Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Br:16][C:17]1C=CC(OC(F)(F)F)=CC=1>>[Br:16][CH2:17][C:7]([C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][C:12]([F:15])([F:14])[F:13])=[O:9]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: O=C(O)c1cc(Br)ccc1OC(F)(F)F
Product: O=C(CBr)c1cc(Br)ccc1OC(F)(F)F

Procedure:
The title compound was synthesized from 5-bromo-2-trifluoromethoxy-benzoic acid (prepared from 1-bromo-4-trifluoromethoxy-benzene by the orth-lithiation method according to Schlosser et al. Eur. J. Org. Chem. 2001, 21, 3991-3997) according to the general scheme 12.
Reaction SMILES: C([NH:4][C:5]([CH2:25][OH:26])([CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)[OH:10])[CH2:6][OH:7])(=O)C.[Li+].[OH-]>CO.O>[NH2:4][C:5]([CH2:8][CH:9]([OH:10])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)([CH2:6][OH:7])[CH2:25][OH:26]
Reactant: CCCCCCCCc1ccc(C(O)CC(CO)(CO)NC(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCc1ccc(C(O)CC(N)(CO)CO)cc1

Procedure:
2-Acetamido-4-(4-octylphenyl)-2-hydroxymethylbutane-1,4-diol (21′) (0.73 g) is dissolved in methanol (10 ml). Thereto is added a solution of LiOH (0.86 g) in water (10 ml), and the mixture is refluxed under heating for 2 hr. The reaction mixture is cooled and extracted with ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate. The solvent is distilled away and the mixture is purified by silica gel column chromatography to give the title compound (22) as a colorless and amorphous powder. The resulting Compound (22) has the same physico-chemical characteristics as indicated in Example 2.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][C:18]([NH2:25])=[N:19][C:20]=3Cl)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CN(C)C.N1C(=[O:40])C2NC=NC=2N=C1N>O.C1COCC1>[CH2:1]([O:3][P:4]([CH:9]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:23]=[N:22][C:21]3[C:20](=[O:40])[NH:19][C:18]([NH2:25])=[N:17][C:16]2=3)[O:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C1CCC(Cn2cnc3c(Cl)nc(N)nc32)O1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: CN(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C1CCC(Cn2cnc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To [5-(2-Amino-6-chloro-purin-9-ylmethyl)-tetrahydro-furan-2-yl]-phosphonic acid diethyl ester (100 mg, 0.25 mmol) in water (7 mL) and THF (5 mL) was added trimethylamine (1.6 mL, 6.4 mmol). The reaction mixture was stirred at RT under nitrogen overnight. Conversion to guanine was confirmed by UV spectroscopy. The THF was removed in vacuo and the reaction mixture lyophilized. The sample was chromatographed eluting with 10% methanol/dichloromethane to give [5-(2-Amino-6-oxo-1,6-dihydro-purin-9-ylmethyl)-tetrahydro-furan-2-yl]-phosphonic acid diethyl ester as a white powder (40 mg, 42%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:2][C:1]1[NH:8][C:6](=[O:7])[C:5]2[C:4]([CH:3]=1)=[CH:12][CH:11]=[C:10]([CH3:13])[CH:9]=2
Reactant: Cc1ccc(CC#N)c(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc2cc(N)[nH]c(=O)c2c1
Yield: 88.1 %

