Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH:20]=O)[C:11]3=[O:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@:10]3([C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][CH2:20][N:29]4[CH2:30][CH2:31][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:27][CH2:28]4)[C:11]3=[O:22])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=CCN1C(=O)[C@]2(C[C@@H]2c2ccc(Cl)cc2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCN(CCN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
A mixture of (1R,2S) and (1S,2R)-2-(2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)acetaldehyde (0.1 mmol), (1-Isopropyl)piperazine (0.15 mmol) and acetic acid (catalytic amount) in DCM (2 ml) was stirred for 20 minutes at room temperature. The mixture was cooled to 0° C. and NaBH(OAc)3 (2 mmol) was added carefully. The mixture was warmed to room temperature and stirred for 14 hours at room temperature. The mixture was concentrated under reduced pressure and dissolved in DMF. Purification by preparative HPLC gave the title product as colorless oil (35 mg). LC/MS m/e calcd. for C25H30ClN3O: 423, observed (M+H)+: 424.1 1HNMR (400 MHz, MeOD-d4) δppm 1.37 (d, J=6.57 Hz, 6 H) 2.18 (dd, J=8.46, 5.94 Hz, 2 H) 2.46-2.64 (m, 1H) 2.85 (d, J=3.54 Hz, 2 H) 3.22 (s, 2 H) 3.50 (d, J=6.57 Hz, 2 H) 3.90-4.27 (m, 2 H) 6.09 (d, J=7.58 Hz, 1H) 6.76 (s, 1 H) 7.10 (d, J=7.83 Hz, 1 H) 7.16-7.25 (m, 3 H) 7.33 (d, J=8.59 Hz, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][CH:2]=1.[H][H]>CO>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2oc(NCc3ccncc3)nc2c1
Reactant: [H][H]
Solvent: CO
Product: c1ccc2oc(NCC3CCNCC3)nc2c1

Procedure:
A mixture of 4.5 parts of N-(4-pyridinylmethyl)-2-benzoxazolamine and 120 parts of methanol was hydrogenated at normal pressure at about 50° C. with 2 parts of rhodium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 4.6 parts of N-(4-piperidinylmethyl)-2-benzoxazolamine as an oily residue (intermediate 75).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([OH:15])=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19].C(Cl)CCl>CN(C=O)C.CCN(C(C)C)C(C)C.C(OCC)(=O)C>[CH2:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C@@H:30]([NH:40][C:13]([C:9]2[CH:10]=[C:11]([OH:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[O:15])[CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:25][CH2:24]1)=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.75 g 1-phenyl-3-carboxy-5-pyrazolone and 5.00 g 4-((S)-2-amino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid butyl ester in 15 ml DMF 2.06 g HOBt, 4.5 ml DIPEA and 2.58 g EDC were added and the reaction mixture was stirred for 12 h at RT. Then the reaction mixture was diluted with ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w), 0.1 M HCl and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[C:16]([O:20][C:21]([N:23]([CH3:27])[CH2:24][CH:25]=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([NH:15][CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:22])[CH3:27])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(N)cc1NC(C)=O
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc(NCCN(C)C(=O)OC(C)(C)C)cc1NC(C)=O
Reaction time: 64 h
Yield: 85.7 %

Procedure:
To a cooled solution of methyl 2-acetylamino-4-aminobenzoate (300 mg, 1.44 mmol) and N-tert-butoxycarbonyl-N-methylglycinal (499 mg, 2.88 mmol) in 1,2-dichloroethane (30 ml), was added NaBH(OAc)3 (964 mg, 4.32 mmol) and the stirring was continued for 64 h at 0° C. The mixture was poured into sat. NaHCO3 and was extracted with CHCl3 (50 ml×3), washed with brine, and dried over MgSO4. After removal of the solvent in vacuo, the residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient of hexane-EtOAc from 9:1 to 2:1) to give methyl 2-acetylamino-4-[2-(N-tert-butoxycarbonyl-N-methylamino)ethylamino]benzoate (451 mg, 86%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ 1.48 (s, 9 H), 2.22 (s, 3 H), 2.90 (s, 3 H), 3.32 (m, 2 H), 3.50 (m, 2 H), 3.80 (s, 3 H), 6.20 (dd, J=2.2 Hz, 8.8 Hz, 1 H), 7.80 (m, 1 H), 7.95 (m, 1 H), 11.30 (br s, 1 H); MS (FAB) m/z 366 (M++1).
Reaction SMILES: C1(=O)N[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.NN.Cl.N[CH2:16][C:17]1[CH:18]=[N:19]C(C#N)=N[CH:22]=1.Cl>>[NH2:19][CH2:18][C:17]1[CH:16]=[CH:22][C:17]([C:18]#[N:19])=[CH:16][C:22]=1[O:6][CH2:4][C:3]1[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ncc(CN)cn1
Agent: Cl
Agent: NN
Product: N#Cc1ccc(CN)c(OCc2ccccc2)c1

