Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[N-:19]=[N+:20]=[N-:21].[Na+].CN(C)C=O>C(Cl)(Cl)Cl>[N:19]([CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3)=[N+:20]=[N-:21]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CBr)O3
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CN=[N+]=[N-])O3
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To 2-Bromomethyl-5,8-dimethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (3.36 g, 10.9 mmol) and sodium azide (5.1 g, 78.5 mmol), dimethylformamide (73.2 ml) were added, and stirred for 1 hour in a bath at 100° C. After cooling, the mixture was condensed, and the resultant residue was dissolved in chloroform, which was washed with water and dried. After condensation, the precipitated crystals were subjected to recrystallization (chloroform-ether) to obtain 2.76 g of the title compound as colorless crystals (93.8%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: C1COCCN1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(N2CCOCC2)n1

Procedure:
5 g (0.0265 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 4.62 ml (0.053 mol) of morpholine were placed in a fully equipped round-bottomed flask.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[Cl:32][C:33]1[C:38]([S:39](Cl)(=[O:41])=[O:40])=[CH:37][CH:36]=[C:35]([Cl:43])[N:34]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:32][C:33]1[C:38]([S:39]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:41])=[O:40])=[CH:37][CH:36]=[C:35]([Cl:43])[N:34]=1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)nc1Cl)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a 20-mL vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.40 g, 1.0 mmol, Example 91), CH2Cl2 (8 mL), and triethylamine (0.70 mL, 5.0 mmol). To this solution was added 2,6-dichloropyridine-3-sulfonyl chloride (0.30 g, 1.2 mmol, Organic Process Research and Development 2009, 875). After stirring overnight at room temperature, saturated aqueous sodium bicarbonate and CH2Cl2 were added to the reaction mixture. After stirring for 5 min, the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was purified by silica gel chromatography (0 to 70% EtOAc in hexanes) to afford 2-(4-(4-((2,6-dichloropyridin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.43 g) as an off-white solid.
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[Cl:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>O1CCCC1.C(OCC)C>[NH2:10][C:9]([C:8]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:7]=1[Cl:6])=[CH:4][C:3]#[N:5]
Reactant: CC#N
Reactant: N#Cc1ccc(Cl)cc1Cl
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC=C(N)c1ccc(Cl)cc1Cl

Procedure:
A 150 ml. portion of ammonia is condensed in a reaction flask and a small piece of sodium is added. The blue color is discharged by the addition of ferric chloride and 3.22 g. of sodium are added. After the color is discharged, 5.75 ml. of acetonitrile in 10 ml. of diethyl ether are added. The reaction is cooled in a dry ice-acetone bath and 16.6 g. of 2,4-dichlorobenzonitrile in 25 ml. of tetrahydrofuran are added dropwise. The ammonia is allowed to evaporate, the solvent is blown off with nitrogen and water is added. The mixture is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and filtered through Magnesol®. The filtrate is evaporated with the addition of hexanes giving β-amino-2,4-dichlorocinnamonitrile as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:12][NH:5][C:4]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CNc1cc(OC)ccc1OC
Temperature: 40 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
To a 100 ml three neck round bottom flask was added 2,5-dimethoxyaniline (1.53 g), anhydrous potassium carbonate (1.66 g), acetonitrile (25 ml) and iodomethane (1.42 g). The reaction mixture was stirred at 40° C. for 3 days under nitrogen in the dark. The reaction mixture was quenched with ethyl acetate (50 ml) and filtered. The residue was washed with ethyl acetate (3×20 ml) The filtrate and the washings were combined and washed with water (3×30 ml). The organic layer was filtered through MgSO4 and evaporated under reduced pressure. The residue was dissolved in a minimum amount of ethyl acetate/hexane 1:8. The solution was placed on a wet column of silica gel (80 g) and eluted with ethyl acetate/hexane: 300 ml (1:8), 500 ml (1:5) to afford 0.51 g of N-methyl-2,5-dimethoxyaniline. To a 50 ml three neck round bottom flask with compound 117 (0.32 g, 1.61 mmol), N-methyl-2,5-dimethoxyaniline (0.40 g) and anhydrous potassium carbonate (0.27 g) was added anhydrous DMSO (3 ml) and the reaction mixture stirred at 45° C. for 8 h under nitrogen in the dark. Distilled water (10 ml) was added to precipitate the product and the suspension stirred for 2 h and then cooled to 5° C. and filtered. The solid was washed with cold water (2×2 ml) suspended in MeOH (200 ml). Silica gel (1 g) was added and the suspension sonicated and then heated to 50° C. for 15 min. The suspension was then evaporated under reduced pressure and dried in vacuo at room temperature for 10 h. The residue was powdered and poured on top of a wet column of silica gel (40 g) and eluted with 5% of MeOH in CHCl3. Fractions corresponding the product spot (TLC) were pooled and evaporated. The residue was washed with ether and air dried to afford 0.15 g (28%) of compound 434 as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.NCCCN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C1CCCC(=O)O1
Agent: NCCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CCCC(=O)O)CC1
Reaction time: 2 h

