Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:26](=[O:27])[N:25]([C:28]3[CH:43]=[CH:42][C:31]([O:32][C:33]4([C:38](OC)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:30][CH:29]=3)[C:24]([CH2:44][CH3:45])=[N:23][C:22]=2[CH2:46][CH2:47][CH3:48])=[CH:16][CH:15]=1)#[N:7]>CO.O1CCCC1.C(OCC)(=O)C.Cl>[CH2:44]([C:24]1[N:25]([C:28]2[CH:43]=[CH:42][C:31]([O:32][C:33]3([CH2:38][OH:39])[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:30][CH:29]=2)[C:26](=[O:27])[C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[C:8]([C:6]#[N:7])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:19][CH:18]=2)=[C:22]([CH2:46][CH2:47][CH3:48])[N:23]=1)[CH3:45]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3(C(=O)OC)CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc(CC)n(-c2ccc(OC3(CO)CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
To a solution of sodium borohydride (0.39 g) in methanol (10 mL)-tetrahydrofuran (10 mL) was added calcium chloride (0.57 g) under ice-cooling, and the mixture was stirred for 15 min. A solution of methyl 1-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}cyclopentanecarboxylate (0.94 g) in tetrahydrofuran (10 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added in the reaction mixture and the mixture was stirred for 15 min. The mixture was diluted with ethyl acetate and 1 M hydrochloric acid. The organic layer was separated, washed with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (0.83 g, 93%) as a colorless solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:27]=1[NH2:28]>C(O)C>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=[N:28][C:27]2[C:29]([CH3:34])=[CH:30][C:31]([CH3:33])=[CH:32][C:26]=2[CH3:25])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(N=Cc2cccc(-c3c(CNC(C)(C)C)ccc4ccccc34)n2)c(C)c1

Procedure:
A mixture of 4.80 g (15.0 mmol) of 6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridine-2-carbaldehyde and 2.00 g (15.0 mmol) of 2,4,6-trimethylaniline in 50 ml of dry ethanol was refluxed overnight. The resulting mixture was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-methanol-triethylamine=100:10:1, vol.). Yield 5.80 g (88%) of orange oil. Anal. calc. for C30H33N3: C, 82.72; H, 7.64; N, 9.65. Found: C, 82.89; H, 7.73; N, 9.54. 1H NMR (CDCl3): 8.40-8.42 (m, 2H, CH═N and 3-H in Py), 7.99 (m, 1H, 4-H in Py), 7.91 (d, J=8.4 Hz, 1H, 4-H in naphthyl), 7.87 (m, 1H, 8-H in naphthyl), 7.66 (d, J=8.4 Hz, 1H, 3-H in naphthyl), 7.55 (m, 1H, 5-H in Py), 7.36-7.47 (m, 3H, 5,6,7-H in naphthyl), 6.90 (s, 2H, 3,5-H in mesityl), 3.60 (d, J=10.9 Hz, 1H, CHH′N), 3.53 (d, J=10.9 Hz, CHH′N), 3.40 (s, 1H, NH), 2.29 (s, 3H, 4-Me in mesityl), 2.17 (s, 6H, 2,6-Me in mesityl), 0.96 (s, 9H, tBu).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22](OCC)=[O:23])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(C[AlH]CC(C)C)C>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([S:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:22][OH:23])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(S(C)(=O)=O)cc2)cc1)Sc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CCOc2ccc(CC(CO)Sc3ccccc3)cc2)cc1
Temperature: -78 °C

