Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH:6](O)[CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].C(=O)CCC>>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[CH2:1]([C:3](=[CH:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: CCCC(O)C(CC)CO
Solvent: CCCC=O
Product: CCCC=C(C=O)CC
Product: CCCCC(CC)CO
Reaction time: 1.6 h

Procedure:
According to the present invention, 2-ethyl-1,3-hexane diol is thus prepared from n-butyraldehyde. 0.5-10% by weight, preferably 5-15% by weight, of a neutral phase-transfer catalyst is added to n-butyraldehyde, one such catalyst being, for example, polyethylene glycol (PEG 400), whereafter the mixture is cooled to 0°-20° C. The reaction may also be started from room temperature, but preferably so that the mixture is first cooled. Most preferably the reaction mixture is cooled to a temperature of 5°-15° C., and thereafter an aqueous solution of an alkali metal hydroxide or alkali earth metal hydroxide catalyst is added to the mixture drop by drop at such a rate that the reaction clearly starts, i.e. the temperature of the mixture clearly rises from its original value. The alkali metal hydroxide or alkali earth metal hydroxide is used in a proportion of 0.01-5% by weight, preferably 0.1-1% by weight, to n-butyraldehyde. The adding of the aqueous solution of the catalyst is discontinued when the temperature of the mixture has risen to the range 25°-45° C., preferably, however, to the range 30°-40° C. After the discontinuation of the adding of the catalyst, the mixture is further stirred for 0-5 h, preferably 0.2-3 h, whereafter the organic phase and the aqueous phase are separated from each other. Before the separation of the phases the reaction mixture may be neutralized with a mineral acid or an organic acid. The organic phase is recovered, and it is hydrogenated by catalytic hydrogenation at a temperature of 30°-200° C. and a pressure of 5-100 bar, preferably at a temperature of 60°-140° C. and a pressure of 10-60 bar. The hydrogenation may be carried out by using, for example, a Raney nickel catalyst. After the hydrogenation the product is vacuum distilled. The boiling point of 2-ethyl-1,3-hexane diol is 100° C./6 mbar, and a yield of up to more than 55% is obtained. When the process according to the invention is used, the worst byproduct, 2-ethyl hexanol via 2-ethyl hexenal, is formed at maximum at a rate of 2.6%. The rest of the reaction mixture is unreacted n-butyraldehyde which has become reduced to 1-butanol.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])[C@@H:19]([CH3:21])[OH:20].[CH:28]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[CH2:29]>C(OCC)(=O)C>[CH:31]1([O:30][CH:28]([O:20][C@H:19]([CH3:21])[C:18]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:29])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C=COC1CCCCC1
Reactant: CC(C)COC(=O)[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)[C@@H](C)OC(C)OC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
A catalytic amount of pyridinium para-toluenesulfonate was added to 29.2 g (0.2 mole) of isobutyl (R)-(+)-lactate and 28.0 g (0.22 mole) of cyclohexyl vinyl ether. The resulting mixture was stirred at room temperature for 4 hours to give rise to a reaction. Thereto was added 100 ml of ethyl acetate, followed by washing with 100 ml of a saturated aqueous sodium hydrogen carbonate solution, 40 ml of water and 40 ml of a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 54.2 g (yield: 99.4%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)C.[CH3:7][Si:8]([CH3:23])([CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[CH2:16][O:15]1>O>[CH3:1][N:2]([CH3:3])[CH2:16][CH:14]([OH:15])[CH2:13][O:12][CH2:11][CH2:10][CH2:9][Si:8]([CH3:23])([CH3:7])[CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CNC
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Solvent: O
Product: CN(C)CC(O)COCCC[Si](C)(C)CC[Si](C)(C)C
Temperature: 50 °C

