:20])=[CH:17][CH:16]=1)[CH2:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: CCCN(CCC)CCN1CCNCC1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)CCN1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
The compound (103.8 mg) obtained in Example 2-2 was dissolved in DMF (3.1 ml) and then added with DCC (68.8 mg) and HOBt (45.0 mg), followed by stirring at room temperature for 10 days. The solution was added with 1-(2-dipropylaminoethyl)piperazine (71.1 mg) and further stirred at the same temperature for 4 days. The reaction solvent was distilled off and the residue was then added with 1 mol/l hydrochloric acid, followed by washing with chloroform. The aqueous layer was adjusted to pH 12 with a 1 mol/l sodium hydroxide aqueous solution and then subjected to separation/extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloride acid, thereby obtaining hydrochloride (52.5 mg) of the subject compound as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[C:17](OC)=[O:18])=[O:6])[CH:2]=[CH2:3].O1CCCC1.[BH4-].[Na+].Cl>C(O)C.C(OCC)(=O)C.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Temperature: -60 °C
Reaction time: 3.5 h
Yield: 88.8 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-methoxycarbonyl-4-methanesulfonyloxypyrrolidine (281 g) in a mixture of ethanol (0.9 () and tetrahydrofuran (0.6 l) was added sodium borohydride (69.2 g) at 5° C. and the resulting mixture was allowed to stir for 3.5 hours at 20°-27° C. After cooling to -60° C., the reaction mixture was taken up into a mixture of 12N hydrochloric acid (152.4 ml), water (2.5 l) and ethyl acetate (2.5 l) at 0° C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 l). The organic layer and the extract were combined, washed with 2 portions of brine (500 ml×2 ), dried over magnesium sulfate and evaporated to give (2S,4R)-1-allyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (226.9 g).
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH2:18][CH2:19]Br.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccccc1
Reactant: CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Yield: 34.7 %

Procedure:
3.0 g (0,014 mol) of 1-benzyl-6-aminouracil are stirred for 3 hours at 70° C. with 2.2 g (0.018 mol) of n-propyl bromide, 4.2 ml of 15% sodium hydroxide solution and 7 ml of ethanol. The mixture is poured onto ice and extracted with methylene chloride. The organic phases are dried and evaporated down. The residual oil is crystallised from a mixture of methylene chloride and methanol. 1.62 g of the title compound are obtained in the form of white crystals (47% of theory), m.p. 189°-192° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][C:26]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:27]
Reactant: O=C(Cl)CCCl
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCl)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
1-(4-Chlorophenyl)piperazine dihydrochloride (1.88 g, 6.973 mmol) was dissolved in methylene chloride and, after slowly adding triethylamine (1.9 mL, 13.946 mmol) at 0° C., stirred for 5 minutes. After adding 3-chloropropionyl chloride (0.67 mL, 6.973 mmol), the reaction solution was stirred at room temperature. After extracting with methylene chloride, the organic layer was dried with desiccant and then filtered. The filtrate was concentrated and purified by column chromatography (EtOAc/hexane, 4:1). A target compound (1.03 g, 3.586 mmol, 51.5%) was yielded as white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClCCl.[CH2:20]([O:22][P:23]([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O:25][CH2:26][CH3:27])=[O:24])[CH3:21]>CN(C)C1C=CN=CC=1.ClC(Cl)C.O>[CH2:26]([O:25][P:23]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:34])=[CH:36][CH:37]=1)([O:22][CH2:20][CH3:21])=[O:24])[CH3:27]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(=O)N2CCc3ccccc32)cc1)OCC
Reaction time: 10 h