Procedure:
The compound (1.46 g) obtained in the above (1) is dissolved in dichloromethane (20 ml), and thereto are added glutaric anhydride (0.86 g) and triethylamine (1.14 ml), and the mixture is stirred for two hours. To the mixture is added dropwise N-(3-aminopropyl)morpholine (0.3 ml), and the mixture is further stirred for 30 minutes. The mixture is evaporated under reduced pressure to remove the solvent, and thereto is added 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and the desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (1.54 g).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][CH3:3].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([Br:35])[CH:34]=1.CN1CCOCC1>CN(C=O)C>[Br:35][C:33]1[CH:34]=[C:29]([NH:28][C:1](=[O:5])[CH2:2][CH3:3])[CH:30]=[N:31][CH:32]=1
Reactant: Nc1cncc(Br)c1
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCC(=O)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of propionic acid (Sigma-Aldrich, St. Louis, USA) (1.5 eq, 8.4 mmol, 0.63 ml) in DMF (15 ml), HOBt (1.2 eq, 6.7 mmol, 0.910 g) and EDC hydrochloride (1.5 eq, 8.4 mmol, 1.65 g) are added. The resulting mixture is stirred for 1 h at r.t. Then 3-amino-5-bromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 5.6 mmol, 1.00 g) and N-methyl-morpholine (3 eq, 16.8 mmol, 1.85 ml) are added and stirring is continued for 18 h at r.t. The solvents are evaporated and the residue is purified by column chromatography (hexane/EtOAc) yielding the title compound; [M+H]+=230.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][O:11][CH2:12]Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(Cl)cc1Br
Yield: 89.7 %

Procedure:
A solution of 2-bromo-4-chlorophenol (3.00 g; 14.5 mmol) in DCM (20 ml) was treated with chloromethyl methyl ether (1.3 ml; 17 mmol) DIEA (3.3 ml; 19 mmol) for 18 hours. The solvents were evaporated, the residue was taken up in EtOAc, washed with sat. NH4Cl solution and brine, dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound as a colorless oil (3.27 g, 90%).
Reaction SMILES: [CH:1]1([NH:5][CH2:6][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[OH:8])[CH2:4][CH2:3][CH2:2]1.[N:17]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)=[C:18]=[O:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]([OH:8])[CH2:6][N:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:18](=[O:19])[NH:17][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[CH:32][CH:33]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(N=C=O)cc1
Reactant: OC(CNC1CCC1)c1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCc1ccc(NC(=O)N(CC(O)c2cccc(Cl)c2Cl)C2CCC2)cc1
Reaction time: 1.5 h

Procedure:
To a test tube containing 0.3 mmol 2-cyclobutylamino-1-(2,3-dichlorophenyl)ethanol in 1 ml CH2Cl2 was added 314 μl of a 0.1 M solution of N-(4-isocyanato-benzyl)-2,2-dimethyl-propionamide and 0.43 μl triethylamine. The solution was allowed to stand for 1.5 h, then saturated sodium bicarbonate (1 ml) was added and the resulting mixture extracted with 1 mL EtOAc. The EtOAc extract was washed with water (2×1 ml), and the solvent removed by vacuum centrifugation over 48 h. The resulting solid was dissolved in 450 ml DMF and purified by reverse phase preparatory HPLC (Zorbax 2.5×7 cm C8 column, linear gradient 5-100% CH3CH/H2O (0.1% TFA), 15 mL/Min). The desired fractions were combined and the solvent removed by vacuum centrifugation to give. The desired fractions were combined and placed on a speed vacuum overnight for 15 h to give N-(4-{3-[2-(2,3-Dichloro-phenyl)-2-hydroxy-ethyl]-3-cyclobutyl-ureido}-benzyl)-2,2-dimethyl-propionamide. 1H NMR δH (CD3OD) 7.67-7.66 (d, 1H, J 1.22 Hz), 7.64-7.63 (d, 1H, J 1.23 Hz), 7.38-7.36 (t, 1H, J 7.94 Hz), 7.28-7.25 (d, 2H, J 8.55 Hz), 7.20-7.17 (d, 2H, J 8.24 Hz), 5.33-5.31 (t, 1H, J5.5 Hz), 4.38-4.31 (m, 4H), 3.59-3.57 (d, 2H, J 5.5 Hz), 2.20-1.99 (m, 4H), 1.68-1.56 (m, 3H), 1.20 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:21](O)=[O:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[NH3:37].Cl>C1COCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@:9]([C:21](=[O:22])[NH2:37])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@](CC(=O)OCc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)O
Reactant: N
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@](CC(=O)OCc1ccccc1)(NC(=O)OC(C)(C)C)C(N)=O
Yield: 55 %

