Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:21])[CH:9]=1)([CH3:3])[CH3:2].Cl[C:25]1[N:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:27][N:26]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH2:20][NH:21][C:25]2[N:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:29][N:30]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCCOc1cnc(Cl)nc1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(OCCCC(=O)OC(C)(C)C)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
C-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (1.54 g) is dissolved in toluene (25 ml), and thereto are added tert-butyl 4-(2-chloro-pyrimidin-5-yloxy)-butyrate (1.96 g), palladium acetate (II) (195 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (543 mg), tetra-n-butyl ammonium iodide (359 mg) and sodium tert-butoxide (560 mg), and the mixture is stirred under nitrogen flow at 85° C. overnight. The reaction solution is allowed to cool to room temperature, and thereto is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=47:3→3:1) to give tert-butyl 4-{2-[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (895 mg). MS (m/z): 560 [M+H]+
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]1[C:13](=[O:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]1[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]1[C:13](=[O:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C(=O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1C(=O)C[C@H](O)[C@@H]1CCCCCCC(=O)O

Procedure:
A solution of PGD2 (Example 16) in ethyl acetate is shaken with hydrogen at about one atmospheric pressure at ambient temperature in the presence of a 5 percent palladium-on-charcoal catalyst. Hydrogenation is stopped when one equivalent of hydrogen per equivalent of PGD2 is absorbed. Catalyst is removed by filtration and the filtrate is then concentrated under reduced pressure and the residue chromatographed on silica gel, eluting with ethyl acetate and Skellysolve B. Fractions shown to contain pure product are combined yielding the title compound.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](I)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)CCC>CN(C)C=O.[Cu]=O>[F:1][C:2]1[N:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:5]([O:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1ccc(F)nc1I
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: COc1ccc(F)nc1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
6-Fluoro-2-iodo-3-methoxypyridine (84 mg), tetrakistriphenylphosphine palladium (0) (38 mg), and copper(II) oxide (53 mg) were suspended in N,N-dimethylformamide (2 ml). 2-Tributylstannylpyridine (244 mg) was added to the suspension, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature. The reaction solution was then filtered, the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 6-fluoro-3-methoxy-[2,2′]bipyridine (12 mg, yield 18%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[H-].[Na+].[CH3:14]I>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:11]([CH3:14])[C:10]2[C:5]([N:4]=1)=[N:6][CH:7]=[CH:8][CH:9]=2
Reactant: CI
Reactant: OCc1nc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2ncccc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 45 g of 2-hydroxymethyl-3H-imidazo[5,4-b]pyridine, 13.17 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 20.7 ml of methyl iodide and 1.43 liter of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 1:1 by volume as the eluent, to give 3.24 g of the title compound, melting at 130°-132° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[C:22]([N+:23]([O-])=O)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.O>C(O)(=O)C.C(O)C.C(O)(=O)C.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:23][C:22]1[C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:9])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1cccc(F)c1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cccnc1Nc1ccccc1C(=O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Under an atmosphere of nitrogen, 30 g of titanium trichloride was added portionwise (cautiously) with stirring to 200 ml of ice. The resulting solution was added all at once to a stirred solution of 10.0 g (0.0297 mole) of (3-fluorophenyl)[2-[(3-nitro-2-pyridinyl)amino]phenyl]methanone in 150 ml of acetic acid: ethanol (1:1) and 150 ml of acetic acid: water (1:1). After 30 min stirring, the reaction mixture was poured into one liter of water. The mixture was filtered and the resulting filter-cake was suspended in 100 ml of water. The mixture was again filtered and the filter-cake (10.0 g) was partially dissolved in 100 ml of hot methanol. The solution was basified with 25 ml of concentrated ammonium hydroxide, stirred for an additional 15 min and then diluted with 500 ml of water. The mixture was extracted three times with 75 ml portions of methylene chloride. The combined methylene chloride extracts were washed with 50 ml of water, dried over sodium sulfate and concentrated in vacuo. The residue (6.9 g) was twice recrystallized, treating once with charcoal, from ethyl acetate-isopropyl ether to give 4.5 g (49%) of a dark gold solid, m.p. 135°-137° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33](O)=[O:34])[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:34])[CH2:27][CH2:26]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: CN1CCN(c2ccccc2C(=O)O)CC1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccccc2N2CCN(C)CC2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-(4-Methyl-piperazin-1-yl)-benzoic acid. LC-MS (basic): tR=0.86 min; [M+H]+=530.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12](Cl)=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].[CH3:28][NH:29][CH3:30].CCCCCCC.C(OCC)(=O)C.O>O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([N:29]([CH3:30])[CH3:28])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:25])([F:27])[F:26])(=[O:22])=[O:23]
Reactant: CNC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: CN(C)c1cc(C(F)(F)F)cc(Cl)c1-n1nc(C#N)c(S(=O)(=O)C(F)(F)F)c1N
Temperature: 200 °C