Procedure:
1.80 Grams (15 mM) of indoline, 1.82 g (18 mM) of triethylamine and 0.37 g (3 mM) of 4-dimethylaminopyridine were dissolved in 30 ml of dry dichloroethane, to this solution was added dropwise slowly 30 ml of dry dichloromethane solution with 5.21 g (15 mM) of 4-diethoxyphosphinoylmethylbenzoyl chloride at 0° C. with stirring. After the stirring was continued for 10 hours at room temperature, 50 ml of water was added to the reaction mixture and extracted with chloroform. The extracts were dried over anhydrous sodium sulfate, and concentrated. The residue thus obtained was purified by means of a silica gel column chromatography (eluted with chloroform:ethyl acetate=1:1). The crude crystals were recrystallized from benzene-n-hexane to yield 3.90 g of 1-(4-diethoxyphosphinoylmethylbenzoyl)indoline as colorless crystals Melting point 93.0°-94.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH:25]=O)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1.N1C=CC=CC=1.Cl.[NH2:34][OH:35]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([CH:25]=[N:34][OH:35])=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=Cc1ccc2c(c1)ncn2-c1cccc(COCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of compound 12a (220 mg, 0.64 mmol) and pyridine (0.08 mL, 1.5 equiv) in ethanol (2 mL) was added hydroxylamine hydrochloride (500 mg) and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 mL), washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and pet-ether as the eluent to afford compound 14a (180 mg, 78%) as a solid. Mp 154-154.8° C. In analogy herewith, the following compounds were prepared: 1-[3-(1-Methyl-1H-imidazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14b) from 12b. Mp 209.8-211.7° C. and 1-[3-(2-Methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14c) from 12c. Mp 145.8-147.7° C. O-Methyl 1-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14h) from 12c and O-methyl hydroxylamine. LC-ESI-HRMS of [M+H]+ shows 377.1724 Da. Calc. 377.172525 Da, dev. −0.3 ppm 1-[3-(2-Methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14e) from 12e. LC-ESI-HRMS of [M+H]+ shows 362.1603 Da. Calc. 362.161625 Da, dev. −3.7 ppm O-Methyl 1-[3-(2-methyl-2H-pyrazol-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14i) from 12e and O-methyl hydroxyl amine. LC-ESI-HRMS of [M+H]+ shows 376.1755 Da. Calc. 376.177325 Da, dev. −4:9 ppm 1-[3-(1,3-Thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14j) from 12g. LC-ESI-HRMS of [M+H]+ shows 365.1074 Da. Calc. 365.107225 Da, dev. 0.5 ppm O-Methyl 1-[3-(1,3-thiazol-2-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14g) from 12g and O-methyl hydroxylamine. LC-ESI-HRMS of [M+H]+ shows 379.1238 Da. Calc. 379.122825 Da, dev. 2.6 ppm and 1-[3-(Pyridin-3-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14d) 1-[3-(Pyrimidin-4-ylmethoxymethyl)-phenyl]-1H-benzoimidazole-5-carbaldehyde oxime (14f) are prepared likewise.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[NH:21][CH2:22][CH3:23])(=[O:3])[CH3:2].Cl.O.[CH2:26](O)[CH3:27]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:26][CH3:27])=[O:19])[CH:8]=[C:7]2[NH:21][CH2:22][CH3:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(NCC)cc(C(=O)O)nc12
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc2c(NCC)cc(C(=O)OCC)nc12

Procedure:
The product of step (a) in ethanol was saturated with hydrogen chloride gas and, when the heat of solvation subsided, the brown solution was heated to reflux on a steambath for 5 hours. The mixture was cooled and was treated with water, then concentrated and the pH of the mixture was adjusted to about 7 before extracting into ethyl acetate. The extract was washed with water, dried and evaporated to give a yellowish solid (6.2 g; 82%). NMR and mass spectra were consistent with the required structure.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH:11]([CH3:13])[CH3:12])[O:10][CH2:9][CH2:8][O:7]1)C.[BH4-].[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[CH:11]([C:6]1([CH2:5][CH2:4][OH:3])[O:10][CH2:9][CH2:8][O:7]1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)CC1(C(C)C)OCCO1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C1(CCO)OCCO1
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of (2-isopropyl-[1,3]dioxolan-2-yl)-acetic acid ethyl ester (83 g, 0.41 mol) in MeOH (1600 mL) was added NaBH4 (78 g, 2.05 mol) and ZnCl2 (8.3 g). The mixture was stirred overnight. The mixture was concentrated, and the residue was dissolved in the mixture of EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic phase was dried over Na2SO4, and concentrated to give the crude product, which was purified by column to give 2-(2-isopropyl-[1,3]dioxolan-2-yl)-ethanol (30 g, crude).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])=O.[NH:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)[NH2:21]>CN(C)C=O>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([N:20]2[CH2:2][CH2:3][C:4]([C:6]3[CH:15]=[CH:14][C:13]4[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:18])([CH3:19])[C:8]=4[CH:7]=3)=[N:21]2)=[CH:30][CH:29]=1)([OH:28])=[O:27]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(C3=NN(c4ccc(C(=O)O)cc4)CC3)ccc21

