Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22]([OH:24])=[O:23])[CH2:10]2)=[CH:5][CH:4]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22]([OH:24])=[O:23])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: O=C(O)C1=NN(c2ccc(Cl)cc2Cl)[C@@H](c2ccc(Cl)cc2)C1
Agent: Cl
Product: O=C(O)C1=NN(c2ccc(Cl)cc2Cl)[C@H](c2ccc(Cl)cc2)C1
Yield: 354.9 %

Procedure:
The residue obtained from the evaporation of the mother liquor obtained from the crystallisation of (R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid with (+)-Cinchonine was treated with 6N HCl as described above for obtaining the free acid After evaporating the organic phase 23.63 g of a mixture with a theoretical composition of 13.34 mmoles of (R)-5-(4chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid and 47.34 mmoles of (S)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid were obtained. Said mixture, dissolved in 118 ml of acetone, was added on top of a solution of 18.7 g (47.4 mmoles) of brucine in 650 ml of acetone, stirred for a couple of minutes and left to crystallize at room temperature overnight. A creme-coloured solid was obtained that was filtered off and dried to yield 28 g (77.5% relative to the (S)-salt).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a stirred solution of 4-bromo-2-fluorophenyl-methanamine (5.834 g, 28.592 mmol) in pyridine was added methanesulfonyl chloride (4.2 mL, 54.325 mmol) at 0° C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(4-bromo-2-fluorobenzyl)methanesulfonamide (7.597 g) was obtained as 93% yield.
Reaction SMILES: [BH4-].[Na+].[I-].[CH2:4]([O:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][N+:24]([CH3:27])=[CH:23][C:22]=2[O:28][CH3:29])=[CH:17][C:16]=1[O:30][CH:31]([CH3:33])[CH3:32])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:29][O:28][C:22]1[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[O:11][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[C:16]([O:30][CH:31]([CH3:33])[CH3:32])[CH:17]=1
Reactant: COc1c[n+](C)ccc1-c1ccc(NC(=O)OCc2ccccc2)c(OC(C)C)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [I-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COC1=C(c2ccc(NC(=O)OCc3ccccc3)c(OC(C)C)c2)CCN(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
486 mg of NaBH4 are added, in portions, to a suspension of 4.57 g of 4-[4-{[(benzyloxy)carbonyl]amino}-3-(propan-2-yloxy)phenyl]-3-methoxy-1-methylpyridinium iodide in 100 ml of ethanol brought to 5° C. The reaction medium is stirred for 1 h 30 at ambient temperature. 50 ml of water, 50 ml of a saturated aqueous sodium bicarbonate solution and 100 ml of ethyl acetate are added. The two phases are separated, and the aqueous phase is washed with twice 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and (MeOH+10% NH4OH) (99/1 to 90/10). 1.87 g of benzyl [4-(5-methoxy-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate are obtained in the form of an orangey-coloured oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: CCCCCCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Solvent: CCOC(C)=O
Product: CCCCCCOC(Cc1ccc(O)cc1)C(=O)OC

Procedure:
2-Hexyloxy-3-(4-hydroxyphenyl)propanoic acid methyl ester was prepared from 3-(4-benzyloxyphenyl)-2-hexyloxypropanoic acid methyl ester in ethyl acetate using the same method as described in Example 14b.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5](O)(=[O:15])[C:6]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[C:8]([OH:9])[CH:7]=1.[Na+].[Cl-]>OS(O)(=O)=O>[OH:3][CH2:2][CH2:1][O:4][C:5](=[O:15])[C:6]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[C:8]([OH:9])[CH:7]=1
Reactant: OCCO
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: O=C(OCCO)c1cc(O)c(O)c(O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
A mixture consisting of ethylene glycol (105 g, 1.11 mol), gallic acid (28.5 g, 168 mmol), and concentrated H2SO4 (10 drops) was stirred at 90° C. overnight before mixing with ice water (1500 ml). Upon adding NaCl (100 g), the solution was extracted with ethyl acetate (150 ml×4). The combined organic portion was evaporated to dryness to obtain (m) (9.98 g, 28%). Proton-NMR spectral data (DMSO-d6), δ (ppm): 3.64 (t, HOCH2CH2, 2H), 4.15 (t, ArOCH2CH2, 2H), 6.93 (s, aromatic, 2H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[C:15]2([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(Nc2nc(Cl)ncc2Cl)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (500 mg, 2.73 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (687.37 mg, 2.86 mmol) in EtOH (20 mL) was added Et3N (552.50 mg, 5.46 mmol) and the reaction mixture was stirred at rt overnight. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 5/1) to give the product as a white solid (930 mg, 88.2%).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6](=[S:8])[NH:5][N:4]=1)[CH3:2].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30]Cl)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30][S:8][C:6]3[NH:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=3)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: CCc1n[nH]c(=S)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nnc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)[nH]1
Reaction time: 18 h
Yield: 72.7 %