Procedure:
To a mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonylpyrazole (0.5 g, 1.1 mmol) in dioxan (5 ml) was added dimethylamine (aqueous solution 60%, 0.33 g, 4.4 mmol). The mixture was heated at 200° C. for 30 min in the microwave oven (Smith Synthesizer) under pressure. After extractive workup (heptane-ethyl acetate, water) and column chromatography the title product was obtained (0.18 g), mp 197° C., 1H-NMR: 2.75 (6H), 6.27 (2H), 7.13 and 7.24 (2H); 19F-NMR: −64.0, −80.6.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2)[NH2:2].CN(/[CH:16]=[C:17](/[C:22](=O)[CH:23]1[CH2:25][CH2:24]1)\[C:18]([O:20][CH3:21])=[O:19])C>>[CH3:21][O:20][C:18]([C:17]1[CH:16]=[N:2][N:1]([C:3]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:4]=2[CH:5]=[CH:6][CH:7]=[N:8]3)[C:22]=1[CH:23]1[CH2:25][CH2:24]1)=[O:19]
Reactant: NNc1cccc2ncccc12
Reactant: COC(=O)/C(=C\N(C)C)C(=O)C1CC1
Product: COC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
combining 5-hydrazinoquinoline made by a method of this invention with α-[(dimethylamino)methylene]-β-oxo-cyclopropanepropanoic acid, (αZ)-methyl ester to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11]([OH:13])=[O:12])[CH2:5]2.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:18][C:19]([CH3:24])=[CH:20][C:21](Cl)=[O:22].Cl>[N+](C1C=CC=CC=1)([O-])=O.C(Cl)Cl.C(=S)=S>[CH3:18][C:19]1([CH3:24])[CH2:20][C:21](=[O:22])[C:10]2[CH:9]=[C:8]3[CH2:7][CH:6]([C:11]([OH:13])=[O:12])[CH2:5][C:4]3=[CH:3][C:2]=2[O:1]1
Reactant: CC(C)=CC(=O)Cl
Reactant: O=C(O)C1Cc2ccc(O)cc2C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CC1(C)CC(=O)c2cc3c(cc2O1)CC(C(=O)O)C3
Temperature: 90 °C

Procedure:
9.8 g (5.5 mmol) of 5-hydroxy-indan-2-carboxylic acid are dissolved in 20 ml of nitrobenzene and 20 ml of carbon disulphide and 16.12 g (121 mmol) of aluminum trichloride are added in portions. 7.8 g (66 mmol) of dimethylacryloyl chloride in 20 ml of nitrobenzene are then added dropwise and the mixture is heated to 90° C. for 3 h. After cooling, 40 ml of concentrated hydrochloric acid and 40 g of ice are added and the mixture is shaken twice with 100 ml of CH2Cl2 each time. The combined CH2Cl2 phases are evaporated, the nitrobenzene is distilled off in a water jet vacuum and the residue is taken up in 100 ml of 10% strength NaOH solution. The NaOH phase is shaken twice with 100 ml of CH2Cl2 each time, then acidified using concentrated HCl solution with ice cooling and extracted 3 times using 100 ml of CH2Cl2 each time. After drying over Na2SO4, the solution is evaporated and the residue is flash chromatographed on silica gel (eluent: CH2Cl2 /acetone 10:1)
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:14]#CBr>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]#[N:14])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2cccc(Cl)c2CC1
Reactant: N#CBr
Solvent: Cc1ccccc1
Product: N#CN1CCc2cccc(Cl)c2CC1

