Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19].[C:23](O)([CH3:26])([CH3:25])[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl>[C:23]([O:19][C:18](=[O:20])[C:17]1[CH:21]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[CH3:22])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc(Br)cc1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a suspension of anhydrous magnesium sulfate (4.5 g, 37.28 mmol) in dichloromethane (37 mL) is added concentrated H2SO4 (516 μl, 9.302 mmol) and the mixture is stirred vigorously for 15 min. 5-Bromo-2-methyl-benzoic acid (2 g, 9.302 mmol) is added, followed by t-butanol (4.39 mL, 46.51 mmol). The flask is capped tightly and stirred at room temperature for 24 h. After adding saturated sodium bicarbonate, the resulting solution is extracted with ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 3:7) to furnish 5-bromo-2-methyl-benzoic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (s, 9H), 2.51 (s, 3H), 7.08 (d, J=8.1 Hz, 1H), 7.46 (dd, J=8.3, 2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H)
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:3].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32](Cl)=[C:27]3[CH:26]=[N:25]2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([N:24]2[C:28]3=[N:29][CH:30]=[N:31][C:32]([O:10][C:7]4[CH:8]=[CH:9][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=4)=[C:27]3[CH:26]=[N:25]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CS(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 36.8 %

Procedure:
A mixture of 4-methanesulfinyl-phenol (Combi-Blocks Inc, San Diego, Calif., USA; 14 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-methanesulfinyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (15 mg, 36%) as a white solid. Mass spectrum MH+=458.
Reaction SMILES: C([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2C(C)C)=[CH:7][CH:6]=1)(OC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.[OH-].[Na+]>O1CCCC1>[NH:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][CH:13]=2)[CH:9]=[CH:10]1
Reactant: COC(=O)c1ccc2ccn(C(C)C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 158.8 %

Procedure:
A solution of 0.250 g (1.15 mmole) of 6-carbomethoxy-1-(2-propyl)indole in 2 mL of anhydrous tetrahydrofuran was added dropwise to a stirring slurry of lithium aluminum hydride (52.4 ing 1.38 mmole) in 7 mL of anhydrous tetrahydrofuran under argon it 0° C. and then stirred at 25° C. for 45 min. The solution was cooled to 0° C. and 0.340 mL of methanol was added dropwise, followed by 0.58 mL of 1N sodium hydroxide solution. The slurry was stirred at 25° C. for 15 min. The white precipitate was filtered through celite, and the solution concentrated. The residue was suspended in 20 mL of ethyl acetate and 20 mL of water. The layers were separated. The aqueous layer was back-extracted with ethyl acetate and both ethyl acetate layers were combined and dried over magnesium sulfate. Concentration gave 6-hydroxymethyl-1-(2-prol:)yl)indole as an oil (214 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:13]([NH:20][OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:13]([N+:20]([O-:21])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ONCc1ccccc1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Nc1ccc(C=[N+]([O-])Cc2ccccc2)cc1

Procedure:
Using 4-acetamidobenzaldehyde and N-benzylhydroxylamine (prepared from the hydrochloride salt by treatment with K2CO3) and following the procedures described herein, the title compound was prepared as a yellow powder, m.p. 230.7-237.7° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][N:10]=1)(=[O:4])=[O:3]
Reactant: OCCc1ccncn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccncn1

Procedure:
A solution of methanesulphonyl chloride (137 mg) in dichloromethane (2 ml) was added to a solution of 4-(2-hydroxyethyl)pyrimidine (124 mg) (prepared by the method of C. G. Overberger and I. C. Kogon, JACS, 76, 1879 (1954)) and triethylamine (121 mg) in dichloromethane (10 ml), the mixture stirred at room temperature for 3 hours and evaporated under reduced pressure to give the crude title compound as a pale yellow oil which was used directly in Example 10 without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:17])=[O:14]
Reactant: OCCCCCCCCCCCCBr
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCCCCCCBr

Procedure:
To this end, 12-bromo-1-dodecanol is oxidized with Jones' reagent to form 12-bromo-1-dodecanoic acid. Then the white solid acid is esterified with diazomethane to form the corresponding methyl ester. The methyl ester is treated directly with imidazole and reacted at 80° C. for five hours until it forms 12-imidazolyl-1-dodecanoic acid methyl ester. The thick mass, which is obtained in this way, is split between water and dichloromethane; and the organic phase is dried over Na2SO4 and concentrated by evaporation. The oily residue is cleaned chromatographically on silica gel and then dissolved in a mixture of methanol and tetrahydrofuran (3:4), treated with LiOH.H2O, and the mixture is heated under reflux for two hours. Following evaporation of the solvent, the white residue is dissolved again in water, extracted with dichloromethane, acidified to a pH 5-6, and extracted again with ethyl acetate. The ethyl acetate extract is dried over Na2SO4, filtered and concentrated by evaporation. The white solid is recrystallized from methanol/ether and yields 12-imidazolyl-1-dodecanoic acid.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:30][C:31]1([NH2:34])[CH2:33][CH2:32]1.FC(F)(F)C([O-])=O>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:30][C:31]1([NH:34][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:32][CH2:33]1
Reactant: COc1ccc(CC2(N)CC2)cc1OC
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: COc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1OC