Procedure:
2.8 g (10 millimoles) of 6-3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (for preparation see Example 9) and 1.5 g (10 millimoles) of 4-hydrazinobenzoic acid in 40 ml of dimethylformamide was stirred until the reaction was complete (check by thin-layer chromatography). The mixture was poured onto water and the resulting crystals were filtered off under suction and washed with water and ethanol. Drying gave 2.2 g of the title compound of melting point 276°-278° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Cl:49][C:50]1[N:55]=[CH:54][C:53](O)=[CH:52][C:51]=1[CH3:57]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:16][C:53]2[CH:54]=[N:55][C:50]([Cl:49])=[C:51]([CH3:57])[CH:52]=2)[CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:6][CH:5]=1
Reactant: Cc1cc(O)cnc1Cl
Reactant: COC(=O)c1ccc(C(O)CC(C)(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)(C)C)Oc2cnc(Cl)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-3,3-dimethyl-butyl)-benzoic acid methyl ester (450 mg, 1.91 mmol) in toluene (19 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 722 mg, 2.86 mmol) at 0° C., followed by the additions of tributylphosphine (0.71 mL, 2.86 mmol) and 6-chloro-5-methyl-pyridin-3-ol (327 mg, 2.29 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving the titled compound (440 mg).
Reaction SMILES: [ClH:1].C([N:4]1[C:11]2[N:7]([N:8]=[C:9](C3C=CC=C(C(F)(F)F)C=3)[CH:10]=2)[CH:6]=[CH:5]1)C.Cl>O1CCOCC1>[ClH:1].[N:4]1[CH:5]=[CH:6][N:7]2[C:11]=1[CH:10]=[CH:9][NH:8]2
Reactant: CCn1ccn2nc(-c3cccc(C(F)(F)F)c3)cc12
Agent: Cl
Solvent: C1COCCO1
Product: c1cn2[nH]ccc2n1

Procedure:
800 mg of 6-(3-trifluoromethylphenyl)-1H-imidazo-[1,2-b]pyrazole and 5 ml of dimethylformamide were slowly added dropwise at room temperature, whilst stirring, to 76 mg of a 55% w/w suspension of sodium hydride in mineral oil, which was itself suspended in 10 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes at room temperature. 497 mg of ethyl bromide were then added dropwise, whilst cooling with ice water, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then partitioned between ethyl acetate and water. The ethyl acetate layer was washed With water and with an aqueous solution of sodium chloride, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure. The product was then purified by silica gel column chromatography using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to afford the title compound as an oil. The hydrochloride was formed from this oil by adding a 4N solution of hydrogen chloride in dioxane, and this was recrystallized from a mixture of acetone and diethyl ether, to afford 750 mg of 1-ethyl-6-(3-trifluoromethyl-phenyl)-1M-imidazo[1,2-b]pyrazole hydrochloride as pale brown prismatic crystals, melting at 135° to 141° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+].O1CCC[CH2:37]1>>[CH3:37][N:5]([CH2:4][CH2:3][S:2][CH3:1])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: C1CCOC1
Reactant: CSCCNC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: CSCCN(C)C(=O)OC(C)(C)C

Procedure:
To a mixture of tert-butyl 2-(methylsulfanyl)ethylcarbamate (3.5 g) and tetrahydrofuran (20 mL) was added lithium aluminum hydride (1.39 g) with stirring under ice-cooling and the mixture was heated under reflux for 2 hrs. After cooling the reaction mixture, sodium sulfate 10 hydrate (5 g) was added, and the solid was filtered off. The filtrate was concentrated and diluted with tetrahydrofuran, and di-tert-butyl dicarbonate was added dropwise with stirring under ice-cooling. After stirring at room temperature for 30 min, the reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and tert-butyl N-methyl-N-[2-(methylsulfanyl)ethyl]carbamate was obtained as a colorless oil (0.82 g, yield 22%) from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
A solution of triphenylphosphine (160 mg, 0.61 mmol) in methylene chloride (4 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (109 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid (150 mg, 0.51 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (112 mg, 1.12 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% diethyl ether then 1/1 diethyl ether/ethyl acetate then 1/3 diethyl ether/ethyl acetate) to afford 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-N-thiazol-2-yl-propionamide (15 mg, 8%) as a pale yellow foam: mp 48-52° C.; EI-HRMS m/e calcd for C22H23N3OS (M+) 377.1562, found 377.1564.