Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8](C(OCC(Cl)(Cl)Cl)=O)[C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1.[OH-].[K+]>C1COCC1>[Br:1][C:2]1[C:3]([NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]([Cl:14])([Cl:16])[Cl:15])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(Br)c(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To bis(2,2,2-trichloroethyl) 4-bromo-1-methyl-1H-pyrazol-3-ylimidodicarbonate (5.73 g, 10.87 mmol) in THF (50 mL) was added dropwise an aqueous potassium hydroxide solution (2.0 M, 5.7 mL, 11.4 mmol) and the reaction was stirred at rt for 30 minutes. An additional aliquot of aqueous potassium hydroxide (2.0 M, 1.4 mL, 2.8 mmol) was added and the reaction stirred for ½ hour. The reaction was quenched with aqueous saturated ammonium chloride, water was added, the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 1/1) to afford 2,2,2-trichloroethyl 4-bromo-1-methyl-1H-pyrazol-3-ylcarbamate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].[CH:11]1(OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15][CH:14]=[CH:13][CH2:12]1.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH:14]1[CH2:13][CH:12]=[CH:11][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OC2CC=CC2)cc1
Reactant: Sc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccccc1SC1CC=CC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
NaH (316 mg, 55% in mineral oil, 7.24 mmol) was suspended in DMF (6 ml) and the suspension was cooled to 0° C. A solution of 2-chloro-thiophenol (880 ml, 97% purity, 7.55 mmol) in DMF (2 ml) was added dropwise. After stirring for 45 min at 0° C. a solution of toluene-4-sulfonic acid cyclopent-3-enyl ester (1500 mg, 6.29 mmol) in DMF (3 ml) was added dropwise and the reaction mixture was stirred at room temperature for 2 days. Water was added and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed with water, saturated NaHCO3 solution and brine, dried over Na2OS4 and evaporated. The remaining brown oil was purified by silica gel chromatography (heptane/EtOAc 100:0-99:1) to obtain the title compound (1.047 g, 79%) as colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[C:16]([CH3:17])=[CH:15][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21]>O1CCCC1>[CH3:17][C:16]1[C:2]([CH3:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3[C:13]([NH:14][C:20]([NH:19][CH3:18])=[O:21])=[CH:12][NH:11][N:10]=3)=[N:6][C:5]=2[CH:15]=1
Reactant: CN=C=O
Reactant: Cc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1C
Solvent: C1CCOC1
Product: CNC(=O)Nc1c[nH]nc1-c1nc2cc(C)c(C)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [0.500 g, Example 233(c)] in tetrahydrofuran (5 ml) was treated with methyl isocyanate (0.502 ml) and the mixture stirred at ambient temperature for 16 hours. The mixture was then concentrated in vacuo and the residue was redissolved in 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran (1:3, 5 ml). The mixture was stirred for a further 1 hour, then concentrated and then partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate and the combined organic extracts were washed with brine, then dried over magnesium sulfate, and then evaporated. The residue was subjected to flash column chromatography on silica eluting initially with a mixture of ethyl acetate and hexane (1:1, v/v) and then with ethyl acetate to afford 1-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-methyl-urea (230 mg) as a white solid. MS: 269 (M+H)+. HPLC (METHOD D1): RT=5.97 minutes. (b) 1-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-3-isopropyl-urea
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14](=O)[CH2:15][CH3:16])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>C(#N)C>[Cl:38][C:1]1[N:2]=[C:14]([CH2:15][CH3:16])[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC(=O)NC(C#N)COCc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCc1nc(Cl)c(COCc2ccccc2)[nH]1
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}propanamide (3.62 g, 15.6 mmol), triphenylphosphine (10.2 g, 39.0 mmol), and carbon tetrachloride (3.8 mL, 39.0 mmol) in acetonitrile (150 mL) was heated at 45° C. for 4.5 h. The reaction was concentrated and the residue was stirred in CH2Cl2 (170 mL) and 0.5 N NaOH (150 mL) for 15 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-50% EtOAc:hexanes) to give the title compound (2.51 g, 64%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.38 (m, 5H), 4.52 (s, 2H), 4.50 (s, 2H), 2.65 (q, 2H), 1.26 (t, 3H). ES-LCMS: m/z 250.6, 252.9 (M+H).
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21](=O)[CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])=O)=[CH:11][CH:10]=1>C(O)(=O)C.O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[N:2]([CH3:1])[C:21]([CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])=[CH:20][N:19]=2)=[CH:11][CH:10]=1
Reactant: CN
Reactant: CCC(C)(C)CC(=O)CNC(=O)CCc1ccc(Br)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cnc(CCc2ccc(Br)cc2)n1C
Temperature: 25 °C