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 207 mg (1 mmol) 1-(3,4-dimethoxy-benzyl)-cyclopropylamine. Yield: 15 mg (3%, trifluoroacetate); mass spectroscopy: [M+H]+=415.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10]3([O:16][C:7]=2[C:6]([O:17][CH3:18])=[CH:5][CH:4]=1)[CH:14]([OH:15])[CH2:13][O:12][CH2:11]3)#[N:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[C:1]([C:3]1[C:8]2[CH2:9][C:10]3([O:16][C:7]=2[C:6]([O:17][CH3:18])=[CH:5][CH:4]=1)[CH:14]([O:15][CH3:21])[CH2:13][O:12][CH2:11]3)#[N:2]
Reactant: COc1ccc(C#N)c2c1OC1(COCC1O)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c2c1OC1(COCC1OC)C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
2.0 g (8.0 mmol) of 2,3-dihydro-4-cyano-4′-hydroxy-7-methoxybenzofuran-2-spiro-3′-tetrahydrofuran (A11) in 15 ml of dimethylformamide are added dropwise under a nitrogen atmosphere to a solution of 270 mg (8.8 mmol) of 80% strength sodium hydride in 10 ml of dimethylformamide and the mixture is heated at 40° C. for 1 h. 700 μl (10.6 mmol) of methyl iodide, dissolved in 5 ml of dimethylformamide, are then added dropwise at RT. The mixture is stirred at RT for 2 h, concentrated, and the residue is crystallized from 50 ml of water. 1.97 g of the title compound of m.p. 151-156° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:11]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:38][C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41].[OH-].[Na+]>C(Cl)Cl.C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16][N:17]([C:40](=[O:41])[C:39]([CH3:44])([CH3:43])[CH3:38])[CH2:18][CH2:19]3)[N:11]([CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2C2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCC(c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the intermediate from step F (100 mg, 0.225 mmol) in DCM (3 mL) was added triethyl amine (94 μl, 0.675 mmol) followed by trimethyl acetyl chloride (33.25 μL, 0.27 mmol). After 2 hours the reaction was diluted with DCM (10 mL) and washed with 1N HCl, saturated Na2CO3, dried over brine and concentrated in vacuo to give a colorless oil. This material was dissolved in THF (2 mL) and MeOH (1 mL) and 2N NaOH (2 mL) were added and the reaction left stirring at room temperature for 16 hours. The reaction was concentrated in vacuo. The residue was suspended in 1N HCl (until the pH was less then 2). The resulting suspension was extracted with EtOAc (3×), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid. 1H NMR (DMSO, 500 MHz): δ 7.93(d, J=8.2 Hz, 2H), 7.81(d, J=1.8 Hz, 2H), 7.51(t, J=2.1 Hz, 1H), 7.26(d, J=8.3 Hz, 2H), 6.94(s, 1H), 5.54(s, 2H), 4.34(d, J=13.3 Hz, 2H), 3.0(m, 1H), 2.86(t, J=12.9 Hz, 2H), 2.51(t, J=1.6 Hz, 1H), 1.74 (d, J=1 Hz, 2H), 1.44 (dq, J=3.4, 12.8 Hz, 2H), 1.2(s, 9H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1)[NH2:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH2:28][CH2:29][CH2:30]3)[C:25](=[O:32])N(CCO)N=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@H:31]3[C@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:1]([C:3]3[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[CH:7][CH:8]=3)[N:2]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1ccc(CCO)cc1
Product: COc1ccc(C2=NN(c3ccc(CCO)cc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 2-(4-hydrazinophenyl)ethanol as described for compound 35. Crystallized from diethyl ether. M.p. 137°-139° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(N(CC)CC)C.[CH2:28]([N:30]([CH2:34][CH3:35])[C:31]([NH2:33])=[S:32])[CH3:29]>C(Cl)Cl>[CH2:28]([N:30]([CH2:34][CH3:35])[C:31]([S:32][CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4])=[NH:33])[CH3:29]
Reactant: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Reactant: CCN(CC)C(N)=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=N)SCC(=O)NC1C(=O)N2C(c3nnn[nH]3)C(C)(C)S[C@H]12
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1.40 g (0.039 mole) of 6-(2-bromoacetamido)-2,2-dimethyl- 3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.54 ml (0.039 mole) of triethylamine, followed by 0.52g (0.039 mole) of N,N-diethylthiourea. Stirring is continued for a further 45 minutes, and then the solvent is decanted from the oil which has separated. The oil is triturated with ether, giving a while solid, which is filtered off. The yield is 1.28 g (76% of theory) of 6-(2-[N,N-diethylamidinothio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm-1 (β-lactam) and 1670 cm-1 (amide I). The NMR spectrum (DMSO-d6) shows absorption bands at 5.65 ppm (multiplet, C-5 and C-6 hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 4.10 ppm (singlet, methylene hydrogens), 3.45 ppm (quartet, ethyl hydrogens), 1.60 ppm (singlet, C-2 methyl hydrogens), 1.10 ppm (triplet, ethyl hydrogens) and 1.00 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: C(OC(C1C=C([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)C=CC=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](C2C=CC=CC=2CSCCO)=[CH:36][CH:35]=1)=[O:33])[CH3:30].C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:29]([O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:14]2[CH:13]=[CH:12][CH:17]=[CH:16][C:15]=2[CH2:18][S:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:36][CH:35]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ccc(-c2ccccc2CSCCO)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl4-carboxylic acid ethyl ester (4.15 g, 13.12 mmol, 1 eq.) in anhydrous THF was treated with phenol (1.61 g, 17.06 mmol, 1.3 eq.), triphenylphosphine (4.47 g, 17.06 mmol, 1.3 eq.), and diisopropyl azidocarboxylate (3.45 g, 17.06 mmol, 1.3 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][NH2:6].F[C:9]1[C:22]2C(=O)[C:20]3[CH:19]=[N:18][CH:17]=C[C:15]=3[C:14](=[O:24])[C:13]=2[C:12]([O:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:11][CH:10]=1.ClC1C2C(=O)C3C=NC=CC=3C(=O)C=2C(OS(C2C=CC(C)=CC=2)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C>C1COCC1.O>[C:32]1([CH3:35])[CH:31]=[CH:30][C:29]([S:26]([O:25][C:12]2[CH:11]=[CH:10][C:9]3[NH:6][N:5]=[C:4]4[C:3]5[CH:17]=[N:18][CH:19]=[CH:20][C:15]=5[C:14](=[O:24])[C:13]=2[C:22]=34)(=[O:28])=[O:27])=[CH:34][CH:33]=1
Reactant: CN(C)CCNN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Agent: Cc1ccc(S(=O)(=O)Oc2ccc(Cl)c3c2C(=O)c2ccncc2C3=O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)Oc2ccc3[nH]nc4c3c2C(=O)c2ccncc2-4)cc1