Procedure:
A stirred solution of 1.2 g. of 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 30 ml. of toluene was treated at 50° by dropwise addition with a solution of 0.7 g. cyanogen bromide in 25 ml. of toluene. Following the addition, the mixture was stirred and heated at 50° for one hour. A stream of nitrogen was passed over the surface of the solution during the reaction. The mixture was cooled, filtered and the filtrate concentrated in vacuo to yield 6-chloro-3-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine melting at 81°-82° from hexane-ether solution.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][S:26]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27].CC(C)([O-])C.[K+].O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:25][S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
A solution of 1-benzyl-4-(4-nitrophenoxy)piperidine (3.00 g, 9.60 mmol) and 1-chloromethanesulfonyl-naphthalene (2.35 g, 9.76 mmol) in THF was chilled in an ice bath, treated dropwise with 1.0 M potassium tert-butoxide in THF (20 mL, 20 mmol), stirred at ambient temperature for 1 hour, 20 minutes under nitrogen, poured into water and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 40-80% ethyl acetate in hexane to give 1-benzyl-4-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-piperidine as a brown gum/foam, 2.36 g (47.6% yield), Mass spectrum (+EI, [M+H]+) m/z 517. 1HNMR (500 MHz, DMSO-d6): δ8.44-8.47 (m, 1H), 8.28 (d, 1H, J=8.17 Hz), 8.06-8.09 (m, 1H), 7.91-7.96 (m, 2H), 7.59-7.68 (m, 3H), 7.20-7.32 (m, 5H), 7.03 (dd, 1H, J=9.15 Hz and 2.80 Hz), 6.62 (d, 1H, J=2.81 Hz), 5.24 (s, 2H), 4.07-4.10 (m, 1H), 3.44 (s, 2H), 2.49-2.53 (m, 2H), 2.05-2.09 (m, 2H), 1.65-1.69 (m, 2H), 1.38-1.46 ppm (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][CH:10]([C:13]#[N:14])[C:11]#[N:12])=[O:8])=[CH:5][CH:4]=1.Cl.O>C(O)(=O)C>[NH2:12][C:11]1[O:8][C:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)=[CH:9][C:10]=1[C:13]#[N:14]
Reactant: COc1ccc(C(=O)CC(C#N)C#N)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2cc(C#N)c(N)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a suspension of α-((4-methoxybenzoyl)methyl)malononitrile (9.66 g, 45.1 mmol) in acetic acid (50 ml) was added conc. hydrogen chloride (11,3 ml). The mixture was stirred at room temperature for 2 hours, and then poured into water. The resultant precipitation was filtrated, washed with water and ethanol, and dried under reduced pressure to give the Intermediate of Example 2(A) (5.54 g, 56%) as a solid. 1H NMR (400 MHz, CDCl3) ppm 3.83 (s, 3H), 4.74 (brs, 2H), 6.39 (s, 1H), 6.90 (m, 2H), 7.42 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])[CH3:21]>CN(C)C=O>[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)([CH3:22])[CH3:21]
Reactant: CC(C)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C

Procedure:
To a vial was added 4-fluoronitrobenzene (1.41 g, 1.06 mL, 0.01 mol), N,N-diisopropylethylamine (1.92 mL, 0.011 mmol), isopropylpiperazine (1.41 g, 0.011 mmol), and N,N-dimethylformamide (10 mL). Mixture was heated at 100° C. for 48 h in a sealed tube. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via silica gel column chromatography (gradient elution with 0 to 10% methanol in dichloromethane) to afford 1-isopropyl-4-(4-nitrophenyl)piperazine.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[C:31]([CH:35]1[CH2:40][CH2:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([CH:35]1[CH2:40][CH2:39][C:38]([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:12][CH2:13][N:14]([C:17]5[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:15][CH2:16]4)[NH:7][C:6]=3[CH:5]=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=2)=[CH:37][CH2:36]1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Product: CC(C)(C)C1CC=C(c2cc(C(F)(F)F)cc3[nH]c(N4CCN(c5ncccc5C(F)(F)F)CC4)nc23)CC1

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (250 mg, 0.5 mmol, Example 7) and 2-(4-tert-butyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane from step (b) above (200 mg, 0.76 mmol) reacted under the conditions of Example 10 to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 552 (M+1). M.p. 96-97.7° C.
Reaction SMILES: [OH:1][C:2]1[CH:7](C(OCC)=O)[CH:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:25]([F:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=3)=[CH:15][CH:14]=2)[CH2:5][C:4](=[O:31])[CH:3]=1.[OH-].[Na+]>>[OH:1][C:2]1[CH2:7][CH:6]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[C:25]([F:26])=[CH:24][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:22][N:21]=3)=[CH:17][CH:18]=2)[CH2:5][C:4](=[O:31])[CH:3]=1
Reactant: CCOC(=O)C1C(O)=CC(=O)CC1c1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C1C=C(O)CC(c2ccc(Oc3ncc(C(F)(F)F)cc3F)cc2)C1
Temperature: 25 °C

