Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+].CC1(C)N(Br)C(=O)N(Br)C1=O>>[C:1]([O:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 70 °C

Procedure:
A solution containing 80 mg of 24-oxocholesterol acetate, 50 mg of NaHCO3, and 40 mg of dibromantin in 3 ml of Shellysolve B was heated to 70° C. under nitrogen for 30 min. The solution was cooled, the precipitate removed by filtration, and solvent was evaporated. The residue was redissolved in 2 ml of xylene and 0.2 ml of s-collidine and refluxed at 145° C. under nitrogen for 90 min. After cooling, the solution was diluted with benzene/ether, washed with 2% HCl and sat. NaCl solution, dried and passed through a short column of Silica Gel (10 g) using ethyl acetate/Shellysolve B (25:75) as eluent, to obtain after evaporation of solvent, a residue which contains the desired 5,7-diene as well as 4,6-diene material. This mixture was treated with p-toluenesulfonic acid (about 15 mg) in about 10 ml of dry dioxane, under N2, at 70°-75° C., for ca. 2 hr. After cooling, the mixture was diluted with ether, washed with H2O, and saturated NaHCO3 solution, dried (Na2SO4) and solvent was evaporated. After purification of the residue by preparative TLC (Silica gel, ethyl acetate/Shellysolve B, 10:90) there was obtained the desired 5,7-diene (3β-acetoxy-5,7-cholestadien-24-one).
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:30]3[CH2:29][CH2:28][N:27]([C:24]4[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=4)[CH2:32][CH2:31]3)[C:3]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][C:5]=2[O:9]1
Reactant: CC1(C)Cc2cc(Br)c(-c3cccnc3)cc2O1
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(c3cc4c(cc3-c3cccnc3)OC(C)(C)C4)CC2)cc1
Yield: 45.8 %

Procedure:
By using 3-(5-bromo-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)pyridine (160 mg, 0.526 mmol) synthesized in Reference example 11 and 1-(4-methoxyphenyl)piperazine (303 mg, 1.58 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 100 mg (yield 46%).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=C[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:26][CH:27]=[CH:28][C:29]=1[CH:24]([CH3:25])[CH3:23])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C(C)C)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15, 1), 251 (19), 250 (100) 163 (5), 122 (5), 121 (53), 114 (8), 104 (6), 103 (6), 91 (24), 77 (14).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C)C=O>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]2[CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:1]=[C:2]2[CH:11]=1
Reactant: COc1cc2nc(N)cc(OC)c2cc1OC
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(cc(OC)c3cc(OC)c(OC)cc32)n1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To 50 ml. of N,N-dimethylformamide was added 5.2 g. (0.022 mole) of 2-amino-4,6,7-trimethoxyquinoline, and 3.38 g. (0.0244 mole) potassium carbonate. To the resulting slurry was added dropwise over 15 minutes 4.76 g. (0.0244 mole) ethyl bromopyruvate. The reaction mixture was stirred at room temperature 1.75 hours, during which the mixture became orange and a solid precipitated. Upon pouring onto 400 ml. of cold water a solid material formed which was filtered, dried, then dissolved in the minimum amount of chloroform. The solution was charged onto a column made up of 100 g. of silica gel in chloroform and elution with chloroform started. After 200 ml. of eluate was collected, elution with chloroform/ethanol (98:2 v/v) was started and 200 ml. fractions were collected. Fractions 1 through 4 were combined and evaporated to dryness to afford 3.0 g. of product. Recrystallization from benzene/cyclohexane yielded 2.7 g. of colorless solid, M.P. 195°-197° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:29][NH:30][CH3:31]>CCOC(C)=O>[CH3:29][N:30]([CH3:31])[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:6][N:7]=1
Reactant: O=C(c1ccc(Cl)nc1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: CNC
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)cn1
Yield: 55.2 %

Procedure:
A solution of 1-[(6-chloro-3-pyridinyl)carbonyl]-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 51) (300 mg, 0.692 mmol) and dimethylamine (2M, 0.35 ml, 6.921 mmol) was irradiated to 100° C. for 3 h. The mixture was concentrated under vacuum, re-dissolved in DCM (20 ml), washed with water (3×10 ml), dried (Na2SO4) and concentrated under vacuum to leave the crude product. Flash chromatography (silica; 50% EtOAc in pet. ether) gave the title compound as a solid (169 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]1)=[O:34])[C:3]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=[N:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH3:1][N:2]([CH2:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34])[C:3]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=[N:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: CN(CC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1)C(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)N[C@H]1CCNC1)C(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of the compound (1.48 g), which had been obtained in (1), in anhydrous dichloromethane (8 ml), trifluoroacetic acid (4 ml) was added dropwise under ice cooling. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13](Cl)=[O:14]>CN(C=O)C>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1)=[O:14]
Reactant: Nc1ccncn1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccncn1)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 9.9 %