Procedure:
2-Cyanomethyl-5-methylbenzamide (10.9 g) was suspended in methanol (100 mL), and 10% aqueous potassium carbonate solution (100 mL) was added. The mixture was heated under reflux for 1 hr. The precipitated crystals were collected by filtration to give 3-amino-7-methyl-2H-isoquinolin-1-one (9.6 g).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:12])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[CH:8][CH:7]=2.[NH2:13][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CCO>[O:12]=[C:4]1[NH:5][C:6]2[C:11](/[C:3]/1=[CH:2]/[NH:13][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: CCO
Product: NS(=O)(=O)c1cccc(N/C=C2\C(=O)Nc3ccccc32)c1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
A mixture of 0.161 g (1.0 mmol) of (3Z)-3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one 1,2 and 0.180 g (1.05 mmol) of 3-aminobenzene-1-sulfonamide in 5 ml of EtOH was heated to 80° C. for 45 min. After cooling to ambient temperature, the solid was collected by vacuum filtration and air dried to afford 3-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-methyl]amino}benzenesulfonamide as a yellow solid (0.25 g, 79%). mp>250° C.; 1H NMR (DMSO-d6): 6.82 (d, J=7.7 Hz, 1H), 6.87-6.94 (m, 1H), 6.97-7.30 (m, 1H), 7.35 (s, 2H), 7.42-7.47 (m, 1H), 7.50-7.63 (m, 3H), 7.75 (t, J=1.8 Hz, 1H), 8.59 (d, J=12.1 Hz, 1H), 10.53 (s, 1H), 10.85 (d, J=12.3 Hz, 1H); APCI-MS: m/z 316 (m+H)+. Anal. Calcd for C15H13N3O3S: C, 57.13; H, 4.16; N, 13.32; S, 10.17. Found: C, 57.01; H, 4.23; N, 13.30; S, 10.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:26][CH2:25][C@@H:24]4[C:27](O)=[O:28])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1.C([N:34](CC)C(C)C)(C)C.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:26][CH2:25][C@@H:24]4[C:27]([NH2:34])=[O:28])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(N3CC[C@@H]3C(=O)O)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cc2ccc(N3CC[C@@H]3C(N)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled 0-5° C. and stirred solution of (R)-1-[5-(3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid (I-144, 0.14 g, 0.33 mmol) in THF (2.5 mL) was added N,N-diisopropylethylamine (0.09 g, 0.69 mmol). The reaction mixture was stirred for 5 min, isobutylchloroformate (0.05 g, 0.36 mmol) was added, and the reaction stirred at 0-5° C. for 30 min. Ammonium hydroxide solution (28%, 1.0 mL, 8.0 mmol) was added, the reaction warmed to room temperature, and stirred for 0.5 h. The reaction mixture was diluted with water (5 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane, followed by preparative thin layer chromatography using 5% methanol in dichloromethane to afford 0.07 g (47%) of P-617 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 7.99 (d, J=2.8 Hz, 1H), 7.51 (br s, 1H), 7.38-7.46 (m, 3H), 7.4 (br s, 1H), 7.24-7.3 (m, 2H), 7.14 (br s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 4.39 (dd, J=9.6, 6.8 Hz, 1H), 3.7-3.9 (m, 2H), 3.84 (s, 2H), 3.72 (s, 3H), 2.26-2.48 (m, 2H) ppm; MS (APCI+): 426.9 (M+1), LC-MS: 100%.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)([OH:3])=[O:2].[CH:19](O)([CH3:21])[CH3:20]>>[CH:19]([O:2][C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=2)=[C:6]([CH2:17][CH3:18])[CH:5]=1)=[O:3])([CH3:21])[CH3:20]
Reactant: CC(C)O
Reactant: CCc1cc(C(=O)O)c2cc(C(C)C)cccc1-2
Product: CCc1cc(C(=O)OC(C)C)c2cc(C(C)C)cccc1-2