Procedure:
A solution of 33.1 g (0.0753 mol) of 3-hydroxy-5-(4-(5-(trifluoromethyl)-3-fluoro-2-pyridyloxy)-phenyl)-4-(carboethoxy)cyclohex-2-en-1-one in 300 mL (0.30 mol) of 1N sodium hydroxide was heated at 60° C. for 6 hours and cooled to room temperature. The solution was filtered and the filtrate acidified with 30 mL of concentrated HCl and the desired product crystallized out of the solution. The crude product was recovered by filtration and the filtrate thoroughly washed with water and dried in vacuo at 100° C. leaving 23.9 g (86.6 percent of theoretical) of the product which melted at 162°-167° C. The product was further purified by heating it in refluxing methylene chloride, cooling anf filtering. The product was recovered in a yield of 19.6 g (71.0 percent of theoretical) melted at 173°-176° C., with decomposition; Rf -0.48 (silica gel, 75:24:1 EtOAc:hexane:HOAc), 1H NMR (CDCl3 +D6 --DMSO): δ 2.35-2.80 (m, 4H, --CH2 --), 3.40 (m, 1H, --CH--), 5.41 (s, 1H, vinyl), 7.1-8.37 (m, 6H, ArH), 9.5-11 (b, 1H, --OH).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[F:14].[CH3:16][O-:17].[Na+]>CO>[F:14][C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([O:17][CH3:16])=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of methyl-2,5-difluoro-4-nitrobenzoate (1 g, 4.6 mmol) in methanol (10 mL) was added sodium methoxide (95%, 393 mg, 6.9 mmol). The reaction mixture was stirred at room temperature overnight. It was then concentrated, acidified with HCl. Solid was filtered and dried to give the product as light yellow powder (728 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H) 7.66 (d, J=4 Hz, 1H) 8.01 (d, J=8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24](O)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1.[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:21][CH:20]=[C:19]([C:22]#[N:23])[N:18]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]([N:34]3[CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32][CH2:33]3)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: CCN1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN1CCN(C(C)(C)c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)n2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-amide (as prepared in the previous step), N-ethylpiperizine, and thionyl chloride in DCM solvent according to the procedure in Example 14, step (e).
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C@H:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.C([O:34][C@@H:35]1[C@@:63]2(C)[C:39](=[CH:40][CH2:41][C@@H:42]3[C@@H:62]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(OC(=O)C)C(C)C)C[C@@H](OC(=O)C)C1)(=O)C>>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C@H:17]([O:21][C:2](=[O:1])[C:27]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:26]=2)[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:30][C:35](=[O:34])[C:63]2[CH:62]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: CC(C)[C@@H](O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Product: CC(C)[C@H](CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1

Procedure:
The 1α,3β,24(S)-trihydroxycholesta-5,7-diene obtained in Example 16 was benzoylated in quite the same way as in Example 22, (A) to form 1α-hydroxy-3β,24(S)-dibenzoyloxycholesta-5,7-diene. 15 mg of this product was treated in quite the same way as in Example 25 to afford 1.5 mg of a product whose properties corresponded with 1α,24(S)-dihydroxycholecalciferol. From this, it was confirmed that the product obtained after the isomerization was 1α-hydroxy-24(S)-benzoyloxycholecalciferol-3β-benzoate.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[N:13][C:14]=1[CH3:15])[NH:11][C:10](=[O:16])[C:9]([C:17]([O:19]CC)=[O:18])=[CH:8]2)(=[O:3])[CH3:2].[OH-].[K+].C(O)(=O)C>O>[C:1]([NH:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[N:13][C:14]=1[CH3:15])[NH:11][C:10](=[O:16])[C:9]([C:17]([OH:19])=[O:18])=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C)c(NC(C)=O)c(C)nc2[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(C)nc2[nH]c(=O)c(C(=O)O)cc2c1C

Procedure:
Ethyl 6-acetamido-5,7-dimethyl-1,8-naphthyridin-2(1H)-one-3-carboxylate (321 mg., 1 mmole), prepared as described in Example 28, is dissolved in water (2 ml.) to which has been added 40% w/w potassium hydroxide solution (0.28 ml.) and the clear solution heated on a steam bath for 2 hours. The solution is cooled and acidified to pH 5.5 with dilute acetic acid giving initially a gelatinous precipitate which becomes denser and more crystalline on standing at ambient temperature. The product is collected, washed with water and dried yielding 195 mg. (66%) of product, m.p. 305° C. (dec.). The product is purified by dissolving in dilute ammonium hydroxide solution, treating with charcoal and reprecipitating with acetic acid with no change in melting point.