Procedure:
Dissolve 5-ethyl-1H-1,3,4-triazole-2-thione (92 mg, 0.71 mmol) in anhydrous DMF (5 mL). Add sodium hydride (40 mg, 0.925 mmol, 60% dispersion in mineral oil) at room temperature under a nitrogen atmosphere and stir for 10 min. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (210 mg, 0.65 mmol) in anhydrous DMF (5 mL) at room temperature over 3 min and stir under nitrogen for 18 h. Quench with saturated aqueous NH4Cl (ca. 1 mL) and pour into water (100 mL). Extract the aqueous phase with EtOAc (3×25 mL) and wash the combined organic extracts with brine. Dry the organic solution over Na2SO4, filter and concentrate in vacuo to obtain crude 3-tert-butoxycarbonyl-7-chloro-6-(5-ethyl-1H-1,3,4-triazol-2-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 73%) suitable for use without further purification. MS (ES+) m/z: 423 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[C:23]([CH2:34][CH3:35])(C(OCC)=O)[C:24]([O:26]CC)=[O:25])[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH:23]([CH2:34][CH3:35])[C:24]([OH:26])=[O:25])[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CC)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
13B (820 mg, 1.685 mmol) was dissolved in EtOH (20 mL), sodium hydroxide (8.43 mL, 16.85 mmol) was added. The reaction mixture was stirred at 100° C. for 1 h. The mixture was concentrated, acidified to pH 2 with 1N HCl; extracted with EtOAc. The organic layer was washed with brine, dried and concentrated gave 13C (620 mg, 1.605 mmol, 95% yield). MS (ESI) m/z: 386.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[CH:9]3[CH2:14][CH:6]([CH:7]=[CH:8]3)[C:5]=2[C:4]=1[OH:15].CCOC(C)=O.C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[C:4](=[O:15])[C:5]2[CH:6]3[CH2:14][CH:9]([C:10]=2[C:11](=[O:13])[CH:12]=1)[CH:8]=[CH:7]3
Reactant: COc1cc(O)c2c(c1O)C1C=CC2C1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC1=CC(=O)C2=C(C1=O)C1C=CC2C1
Yield: 90.3 %