Procedure:
4-aminopyrimidine (0.16 g, 1.72 mmol) was added to a cooled (0° C.) mixture of NaH (0.17 g, 4.25 mmol, 60% in mineral oil) in DMF (5 mL). The resulting mixture was stirred for 20 minutes under N2 at 0° C. and then 2,6-dichlorobenzoyl chloride (0.3 g, 1.43 mmol) was added dropwise. After one hour the reaction was poured into the ice-water (20 mL). The mixture was extracted with EtOAc (2×50 mL) and the combined organic extracts were concentrated under reduced pressue. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to afford the desired product (38 mg, yield 10%). 1HNMR: (DMSO-d6, 400 MHz): 611.73 (s, 1H), 8.91 (s, 1H), 8.74 (d, J=5.6 Hz, 1H), 8.17 (d, J=5.6 Hz, 1H), 7.55-7.47 (m, 3H). LCMS (ESI) m/z: 267.8 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH2:12][C:13]2[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=2)=[N:6][CH:5]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[C:7]([O:11][CH2:12][C:13]2[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=2)=[N:6][CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cnc(OCc2nccn2C)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(OCc2nccn2C)c(-c2ccc(Cl)cc2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
5-Bromo-6-(1-methyl-1H-imidazol-2-ylmethoxy)-nicotinic acid methyl ester (0.35 g, 1.1 mmol) was dissolved in toluene (6 mL). To this solution was added (4-chloro-phenyl)-boronic acid (0.17 g, 1.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloro-methane complex (43 mg), and 2 N sodium carbonate solution (2 mL). The whole mixture was heated with stirring at 90° C. for 18 h, cooled to room temperature and eluted with ethyl acetate over 10 g ChemElut (Varian). The solvent was evaporated and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 0.29 g of the title compound as an off-white solid, MS (ISP) 358.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][NH:12][CH:13]=[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6]1=[O:16])[CH:2]([CH3:4])[CH3:3].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:31][C:27]1[N:26]=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:12]3[CH:13]=[C:9]4[C:10]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6](=[O:16])[N:7]([CH3:15])[C:8]4=[O:14])=[CH:11]3)=[CH:24][CH:23]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]cc21
Reactant: Fc1cccc(-c2ccc(CCl)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
A suspension of 1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (540 mg, 2.46 mmol), 2-(4-(chloromethyl)phenyl)-6-fluoropyridine (0.60 g, 2.7 mmol) and cesium carbonate (1.6 g, 4.9 mmol) in anhydrous DMF is stirred at room temperature for 10 minutes. The mixture is diluted with 200 mL of water, and then extracted with CH2Cl2 three times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is concentrated under vacuum. The residue is purified by silica gel chromatography to give product as pale yellow solids (705 mg, yield: 71%). MS (ESI) m/z 407.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.CC1(C)[O:30][CH:29]([CH2:31][NH2:32])[CH2:28][O:27]1>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:13]1[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:24])[CH2:15][CH2:14]1)[CH:3]=[C:2]2[NH:32][CH2:31][CH:29]([OH:30])[CH2:28][OH:27]
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC1(C)OCC(CN)O1
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCC(O)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 32-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (prepared in analogy to the one in Example 18-1) and 1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 7.78 (d, J=7.33 Hz, 1 H), 7.74 (dd, J=7.58, 1.26 Hz, 1 H), 7.62 (s, 1 H), 7.55-7.39 (m, 3 H), 7.33 (dd, J=8.34, 1.52 Hz, 1 H), 6.13 (s, 1 H), 5.24 (dd, J=16.04, 2.91 Hz, 2 H), 4.82 (d, J=7.58 Hz, 1 H), 4.76 (d, J=14.15 Hz, 2 H), 4.06-3.83 (m, 1 H), 3.75-3.63 (m, 2 H), 3.63-3.52 (m, 1 H), 3.45 (d, J=3.79 Hz, 2 H), 3.37 (td, J=6.88, 4.42 Hz, 1 H), 2.43 (s, 3 H).