Procedure:
A solution of (R)-1-benzyl hydrogen 3-t-butyloxycarbonylamino-3-ethoxycarbonylsuccinate (1.0 g) obtained in Example 19 in THF (20 mL) was added with triethylamine (0.62 mL) and isobutyl chloroformate (0.55 mL, 0.57 g) in this order at −15° C. with stirring, and the mixture was stirred for 30 minutes. A solution of 25% aqueous ammonia (0.30 mL) was dropped into the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 30 minutes, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and then the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then crystallized from ethyl acetate/n-hexane to obtain the title compound (0.60 g, yield: 55%) as colorless crystals. Optical rotation [α]D25 was +1.28° (c 0.50, ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].BrC1C=C2C(=CC=1)NC(=O)C(C1C=CC=CC=1Cl)=C2O.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][N:37]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:40][C:39]1[CH:38]=[N:37][C:36]([C:35]([F:45])([F:34])[F:44])=[CH:43][CH:42]=1)=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Oc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-4-hydroxyquinolin-2(1H)-one (3.2 g, 18.3 mmol, Intermediate 8: step a), 6-(trifluoromethyl)nicotinaldehyde (4.0 g, 16.7 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.2 g, 16.7 mmol), in pyridine (34 mL) were heated to 105° C. for 3 hours. The solution was allowed to cool to ambient temperature, resulting in the formation of a solid. Minimal isopropanol was added to the mixture and the slurry was stirred for 1 hour, sonicated, and filtered. The filtered solids were rinsed with isopropanol and dried under continuous air flow to provide the title compound as an off-white solid. Additional product was recrystallized from the filtrate, filtered, and rinsed with isopropanol.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].[H-].[Na+].C1COCC1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](OC)=[O:18]>O>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=[O:18])[CH2:1][S:2]([CH3:4])=[O:3]
Reactant: COC(=O)c1ccco1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)CC(=O)c1ccco1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
DMSO (35 ml., dry, distilled from CaH2) and NaH (3.08 g., 0.076 mol as a 60% suspension in oil) was heated under nitrogen until evolution of H2 was complete, cooled to 0° C., and diluted with 35 ml. THF. Methyl furan-2-carboxylate (5 ml., 5.89 g., 0.047 mol) was added, the mixture warmed to ambient temperature, stirred 2 hours, poured into an equal volume of water, and extracted with one half volume of ether. The aqueous layer was adjusted to pH3 with 6N HCl and extracted 3×150 ml. CHCl3. The CHCl3 extracts were combined, dried and evaporated to an oil which crystallized on standing in vacuum. The latter was slurried in minimal 1:1 CHCl3 :hexane and recovered by filtration, 2.84 g.; tlc Rf 0.7 (3:1 ethyl acetate: methanol); 1H-nmr 2.75 (s, 3H), 4.21 (ABq, 2H), 6.58 (dd, 1H), 7.32 (d, 1H), 7.62 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[CH2:16][NH:15][C@H:14]([CH3:17])[CH2:13][N:12]1[C@H:18]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[CH3:10][C@H:11]1[CH2:16][N:15]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)[C@H:14]([CH3:17])[CH2:13][N:12]1[C@H:18]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3ccc(O)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.05 %

