Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>O.C(#N)C.CC(C)=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1

Procedure:
To a solution composed of 108 mg (90.2 weight %, 0.3 mmol) of the (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 62.4 mg (0.6 mmol) of 2,2-dimethoxypropane, and 5 mL of acetone were added 5.7 mg (0.03 mmol) of p-toluenesulfonic acid.1H2O and 11.9 mg (0.15 mmol) of pyridine, and the mixture was stirred at 40° C. for 16 hours. This reaction mixture was analyzed by high-performance liquid chromatography (column: Develosil ODS-HG-3 4.6×250 mm, product of Nomura Chemical, eluent: water/acetonitrile=50/50, flow rate: 1.0 mL/min, detector: UV 220 nm, column temperature: 40° C.). The compositional yield values were as follows.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:14])[CH3:13])[CH3:5].C([BH3-])#N.[Na+]>C(O)(=O)C.ClCCl.[OH-].[Na+]>[CH3:1][O:2][NH:3][CH:4]([CH:6]1[CH2:11][CH2:10][C:9]([CH3:12])=[CH:8][C:7]1([CH3:13])[CH3:14])[CH3:5]
Reactant: CON=C(C)C1CCC(C)=CC1(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CONC(C)C1CCC(C)=CC1(C)C
Temperature: 24 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
To a stirred solution of 1-(2,2,4-trimethyl-cyclohex-3-enyl)-ethanone O-methyl-oxime (0.27 g; 1.40 mmol) in acetic acid (3 mL) was added portionwise sodium cyanoborohydride (0.20 g; 3.00 mmol). The reaction mixture was stirred at 24° C. for 16 hours under nitrogen atmosphere. Most of acetic acid was removed under reduced pressure. The yellow sticky oil obtained was dissolved in dichloromethane and poured in 1M sodium hydroxide which was extracted with dichloromethane. Combined organic layers were washed with sodium bicarbonate and dried over sodium sulfate. The solvent was removed in vacuo to afford 0.26 g of colorless oil which was subject to flash-master column chromatography (Elution gradient: cyclohexane/ethyl acetate 99:1 to 80:20) to afford 88 mg (33% of theory) of diastereomer A as a clear oil and 58 mg (22% of theory) of diastereomer B as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH:11][CH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20](B(O)O)[C:15]=2[O:14][C:13]1([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:20]2[C:15]3[O:14][C:13]([CH3:24])([CH3:25])[CH:12]([OH:11])[C:16]=3[CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: CC1(C)Oc2c(B(O)O)cccc2C1O
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: Cc1ccccc1
Product: CC1(C)Oc2c(-c3cnc(N)c(C#N)n3)cccc2C1O

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 4, using 1.6 grams (0.008 mole) of 2-amino-3-cyano-5-bromopyrazine, 2.5 grams (0.012 mole) of 2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-ylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-5-(2,3-dihydro-3-hydroxy-2,2-dimethylbenzofuran-7-yl)pyrazine.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[NH:15][C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[N:15]([C:30]([O:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:31])[C:14]([O:25][CH3:26])=[N:13][C:12]=1[CH2:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)NC(OC)=N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCC1=C(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(OC)=N1
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a well stirred solution of 5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine (17.0 g, 44.04 mmol) and 4-dimethyl aminopyridine (6.99 g, 57.25 mmol) in CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl chloroformate 11.54 g, 57.25 mmol) at room temperature. The reaction mixture was stirred for 12 hours and then the solvent was removed in vacuo. The residue was purified by chromatography (SiO2, EtOAc/Hexane 10-30%) to get 5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine as a colorless viscous oil (12.6 g, 50%). 1H NMR (CDCl3): δ 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq, δA=5.08, δB=5.20, J=12.3 Hz, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:20])[CH:12]=[CH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:9].CC([O-])=O.[Na+]>CC(N(C)C)=O.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:2]1(/[C:13](/[CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:20])=[CH:14]\[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=CCC(=O)OCC
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C(/CC(=O)OCC)c1ccccc1
Temperature: 130 °C
Yield: 28 %

Procedure:
A solution of iodobenzene (1.08 ml, 9.67 mmol) in DMA (5 ml) was added dropwise to a solution of diethylglutaconate (2 g, 10.74 mmol), Pd(OAc)2 (250 mg, 1.07 mmol), NaOAc (880 mg, 10.74 mmol) in DMA (5 ml) at 115° C. under argon. After heating for 8 hours at 130° C., the reaction was cooled, diluted with CH2Cl2 (60 ml), and washed with water (4×10 ml). The organic layer was washed with sat. aq. NaHCO3 (20 ml), brine (20 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The dark oil was purified by column chromatography using CH2Cl2 as the eluent. The product oil was dried overnight in vacuo giving diethyl (2Z)-3-phenylpent-2-ene-1,5-dioate in 28% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>C(NCC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][OH:15])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.58 h
Yield: 50.2 %