Procedure:
To a vigorously stirred solution of NaIO4 (471 mg, 2.20 mmol; Baker) in water (15 mL), there was added solid 1,4-dihydro-6-methoxy-1,4-methanonaphthalene-5,8-diol (48, 150 mg, 734 μmol) in one portion. The reaction immediately became orange and a precipitate formed. The reaction was allowed to stir at rt for 15 min at which point TLC analysis (10% EtOAc, 90% CHCl3) indicated total consumption of 48. The reaction mixture was extracted with CHCl3 (3×15 mL). The extract was washed with half saturated brine (1×25 mL), filtered through cotton and the solvent removed in vacuo to yield a gummy yellow solid. This was triturated with hexanes (2 mL) and dried in vacuo to yield 49 as a yellow powder (134 mg, 90%, pure by TLC and 1H NMR); mp 117°-118° C.; 1H NMR (CDCl3) δ2.26 (d, J=7.2 Hz, 1H), 2.33 (d, J=6.9 Hz, 1H), 3.79 (s, 3H), 4.10 (m, 2H), 5.70 (s, 1H), 6.86 (m, 2H). Note: this material decomposes if stored for extended periods at rt.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]1[O:33][C:32]2[CH:31]=[CH:30][C:15]([CH2:16][C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[S:26](Cl)(=[O:28])=[O:27])=[CH:14][C:13]=2[O:12]1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[CH:31][C:32]2[O:33][CH2:11][O:12][C:13]=2[CH:14]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1c(Cc2ccc3c(c2)OCO3)sc2ccccc12
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride (1.1 mmoles, 0.40 g) and THF (7 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from chloroform and hexanes provided 0.23 g (45%) of a tan crystalline solid, m.p. 164°-165° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1Br)=[O:11].[C:18](=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:18][C:15]1[S:14][C:13]2[O:1][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[NH:9][C:10](=[O:11])[C:12]=2[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2Br)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)Oc1sc(C)cc1C(=O)N2
Temperature: 145 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of N-(2-hydroxy-4-methylphenyl)-2-bromo-3-thiophenecarboxamide (3.4 g) in dimethyl sulfoxide (30 ml) was added potassium carbonate (2.9 g) and the mixture was stirred at 140-150° C. for 1 hour. The reaction system was cooled to room temperature and the reaction mixture was poured into water. The precipitated crystals were collected by filtration, washed with water and purified by silica gel column chromatography (chloroform) to give 2, 8-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.2 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=C(O)C1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(C(=O)O)CC3)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 9.2 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 500 mg, 1.51 mmol) and piperidine-4-carboxylic acid (390 mg, 3.02 mmol) in Dioxane (15 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (59 mg, 50%). 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.00 (d, 2H), 7.60 (d, 2H), 7.42 (s, 1H), 6.35 (d, J=2.3 Hz, 1H), 4.30-4.39 (m, 2H), 3.20 (td, J=11.7, 1.6 Hz, 2H), 2.57-2.69 (m, 1H), 1.97-2.07 (m, 2H), 1.70-1.83 (m, 2H), 1.45 (s, 6H). ESI-MS: m/z 424.0 (M+H)+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][C:16]([CH2:24][OH:25])([CH2:17]3)[CH2:15]1)[CH2:21]2>C(Cl)Cl.C1COCC1.C(OCC)C>[C:14]12([CH:13]=[O:12])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][C:16]([CH:24]=[O:25])([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: OCC12CC3CC(C1)CC(CO)(C3)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=CC12CC3CC(C1)CC(C=O)(C3)C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of pyridinium chlorochromate (PCC, 0.850 g, 4.0 mmol) in CH2Cl2 (˜10 mL) was added a suspension of 1,3-bis(hydroxymethyl)adamantane (0.196 g, 1.0 mmol) in anhydrous THF (˜5 mL). The reaction mixture was stirred at room temperature for 2.5 hours, whereupon it was diluted with anhydrous diethyl ether (˜50 mL) and filtered through a plug of florisil. The filtrate was evaporated in vacuo to afford dicarbaldehyde (0.183 g, 95%). According to GC analysis (DB 210, 150° C.), product had a purity of over 95%. Since dialdehyde is unstable and decomposes on silica gel, the sample was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[C:5]2[N:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7](=[O:17])[C:8]3[CH:13]=[N:12][C:11]4[NH:14][N:15]=[CH:16][C:10]=4[C:9]=3[N:4]2[N:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[C:25]([N:14]1[C:11]2[N:12]=[CH:13][C:8]3[C:7](=[O:17])[N:6]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:5]4[N:4]([N:3]=[C:2]([CH3:1])[CH:24]=4)[C:9]=3[C:10]=2[CH:16]=[N:15]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4[nH]ncc4c3n2n1
Solvent: c1ccncc1
Product: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4c(cnn4C(=O)c4ccccc4)c3n2n1

