Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:14]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([Cl:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(C)nc(N)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)nc(C)c1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
Ethyl 6-amino-2-methylisonicotinate (2.00 g, 11.1 mmol) was dissolved in DMF (20 mL), and the solution was stirred at 50° C. for 1 hour after adding N-chlorosuccinimide (1.48 g, 11.1 mmol). The reaction mixture was allowed to cool to room temperature, and a sodium hydrogen carbonate aqueous solution was added. The precipitated solid was collected by filteration to give ethyl 6-amino-3-chloro-2-methylisonicotinate (1.36 g, yield 57%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:43]>ClCCl.C(OCC)C>[ClH:43].[CH:38]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:28]2=[O:37])[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: COCCOCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
4-{6-[8-Cyclopentyl-6-(2-methoxy-ethoxymethyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.110 g, 0.205 mmol) was dissolved in dichloromethane (2 mL). 2 N HCl in diethyl ether (2 mL) was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated to give 8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.096 g, 92.1%). MS (APCI) Calc'd for M+1: 450.3. Found: 450.1. 1H NMR 6 (400 MHz, DMSO-d6) 9.12 (s, 2H), 8.34 (s, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.76 (d, J=9.5 Hz, 1H), 5.84 (m, 1H), 4.32 (d, J=1.2 Hz, 1H), 3.57 (q, J=6.8 Hz, 2H), 3.38 (m, 4H), 3.23 (m, 4H), 2.26 (m, 2H), 1.89 (m, 2H), 1.75 (m, 2H), 1.58 (m, 2H), 1.19 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl(O)(=O)(=O)=O.O.O.O.O.O.O.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl(O)(=O)(=O)=O.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[K+].[OH:30][C:31]1([S:42]([O-:45])(=[O:44])=[O:43])[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]1[S:38]([O-:41])(=[O:40])=[O:39].[K+].Cl([O-])(=O)(=O)=O.[K+]>O>[OH:30][C:31]1([S:42]([OH:45])(=[O:44])=[O:43])[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]1[S:38]([OH:41])(=[O:40])=[O:39].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: O=S(=O)([O-])C1C=C(O)C=CC1(O)S(=O)(=O)[O-]
Agent: C1CNCCN1
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: O=S(=O)(O)C1C=C(O)C=CC1(O)S(=O)(=O)O

Procedure:
To an aqueous solution of perchloric acid, containing 200 g of said acid in 500 ml of water 40 % solution, the amount of aqueous solution of piperazine hexahydrate required for neutralization is added. The required amount of piperazine hexahydrate is 388.46 g (C4H10N2.6H2O) dissolved in 500 ml of water. Preferably the pH of the neutralizing solution is controlled to a pH close to 6. The piperazine perchlorate solution is mixed with the warm solution of p-dihydroxy benzene disulfonic acid potassium salt, and is stirred until a copious precipitate of potassium perchlorate is formed, which then increases when the solution is left to cool for several hours. After filtering off the potassium perchlorate, the solution of a piperazine p-dihydroxy benzene disulfonate is concentrated in a rotary evaporator, under vacuum, at 60°C, until crystals begin to form, and it is then left in a refrigerator. The product is filtered and recrystallized in water to give 388 g of bis (piperazine) p-dihydroxy benzene disulfonate, having a melting point of 270°C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1([C:28]#[C:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(#N)C.N12CCCN=C1CCCCC2.Cl>>[CH:23]1(/[C:28](/[N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)=[CH:29]\[C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: COC(=O)C#CC1CCCC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a stirred suspension of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (17, 12.08 g, 38.31 mmol) and methyl 3-cyclopentylprop-2-ynoate (18, 8.970 g, 45.97 mmol, 1.2 equiv) in acetonitrile (76 mL, 1400 mmol) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.92 mL, 19.2 mmol, 0.5 equiv). The resulting reaction mixture was stirred at room temperature for 2 h. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (50 mL) and 1 N aqueous HCl solution (20 mL). The quenched reaction mixture was adjusted to pH 4 after treatment with 1 N aqueous HCl solution. The mixture was then extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2, 0-50% EtOAc/hexane gradient elution) to afford (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 6.838 g, 17.92 g theoretical, 38% in yield) as a colorless, very viscous oil. For 19: 1H NMR (CDCl3, 400 MHz) δ ppm 8.93 (s, 1H), 8.55 (bs, 1H), 8.44 (s, 1H), 7.49 (d, 1H, J=3.5 Hz), 6.86 (d, 1H, J=3.5 Hz), 6.34 (s, 1H), 5.74 (s, 2H), 4.56 (m, 1H), 3.84 (s, 3H), 3.60 (t, 2H, J=8.2 Hz), 2.01 (m, 2H), 1.96 (m, 4H), 1.77 (m, 2H), 0.98 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C24H33N5O3Si (MW, 467.64), LCMS (EI) m/e 468.2 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccccc2)c(F)c1
Reaction time: 8 h