Procedure:
Aqueous dimethylamine (25%; 10 g, dimethyl amine 55 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 50° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 50° C. for an additional 8 hours. Ethanol, water and excess dimethyl amine were stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18][C:19]4[S:20][C:21]([C@:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])=[CH:22][N:23]=4)=[CH:15][CH:16]=3)[O:11][C:10](=[O:32])[CH:9]=2)=[CH:4][CH:3]=1.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:43].[Mg+2]>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([C:19]4[S:20][C:21]([C@:24]([OH:31])([C:27]([F:29])([F:30])[F:28])[CH2:25][CH3:26])=[CH:22][N:23]=4)=[O:43])=[CH:15][CH:16]=3)[O:11][C:10](=[O:32])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC[C@](O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC[C@](O)(c1cnc(S(=O)c2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-fluorophenyl)-7-({5-[(1R)-1-hydroxy-1-(trifluoromethyl)propyl]-1,3-thiazol-2-yl}thio)-2H-chromen-2-one (0.100 g, 0.2 mmol) in 7 ml of CH2Cl2 and 0.7 ml of MeOH, was added magnesium monoperoxyphthalate hexahydrate (0.051 g, 0.1 mmol). The mixture was stirred at rt overnight and partitioned between water and CH2Cl2. The layers were separated and the organic phase washed with brine, dried over MgSO4 and evaporated to dryness. The residue was chromatographed on silica gel (hexane/EtOAc; 8:2) to give two diastereoisomers. 1H NMR (400 MHz, CDCl3): δ 7.9 (s, 1H), 7.85 (s, 1H), 7.67 (dd, 2H), 7.45 (m, 2H), 7.25 (m, 2H), 6.47 (s, 1H), 2.12 (m, 2H), 0.92 (t, 3H). Diastereoisomer #2: 1H NMR (400 MHz, CDCl3): δ 7.9 (s, 1H), 7.82 (s, 1H), 7.67 (dd, 2H), 7.45 (m, 2H), 7.25 (m, 2H), 6.47 (s, 1H), 2.15 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH:14](=O)[CH3:15].[BH4-].[Na+]>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:14][CH3:15])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-amino-1-N-Boc pyrrolidine (1 eq, 5.37 mmol) in methanol (20 mL) was added acetaldehyde (0.95 eq) and the resulting mixture was heated to 80° C. and stirred for 2 h., then stirred at room temperature overnight. Sodium borohydride (0.95 eq, 5.1 mmol) was added and reaction mixture was stirred for an additional 2 h. The reaction mixture was concentrated, dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCL3) δ: 1.05 (3H, t), 1.45 (9H, s), 1.60-1.75 (1H, m), 2.00-2.10 (1H, m), 2.68 (4H, q), 2.90-3.15 (1H, m), 3.25-3.65 (4H, m). ESI-MS m/z: 215 (M+1), UV retention time: 0.75 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([CH3:19])=O.[BH3-][C:21]#N.[Na+].C=O>CO>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([N:14]([CH:17]([CH3:19])[CH3:16])[CH3:21])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: [BH3-]C#N
Reactant: CC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CC(C)N(C)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h

Procedure:
A solution of (cis-4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.8 g, 8.3 mmol) in MeOH (20 mL) was charged with acetone (2 mL), stirred for 10 minutes, charged with NaCNBH3 (1.6 g, 24.9 mmol), stirred for 3 h, charged with formaldehyde (1 mL of a 37% aq. Solution), stirred for 1.5 h, and then concentrated in vacuo. The residue was dissolved in EtOAc and the solution was washed successively with water and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via flash chromatography to afford [cis-4-(isopropyl-methyl-amino)-cyclohexyl]-carbamic acid tert-butyl ester (1.4 g, 62% yield). MS found: (M+H)+=271.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[F:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Cc1c(N)cccc1Br
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.5 %

Procedure:
Step 1 A mixture of 3-bromo-2-methylaniline (1.66 mL, 13.4 mmol), 2-fluorobenzoic acid (1.883 g, 13.4 mmol), and HOAT (2.74 g, 20.2 mmol) in EtOAc (60 mL) was treated with DIEA (4.7 mL, 26.9 mmol) and EDC (5.15 g, 26.9 mmol) and the mixture was stirred at rt. After 19 h, the mixture was diluted with EtOAc and washed with water, 1 M hydrochloric acid (twice), NaHCO3 (aq) (twice) and brine, dried and concentrated to provide N-(3-bromo-2-methylphenyl)-2-fluorobenzamide as tan fluffy needles (4.11 g, 99%). 1H NMR (400 MHz, chloroform-d) δ 8.34-8.50 (1 H, m), 8.20 (1H, td, J=7.9, 1.8 Hz), 7.96 (1H, d, J=8.1 Hz), 7.50-7.59 (1H, m), 7.44 (1H, dd, J=8.0, 0.8 Hz), 7.30-7.37 (1H, m), 7.21 (1H, dd, J=12.8, 7.9 Hz), 7.12 (1H, t, J=8.0 Hz), 2.45 (3H, s). Mass spectrum m/z 308, 310 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=[O:4].C1N2CN3CN(C2)C[N:15]1C3>C(Cl)(Cl)Cl>[ClH:11].[NH2:15][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=[O:4]
Reactant: COc1ccc(Cl)cc1C(=O)CBr
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)cc1C(=O)CN
Product: Cl
Temperature: 25 °C
Reaction time: 23 h
Yield: 143.7 %