Procedure:
0.01 mol. of 2-methyl-4-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one and 0.02 mol. of benzoyl chloride are stirred overnight in 50 ml. of dry pyridine at room temperature. On addition of 50 ml. of water, 8-benzoyl-2-methyl-4-phenyl-4H-pyrazolo[1,5-a]pyrazolo4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is filtered off.
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3](O)=[O:4].[P](Cl)(Cl)(Cl)[Cl:11]>>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([Cl:11])=[O:4]
Reactant: C=CCC(F)(F)C(=O)O
Reactant: Cl[P](Cl)(Cl)Cl
Product: C=CCC(F)(F)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask with a distillation head, 57.2 g (0.42 mol) of 2,2-difluoro-4-pentenoic acid are slowly added dropwise to 102.0 g of phosphorus tetrachloride. After stirring for 20 minutes at RT, the reaction mixture is distilled, 42.1 g (65%) of the acid chloride passing over as a colourless oil at 92°-98° C./988 mbar. 1H-NMR (60 MHz, CDCl3): 6.0-5.0 (m, 3H); 2.9 (d x t, J=6; 16 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][Cl:14]
Reactant: OCc1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: ClCc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a stirred solution of 2,4,6-trichlorobenzylalcohol (10.0 g; 47.3 mmol) in chloroform (100 ml) kept under nitrogen atmosphere, thionyl chloride (6.07 ml; 85.1 mmol) was added slowly at 0° C. over a period of 15 minutes followed by catalytic amount of DMF. The reaction mix was allowed to stir at ambient temp for 3 hours. The reaction mixture was quenched with 50 ml of water; the aqueous layer was extracted with DCM (3×100 ml). The combined organic layer was washed with 5% sodium bicarbonate solution (2×50 ml) followed by brine (50 ml) and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure. 10.9 g (100% of theory) of 1,3,5-trichloro-2-chloromethyl-benzene was obtained in form of a white solid.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.CO.C(Cl)(=O)C>[Pd].C(Cl)(Cl)Cl>[OH:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1
Reactant: c1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Agent: [Pd]
Solvent: CC(=O)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OC[C@H]1COCc2nc3cnc4ccccc4c3n21
Reaction time: 264 h
Yield: 35.6 %

Procedure:
(11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (7.5 g, 22 mmol) was added to a mixture of methanol (270 mL) and acetyl chloride (3.0 mL, 43 mmol) in a pressure bottle. Palladium on carbon (10%, 1.5 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 11 days, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol. The combined filtrates were treated with 2 mL of 50% aqueous NaOH solution and the mixture was concentrated under reduced pressure to afford an orange oil. Chromatography (SiO2, 0-30% CMA/CHCl3) gave an oil that was concentrated from acetonitrile under reduced pressure to give 2.0 g of (11S)-11-hydroxymethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:30]3[CH2:31][CH2:32][N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)=[CH:20][C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1oc2ccc(CN3CCN(c4ccccc4)CC3)cc2c1-c1ccccc1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with N-phenylpiperazine in ethanol to provide yellow needles of 4-(2-nitro-3-phenyl-5-benzofuranylmethyl)-1-phenylpiperazine, m.p. 155°-157° C., having the structure ##STR12##
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[CH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C1COCC1>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(C=C4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(CC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Reaction time: 48 h
Yield: 74.1 %

Procedure:
Into a 100 mL round bottom flask was added ethyl 1-((6-((4-(tert-butyl)cyclohexylidene)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylate (200 mg, 0.45 mmol), Pd/C (20%, 20 mg) and THF (30 mL). The reaction mixture was flushed 3 times with hydrogen gas and stirred for 48 h under H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuum to afford the desired compound ethyl 1-((6-((4-(tert-butyl)cyclohexyl)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylate as purple oil (150 mg, yield: 30%). ESI-MS (M+1)+: 450.3.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:19][CH2:18]1)C(=O)OC(C)(C)C>>[CH3:8][NH:9][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:19][CH2:18]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (TFA) (2 ml) was added to a solution of 1,1-dimethylethyl methyl[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]carbamate D12 (287 mg). The mixture was stirred at room temperature during one hour. The solvent was evaporated and the mixture was checked by LCMS, the LCMS showed the desired product. Then the mixture was purified by a cartridge SCX (5 g). The fraction containing the product was evaporated, triturate with diethyl ether to give the title product D13 in 177 mg. LCMS [M+H]+231.99@0.32 min (2 min run)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:42]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Br:42])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Oc2ccc(CCBr)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of 2-(4-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethanol (300 mg, 0.947 mmol) and triphenylphosphine (300 mg, 1.144 mmol) in dichloromethane (5 mL) was added carbon tetrabromide (350 mg, 1.055 mmol) in portions. The reaction mixture was stirred at rt for 2 h, then concentrated. Purification via ISCO system afforded the title product (335 mg) as a colorless liquid.