Procedure:
In 50 ml of diethylamine were dissolved 5.0 g (22 mmol) of 4-bromo-α,α,α-trifluorotoluene and 1.25 g (22 mmol) of propargyl alcohol, and 80 mg (0.11 mmol) of bis(triphenylphosphine)palladium (II) chloride and 40 mg (0.22 mmol) of copper (I) iodide were added to the solution, followed by stirring of the resulting mixture at 50° C. for 35 minutes. To the mixture were added 40 mg (0.06 mmol) of bis(triphenylphosphine)palladium (II) chloride, and the resulting mixture was stirred for a further 35 minutes. After the mixture was dried, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 50 g of silica gel and eluted with a mixed solvent of ethyl acetate-hexane (3:17) to obtain 2.21 g (yield: 50%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]([CH2:14][CH2:15]Cl)[CH3:13].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OC(C)C)(C)C.O>[CH3:11][N:12]([CH3:13])[CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To a suspension of 4-hydroxybenzaldehyde (2.0 g), dimethylaminoethyl chloride hydrochloride (2.83 g), dimethylformamide (8 mL) in diisopropylether (1 mL) is added potassium carbonate (5.53 g) and the mixture was stirred at 60° C. overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (×2). The organic layer is concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=100:0→90:10) to give 4-[2-(dimethylamino)ethoxy]benzaldehyde (674 mg, yield: 21%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([Cl:18])=[CH:10][C:9]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(Br)cc1
Solvent: O
Product: Cc1cc(Cl)nnc1-c1ccc(Br)cc1

Procedure:
A 10 g. portion of 6-(p-bromophenyl)-5-methyl-3(2H)-pyridazinone [J. Medicinal Chem. 17, 281 (1974)] and 100 ml. of phosphorus oxychloride are heated at steam bath temperature for 3 hours. The mixture is added dropwise to cold water while stirring. The resulting solid is filtered and washed with water to afford 3-(p-bromophenyl)-6-chloro-4-methyl pyridazine as a grey solid. A mixture of 1.5 g. of this compound, 0.64 g. of formylhydrazine and 25 ml. of n-butyl alcohol is stirred at reflux for 18 hours. The reaction mixture is cooled in an ice bath, filtered, and the solid is recrystallized from methyl alcohol giving 6-(p-bromophenyl)-7-methyl-1,2,4-triazolo[4,3-b]pyridazine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.IC.[C:17](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc(C2CCC(=O)CC2)cc1
Yield: 126.9 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (5 g) and iodomethane (0.828 ml) in N,N-dimethylformamide (50 ml) was treated with potassium carbonate (4.36 g) at room temperature for 28 hours. Water was poured into the reaction mixture. And the resulting precipitate was collected by filtration and washed with isopropanol and diisopropyl ether to give 4-(4-methoxyphenyl)cyclohexanone (6.815 g).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].C(=O)([O-])O.[K+].[CH2:20]([NH:24][C:25]1[N:30]=[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:28]=[C:27](Cl)[N:26]=1)[CH2:21][CH2:22][CH3:23]>C(#N)C.O.C1(C)C=CC=CC=1>[CH2:10]([NH:14][C:27]1[N:28]=[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:30]=[C:25]([NH:24][CH2:20][CH2:21][CH2:22][CH3:23])[N:26]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN
Reactant: CCCCNc1nc(Cl)nc(NCCCC)n1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCNc1nc(NCCCC)nc(NCCCC)n1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 18.5 g (0.1 mol) of cyanuric chloride in 150 mL of acetonitrile cooled to 0° C. was dropwise added a solution of 14.6 g (0.2 mol) of butylamine in 20 mL of water over 1 hour with stirring by keeping the reaction temperature not to exceed 5° C. Further, while continuing the stirring, a solution of 20.0 g (0.2 mol) of potassium hydrogen carbonate in 100 mL of water was dropwise added at the same temperature. Thereafter, the reaction temperature was gradually elevated and the stirring was continued at 45° C. for 8 hours. After confirming the completion of conversion to 2,4-bis(butylamino)-6-chloro-1,3,5-triazine by high performance liquid chromatography, the reaction mixture was cooled and the product was separated by filtration. The filtration cake was washed well with a large amount of water and this 2,4-bis(butylamino)-6-chloro-1,3,5-triazine was suspended in 100 mL of water. To the suspension was added 29.2 g (0.4 mol) of butylamine and allowed to react by heating under reflux for 6 hours. After cooling, 200 mL of toluene was added and the mixture was stirred vigorously, followed by separation of the aqueous layer. Further, the toluene layer was washed three times with 150 mL of water. Subsequently, toluene in the organic layer was distilled off by heating under reduced pressure to obtain 28.2 g (yield 96%) of the titled compound. Propery: oily product
Reaction SMILES: C([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1)(OC(C)(C)C)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:38].Cl.Cl.CCOCC.Cl>CCOCC.O.CO>[ClH:38].[ClH:38].[NH:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1
Reactant: COC(=O)NCc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)NCc1cncc(OC[C@@H]2CCN2)c1
Yield: 99 %