Procedure:
The acid chloride derivative (12) was produced in the same manner as in the synthesis of the above-mentioned 1-ethoxycarbonyl-3-ethyl-7-isoproylazulene (13) using 1-carboxy-3-ethyl-7-isopropylazulene (11) (1.21 g) as a starting material. Isopropanol was employed in place of the ethanol under the same reaction conditions and treatment as above to obtain the product (14) in a dark purple crystalline form, at a yield of 1.34 g (94.2%), having a melting point of 69 to 71° C.
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:34][S:35][C:36]1[O:37][C:38]2[CH:44]=[C:43]([CH:45]=O)[CH:42]=[CH:41][C:39]=2[N:40]=1>C(Cl)Cl>[Br:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH:6][CH2:45][C:43]2[CH:42]=[CH:41][C:39]3[N:40]=[C:36]([S:35][CH3:34])[O:37][C:38]=3[CH:44]=2)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CSc1nc2ccc(C=O)cc2o1
Reactant: Nc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3cc(Cl)c(Br)cc3[N+](=O)[O-])cc2o1
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 4-bromo-5-chloro-2-nitroaniline (550 mg, 2.19 mmol) from the previous step and TFA (2.26 mL) in DCM (10 mL) at −15° C. was added NaBH(OAc)3 (1.39 g, 5.37 mmol). Then a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (465 mg, 2.41 mmol) in DCM (6 mL) was added to the mixture. After complete addition, the mixture was stirred at −10° C. to 0° C. for 2 h. The reaction mixture was diluted with DCM and washed sequentially with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 5:1 to 2:1 petroleum ether/DCM to give 4-bromo-5-chloro-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline as a yellow solid (451 mg, 48.2%). 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, 1H), 8.34 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.37 (d, J=6.9 Hz, 1H), 7.19 (s, 1H), 4.76 (d, J=6.3 Hz, 2H), 2.74 (s, 3H). LCMS (ESI) m/z 428 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-])=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 85 °C
Yield: 61 %

Procedure:
In a flask equipped with a reflux condenser, the compound obtained in Example 6 1.60 g (3.77 mmol), reduced iron powder 1.05 g (18.85 mmol, 5 eq), glacial acetic acid (2 mL) and methanol (40 mL) were mixed. The mixture was refluxed in an oil bath at a temperature of 85° C. for 2.5 h. Then the iron powder was filtered of, the filtrate was diluted with ethyl acetate, washed sequentially with NaHCO3 solution and water. The organic phase was dried and concentrated to obtain yellow solid, which was identified as the title compound. Yield: 61%.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[NH:25][CH:29]=[CH:28][N:27]=1
Reactant: O=Cc1ncc[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mix carbon tetrabromide (49.8 g, 150 mmol) and methylene chloride (75 mL) and cool to 0° C. Add, by dropwise addition, a solution of triphenylphosphine (78.6 g, 300 mmol) in methylene chloride (75 mL). Stir at 0° C. for 30 minutes. Add, by dropwise addition, a solution of 2-imidazole-carboxaldehyde (7.57 g, 78.8 mmol) in methylene chloride (75 mL). Remove the cooling bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.B(F)(F)F.[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>C(OCC)C>[CH2:19]([O:18][C:16]([CH:15]1[CH2:6][CH2:7][CH:2]([NH2:1])[CH2:3][CH2:4][C:5]1=[O:8])=[O:17])[CH3:20]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: NC1CCC(=O)CC1
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CCC(N)CCC1=O