Procedure:
Ethyl 3-(4-{2-[4-(methylsulfonyl)phenyl]ethoxy} phenyl)-2-(phenylthio)propanoate (0.58 g, 1.20 mmole) was dissolved in dry dichloromethane (15 ml). The solution was cooled to −78° C. and DIBAL-H (1M hexan solution, 3.0 ml, 3.0 mmole) was added. The cooling agent was removed after 20 min. After 2 h the reaction mixture was cooled on an ice-bath before the addition of HCl (1M, 15 ml). The mixture was extracted with dicloromethane, the organic phase was washed twice with water (15 ml) and dried with NaSO4. Evaporation gave 0.554 g, ˜100%; of the desired product as a colorless oil.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12]([C:14]2[C:15](Cl)=[N:16][C:17]([Cl:21])=[C:18]([F:20])[CH:19]=2)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].O>O1CCCC1>[Cl:21][C:17]1[N:16]=[C:15]2[C:14]([C:12](=[O:13])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:19][C:18]=1[F:20]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
The solution of 3.0 g of ethyl 3-cyclopropylamino-2-(2,6-dichloro-5-fluoropyridine-3-carbonyl)acrylate in 36.4 ml of anhydrous tetrahydrofuran was cooled to 10° C. 0.36 g (1.05 eq.) of 60% sodium hydride was added to the reaction mixture, which was then stirred for 18 hours at room temperature. The reaction mixture was cooled to 5˜10° C. 36.4 ml of water was added to the reaction mixture, which was then stirred for 30 minutes. The organic layer was filtered under a reduced pressure and washed with water. The resulting wet cake was dried under a reduced pressure at 50° C. for 5 hours to give 2.34 g of ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (Yield: 87.3%).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([OH:10])[CH:7]=[CH:8][CH3:9]>C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Ti].C1(C)C=CC=CC=1>[CH2:1]([O:5][CH:6]([O:10][CH2:1][CH:2]=[CH:3][CH3:4])[CH2:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4]
Reactant: CCCC=O
Reactant: CC=CCO
Agent: [Ti]
Agent: CC(=O)/C=C(/C)O
Solvent: Cc1ccccc1
Product: CC=CCOC(CCC)OCC=CC
Temperature: 20 °C
Reaction time: 12 h
Yield: 190.7 %

Procedure:
In a 300-ml three-necked flask, 72 g (1 mole) of n-butanal, 144 g of crotyl alcohol, 3 mg of titanium acetylacetonate, 80 g of molecular sieve 4A and 50 g of toluene were charged. The resulting mixture was stirred at 20° C. under atmospheric pressure for 12 hours in a nitrogen atmosphere. After the removal of the molecular sieve 4A from the reaction mixture, the solvent (toluene) and the unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 189.1 g of n-butanal dicrotyl acetal (boiling point: 116° C./25 mmHg) (yield: 95.5%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][NH:31][CH2:30][CH2:29][C:27]=2[N:28]=1.[N:33]1([CH2:38][CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH:37]=[CH:36][N:35]=[CH:34]1.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][N:31]([C:42](=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: O=C(O)CCCCn1ccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCn1ccnc1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 18 h
Yield: 44.8 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288 g; 2.0 equiv; 1.50 mmoles) to a solution of N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.20 m; 1.0 equiv; 0.75 mmoles), 5-imidazol-1-ylpentanoic acid (0.152 g; 1.2 equiv; 0.90 mmoles), and 1-hydroxybenzotriazole (0.203 g; 2.0 equiv; 1.50 mmoles) in dichloromethane (20 mL) and triethylamine (0.52 mL). Stir the mixture for 18 hours, then concentrate, add water (10 mL), and extract with ethyl acetate (3×20 mL). Dry the combined organic extracts over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-5-(1H-imidazol-1-yl)pentan-1-one (0.14 g; 45%) as a colorless oil: MS (m/z): 417 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[O:17])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(#N)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][CH:13]([C:16](=[O:17])[C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=4[F:25])[CH2:14][CH2:15]3)[CH2:4][CH2:3]2)=[O:35])=[CH:29][CH:28]=1
Reactant: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3F)CC2)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)cc1)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3F)CC2)CC1

Procedure:
The title compound was synthesized from Trans-{1-[2-(4-Amino-cyclohexyl)-ethyl]-piperidin-4-yl}-(2,4-difluoro-phenyl)-methanone (example 58, intermediate F) and 4-Chloro phenyl isocyanate in acetonitrile according to the procedure described for example 38. MS (m/e): 504.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[CH:4]([CH3:5])[C:3]1([CH2:9][CH3:10])[C:6](O)=[O:7].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1([Cl:11])[CH:4]([CH3:5])[C:3]1([CH2:9][CH3:10])[C:6]([Cl:14])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CCC1(C(=O)O)C(C)C1(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC1(C(=O)Cl)C(C)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.1 %