Procedure:
Acetic acid (1.08 mL, 18.9 mmol) and 2M methylamine in THF (1.09 mL, 2.2 mmol) were added to a solution of 3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propanamide in xylenes (20 mL). The solution was stirred at reflux with azeotropic removal of water for 1 h. Another batch of acetic acid and methylamine were added and stirring was continued at reflux for another 4 h. After cooling to rt, the solution was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give 2-[2-(4-bromophenyl)ethyl]-5-(2,2-dimethylbutyl)-1-methyl-1H-imidazole.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:31])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCN
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: COCCNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 77.4 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-methoxyethylamine (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 43 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:19])=[C:10]([CH2:17]Br)[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=O)C.[CH3:20][OH:21]>>[CH3:19][C:9]1[C:8]2[C:13](=[C:14]([CH3:15])[C:5]([OH:4])=[CH:6][CH:7]=2)[O:12][C:11](=[O:16])[C:10]=1[CH2:17][O:21][CH3:20]
Reactant: CO
Reactant: CC(=O)Oc1ccc2c(C)c(CBr)c(=O)oc2c1C
Product: COCc1c(C)c2ccc(O)c(C)c2oc1=O
Temperature: 25 °C

Procedure:
7-acetoxy-3-bromomethyl-4,8-dimethylcoumarin (2.50 g, 8.90 mmol) was refluxed in methanol (300 mL) overnight, cooled to room temperature and concentrated under vacuum to give crude 4,8-dimethyl-7-hydroxy-3-methoxymethylcoumarin. 1H NMR (CD3OD): δ7.52 (d, J=8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 4.50 (s, 2H), 3.41 (s, 3H), 2.49 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[S:16])[S-:15])=[N:11][CH:12]=1.C([NH+](CC)CC)C.Cl>C(Cl)(Cl)Cl.C(OCC)C.C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[S:15])[S:16][CH2:4][CH2:3][C:2](=[O:5])[CH3:1])=[N:11][CH:12]=1
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Reactant: C=CC(C)=O
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 1 h
Yield: 48.1 %

Procedure:
A solution of but-3-en-2-one (25.6 g) in anhydrous chloroform (90 cc) is added, at a maximum temperature of 5° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (110.0 g) in anhydrous chloroform (540 cc). The reaction is allowed to proceed for 1 hour at a maximum temperature of 5° C. A 3.7 N solution of hydrogen chloride in diethyl ether (97 cc) is added, at a maximum temperature of 0° C., and the mixture is then diluted with chloroform (500 cc). The chloroform solution is washed three times with distilled water (total 450 cc), dried over sodium sulphate and evaporated. The residue obtained (95.0 g) is dissolved in methylene chloride (300 cc), silica (0.2-0.5 mm; 60.0 g) is added and the solvent is then evaporated off. The silica impregnated with the product is introduced onto a column of diameter 7.5 cm, containing silica (0.2-0.5 mm; 900 g). Elution is carried out with a mixture of cyclohexane (6 liters) and ethyl acetate (1 liter), this eluate being discarded, and then with a mixture of cyclohexane (11.4 liters) and ethyl acetate (6.6 liters), this eluate being collected and evaporated to dryness under reduced pressure (20 mmHg) at 45° C. The product obtained (65.2 g; m.p. 116° C.) is purified by two successive recrystallisations from acetonitrile (210 cc) and then from a mixture of chloroform (250 cc) and diethyl ether (250 cc). 3-Oxobutyl 5-chloropyrid-2-yldithiocarbamate (47.5 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 120° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@H:4]([CH2:59][CH:60]([CH3:62])[CH3:61])[NH:5][C:6](=[O:58])[C@@H:7]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:8][C:9](=[O:50])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:39][OH:40])[NH:14][C:15](=[O:38])[C@H:16]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH:17]C(OCC1C=CC=CC=1)=O>[Pd].CO>[CH3:1][O:2][C:3](=[O:63])[C@H:4]([CH2:59][CH:60]([CH3:61])[CH3:62])[NH:5][C:6](=[O:58])[C@@H:7]([CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[NH:8][C:9](=[O:50])[C@H:10]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)[NH:11][C:12](=[O:41])[C@H:13]([CH2:39][OH:40])[NH:14][C:15](=[O:38])[C@H:16]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH2:17]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
Nα -benzyloxycarbonyl-L-tryptophyl-L-seryl-L-tyrosyl-D-Phenylalanyl-L-leucine methyl ester, 6.0 g., is dissolved in 140 ml. of absolute methanol and 800 mg. of 20% palladium-on-carbon added. The mixture is reduced under a hydrogen atmosphere, monitoring by thin layer chromatography. The catalyst is removed by filtration using a filter aid (Super-Cel). The solvent is evaporated to leave a solid residue which is dried under reduced pressure and used without further treatment.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:21])=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=2)[C:5]([CH3:23])([CH3:22])[CH2:4][C:3]1=[O:24].Br[C:26]1[C:27]([F:37])=[C:28]([CH:31]=[C:32]([F:36])[C:33]=1[O:34][CH3:35])[CH:29]=[O:30].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:37][C:27]1[C:26]([C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:22])([CH3:23])[CH2:4][C:3](=[O:24])[N:2]3[CH3:1])=[CH:7][C:8]=2[CH3:21])=[C:33]([O:34][CH3:35])[C:32]([F:36])=[CH:31][C:28]=1[CH:29]=[O:30]
Reactant: COc1c(F)cc(C=O)c(F)c1Br
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)N(C)C(=O)CC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(F)cc(C=O)c(F)c1-c1cc2c(cc1C)C(C)(C)CC(=O)N2C
Temperature: 25 °C