Reaction SMILES: [CH3:1][P:2]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C([N-]C(C)C)(C)C.[Li+].[C:25]1([CH2:31]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C>O1CCCC1.CCOCC>[C:6]1([CH2:5][O:4][P:2]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([CH2:1][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:3])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CP(C)(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CP(=O)(CCc1ccccc1)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of [methyl(phenylmethoxy)phosphinyl]acetic acid, methyl ester (1.0 gm., 0.004 mole) in 20 ml. of tetrahydrofuran is added over 50 minutes to a solution of lithium diisopropylamide (0.008 mol.) in tetrahydrofuran maintained at -78° under argon. Following the addition, stirring is continued at -78° for 20 minutes. Phenylmethyl bromide (0.684 gm., 0.004 mol.) in tetrahydrofuran (5 ml.) is then added and the mixture is stirred for 2 hours at -78° and for one hour at 0°. The mixture is then neutralized to pH5 with acetic acid and poured into ether. The ether layer is washed with water, 5% potassium bisulfate and brine, and dried over magnesium sulfate. Evaporation in vacuo yields a residue which is chromatographed on silica gel with dichloromethane/ethyl acetate. The product, [(2-phenylethyl)(phenylmethoxy)phosphinyl] acetic acid, methyl ester (0.66 gm., 50%) is identical by TLC and NMR to that prepared in Example 6.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:45])=[CH:30][CH:29]=2)[C@H:10]([O:46][CH2:47][C@H:48]2[CH2:52][O:51]C(C)(C)[O:49]2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[Cl:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[O:38][CH2:37][CH2:36][CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:11]2[C@@H:12]([O:14][CH2:15][C:16]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:13][NH:8][CH2:9][C@H:10]2[O:46][CH2:47][C@H:48]([OH:49])[CH2:52][OH:51])=[CH:29][CH:30]=1
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3Cl)cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: COc1cc(CO[C@H]2CNC[C@@H](OC[C@H](O)CO)[C@@H]2c2ccc(OCCCOc3ccccc3Cl)cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1 (g) the (3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (R)-3-[(3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-diol as colorless oil; MS: 622.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]([C:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[N:25]([CH3:31])[N:24]=1)([CH3:22])([CH3:21])[CH3:20]>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:28]([C:26]2[N:25]([CH3:31])[N:24]=[C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:27]=2)=[O:29])=[CH:5][CH:4]=1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(C(C)(C)C)cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 4 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
4-Trifluoromethylaniline (19.39 g, 120.3 mmol) and triethylamine (13.4 g ,132 mmol) was added to 400 ml of anhydrous dichloromethane in a 1-liter round bottomed flask. This stirred solution was cooled to 4° C. using an ice water bath. 3-tert-Butyl-1-methyl-1H-pyrazole-5-carbonyl chloride 26.57 g (132 mmol) was added drop wise to this cooled solution. The reaction mixture was allowed to warm to room temperature and then was stirred at ambient temperature for 18 hours. The reaction mixture was then placed in an extraction funnel and then extracted first with 400 ml of 1N HCl and subsequently with 300 ml of water. The extraction with water was repeated. The organic layer was then stirred in a 2 liter Erlenmeyer flask and 500 ml of hexane added. The mixture was stirred for 2 hours and provided a precipitate which was collected by filtration on a Buchner funnel. The white solid was then dried in vacuum oven at 40° C. for 24 hours to give 20.63 g of pure product (52% yield). 1H NMR (400 MHz CDCl3) δ: 7.85 (s 1H) 7.74 (s 2H) 7.62 (d 1H) 6.53 (s 1H) 4.16 (s 3H) 1.33 (s 9H). MS: m/z 324.2 (M−1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([C:17]#[N:18])[N:14]=[CH:13]1.C(O)(=O)C.[OH-].[Na+]>CCO.O.[Fe]>[C:17]([C:15]1[N:14]=[CH:13][N:12]([C:4]2[CH:5]=[CH:6][C:7]([NH2:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:16]=1)#[N:18]
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C#N)c1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)ccc1-n1cnc(C#N)c1
Reaction time: 2 h