Procedure:
To generate the acyl chloride, 19.7 g (0.1 mol) of 2,2-dichloro-1-ethyl-3-methylcyclopropane-1-carboxylic acid were dissolved in toluene, and 36.9 g (0.31 mol) of thionyl chloride were added. After a reaction time of 5 hours at reflux, the mixture was stirred at room temperature for a further 14 hours. The reaction solution was concentrated using water pump vacuum. 22 g of a brown liquid were isolated as crude product. This was not purified prior to further use.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].BrCC(C1C=CC=CC=1C1C=CC(F)=CC=1F)=O.[C-:36]#[N:37].[K+]>>[C:36]([CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)=[O:3])#[N:37]
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: [C-]#N
Agent: O=C(CBr)c1ccccc1-c1ccc(F)cc1F
Agent: [K+]
Product: N#CCC(=O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Grignard reagent obtained from 14.2 g. of methyl iodide and 2.4 g. of magnesium in 100 ml. of THF is added dropwise to a solution of 30.4 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-oxopropionic acid ethyl ester, obtained by brominating 4-acetyl-2',4'-difluorobiphenyl to 4 bromacetyl-2',4'-difluorobiphenyl, reacting this with KCN to give 4-cyanoacetyl-2',4'-difluorobiphenyl, hydrolyzing the latter and esterifying the reaction product, in 200 ml. of THF. When the addition is complete, the mixture is heated and stirred for 2 hours more on a water bath and cooled. The resulting alcoholate is hydrolyzed with ice and saturated NH4Cl solution. The ether phase is dried and evaporated to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, m.p. 96°-97°.
Reaction SMILES: CN([CH:4]=[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)C.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17].C[O-].[Na+]>CN(C)C=O.C(#N)C>[C:16]([C:18]1[C:19](=[O:20])[NH:21][C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[CH:4]=1)#[N:17]
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C1C(=O)CCc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1cc2c([nH]c1=O)CCc1ccccc1-2

Procedure:
Heat 11.4 g of 1-dimethylaminomethylene-2-tetralone, 4.46 gm of cyanoacetamide and 6.6 gm of sodium methoxide in 100 ml of dimethylformamide for 8 hours at 80°. Cool and dilute the reaction mixture with 150 ml of acetonitrile. Remove the tan solid by filtration. Dissolve the solid in hot water and filter the mixture. Acidify this aqueous solution with concentrated hydrochloric acid to give a tan precipitate. Filter and wash the tan solid with chloroform to give the title compound, m.p. 301°-3°. Concentrate the remaining dimethylformamide:acetonitrile solution in vacuo to give a green-black residue and chromatograph on 800 ml of silica gel using cloroform:methanol 98:2 as eluant to give an additional amount the title compound.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:14][C:9]2=[CH:10][N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)CCC.Br[C:24]1[N:28]2[N:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.[Cu]I>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]2[N:28]([C:24]([C:6]3[O:14][C:9]4=[CH:10][N:11]=[CH:12][CH:13]=[C:8]4[CH:7]=3)=[CH:25][N:26]=2)[N:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccncc2o1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc2ncc(-c3cc4ccncc4o3)n2n1
Yield: 43.7 %