Procedure:
A mixture of 1,4,4,6-tetramethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinoline-2-one (0.36 g, 1.1 mmol), 3-bromo-2,5-difluoro-4-methoxybenzaldehyde (example 13 a) (0.25 g, 0.1 mmol) and potassium carbonate (0.275 g, 1.99 mmol) in toluene (5 mL), ethanol (1 mL) and water (0.75 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) was added and the mixture heated at reflux under argon for 20 hrs. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (0%–20% ethyl acetate in hexane) to give 97 mg of 2,5-Difluoro-4-methoxy-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:9][C:10](=[O:37])[CH:11]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)[CH2:12][P:13]([CH:16]([NH:18]C(OCC1C=CC=CC=1)=O)[CH3:17])([OH:15])=[O:14])[CH3:8])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:18][CH:16]([P:13]([OH:15])([CH2:12][CH:11]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)[C:10]([NH:9][CH:7]([CH3:8])[C:6]([OH:38])=[O:5])=[O:37])=[O:14])[CH3:17]
Reactant: CC(NC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(C)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)C(Cc1ccc(Br)cc1)CP(=O)(O)C(C)N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound obtained in step 2 is solubilised in a 50:50 CH2Cl2/TFA mixture (40 ml) and the mixture is stirred for 1 hour at ambient temperature. The residue is evaporated to dryness, taken up with water and freeze-dried. 1.0 g of the expected compound is obtained.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C@@H:57]2[CH2:59][O:58]2)=[CH:51][C:50]=1[F:60])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:21]([NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]3[CH:53]=[CH:54][C:49]([OH:48])=[C:50]([F:60])[CH:51]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1F)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)c(F)c3)cc2)CC1
Yield: 31.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide formate (0.376 g, 0.87 mmol) was reacted with tert-butyl{2-fluoro-4-[(2S)oxiranylmethoxy]phenoxy}diphenylsilane (0.368 g, 0.87 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.228 g, 0.271 mmol).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:20][CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 9 h
Yield: 75.8 %

Procedure:
13.4 g (46.6 mmol, 1.0 equivalent) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) and 100 ml of tetrahydrofuran were charged in a 300 ml three-necked flask and dissolved. 7.76 g (56.1 mmol, 1.2 equivalents) of potassium carbonate and 8.20 g (49.1 mmol, 1.05 equivalents) of ethyl bromoacetate were added thereto at room temperature, the mixture was stirred at 60° C. for nine hours. After cooling the mixture to room temperature, salts were removed by filtration, and the solvent was concentrated. The residue was extracted with 250 ml of toluene and 250 ml of a 1N sodium hydroxide aqueous solution. The organic layer was washed with 250 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 13.2 g of 4-[(4-dipropylaminobutyl)ethoxycarbonylmethylamino]methylbenzonitrile (11) as an oily substance (yield: 76%).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH2:19][CH3:20])[CH3:18])[C:12]=1[N:21]=[C:22]=[S:23])([CH2:9][CH3:10])[CH3:8].Cl>>[CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:7]([CH2:9][CH3:10])[CH3:8])[C:12]=1[NH:21][C:22]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[S:23])([CH2:19][CH3:20])[CH3:18]
Reactant: CCC(C)c1cccc(C(C)CC)c1N=C=S
Reactant: NC1CCCC1
Agent: Cl
Product: CCC(C)c1cccc(C(C)CC)c1NC(=S)NC1CCCC1
Reaction time: 12 h