Procedure:
To a solution of 1-(2-methoxy-4-nitrophenyl)-1H-imidazole-4-carbonitrile (689 mg, 2.82 mmol) in EtOH (Ratio: 2, Volume: 15 mL) was added Acetic Acid (Ratio: 1.000, Volume: 7.50 mL) and Iron (630 mg, 11.29 mmol). The resulting mixture was brought to 100° C. and stirred for 2 h. The reaction was then diluted with water and brought to pH 8 by the addition of 1 N aqueous sodium hydroxide. This mixture was extracted with EtOAc (3×5 mL). The combined extracts were washed with water (5 mL), brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo. LC-MS (M+H)+=215.0.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][CH:8]=1>Br.O>[OH:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H]2CCCC[C@H]2N2CCCC2)c1
Agent: Br
Solvent: O
Product: Oc1cccc([C@H]2CCCC[C@H]2N2CCCC2)c1

Procedure:
(1) The above oil (19g) was boiled in 47% hydrobromic acid (60 ml) for six hours. The cooled solution was diluted with water, washed with ether, basified and ether extracted. The dried extract was evaporated. The residue was triturated with petroleum ether (b.p. 40° to 60° C) and crystallised from petroleum ether (b.p. 60° to 80° C)/ ethyl acetate to give cis-2-(3-hydroxyphenyl)-1-pyrrolidinocyclohexane (12g), m.p. 124° to 126° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH3:16])=[N:10][NH:11]2>ClCCl>[CH3:16][C:9]1[C:8]2[C:7]([OH:6])=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11][N:10]=1
Reactant: COc1cccc2[nH]nc(C)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1n[nH]c2cccc(O)c12
Reaction time: 18 h

Procedure:
A 1M solution of BBr3 (6.57 mL) was added to a solution of EXAMPLE 44A (0.71 g) in dichloromethane (30 mL), and the reaction was stirred for 18 hours. The reaction was quenched by the slow addition of methanol, and the mixture was concentrated and chromatographed on silica gel using 10% methanol/ethyl acetate.
Reaction SMILES: B(F)(F)F.[CH3:5][C:6]1[C:12]([CH3:13])=[C:11]([OH:14])[CH:10]=[CH:9][C:7]=1[OH:8].[C:15](O)(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C([O-])(=O)C.[Na+]>C1C=CC=CC=1.C(Cl)Cl>[CH3:5][C:6]1[C:12]([CH3:13])=[C:11]([OH:14])[CH:10]=[C:9]([C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]=1[OH:8]
Reactant: Cc1c(O)ccc(O)c1C
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCC(=O)c1cc(O)c(C)c(C)c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Boron trifluoride was introduced with vigorous refluxing (bath temperature 50° C.) into a mixture of 138 g (1 mole) of 2,3-dimethylhydroquinone, 370 g (1.62 moles) of myristic acid and 700 ml of methylene chloride until saturation. After standing overnight the reaction mixture was decomposed by pouring into 3 l of a 10% by weight sodium acetate solution with stirring. The methylene chloride was evaporated by means of steam. The residual oily layer solidified after cooling to a melt cake that was isolated by decantation. It was melted up and added with stirring to 2 l of high-boiling benzine. The precipitate was filtered with suction and washed with benzine (boiling range: 50°-75° C.). After being dried the precipitate was stirred with acetonitrile and filtered with suction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:30])=[C:6]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:12]2=[O:29])[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2].[CH2:31]([N:33]([CH2:39][CH3:40])[CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH3:32].C(OCC)(=O)C.C(O)C.C(N(CC)CC)C>O1CCOCC1>[CH:24]1([N:13]2[C:14]3=[N:15][C:16]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][N:33]([CH2:39][CH3:40])[CH2:31][CH3:32])=[N:17][CH:18]=[C:19]3[CH2:20][N:11]([C:6]3[C:7]([F:10])=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=3[F:30])[C:12]2=[O:29])[CH2:27][CH2:28][CH2:26][CH2:25]1
Reactant: CCOc1ccc(F)c(N2Cc3cnc(S(C)=O)nc3N(C(CC)CC)C2=O)c1F
Reactant: CCN(CC)CCCCN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1ccc(F)c(N2Cc3cnc(NCCCCN(CC)CC)nc3N(C3CCCC3)C2=O)c1F
Yield: 86 %

Procedure:
Using Procedure K, described above, 0.74 g (1.69 mmol) of 3-(3-ethoxy-2,6-difluoro-phenyl)-1-(1-ethyl-propyl)-7-methanesulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 4-(diethylamino)butylamine in 20 mL of dioxane were reacted. Chromatography with 9:1:0.5 ethyl acetate/ethanol/ triethylamine gave 0.75 g (86%) of the title compound as a solid: mp 129° C.–130° C. 130° C. MS (APCI) (m+1)/z 5127.47. Analysis calculated for C27H38N6F2O2: C, 62.77; H, 7.41; N, 16.27.Found: C, 62.79; H, 7.35; N, 16.10.