Procedure:
Under a nitrogen atmosphere a solution of N-[2-(dimethylamino)ethyl]hydrazine (J. Med. Chem. 7, 493, 1964) (1.86 g) in anhydrous THF (6.0 mL) is added during 30' to the stirred 9:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy) benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy) benzo [g]isoquinoline-5,10-dione of Preparative Example 15b (2.4 g) in THF (24 mL) containing N,N-diisopropylethylamine (1.10 mL). A slightly exothermic reaction ensures, and the reaction temperature increases from 20° C. to 25° C. After one hour at room temperature the reaction mixture is poured in water (240 mL) and the suspension obtained is stirred for 30'. The solid is separated by suction, washed with water and dried at 40° C. to give 2-[2-(dimethylamino)ethyl)]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one (1.44 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13]1([C:18]2[CH:19]=[CH:20][C:21]3[CH2:22][C@H:23]4[C@@H:28]([C:29]=3[CH:30]=2)[CH2:27][CH2:26][CH2:25][NH:24]4)[CH2:17][CH2:16][CH2:15][CH:14]=1>>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[CH2:25][CH2:26][CH2:27][C@@H:28]4[C:29]5[CH:30]=[C:18]([C:13]6[CH2:17][CH2:16][CH2:15][CH:14]=6)[CH:19]=[CH:20][C:21]=5[CH2:22][C@H:23]34)=[O:12])=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: C1=C(c2ccc3c(c2)[C@H]2CCCN[C@H]2C3)CCC1
Product: O=C(c1ccc2nc[nH]c2c1)N1CCC[C@@H]2c3cc(C4=CCCC4)ccc3C[C@@H]21
Yield: 49 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-cyclopent-1-enyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 49% of theory; LC (method 1): tR=2.64 min; Mass spectrum (ESI+): m/z=384 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][C:3]1=[O:13].B(F)(F)F.[CH3:23]COCC>CO>[OH:1][C:2]1([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:23])=[CH:4][C:3]1=[O:13]
Reactant: CCOCC
Reactant: CC(C)CCC1(O)C(=O)CC(=O)c2ccccc21
Agent: FB(F)F
Solvent: CO
Product: COC1=CC(=O)C(O)(CCC(C)C)c2ccccc21
Temperature: 60 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
To a solution of Example 2D (0.43g, 1.7 mmol) in methanol (2 mL) heated at 60° C. was added boron trifluoride diethyl etherate (0.135 mL, 1.0 mmol). The reaction solution was stirred at 60° C. for 5 h. The solution was quenched with saturated NH4Cl and extracted with ethyl acetate. The organic extract was concentrated in vacuo. Column chromatography on silica (2.5% methanol/dichloromethane) afforded the title compound as a white solid (0.17 g, 37.4%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.70 (dd, J=6.43, 2.39 Hz, 6H), 0.74-0.88 (m, 1H), 0.88-1.06 (m, 1H), 1.16-1.38 (m, 1H), 1.51-1.88 (m, 2H), 3.93 (s, 3H), 5.56 (s, 1H), 5.64 (s, 1H), 7.39 (t, J=7.54 Hz, 1H), 7.52 (t, J=7.54 Hz, 1H), 7.62 (d, 1H), 7.73 (d, J=7.72 Hz, 1H); MS m/z 260.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[OH:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:17](I)[CH:18]=[CH2:19]>>[CH2:19]([O:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1)[CH:18]=[CH2:17]
Reactant: N#Cc1ccc(O[C@@H]2CCC[C@@H]2O)cc1Cl
Reactant: C=CCI
Product: C=CCO[C@H]1CCC[C@H]1Oc1ccc(C#N)c(Cl)c1
Yield: 11.8 %