Procedure:
Synthesis took place via the stage of the corresponding phthalimide as in Example 3.(f). The hydrazine cleavage was carried out as in Example 3.(g). The free amine was generated at pH 9-10 from the initially produced hydrochloride and was extracted from the aqueous solution with ether.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28].FC1C=CC([Mg]Br)=CC=1>O1CCCC1>[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C@@H:24]([C:12]2[C:13]([CH:21]([CH3:22])[CH3:23])=[N:14][C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[CH2:18][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C:10]=3[C:11]=2[I:26])[OH:25])=[CH:34][CH:33]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC(C)(C)Oc1ccc([Mg]Br)cc1
Agent: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(OC(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde. A 0.5 M solution of (4-tert-butoxyphenyl)magnesium bromide in tetrahydrofurane is used instead of 1 M solution of 4-fluorophenyl-magnesium bromide in tetrahydrofurane.
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[O:11]([C@@H:19]1[CH2:23][C:22]([CH3:24])=[C:21]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@H:20]1/[CH:32]=[CH:33]/[CH:34]([O:42][Si](C(C)(C)C)(C)C)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[Si](C(C)(C)C)(C)C>N1C=CC=CC=1>[CH2:26]([S:25][C:21]1[C@@H:20](/[CH:32]=[CH:33]/[CH:34]([OH:42])[CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@H:19]([OH:11])[CH2:23][C:22]=1[CH3:24])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCSC1=C(C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/C(Cc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCSC1=C(C)C[C@@H](O)[C@@H]1/C=C/C(O)Cc1ccccc1
Reaction time: 20 h

Procedure:
To a solution of ice-cooled acetonitrile (2 ml) and pyridine (0.5 mL) was added hydrogen fluoride-pyridine (0.5 mL). To this solution was added (3S,4R)-4-(tert-butyldimethylsiloxy)-2-hexylthio-3-[(1E)-4-phenyl-3-(tert-butyldimethylsiloxy)-1-butenyl]-1-methyl-1-cyclopentene (295 mg) in pyridine (1.5 mL). The ice bath was removed and the solution was agitated for 20 hours while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate and was washed with brine, then was dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, then was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain stereoisomers of (3S,4R)-2-hexylthio-4-hydroxy-3-[(1E)-4-phenyl-3-hydroxy-1-butenyl]-1-methyl-1-cyclopentene separately (less polar compounds: 48.6 mg, 27%; more polar compounds: 53.5 mg, 30%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][S:20]([CH2:22][C:23](=O)[CH3:24])=[O:21]>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:23]([CH3:24])[CH2:22][S:20]([CH3:19])=[O:21])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CC(=O)CS(C)=O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
To a 50 ml volume three-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (2.0 g), tetrahydrofuran (anhydrous) (5 ml), and 1-methylsulfinyl-2-propanone (7-1-1) (1.65 g) were added under a nitrogen atmosphere, and stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure at room temperature. The residue was subjected to silica gel column chromatography (ethyl acetate to chloroform) to give 0.48 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfinyl-2-propylidene)hydrazine ((4-19)-(1)-39).
Reaction SMILES: C[Si](I)(C)C.[F:6][C:7]([F:22])([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:8][O:9]CC1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[F:6][C:7]([F:22])([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH2:8][OH:9]
Reactant: COCCCC(F)(F)COCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCC(F)(F)CO
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Trimethylsilyliodide (5.2 g, 26 mmoles) is added to a solution of 2,2-difluoro-1-benzyloxy-5-methoxypentane (6.3 g, 25.8 mmoles) in dry dichloromethane (30 ml), kept under nitrogen at room temperature. After standing for 1 hour at 25° C., the reaction mixture is treated with triethylamine (5 ml) during 1 hour, diluted with dichloromethane and washed with 1N HCl and twice with diluted brine. Bulb to bulb distillation of the crude oil obtained (4.2 g) (110°-150° C., 15 mm) gives the title compound (2.7 g, contaminated with 10% of 2,2-difluoro-1-benzyloxy-5-hydroxy pentane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccc(Br)cc1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-bromo-2-chlorophenol (1.00 g, 4.82 mmol) and cesium carbonate (3.14 g, 9.64 mmol) in DMF (6.89 mL) at room temperature was added 4-bromo-2-methyl-2-butene (0.68 mL, 5.78 mmol) dropwise via a syringe. The reaction mixture was stirred at 85° C. for 1 hour before it was allowed to cool to room temperature. Water (30.0 mL) was then added and the mixture was extracted with hexane (75.0 mL, 2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to afford the product as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21][CH3:22])=[O:20].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38]CO)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21][CH2:22][CH2:38][N:35]1[CH2:34][CH2:33][N:32]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH2:37][CH2:36]1)=[O:20]
Reactant: OCCN1CCN(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)c1sccc1Nc1ccnc2c(C(F)(F)F)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCCN1CCN(c2ccc(Cl)cc2)CC1)c1sccc1Nc1ccnc2c(C(F)(F)F)cccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
A mixture of 7.04 g of methyl 3-(8-trifluoromethyl-4-quinolylamino)-2-thiophene-carboxylate, 5.5 g of 4-(4-chlorophenyl)-1-piperazine ethanol and 50 ml of anhydrous toluene was refluxed for an hour while passing condensed toluene through a column filled with siliporite and after cooling the mixture to 60° C, 150 ml of sodium hydride were added. The mixture was refluxed with stirring for 16 hours and the toluene was distilled. The residue was extracted with methylene chloride, was washed and dried. The product was crystallized from 95% ethanol, iced and vacuum filtered. The precipitate was washed with ethanol and dried to obtain 8.6 g of 2-[4-(4-chlorophenyl)-1-piperazinyl]-ethyl 3-(8-trifluoromethyl 4-quinolylamino)-2-thiophene-carboxylate melting at 155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([OH:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19]I>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1O
Reactant: CI
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)cc1OC