Procedure:
The product of step 159a (0.23 g, 0.70 mmol) was deprotected and isolated as the free base in 99% yield according to the procedure of Example 20b, followed by conversion to the Dihydrochloride with excess HCl/Et2O. [α]D23 +12.46 (c 0.1, MeOH); 1H NMR (D2O, 300 MHz) δ 2.65-2.75 (m, 2H), 3.66 (s, 3H), 4.08-4.19 (m, 2H), 4.43 (s, 2H), 4.53-4.69 (m, 2H), 4.90 (m, 1H), 8.22 (s, 1H), 8.44 (s, 1H), 8.63 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 252 (M+H)+. Anal. Calcd for C12H17N3O3.2.5 HCl.1.5 H2O.0.4 Et2O: C, 40.93; H, 6.69; N, 10.53. Found: C, 40.96; H, 6.63; N, 10.46.
Reaction SMILES: Br[C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C([O-])(O)=O.[Na+:15].[O-:16][S:17](S([O-])=O)=[O:18].[Na+].[Na+].[Br-]>C(#N)C.O>[OH:6][CH2:5][CH2:4][C:3]([F:8])([F:7])[C:2]([F:10])([F:9])[S:17]([O-:18])=[O:16].[Na+:15]
Reactant: O=S([O-])S(=O)[O-]
Reactant: OCCC(F)(F)C(F)(F)Br
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=S([O-])C(F)(F)C(F)(F)CCO
Temperature: 55 °C

Procedure:
4-Bromo-3,3,4,4-tetrafluoro-1-butanol (19.92 g, 88.54 mmol) was added to a slurry of NaHCO3 (22.31 g, 265.6 mmol) and Na2S2O4 (46.25 g, 265.6 mmol) in 60 mL of acetonitrile and 88 mL of water. The mixture was heated at about 55° C. for two days in a wax bath without stirring due to the large amount of solids present. 19F NMR spectra showed almost no conversion to product. The temperature was then increased to about 80° C. As the temperature increased, sufficient of the inorganic salts (NaHCO3 and Na2S2O4) dissolved to allow for stirring of the mixture. Additional sodium dithionite (17 g) and sodium bicarbonate (15 g) were added. NMR spectra showed that further reaction had occurred. The reaction mixture was allowed to cool to ambient temperature and additional water (100 mL) and acetonitrile (100 mL) were added so that all the solid material dissolved. NMR spectra were taken of each layer. The aqueous layer contains sulfinate and perhaps a small amount of sulfonate, but no starting bromide, while the acetonitrile layer shows a considerable amount of starting material. The layers were separated. The aqueous layer was set aside, and additional sodium dithionite (30 g) and sodium carbonate (38 g) were added to the acetonitrile layer (200 mL) along with about 100 mL of water. The reaction mixture was heated at about 85° C. overnight. The solution was cooled, filtered, combined with the previously separated aqueous layer, and the volatiles were removed on a rotary evaporator. The resulting crunchy solid was washed with about 200 mL of ether and dried under vacuum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C>ClCCl>[OH:4][CH2:3][CH2:2][NH:1][C:6](=[O:7])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
944 mg(15.46 mmol) of 2-aminoethanol was dissolved in 50 ml of dichloromethane, and then 1.8 ml(12.88 mmol) of benzyl chloroformate and 2.7 ml(19.32 mmol) of triethylamine were added thereto. The mixture was stirred at room temperature for one hour. After the reaction was completed, the mixture was concentrated and 50 ml of water was added thereto to obtain a white solid. The obtained white solid was filtered and dried to give 1.94 g(9.93 mmol) of the title compound in a yield of 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15].[H][H]>C(O)C>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: O=[N+]([O-])c1cccc(Cl)c1NCCCO
Reactant: [H][H]
Solvent: CCO
Product: Nc1cccc(Cl)c1NCCCO
Yield: 20 %