Procedure:
Dissolve 2-bromo-1-(5-chloro-2-methoxy-phenyl)-ethanone (17.07 g, 64.78 mmol) in 150 mL of CHCl3 and add hexamethylenetetramine (9.09 g, 64.84 mmol) to the reaction mixture. Allow the reaction to stir at ambient temperature for 23 hours. Collect the solids via filtration and wash the solids with Et2O, Slurry the solid in 100 mL of MeOH and add 50 mL of concentrated HCl to it dropwise. Heat the reaction to reflux and allow it to stir for 23 hours. Cool the reaction to ambient temperature and filter off the solids. Slurry the filtrate in MeOH and again collect the solids via filtration. Concentrate the filtrate to afford 10.99 g of 2-amino-1-(5-chloro-2-methoxy-phenyl)-ethanone hydrochloride.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)OC1C=CC=CC=1)#[N:2].[NH2:44][NH2:45]>C(O)(C)C>[CH3:43][C:35]1[N:34]([CH:29]2[CH2:30][CH:31]3[N:26]([CH2:25][CH2:24][C:15]4([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH2:16][CH2:17][N:12]([C:4]5[NH:45][N:44]=[C:1]([NH2:2])[N:3]=5)[CH2:13][CH2:14]4)[CH:27]([CH2:33][CH2:32]3)[CH2:28]2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=1
Reactant: NN
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=NC#N)Oc2ccccc2)CC1
Solvent: CC(C)O
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(c2nc(N)n[nH]2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a stirred solution of phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate (18 mg, 0.031 mmol) in isopropyl alcohol (1 mL) was added hydrazine (3.6 μL, 0.11 mmol). The resulting mixture was then stirred at 80° C. for 4 hours. After evaporation of the solvents, the residue was purified by flash chromatography to afford 5-(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)-1H-1,2,4-triazol-3-amine as white solid (12.5 mg, 79%). 1H NMR (300 MHz, CDCl3) δ 7.67-7.64 (m, 2H), 7.39-7.29 (m, 5H), 7.25-7.13 (m, 3H), 4.66-4.55 (m, 2H), 4.28 (br, 2H), 3.56-3.49 (m, 3H), 3.27-3.21 (m, 4H), 2.57 (s, 3H), 2.42-2.22 (m, 4H), 1.96-1.82 (m, 9H), 1.64-1.62 (m, 2H). HRMS m/z (M+H)+ calcd: 511.3298, obsd: 511.3289.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:17][NH:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:18]([CH3:19])[CH3:17])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1n[nH]c2cc(Br)ccc12
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)Cc1n[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-1H-indazole-3-carbaldehyde (300 mg, 1.33 mmol) in THF (1 mL) was added acetic acid (0.11 mL, 2 mmol), 2M dimethylamine in THF (1.33 mL, 2.66 mmol) and sodium triacetoxyborohydride (283 mg, 1.33 mmol). The reaction was stirred at RT for 2 hr then allowed to stand at RT for 18 hr. The mixture was concentrated in vacuo, then diluted with EtOAc (50 mL) and washed with 1M aqueous NaHCO3 (10 mL). The organic layer was washed with brine (5 mL), followed by water (5 mL). The organic layer was then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a beige solid: 1H NMR (500 MHz, MeOD) δ 2.31 (6H, s), 3.85 (2H, s), 7.27 (1H, dd, J=8.67, 1.58 Hz), 7.68-7.72 (1H, m), 7.77 (1H, d, J=8.67 Hz). LC-MS: m/z=+253.9/255.9 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][C:11]=1[F:41].C(N(CC)CC)C>ClCCl>[F:41][C:11]1[CH:12]=[C:13]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:32]([F:33])([F:34])[F:35])[C:36]([F:38])([F:39])[F:37])=[CH:27][CH:26]=3)[CH2:22][CH2:23]2)=[O:17])[CH:14]=[CH:15][C:10]=1[NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH3:8])[CH3:1]
Reactant: CC(C)CCC(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Yield: 9 %

Procedure:
4-Methylvaleric acid (4.30 mmol, 0.543 mL, 0.5 g) was stirred in dichloromethane (5 mL) at 0° C. Oxalyl chloride (21.52 mmol, 1.848 mL, 2.73 g) was added. The reaction mixture allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated under vacuum to give the intermediate 4-methylpentanoyl chloride. A mixture of 4-methylpentanoyl chloride (1.564 mmol, 0.211 g), (4-amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (1.043 mmol, 0.5 g) and triethylamine (2.086 mmol, 0.290 mL, 0.211 g) were stirred in dichloromethane at 0° C. for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate, concentrated under vacuum and purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (54 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH3:14])=[C:4]([CH3:15])[CH:3]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[S:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[C:16]2=[S:17])=[C:4]([CH3:15])[CH:3]=1
Reactant: CCNCCCNc1ccc(Cl)cc1C
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCCN(c2ccc(Cl)cc2C)C1=S