Procedure:
E1 was prepared from D1 following the general procedure reported in Preparative Example 16 Step 2 using methyl iodide for the alkylation. MS (ES) C13H13FN2O3 requires: 264. Found: 265 (M+H)+ and 287 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][O:13][CH:14]([O:22][CH3:23])[C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:16]([C:15]([CH:14]([O:13][CH3:12])[O:22][CH3:23])=[O:21])[C:17]([O:19][CH3:20])=[O:18])([O-:3])=[O:2]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC(=O)C(OC)OC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccccc1[N+](=O)[O-])C(=O)C(OC)OC
Yield: 105.8 %

Procedure:
To a solution of 2-nitrobenzaldehyde (6.80 g), methyl 4,4-dimethoxyacetoacetate (8.72 g) and acetic acid (0.54 g) in benzene (30 ml), was added piperidine (0.46 g), in a similar manner to aforementioned examples (1-i) and (2-i), and the mixture was heated to reflux for 2 hours under azeotropic dehydration. The reaction mixture, after cooling, was diluted with benzene (100 ml), washed three times with water, and in turn with diluted aqueous sodium bicarbonate solution and water, dried over magnesium sulfated and evaporated to dryness under reduce pressure to give oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (14.73 g). A mixture of the above obtained oil (14.70 g) and isopropyl 3-aminocrotonate (7.09 g) was heated at 60° to 63° C. for 2 hours and at 85° to 90° C. for about 10 hours. The reaction mixture was treated with ethyl acetate to give yellowish crystals which were collected by filtration and washed with methanol. The filtrate was concentrated and the residue was treated with methanol to give additional crystals. The combined crystals (11.10 g) were recrystallized from methanol to give pure crystals of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 143°-145° C.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[CH3:21][C:22]1[CH:23]=[C:24]([CH2:25][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(C=O)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Product: Cc1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methylbenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methylphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](O)[C:3]=1[NH:12][C:13](=[O:15])[CH3:14].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C1C=CN=CC=1)C.ClC1C=CC=C(Cl)C=1>[Br:1][C:2]1[C:3]2[N:12]=[C:13]([CH3:14])[O:15][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(=O)Nc1c(O)cc([N+](=O)[O-])cc1Br
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1cccc(Cl)c1
Product: Cc1nc2c(Br)cc([N+](=O)[O-])cc2o1