Procedure:
The appropriate 4-aminocyclohexanone in an appropriate solvent, for example diethyl ether, is treated with an appropriate Lewis acid such as boron trifluoride for about 20 minutes to about an hour at room temperature. To this solution is then added ethyl diazoacetate and the resulting mixture is stirred for about 1 hour to about 24 hours at room temperature. The resulting 2-ethoxycarbonyl-5-aminocycloheptanone is isolated by diluting the reaction mixture with aqueous sodium carbonate and extracting with a water immiscible solvent such as diethyl ether. The reaction product is then directly dissolved in dimethylsulfoxide which contains sodium chloride and water. The reaction mixture is heated to about 170° for from about 1 to about 24 hours to effect the decarboxylation. The desired 4-aminocycloheptanone is recovered by diluting the reaction mixture with water and extracting with an appropriate solvent such as diethyl ether. The reaction product may be purified by column chromatography, if desired, prior to further reaction.
Reaction SMILES: [Si]([O:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@H:18]([NH:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10])(C(C)(C)C)(C)C.F.C(=O)(O)[O-:33].[Na+]>C(#N)C>[OH:8][CH:9]([C@@H:11]1[C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C@H:18]([NH:19][C:20](=[O:33])[CH2:21][CH2:22]2)[CH2:17][C@@H:16]3[CH3:30])[CH2:13][CH2:12]1)[CH3:10]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C([O-])O
Agent: F
Agent: [Na+]
Solvent: CC#N
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of crude 20-tert-butyldimethylsilyloxy-7β-methyl-5α-4-azapregnane (25.2 g, product of Step 9) in acetonitrile (300 mL) was added an aqueous solution of hydrofluoric acid (12 mL). After stirring for 8 hr at room temperature, the reaction mixture was cooled to 0° C. and saturated sodium bicarbonate solution was slowly added. The mixture was extracted with methylene chloride (3×500 mL) and the combined extracts washed with water, saturated salt solution and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the title compound which was used without purification in the subsequent reaction.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[CH2:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][N:20]([S:38]([CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:40])=[O:39])[CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:23][CH:24]=1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCc2csc(N3CCNCC3)n2)cc1
Reactant: CC(C)CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CS(=O)(=O)N1CCN(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperazine hydrochloride (100 mg, 0.26 mmol) and DIPEA (134 mL, 3 eq.) in CH2Cl2 (5 mL) was added isobutanesulfonyl chloride (41 mL, 1.2 eq.). The mixture was stirred for 1 hour, then the reaction solution was directly purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a pale yellow solid. 1H NMR (CDCl3): δ 7.87 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.62 (1H, s), 5.05 (2H, s), 3.61 (4H, m), 3.39 (4H, m), 3.04 (3H, s), 2.78 (2H, d, J=6.8 Hz), 2.32 (1H, m), 1.12 (6H, d, J=6.8 Hz).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[OH:18][CH:17]([C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])[C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CNC(=O)c1ccccc1Br
Product: CNC(=O)c1ccccc1C(O)c1ccc(F)cc1

Procedure:
Reaction of 2-bromo-N-methylbenzamide with 4-fluorobenzaldehyde as described in the preparation of Intermediate 2A gave the title material as a white solid: mp: 133-134° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.81 (3H, d, J=5.1 Hz, NCH3), 5.89 (2H, broad s, CH and NH), 7.01 (2H, m, aromatics), 7.28-7.45 (6H, m, aromatics). Anal. Calcd for C15H14FNO2: C, 69.49; H, 5.44; N, 5.40. Found: C, 69.46; H, 5.44; N, 5.41.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCc2ccccc2)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
0.25 g (0.47 mmol) of benzyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate was hydrogenated in 10 ml of ethanol with 0.12 g of 10% palladium-on-charcoal at 50° C. and a pressure of 5 bar of hydrogen. After 5 hours the catalyst was filtered off through diatomaceous earth, and the filtrate was evaporated in vacuo. The evaporation residue was crystallized from petroleum ether/ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[C:37]2[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:35][CH:36]=2)[N:31]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:30]=1>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[N:8]([CH2:28][C:29]2[C:37]3[C:32](=[N:33][C:34]([NH:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=4)=[CH:35][CH:36]=3)[N:31]([CH2:48][C:49]3[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=3)[N:30]=2)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14]
Reactant: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ccc3c(Cn4ccc(C(F)(F)F)c(Oc5cc(Cl)cc(Cl)c5)c4=O)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(3,5-dichlorophenoxy)-4-(trifluoromethyl)pyridine-2(1H)-one (0.400 g, 1.23 mmol) and potassium carbonate (0.171 g, 1.23 mmol) suspended in dimethylformamide (5 mL) was added 3-(chloromethyl)-N,1-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-6-amine (0.522 g, 1.23 mmol) as a solution in dimethylformamide (2 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound as a solid. 1H NMR (DMSO-d6) δ 7.90 (d, J=7.3 Hz, 1H), 7.75-7.67 (m, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.34-7.30 (m, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 7.07-7.03 (m, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 6.59 (d, J=7.3 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 5.31 (s, 2H), 5.29 (s, 2H), 4.48 (d, J=4.3 Hz, 2H), 3.71 (s, 3H), 3.69 (s, 3H). HRMS (M+1)=710.1557.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].[H][H]>[Pt]=O.CO>[NH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: Nc1cc(Cl)cc(Cl)c1O