Procedure:
The product of Example 34, Step A (87 mg) was alkylated with allyl iodide (73.6 mg) according to the procedure of Example 34, Step B to give 12 mg of the title compound.
Reaction SMILES: C(OC(=O)[N:7]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:26]2[C:34]3[C:33](Cl)=[N:32][CH:31]=[N:30][C:29]=3[NH:28][CH:27]=2)O)=[CH:20][N:19]=1)[CH2:8][C:9]1[C:10]([O:16][CH3:17])=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)(C)(C)C.FC(F)(F)C(O)=[O:40].C([SiH](CC)CC)C.C(#N)C>O>[F:15][C:13]1[CH:14]=[C:9]([CH2:8][NH:7][C:18]2[N:19]=[CH:20][C:21]([CH2:24][C:26]3[C:34]4[C:33]([OH:40])=[N:32][CH:31]=[N:30][C:29]=4[NH:28][CH:27]=3)=[CH:22][CH:23]=2)[C:10]([O:16][CH3:17])=[N:11][CH:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ncc(F)cc1CN(C(=O)OC(C)(C)C)c1ccc(C(O)c2c[nH]c3ncnc(Cl)c23)cn1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O
Product: COc1ncc(F)cc1CNc1ccc(Cc2c[nH]c3ncnc(O)c23)cn1
Yield: 44 %

Procedure:
{5-[(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-pyridin-2-yl}-(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (78, 0.022 g, 0.043 mmol), trifluoroacetic acid (0.062 mL, 0.80 mmol), triethylsilane (0.15 mL, 0.97 mmol) and 0.46 mL acetonitrile were combined in a round bottom flask. The reaction was heated at reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with methanol in dichloromethane. Appropriate fractions were combined and solvents removed under vacuum to provide the desired compound (P-0099, 0.0072 g). MS (ESI) [M+H+]+=380.8.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:20][CH:21]=[CH2:22]>CC(N(C)C)=O>[CH2:22]([O:1][CH2:2][C:3]1([CH3:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH:21]=[CH2:20]
Reactant: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
To a solution of e tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (479 mg, 2.089 mmol) in DMA (3 mL) was added 60 wt % sodium hydride (125 mg, 3.13 mmol). Reaction immediately turned yellow. Stirred for 5 min and added 3-bromoprop-1-ene (1263 mg, 10.44 mmol). After 3 h, partitioned between EtOAc and sat.aq.NH4Cl. The organic phase was washed with water (3×), brine and dried (MgSO4), filtered, and concentrated to give 471 mg (75%) of tert-butyl 4-((allyloxy)methyl)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.91 (ddt, J=17.2, 10.5, 5.3 Hz, 1H), 5.29 (dq, J=17.1, 1.7 Hz, 1H), 5.19 (dq, J=10.4, 1.5 Hz, 1H), 3.98 (dt, J=5.3, 1.5 Hz, 2H), 3.62 (br. s., 2H), 3.23-3.14 (m, 4H), 1.56-1.49 (m, 2H), 1.48 (s, 9H), 1.37-1.28 (m, 2H), 1.02 (s, 3H). LCMS (M+1)=270.25.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[O:29][CH:30]=1>>[F:42][C:39]([F:40])([F:41])[C:36]1[CH:37]=[CH:38][C:33](/[CH:32]=[CH:31]/[C:28]2[O:29][CH:30]=[C:26]([CH2:25][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[C:13]4[CH2:17][CH:18]([OH:21])[CH2:19][OH:20])=[CH:4][CH:3]=3)[N:27]=2)=[CH:34][CH:35]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: OCC(O)Cc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 74.9 %

Procedure:
Using 3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol (204 mg), 65% oily sodium hydride (28 mg) and 4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole (212 mg), the same reaction as Example 2 was carried out to yield the titled compound (285 mg).