Procedure:
A solution of 1.15 g of N-(2-bromo-6-hydroxy-4-nitrophenyl)acetamide, 80 mg Tosic acid, 26 mg DMAP, in 25 mL 1,3-dichorobenzene was heated at 170° C. overnight. Reaction was then washed with satd. NaHCO3 and brine, dried over MgSO4, and conc. in vacuo. The product was purified on a silica gel column, eluting with 80% hexane/20% EtOAc. 910 mg of title compound was recovered.
Reaction SMILES: ClCCN(CC1C=CC=CC=1)CCCl.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][OH:29]>>[OH:23][CH2:24][CH2:25][N:26]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:27][CH2:28][OH:29]
Reactant: ClCc1ccccc1
Reactant: OCCNCCO
Agent: ClCCN(CCCl)Cc1ccccc1
Product: OCCN(CCO)Cc1ccccc1

Procedure:
In one of its aspects, the invention resides in an improved process for preparing N,N-bis(2-chloroethyl)benzylamine by first reacting benzyl chloride with bis(2-hydroxyethyl)amine to produce N,N-bis(2-hydroxyethyl)benzylamine and then reacting N,N-bis(2-hydroxyethyl)benzylamine with thionyl chloride to produce N,N-bis(2-chloroethyl)benzylamine, wherein the improvements comprise adding about one molar equivalent of benzyl chloride to a warmed mixture containing about one molar equivalent of N,N-bis(2-hydroxyethyl)amine and about one molar equivalent of sodium carbonate, the addition rate of benzyl chloride being so as to maintain the exothermic reaction temperature at about 70°-100° C.; maintaining the reaction temperature at about 70° to 100° C. for a short period; adding toluene to the reaction mixture; separating and drying the toluene solution containing N,N-bis(2-hydroxyethyl)benzylamine; adding said dry toluene solution to more than two molar equivalents of thionyl chloride heated to about 65° to 75° C., the rate of addition being so as to maintain the reaction temperature at about 65°-75° C.; treating the reaction mixture with aqueous alkali; and, separating the toluene solution containing a substantially quantitative yield of N,N-bis(2-chloroethyl)benzylamine, which can be used directly in the next step of the synthesis of 1-benzyl-4-cyano-4-phenylpiperidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:31])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)[C:19]1=[O:30])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH:38]([Si:41](OS(C(F)(F)F)(=O)=O)([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])([CH3:40])[CH3:39]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:31])[C:16]=1[CH2:17][C@@H:18]1[CH2:22][CH2:21][N:20]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][Si:41]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:38]([CH3:40])[CH3:39])[CH2:25][CH2:24]2)[C:19]1=[O:30])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(Oc2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(Oc4ccc(C#N)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Yield: 95.7 %

Procedure:
Stir a mixture of (R)-4-{3,5-dichloro-4-[1-(4-hydroxy-piperidin-1-yl)-2-oxo-pyrrolidin-3-ylmethyl]-phenoxy}-benzonitrile (0.238 g, 0.5 mmol) and 15 mL dichloromethane in an ice bath. Add pyridine (0.205 g, 2.59 mmol) followed by triisopropylsilyltrifluoromethane sulfonate (0.19 g, 0.62 mmol). Remove the cold bath and stir the reaction 1 hour at room temperature. Dilute the reaction with dichloromethane and wash with water. Dry the organic phase over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography by eluting with 0% to 50% ethyl acetate in hexanes gradient to afford 0.295 g of the title compound. MS (m/z): 615 (M+).
Reaction SMILES: [CH3:1][C:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4](O)[O:3]2>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CCCC)C=CC=CC=1>[CH3:1][C@@:2]1([OH:3])[CH2:8][CH2:7][C@@H:6]([CH2:5][CH:4]=[CH:1][CH2:2][CH2:8][CH3:7])[C:9]1([CH3:11])[CH3:10]
Reactant: CC12CCC(CC(O)O1)C2(C)C
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCC=CC[C@@H]1CC[C@@](C)(O)C1(C)C
Yield: 129.5 %

Procedure:
Using the procedure of Example 7, 5 g of 1,8,8-trimethyl-2-oxa bicyclo [3,2,1] octan-3-ol and 15 g of triphenyl butyl phosphonium bromide were reacted and the product was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 4 g of (1R,S) 1,2,2-trimethyl-3-(2-hexenyl)-cyclopentanol.