Procedure:
2-Fluoro-4-nitro-1-phenoxybenzene and 7.2 g of 10% Pd/C were dissolved in 200 mL EtOH and stirred under 1 atmosphere of H2 overnight. The reaction mixture was filtered through Celite with the aid of 50 mL EtOH and concentrated to provide 3-fluoro-4-phenoxybenzenamine as an oil which was used in Step C without further purification.
Reaction SMILES: [CH:1]1([CH:4]([NH:8][C:9]2[C:21]3[C:20]4[CH:19]=[CH:18][C:17](B5OC(C)(C)C(C)(C)O5)=[CH:16][C:15]=4[NH:14][C:13]=3[C:12]([C:31]([NH2:33])=[O:32])=[CH:11][N:10]=2)[CH:5]2[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:35]1[N:36]=[N:37][CH:38]=[CH:39][CH:40]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([CH:4]([NH:8][C:9]2[C:21]3[C:20]4[CH:19]=[CH:18][C:17]([C:35]5[N:36]=[N:37][CH:38]=[CH:39][CH:40]=5)=[CH:16][C:15]=4[NH:14][C:13]=3[C:12]([C:31]([NH2:33])=[O:32])=[CH:11][N:10]=2)[CH:5]2[CH2:6][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c2c(C(N)=O)cnc(NC(C4CC4)C4CC4)c23)OC1(C)C
Reactant: Clc1cccnn1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: NC(=O)c1cnc(NC(C2CC2)C2CC2)c2c1[nH]c1cc(-c3cccnn3)ccc12
Temperature: 100 °C

Procedure:
A mixture of 1-[(dicyclopropylmethyl)amino]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamide (30 mg, 0.067 mmol), 3-chloropyridazine (12 mg, 0.10 mmol), Pd2(dba)3 (6.2 mg, 0.0067 mmol), tricyclohexylphosphine (4.7 mg, 0.017 mmol), and K3PO4 (1.27 M, 220 μL, 0.27 mmol) in dioxane (1.3 mL) was purged with nitrogen for 10 min, heated to 100° C. for 3 h, and cooled to room temperature. The mixture was concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.75 (s, 1H); 9.21 (d, 1H); 8.56 (d, 1H); 8.55 (s, 1H); 8.49 (s, 1H); 8.24 (d, 1H); 8.03 (d, 1H); 7.85 (br s, 1H); 7.81 (dd, 1H); 7.18 (br s, 1H); 6.66 (d, 1H); 3.65 (m, 1H); 1.40 (m, 2H); 0.55 (m, 2H); 0.37 (m, 6H). LRMS (APCI) calc'd for (C23H22N6O) [M+H]+, 399.2. found 399.1.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.[CH:9]([NH2:12])([CH3:11])[CH3:10]>C(O)C.C(O)CO>[CH:9]([NH:12][C:3](=[O:5])[CH:2]([F:1])[F:8])([CH3:11])[CH3:10]
Reactant: CC(C)N
Reactant: CCOC(=O)C(F)F
Solvent: OCCO
Solvent: CCO
Product: CC(C)NC(=O)C(F)F