Procedure:
4-Hydroxybenzaldehyde (488 mg, 4.0 mmol) was dissolved in a solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (759 mg, 2.0 mmol, Example 2) and acetic acid in tetrahydrofuran (10 mL). Sodium triacetoxy borohydride (848 mg, ˜4 mmol) was added portionwise over 5 min, then the reaction mixture sealed under nitrogen and stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue partitioned between water (6 mL) and ethyl acetate (20 mL). The aqueous solution was further extracted with ethyl acetate (2×10 mL) and the combined extract and washings diluted with an equal volume of ether. The organic solution was extracted with 3M-HCl and the acidic aqueous solution carefully neutralized, initially with 5M-NaOH, then saturated NaHCO3. At pH 4 the solution was filtered through a 0.45 mM syringe filter to remove a small quantity of an off-white gummy solid. The pH of the filtrate was adjusted to 8.5 to precipitate a flocculent white solid which was filtered off, washed well with cold water and dried overnight at 2 mm Hg at room temperature to yield 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(4-hydroxybenzyl)-1-piperazinyl)-benzyl)-N,N-diethylbenzamide (73.05%). Calc. for C31H39N3O2 1.5H2O C, 72.62; H, 8.26; N, 8.20. Found C, 72.58; H, 7.83; N, 8.40% 1H NMR (1% NaOD in D2O, 300 MHz); □□0.75 (br m, 3H); 0.81 (br d, J=7.3 Hz, 6H); 0.94 (br m, 3H); 1.71 (m, 1H); 1.84 (m, 1H); 2.29 (m, 2H); 2.49 (br m, 2H); 2.91 (m, 3H); 3.22 (m, 2H); 3.57 (br m, 2H); 5.02 (s, 1H); 6.39 (d, J=7.5 Hz, 2H); 6.80 (d, J=7.3 Hz, 2H); 7.01 (m, 7H); 7.17 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]#[N:19])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(O)=C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[C:18]#[N:19])[CH:12]=1
Reactant: N#CCc1cccnc1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: C=CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#CC(=Cc1ccc(Cl)cc1Cl)c1cccnc1
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
To a stirred solution of 2,4-dichlorobenzaldehyde (5.0 g, 29 mmole) and 3-pyridylacetonitrile (3.05 ml, 29 mmole) in 150 ml absolute ethenol were added 3.95 g K2CO3. After stirring for about 15 minutes, a white solid precipitated out of the reaction mixture. The reaction mixture was stirred overnight and filtered. The filter cake was washed with absolute ethanol and dissolved in CH2Cl2. The CH2Cl2 solution was filtered and concentrated in vacuo. The resulting white solid was recrystallized from 3:2 hexane/ethyl acetate to give 6.0 g (76%) of the title compound.
Reaction SMILES: [Br:1][CH:2]([CH:14]([Br:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[C:10]([OH:12])=[O:11].[CH3:24]O.B(F)(F)F>CO>[Br:1][CH:2]([CH:14]([Br:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[C:10]([O:12][CH3:24])=[O:11]
Reactant: C=C(CCCCCCC(Br)C(Br)CCCCCCCC)C(=O)O
Reactant: CO
Agent: FB(F)F
Product: C=C(CCCCCCC(Br)C(Br)CCCCCCCC)C(=O)OC

Procedure:
The crude dibromo acid, 2-(7,8-dibromohexadecyl)-acrylic acid is dissolved in 50 ml of methanol and 5 ml of boron trifluoride methanol solution is added. The solution is heated under reflux for 6 hours. The solution is concentrated to 1/2 volume and the acid is neutralized with saturated NaHCO3 solution to about pH 7. The oily material is extracted with ether, washed with water and dried over Na2SO4. The ether solvent is removed under reduced pressure to give 4.80 g of crude product, methyl 2-(7,8-dibromohexadecyl)-acrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: COc1ccccc1O
Product: COc1ccccc1Oc1nc(Nc2cc(C)[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from 2-methoxy-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@@H:26](O)[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.C(N(S(F)(F)[F:38])CC)C>C(Cl)Cl.O>[CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([F:38])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@@H](O)CC2)c(C(=O)O)s1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](F)CC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (102 mg, 0.23 mmol) in dry CH2Cl2 (2 mL) is added DAST (Diethylaminosulphurtrifluoride) (90 μL, 0.69 mmol), and the mixture is stirred for 4 h at room temperature. Then it is diluted with CH2Cl2, water is added to the mixture, and it is vigorously stirred for 20 min. Organic fraction is separated, dried over Na2SO4, concentrated, and the residue is purified by preparative HPLC to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid.
Reaction SMILES: C(N(CC)CC)C.[C:8](#[N:12])[CH2:9][C:10]#[N:11].[Cl-].Cl[C:15]([Cl:21])=[N+:16]([CH2:19][CH3:20])[CH2:17][CH3:18]>ClC1C=CC=CC=1>[Cl:21][C:15]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[C:9]([C:8]#[N:12])[C:10]#[N:11]
Reactant: N#CCC#N
Reactant: CC[N+](CC)=C(Cl)Cl
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Product: CCN(CC)C(Cl)=C(C#N)C#N
Reaction time: 4 h
Yield: 33.7 %

Procedure:
A solution of 12.1 g of triethylamine, 4.0 g of malononitrile, and 20 ml of chlorobenzene was added to a slurry of 11.4 g of N-(dichloromethylene)-N,N-diethylammonium chloride and 50 ml of chlorobenzene, at ambient temperature. The reaction temperature was kept below 50° by controlling the rate of addition (time required for complete addition, 30 minutes). After addition, the reaction mixture was stirred for four hours while it returned to ambient temperature. The reaction mixture was filtered and the filtrate concentrated on the rotary evaporator to give a brownish-red liquid. Vacuum distillation gave 3.7 g of liquid 3-chloro-2-cyano-3-(diethylamino)propenenitrile; b.p. 127°-131°/0.05 mm Hg. The ir and nmr spectra were consistent with the assigned structure.