Procedure:
To a stirred solution of crude 2-(tributylstannyl)furo[2,3-c]pyridine (1.9 g) in THF (20 mL) in an inert atmosphere was added 3-bromo-6-chloroimidazo[1,2-b]pyridazine (676 mg, 2.9 mmol), copper (I) iodide (55 mg, 0.29 mmol) bis(triphenylphosphine) palladium(II)chloride (102 mg, 0.145 mmol) and triphenylphosphine (38 mg, 0.145 mmol). The mixture was heated to reflux for 2 h. The solvent was removed in vacuum. The residue was dissolved in a mixture of dichloromethane and methanol, filtered through an aminophase-silica-gel column and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with a mixture of ethyl acetate and hexane to give 343 mg of the title compound, which was used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([OH:19])(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)O
Reactant: BrCc1cccc(Oc2ccccc2)c1
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
The resulting m-phenoxybenzyl bromide can be easily esterified in a solvent such as acetic acid to produce m-phenoxybenzyl acetate. The product can be easily converted into m-phenoxybenzyl alcohol by a hydrolysis with a base in a solvent such as methanol. In accordance with the aforementioned treatment, m-phenoxybenzylidene dibromide is converted into m-phenoxybenzaldehyde. Thus, m-phenoxybenzyl acetate and m-phenoxybenzaldehyde are produced by the treatment of the mixture of m-phenoxybenzyl bromide and m-phenoxybenzylidene dibromide, m-phenoxybenzyl acetate and m-phenoxybenzaldehyde can be separated from the mixture by a distillation under a reduced pressure.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)[CH2:6][CH3:7])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1>[CH2:15]([CH:12]1[CH2:11][CH2:10][CH:9]([CH2:8][CH:5]([CH2:6][CH3:7])[CH2:4][OH:3])[CH2:14][CH2:13]1)[CH2:16][CH3:17]
Reactant: CCCC1CCC(CC(CC)C(=O)OCC)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCC1CCC(CC(CC)CO)CC1

Procedure:
A solution of 2-(4-propyl-cyclohexylmethyl)-butyric acid ethyl ester (35.0 g, 138 mmol) in THF (300 ml) is added dropwise to a suspension of lithium-aluminiumhydride (6 g, 158 mmol) in THF (300 ml) at reflux temperature. The reaction mixture is heated under reflux for 1 h, cooled and poured onto sat. ammonium chloride solution. The mixture is acidified, extracted with ether and the combined organic layers are washed with brine and dried over sodium sulfate. The solvent is evaporated and the crude product is crystallised from isopropanol to give 2-(4-propyl-cyclohexylmethyl)-butan-1-ol as colourless crystals.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I.Cl>O.CO>[I:15][C:5]1[N:4]=[C:3]([CH3:8])[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: Cc1ncccc1O
Reactant: II
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc(I)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A solution of 3-hydroxy-2-methylpyridine (20.0 g, 183 mmol) and Na2CO3 (38.8 g, 367 mmol) in H2O (320 mL) and MeOH (200 mL) was treated with I2 (46.5 g, 183 mmol) and stirred at RT for 1 h. The mixture was acidified with HCl (2 M), extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was suspended in 1:1 EtOAc/Hex, sonicated and the solid collected via filtration and dried. The filtrate was concentrated to dryness, treated with DCM, the solid collected via filtration and combined with the first solid to afford 6-iodo-2-methylpyridin-3-ol (20.5 g, 48%). MS (ESI) m/z: 236.0 (M+H+).
Reaction SMILES: [CH:1]1([NH:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:21]=[N+:22]=[N-:23]>C1C=CC=CC=1>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:23]=[N:22][N:21]=1
Reactant: O=C(CCCCCl)NC1CCCCC1
Reactant: [N-]=[N+]=N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: ClCCCCc1nnnn1C1CCCCC1
Temperature: 18 °C
Reaction time: 2 h