Procedure:
A solution of 20 grams (0.16 mole) of ethyl difluoroacetate in 20 milliliters ethyl alcohol was added slowly in a solution of 9.5 grams (0.16 mole) isopropylamine amine and 5 drops of ethylene glycol in 30 milliliters ethyl alcohol. The temperature rose slowly to 27° C. The mixture was then refluxed for 3 days. After this reflux period, the solution was evaporated at 100 millimeters and the residue was distilled at atmospheric pressure to yield 18.0 grams, b.p. 86°-88°, identified by infrared spectroscopy as the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11](Cl)=[O:12].[OH:14][CH:15]([CH:18]1[CH2:23][CH2:22][N:21]([O:24][CH3:25])[CH2:20][CH2:19]1)[C:16]#[N:17].CCN(CC)CC>C1COCC1>[C:16]([CH:15]([O:14][C:11](=[O:12])[CH2:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[CH3:9])[CH:18]1[CH2:19][CH2:20][N:21]([O:24][CH3:25])[CH2:22][CH2:23]1)#[N:17]
Reactant: CON1CCC(C(O)C#N)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON1CCC(C(C#N)OC(=O)Cc2c(C)cc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2,4,6-Trimethyl-phenyl)-acetyl chloride (588 mg, 3 mmol) was added slowly to a mixture of hydroxy-(1-methoxy-piperidin-4-yl)-acetonitrile (390 mg, 2.3 mmol) and Et3N (505 mg, 5 mmol) in THF (10 ml) at 0° C. After the addition was completed, the mixture was stirred at room temperature for 16 h. Then, the mixture was concentrated under vacuum to dryness, the residue was purified by column chromatography on silica.
Reaction SMILES: [NH2:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:9][C:10]1[N:15]=[C:14]([NH:1][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4])[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)[C@@H](N)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@@H](Nc1nc(Cl)ncc1Cl)C(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
A mixture of (R)-2-amino-3-methyl-butyramide (50 mg), 2,4,5-trichloropyrimidine (67 mg) and K2CO3 (116 mg) in DMF (3 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and washed with brine three times. The organic layer was dried with sodium sulfate and concentrated. The residue was purified by silica gel chromatography to provide 60 mg of (R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide: 1H NMR (300 MHz, CDCl3) 8.2 (s, 1H), 6.2 (bs, 1H), 5.8 (bs, 1H), 5.6 (bs, 1H), 4.6 (dd, 1H), 2.4 (m, 1H), 1.2 (d, 6H). MS (m/e) 263 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]#[N:10].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH2:19][CH2:20][CH3:21]>CC(C)=O>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([O:8][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:6][CH:7]=1
Reactant: N#Cc1[nH]c(=O)ccc1Br
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(Br)c(C#N)n1

Procedure:
A solution of 3-bromo-6-oxo-1,6-dihydropyridine-2-carbonitrile (from Example 15/Step 2) (1.0 eq.), potassium carbonate (1.3 eq.), and 1-iodobutane (1.2 eq.) in acetone (0.3 M) was stirred at 70° C. overnight. The solvent was concentrated en vacuo, and the resulting residue was taken up in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by a COMBIFLASH® system (ISCO) using 0-30% ethyl acetate in hexane to give a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24]([O:26]C)=O)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:29]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[C:19]([CH3:22])[CH:18]=[C:17]([OH:23])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:24](=[O:26])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1cccc(F)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(O)c2c3c(C(N)=O)cccc3n(Cc3cccc(F)c3)c2c1
Yield: 57 %

Procedure:
A solution of the 9-[(3-fluorophenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole (0.33 g, 0.91 mM) in 14 ml THF and 54 mL concentrated aqueous ammonium hydroxide was sonicated for 6.5 h at 30-40° C. The precipitated solid was filtered, washed with water, and triturated with 35 ml Et2O to afford 182 mg (57%) of 9-[(3-fluorophenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (bs, 1H), 8.4 (bs, 1H), 7.75 (m, 1H), 7.4 (m, 2H), 7.25 (m, 1H), 7.05 (m, 1H), 6.9 (m, 2H), 6.85 (d, J=8 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 2.4 (s, 3H). MS (ES) m/e 332, 349.
Reaction SMILES: [H][H].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH2:8]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:3][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: c1ccccc1
Reactant: [H][H]
Product: C=CCCCCCCCCCC