Procedure:
The cyclization of the crude diamine of Step D was carried out with one equivalent of 1,1′-thiocarbonyldiimidazole in refluxing dioxane under nitrogen for one hour. Subsequently, two equivalents of para-toluenesulfonic acid hydrate were added and the mixture was refluxed for 48 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL). The solution was washed with water, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (on Merck-60 silica gel) eluting with 10-25% petroleum ether/ethyl acetate. The title compound was obtained as a white solid (4.4 g, 52%), m.p. 116-118° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([N:10](C2CCCCC2)[CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[P:30](=[O:34])([OH:33])([OH:32])[OH:31].CCO[CH2:38][CH3:39]>C(O)C>[P:30]([OH:34])([OH:33])([OH:32])=[O:31].[CH:1]1([NH:7][C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[N:9][CH:39]2[CH2:38][CH2:3][CH2:2][CH2:1][CH2:6]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCC
Reactant: N=C(NC1CCCCC1)N(CCOc1ccc2ccccc2c1)C1CCCCC1
Agent: O=P(O)(O)O
Solvent: CCO
Product: c1ccc2cc(OCCNC(=NC3CCCCC3)NC3CCCCC3)ccc2c1

Procedure:
10.0 g of 1,3-dicyclohexyl-3-[2-(2-naphthyloxy)ethyl]guanidine was dissolved in ethanol (100 ml) and 5.7 g 85% phosphoric acid in 100 ml ethanol was added to this solution. After 16 hours 1400 ml ether was added to the solution. The resulting precipitate was removed by filtration and dried under vacuum to afford the title compound (mp 132°-134°).
Reaction SMILES: [CH2:1]([C:5](O)([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br-].[Br:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([C:5]([Br:19])([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(O)(CCCC)c1ccc(F)cc1
Reactant: Br[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(Br)(CCCC)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 126.1 %

Procedure:
To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at -40 C was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed to warm to 0 C. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed a few times with water, dried (MgSO4), and concentrated in vacuo. The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture. The combined filtrate was concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil: 1H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J=8.46, 3.02 Hz, 1H), 7.15 (dd, J=9.47, 2.82 Hz, 1H), 7.46 (dd, J=8.67, 5.64, 1H), 9.45 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16]3[O:19][CH:20]=[CH:21][C:15]=3[CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][NH:23][CH3:24].[CH2:25]=O>C(O)(=O)C>[CH3:22][N:23]([CH2:25][C:20]1[O:19][C:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:14][C:15]=2[CH:21]=1)[CH3:24]
Reactant: C=O
Reactant: CNC
Reactant: c1ccc(CCCCCCN2CCc3occc3C2)cc1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(CCCCCCc1ccccc1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.288 g (1.016 mmol) of 5-(6-phenylhexyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.11 g (1.2 mmol) of 50% aqueous dimethylamine and 0.10 g (1.2 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=2/1) to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:19]1([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:26]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of (4-bromophenyl)methanamine (2.5 g, 13 mmol) in dichloromethane (45 mL) was added N,N-diisopropylethylamine (3.5 mL, 20 mmol), followed by phenylmethanesulfonyl chloride (3.1 g, 16 mmol) and the reaction was stirred at ambient temperature for 1 hour. The precipitate was then collected by filtration, washed with dichloromethane and dried under reduced pressure to give N-[(4-bromophenyl)methyl]-1-phenyl-methanesulfonamide (2.79 g, 61% yield). LCMS (m/z) ES+ 340.0 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([Li])[CH:6]=[CH:7][CH:8]=1.[CH2:12]([N:14]([CH2:28][CH3:29])[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:27])[CH2:25][CH3:26])=[CH:20][CH:19]=1)[CH3:13].[Cl-].[NH4+]>CCOCC>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:24]([CH2:25][CH3:26])([OH:27])[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:14]([CH2:28][CH3:29])[CH2:12][CH3:13])=[CH:23][CH:22]=1
Reactant: CCC(=O)c1ccc(OCCN(CC)CC)cc1
Reactant: [Li]c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCN(CC)CCOc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 250 ml. of a 0.4 molar solution of 3-trifluoromethylphenyl-lithium in ether a solution of 6.3 g. of 4'-[2-(diethylamino)-ethoxy]-propionphenone in 60 ml. of dry ether is added dropwise, under argon atmosphere, at -30° C., and the reaction mixture is stirred at room temperature for two hours. After cooling the reaction mixture is decomposed with a saturated, aqueous ammonium chloride solution, and the aqueous phase is extracted with ether. The ethereal phases are combined, washed to neutral with water and dried over anhydrous magnesium sulfate. Ether is distilled off under reduced pressure. The residue is chromatographed on a silica gel column with a 7:3 mixture of benzene and ethyl acetate. The solvent mixture is distilled in vacuo, and the residue is crystallized from n-hexane. 3.2 g. of the title compound are obtained, melting at 74° to 75° C.