Procedure:
The starting material, 2,4-dichloro-6-nitrophenol (260 g, 1 mole, 20% in water), was mixed with methanol (2 liters) and platinum oxide catalyst, and the resulting slurry was reacted with hydrogen at 4.2 kg/cm2 (60 psi) and room temperature.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:19])(=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17].[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH:27]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][CH:29]=[O:30].Cl>C1COCC1>[CH2:15]([CH:14]([CH:29]([OH:30])[CH2:28][CH:27]([O:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:13]([OH:19])=[O:18])[CH:16]=[CH2:17]
Reactant: C=CCCC(=O)O
Reactant: CCCCCCCCCCCC(CC=O)OC1CCCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)C(O)CC(CCCCCCCCCCC)OC1CCCCO1
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
C)a) 2 ml of diisopropylamine in 30 ml of dry THF were cooled to -20° C. and thereupon 9.68 ml of butyl lithium (1.6 M/hexane) were added dropwise in such a manner that the temperature did not exceed -20° C. The mixture was subsequently stirred for 15 minutes and then cooled to -50° C. Thereafter 0.720 ml of 4-pentenoic acid in 10 ml of THF was added dropwise and the mixture was stirred at 50° C. for a further 10 minutes. The mixture was stirred at room temperature for 1 hour and subsequently again cooled to -50° C. 2 g of rac-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal in 10 ml of THF were now added dropwise and the mixture was stirred at -50° C. for a further 30 minutes, then at room temperature for 72 hours. After hydrolysis with 2N hydrochloric acid the reaction mixture was evaporated. The residue was extracted with ether. The organic phase was dried over sodium sulfate, filtered and evaporated. The material obtained was filtered through a column of silica gel. There was obtained 2-allyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl) oxy]hexadecanoic acid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]([CH2:6][CH2:7][CH:8]1[CH:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:16]=32)[CH2:11][CH2:10][CH2:9]1)=[O:5].[C:25](=O)([O-])[O-].[Na+].[Na+]>ClCCl>[ClH:1].[CH2:2]([O:3][C:4]([CH2:6][CH2:7][CH:8]1[CH:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:16]=32)[CH2:11][CH2:10][CH2:9]1)=[O:5])[CH3:25]
Reactant: COC(=O)CCC1CCCN2CCc3c([nH]c4ccccc34)C12
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCC1CCCN2CCc3c([nH]c4ccccc34)C12
Reaction time: 2 h

Procedure:
0.35 g (1 mmole) of 1-(2'-methoxycarbonyl-ethyl)-1,2,3,4,6,7.12,12b-octahydro-indolo[2,3-a]quinolizine hydrochloride are partitioned between 10 ml of dichloromethane and 3 ml of 5% aqueous sodium carbonate solution, and the aqueous phase is extracted with 2×3 ml of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The oily residue is dissolved in 15 ml of absolute ethanol, 50 mg of sodium ethoxide are added to the solution, and the mixture is boiled for 2 hours. Thereafter the mixture is cooled, the sodium ethoxide is decomposed with glacial acetic acid, and the solution is evaporated to dryness in vacuo. The residue is admixed with 10 ml of 5% aqueous sodium carbonate solution, and the mixture is extracted with 20 ml of dichloromethane. The organic phase is filtered, the filtrate is dried over magnesium sulfate, filtered again, and then evaporated in vacuo to dryness. The obtained 0.30 g of oily residue are dissolved in 2 ml of ethanol, the solution is acidified to pH 6 with ethanolic hydrochloric acid, the separated salt is filtered off, washed with ethanol and ether, and dried.