Procedure:
Nafion™ fiber (3.5 g., 0.006" diameter, 1200 equivalent weight, hydrogen form) was loosely packed into a 1 cm. diameter vacuum-jacketed column and dried at 150° C. for 2 hours in a stream of dry nitrogen. The column was fitted onto a 50 ml. round bottom flask equipped with a side arm for sampling. A condenser and drying tube were fitted above the catalyst column. Dodecene-1 (15.0 z.), dry benzene (15.0 g.) and marble boiling chips were added to the flask; reflux was established up to the condenser. Samples (0.2 ml.) were periodically withdrawn via the side arm and analyzed by gas chromatography. The results are shown in Table XV. The residual pot (refluxing flask) contents were distilled through a 1×12 cm. vigreaux column equipped with a reflux ratio take off. The results are shown in Table XVI and illustrate that the integrated reactor fractionator is preferred for obtaining monoalkylated products. Although the conversion is somewhat slower by the refluxing of the mixture up to the catalyst, this method provides that only dodecene and benzene are present at the catalyst surface, in a ratio determined by their contributory vapor pressures, resulting in specific conversion to dodecylbenzene with no polyalkylated benzenes produced.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1Br.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:3]2[C:4]3[O:8][CH:7]=[CH:6][C:5]=3[CH:9]=[CH:10][C:2]=2[F:1])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Fc1ccc2ccoc2c1Br
Product: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)ccc2ccoc12
Yield: 59.3 %

Procedure:
Beginning with 5.22 gm (24.3 mMol) 6-fluoro-7-bromobenzofuran and 5.19 gm (25.5 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 4.89 gm (59%) of the desired compound were prepared as a mixture of cis- and trans-isomers, essentially as described in EXAMPLE 3.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10](OCC)=[O:11])[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][O:23][CH2:24][O:25][CH3:26])=[CH:18][CH:17]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][OH:11])[N:7]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1Cc1ccc(COCOC)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCOCc1ccc(Cn2nc(C(C)(C)C)cc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of ethyl 3-tert-butyl-1-{4-[(methoxymethoxy)methyl]benzyl}-1H-pyrazole-5-carboxylate (1.95 g, 5.41 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (0.26 g, 5.5 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Ethanol (10 mL) and saturated aqueous ammonium chloride solution (1.0 mL) were added to the reaction mixture, and the precipitated solid was filtered off. The filtrate was concentrated and the residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title compound (1.45 g, yield 84%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2O.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH:22]([O:21][C:19]([C:17]1[N:16]([CH:8]2[C:9]3[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6][CH2:7]2)[CH:15]=[N:14][CH:18]=1)=[O:20])([CH3:24])[CH3:23]
Reactant: COc1cccc2c1CCCC2O
Reactant: CC(C)OC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2c1CCCC2n1cncc1C(=O)OC(C)C