Procedure:
A mixture of 115 parts of 3-[(2-chloro-6-nitrophenyl)amino]-1-propanol and 400 parts of ethanol is hydrogenated at normal pressure and at room temperature with 12 parts of a Raneynickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 20 parts (20%) of 3-[(2-amino-6-chlorophenyl)amino]-1-propanol as a residue.
Reaction SMILES: [NH4+].[Cl-].Cl[CH2:4][CH:5]([NH+:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[CH3:26])[CH2:6][CH2:7][CH2:8][C:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)([C:13]#[N:14])[CH:10]([CH3:12])[CH3:11]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C:9]([CH:10]([CH3:11])[CH3:12])([C:13]#[N:14])[CH2:8][CH2:7][CH2:6][CH:5]2[CH2:4][C:33]3[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=3)[CH2:27][N:25]2[CH3:26])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1ccc(C[NH+](C)C(CCl)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC

Procedure:
The ammonium compound of formula 29 is then cyclized to form a compound of formula 1 (step 7). This reaction is performed using 1-1.5 moles of a Lewis acid, such as AlCl3, FeCl3, BF3, and the like, in a suitable aprotic solvent, preferably a halogenated hydrocarbon solvent, nitromethane, or nitrobenzene, particularly CH2Cl2, at a temperature of about -10° to about 80° C., for a period of about 10 minutes to about five hours, preferably about two hours. For example, N-[1-chloro-6-(3,4-dimethoxyphenyl)-6-cyano-6-(prop-2-yl)hex-2-yl]-N-(3,4-dimethoxybenzyl)-N-methylammonium chloride (29) is suspended in CH2Cl2 at 0° C. and stirred with 1.5 moles of AlCl3 for 2 hours to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1).
Reaction SMILES: C1CN([P+]([O:17][N:18]2[N:26]=[N:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C[NH-]>>[CH:22]1[CH:23]=[CH:24][C:19]2[N:18]([OH:17])[N:26]=[N:25][C:20]=2[CH:21]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: C[NH-]
Agent: F[P-](F)(F)(F)(F)F
Product: On1nnc2ccccc21
Yield: 93 %

Procedure:
Because 36 could be prepared very cleanly without any of the bis-acylated product using PS-CCD or PyBOP, ester 36 was converted to N-methyl amide 38 (Scheme 6). Ester 36 was cleanly obtained on a preparative scale from 35 using PS-CCD and HOBt in the absence of base. After purification of 36 only by filtration and aqueous extraction, heating at 90° C. in toluene under anhydrous conditions provided the desired amide product 38 in 93% yield over the two steps.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCCCC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
Cyclohexanol (5.01 g, 50.0 mmol) and p-toluenesulfonyl chloride (10.6 g, 55.6 mmol) were charged into a 100 cc round-bottom flask, and then pyridine (20 ml) was added dropwise thereto under ice-cooling. The mixture was stirred for 8 hours while gradually elevating the temperature to room temperature. After completion of the reaction, cold water (500 ml) was added to the reaction mixture, and the mixture was extracted with ether (100 ml×3). The organic layers were combined, washed successively with 2N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain substantially pure cyclohexyl p-toluenesulfonate as a white solid (12.7 g, 49.9 mmol, 99% yield). 1H-NMR Spectrum (CDCl3, TMS, ppm): δ1.00-1.93 (10H, m), 2.43 (3H, s), 4.30-4.64 (1H, m), 7.30 (2H, d, JHF =9.0 Hz) 7.78 (2H, d, JHF =9.0 Hz).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCCCC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A round-bottomed flask (100 cc) was charged with cyclohexyl alcohol (5.01 9, 50.0 mmol) and p-toluenesulfonyl chloride (10.6 g, 55.6 mmol), followed by the addition of pyridine (20 mL) under ice cooling to form a solution. The solution was stirred for 8 h as it was warmed gradually to room temperature. After completion of the reaction, the reaction mixture was poured into ice water and stirred thoroughly. Following extraction with ether (50 mL×2), the organic layers were washed with 2N HCl, water and saturated brine and dried with anhydrous magnesium sulfate. After the desiccant was removed, the solvent was distilled off under vacuum to give cyclohexyl p-toluenesulfonate as a colorless clear oil (12.7 g; yield=99.0%). 1H-NMR(CDCl3,TMS,ppm): δ1.12-1.88(10H,m), 2.43(3H,s), 4.46(1H,m), 7.28(2H,d,J=8.9Hz), 7.76(2H,d,J=8.9Hz).