Procedure:
20.0 g of cyclopentylamine are taken and 15.0 g of 2,6-di-sec.-butyl-phenyl isothiocyanate are introduced whilst stirring. The reaction takes place exothermically. The batch is left to stand for 12 hours and is then stirred with dilute hydrochloric acid and filtered. The filter cake is triturated with dilute methanol, filtered off, washed and dried. For further purification, the product can be recrystallised from petroleum ether. Yield 18 g; melting point 107°-108° C.
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.C[O:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:36][CH2:35]2)=[C:30]([CH:33]=1)[C:31]#[N:32]>>[OH:25][C:26]1[CH:27]=[CH:28][C:29]([N:34]2[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:36][CH2:35]2)=[C:30]([CH:33]=1)[C:31]#[N:32]
Reactant: COc1ccc(N2CCC(CCCc3ccccc3)CC2)c(C#N)c1
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: N#Cc1cc(O)ccc1N1CCC(CCCc2ccccc2)CC1
Yield: 52.2 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 5-methoxy-2-[4-(3-phenylpropyl)piperidino]benzonitrile (290 mg), and the resulting crude product was purified on TLC (developer, hexane: ethyl acetate=3:1) to provide 5-hydroxy-2-[4-(3-phenyl-propyl)piperidino]benzonitrile (145 mg).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)(=[O:10])=[O:9])[CH2:4]1.[C:18]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]2)=[CH:22][C:21]=1[F:34])#[N:19].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:34][C:21]1[CH:22]=[C:23]([CH2:24][N:25]2[C:29]([CH2:30][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([S:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=4)(=[O:10])=[O:9])[CH2:4]3)=[CH:28][N:27]=[CH:26]2)[CH:32]=[CH:33][C:20]=1[C:18]#[N:19]
Reactant: N[C@@H]1CCN(S(=O)(=O)c2cccc(O)c2)C1
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(S(=O)(=O)c3cccc(O)c3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-(3-hydroxyphenylsulfonyl)pyrrolidine hydrochloride, as described above in Step F. (360 mg, 1.29 nimol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described in Example 1, Step G. (326 mg, 1.42 mmol) were stirred in MeOH (8 mL) and N,N-diisopropylethylamine was added dropwise adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature then NaCNBH3 (97 mg, 1.54 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (10 mL) and CHCl3 (20 mL). The aqueous layer was extracted further with CHCl3 (3×15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of EtOAc—5% MeOH—0.5% NH4OH to EtOAc—10% MeOH—1% NH4OH to yield the titled product as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)(O)[CH:9]=[C:10]([CH3:12])[CH3:11]>COCCOCCOC>[CH3:11][C:10]1([CH3:12])[CH:9]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1
Reactant: CC(C)=CC(O)(c1ccccn1)c1ccccc1O
Solvent: COCCOCCOC
Product: CC1(C)C=C(c2ccccn2)c2ccccc2O1
Temperature: 150 °C
Yield: 58.4 %

Procedure:
4.42 g of 1-(2-hydroxyphenyl)-3-methyl-1-(2-pyridyl)-2-buten-1-ol were dissolved in 70 ml of diethylene glycol dimethyl ether and heated at 150° C. for 2 hours. The mixture was allowed to cool to room temperature, the solvent was removed by evaporation and the residue was partitioned between ethyl acetate and sodium chloride solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution to give 2.4 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran of melting point 80°-82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[C:4](=NN)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[K+]>C(O)COCCO>[F:17][C:14]1[CH:13]=[C:3]([CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:2](=[CH:16][CH:15]=1)[NH2:1]
Reactant: NN=C(c1ccccc1)c1cc(F)ccc1N
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: Nc1ccc(F)cc1Cc1ccccc1

Procedure:
In the manner given in Preparation 11, 2-amino-5-fluorobenzophenone hydrazone is refluxed with potassium hydroxide in diethylene glycol to give 4-fluoro-α-phenyl-o-toluidine.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: OC1COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.5 %

Procedure:
To a stirred mixture of oxetan-3-ol (0.85 g, 11.5 mmol) in DCM (38 mL) were added TEA (3.3 mL, 23 mmol) and 4-methylbenzene-1-sulfonyl chloride (2.7 g, 13.8 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was partitioned between water and DCM. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 30% DCM in petroleum ether to 100% DCM to afford oxetan-3-yl 4-methylbenzenesulfonate (1.3 g, 50%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.7 Hz, 2H), 5.30 (m, 1H), 4.66-4.74 (m, 4H), 2.46 (s, 3H); LCMS (ESI) m/z 229 (M+H)+.