Procedure:
To a suspension of 5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ol (0.150 g, 0.842 mmol) and isopropyl 4-imidazolecarboxylate (0.087 g, 0.564 mmol), which can be prepared as described in Example 1, in THF (5 mL) at 0° C. is added triphenylphosphine (0.221 g, 0.842 mmol) followed by diisopropyl azodicarboxylate (94%, 0.181 g, 0.842 mmol). After 1 hour the mixture is diluted with ethyl acetate and extracted twice with 1M aqueous HCl. The aqueous phase is basified to a pH of ca. 9 with 2M aqueous NaOH and is extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, and concentrated to give a colorless residue, which is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 99:1) to give 3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 315.1 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether, followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(5-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 1.44 (d, J=6.3 Hz, 3 H), 1.45 (d, J=6.0 Hz, 3 H), 1.62-1.72 (m, 1 H), 1.90-1.97 (m, 1 H), 2.26-2.34 (m, 2 H), 2.66-2.74 (m, 1 H), 2.95-3.02 (m, 1 H), 3.92 (s, 3 H), 5.30-5.40 (m, 1 H), 6.53 (t, J=4.7 Hz, 1 H), 6.74 (d, J=8.0 Hz, 1 H), 7.02 (d, J=8.0 Hz, 1 H), 7.27 (t, J=8.0 Hz, 1 H), 8.32 (s, 1 H), 8.56 (s, 1 H).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[C@:7]2([CH2:24][CH2:23][C@H:22]3[C:12](=[CH:13][CH:14]=[C:15]4[C@:20]3([CH3:21])[C@@H:19]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18][C@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:16]4)[C@@H:9]2[CH2:10][CH:11]=1)[CH3:8])(=O)[CH3:2].BrCC[CH2:44][CH2:45][C:46]([O:49][Si:50]([CH2:55][CH3:56])([CH2:53][CH3:54])[CH2:51][CH3:52])([CH3:48])[CH3:47].CO.[OH-].[K+]>O1CCCC1>[Si:26]([O:25][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@H:9]3[CH2:10][CH:11]=[C:6]2[CH2:5][S:4][CH2:1][CH2:2][CH2:44][CH2:45][C:46]([O:49][Si:50]([CH2:55][CH3:56])([CH2:51][CH3:52])[CH2:53][CH3:54])([CH3:47])[CH3:48])[CH2:16][C@@H:17]([O:33][Si:34]([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:35])[CH3:36])[CH2:18]1)([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28]
Reactant: CC[Si](CC)(CC)OC(C)(C)CCCCBr
Reactant: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[Si](CC)(CC)OC(C)(C)CCCCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 93.4 %

Procedure:
17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene (262 mg, 0.434 mmol), 1-bromo-5-triethylsilyloxy-5-methylhexane (266 mg, 0.860 mmol), a 1M potassium hydroxide methanol solution (3 ml) and tetrahydrofuran (2 ml) were subjected to reaction using a procedure similar to that of Example 31(1) (3 hours at room temperature), worked up and purified by column chromatography (hexane:toluene=4:1) to give the titled compound (320 mg, 93%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:11]=[CH:12][S:13][C:3]1=2.[F:14][C:15]([F:26])([F:25])[C:16](OC1C=CC=CN=1)=[O:17].[Al+3].[Cl-].[Cl-].[Cl-].O>ClCCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[C:11]([C:16](=[O:17])[C:15]([F:26])([F:25])[F:14])=[CH:12][S:13][C:3]1=2
Reactant: Cn1c2ccccc2c2ccsc21
Reactant: O=C(Oc1ccccn1)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: Cn1c2ccccc2c2c(C(=O)C(F)(F)F)csc21
Temperature: -10 °C

Procedure:
A mixture of 1 g of (73) and 1.1 g of 2-trifluoromethylcarbonyloxypyridine, prepared according to the literature (Keumi, T. et. al. Chem. Lett. 5 (1990) 783-6), in 25 ml of 1,2-dichloroethane, was cooled to -10° C. with stirring. 1.5 g of AlCl3 was added over 15 minutes at this temperature, the reaction mixture was stirred at 0° C. for 4 hours, and at room temperature overnight. Water was added, the phases separated, and the organic phase dried and evaporated to dryness. Purification by column chromatography on silica gel in toluene gave the pure (74). Yield 590 mg. M.p. 138°-40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C[O:12][P:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([P:13]2(=[O:12])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 130 °C

Procedure:
35 g (0.2 mol) of 4-chlorobenzoyl chloride were warmed to 90° to 100° C. under a nitrogen atmosphere. 46 g of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. The internal temperature was then increased gradually to 130° C. When the reaction was complete, the mixture was digested with 50 ml of toluene. 60 g (85% of theory) of the abovementioned substance of melting point 125° to 131° C. were obtained.