Procedure:
A stirred solution of N-cyclohexyl-5-chloropentanamide (4.36 g, 0.020 mol) in benzene (30 ml) at 0° C. was treated with phosphorous pentachloride (4.4 g, 0.021 mol) in portions over 10 minutes. When the addition was complete the reaction was stirred for an additional 2 hours at 18° C. The solution was then cooled to 0° C. and treated with a solution of hydrazoic acid (0.04 mol) in benzene (50 ml) (prepared according to the method described in Reagents for Organic Synthesis, Volume 1, L. F. Fieser and M. Fieser, John Wiley and Sons (New York: 1967). The resulting solution was stirred at 0° C. for an additional 1.5 hours and at 18° C. for 48 hours and then heated under reflux for an additional 3 hours. The solvent was evaporated off under reduced pressure and the resulting residue was dissolved in ethyl acetate (250 ml). The resulting solution was washed with saturated aqueous sodium hydrogen carbonate (3×100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude product. The crude product was purified by recrystallization from ethyl acetate-hexane to yield 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole as a colorless crystalline solid, having a melting point of 50°-51° C. and the following physical characteristics:
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH3:23])[CH2:5][C@@H:6]([CH3:22])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[CH3:24]I.O>CN(C)C=O>[CH3:24][O:3][C@@H:4]([CH3:23])[CH2:5][C@@H:6]([CH3:22])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@H](C)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
0.13 g of 55% sodium hydride was mixed with 1 ml of dimethylformamide. A solution of 0.56 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]-benzonitrile prepared in the above Example 1 in 2 ml of dimethylformamide was added dropwise thereto under ice-cooling. The obtained mixture was then stirred at room temperature for one hour. Subsequently a solution of 0.36 g of methyl iodide in 2 ml of dimethylformamide was added thereto and the obtained mixture was stirred at room temperature for two hours. 10 ml of water was carefully added to the reaction mixture and the obtained mixture was extracted with diethyl ether. After thoroughly washing with water, drying and desolvating, the obtained residue was purified by silica gel column chromatography, similar to the case of Example 1, with the use of a mixture of n-hexane and ethyl acetate (4:1) as a developing solvent. Thus 0.36 g of the title compound, namely, (R,S)-4-[4'-(3"-methoxy-1"-methylbutoxy)phenyl]benzonitrile was obtained.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:12])[C:5]([O:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+].C(=O)(O)[O-:19].[Na+].CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.O.S([O-])([O-])(=O)=O.[Cu+2].C(OCC)(=O)C>[CH2:14]([O:13][C:5]1[C:6]([CH3:12])=[C:7]([C:2]([OH:19])=[CH:3][CH:4]=1)[C:8]([OH:10])=[O:9])[CH3:15]
Reactant: CCOc1ccc(Br)c(C(=O)OC)c1C
Reactant: O=C([O-])O
Agent: [Cu+2]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ccc(O)c(C(=O)O)c1C
Temperature: 95 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A solution of methyl 6-bromo-3-ethoxy-2-methylbenzoate (114c, 0.298 g, 1.09 mmol) in DMSO (4 mL) was treated with 10M NaOH (1.0 mL, 10 mmol) and heated at 95° C. After 1 hour, the ester was hydrolyzed. The reaction mixture was cooled to room temperature and sodium bicarbonate (0.850 g, 10.1 mmol) and water (3 mL) were added. The suspension was sonicated until homogeneous. A solution of copper(II) sulfate (0.0348 g, 0.218 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.071 mL, 0.44 mmol) in water (2.0 mL) was added. The reaction mixture was heated at 95° C. for 1 hour. The reaction mixture was cooled to room temperature, poured into ethyl acetate, and washed with 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give 3-ethoxy-6-hydroxy-2-methylbenzoic acid (114d, 0.168 g, 79% yield) as a salmon colored solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14](C(OCC)=O)[C:15]3[C:20]([C:21]=2[NH:22][C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=[C:17]([Cl:29])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=O)C.[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:29][C:17]1[CH:16]=[C:15]2[C:20]([C:21]([NH:22][C:23](=[O:28])[CH2:24][CH:25]([CH3:26])[CH3:27])=[C:13]([C:11]([C:8]3[O:9][CH:10]=[C:6]([CH2:5][OH:4])[CH:7]=3)=[O:12])[NH:14]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(NC(=O)CC(C)C)c2ccc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CC(=O)Nc1c(C(=O)c2cc(CO)co2)[nH]c2cc(Cl)ccc12
Reaction time: 5.5 h
Yield: 72.7 %

Procedure:
To a solution of 2-(4-acetoxymethyl-2-furoyl)-6-chloro-1-ethoxycarbonyl-3-(isovalerylamino)indole (step 3, 213.5 mg, 0.437 mmol) in ethanol (1.5 ml) was added 2N aqueous sodium hydroxide (1.5 ml). After stirring for 5.5 h, the mixture was poured into saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (80 ml). The organic layer was washed with brine (20 ml), dried (MgSO4) and cocentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1/3) and recrystallization from 2-propanol/isopropyl ether to give 119 mg (88%) of the titled compound as yellow solids. m.p: 200-201° C.