Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:5]([O:7][CH3:8])=[O:6])=[N+:2]=[N-].C1(P(C2C=CC=CC=2)CCC(ON2C(=O)CCC2=O)=O)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O.[Na+].[Cl-]>[CH2:17]([O:16][C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:4](=[N+:1]=[N-:2])[C:5]([O:7][CH3:8])=[O:6])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(CCCCNC(=O)OCc1ccccc1)N=[N+]=[N-]
Agent: O=C(CCP(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CCCCNC(=O)OCc1ccccc1)=[N+]=[N-]
Reaction time: 8 h
Yield: 76 %

Procedure:
Methyl 2-azido-6-{[(benzyloxy)carbonyl]amino}hexanoate 2f (88 mg, 0.275 mmol) was dissolved in THF/H2O (2 mL/300 μL). To this solution was added phosphine 1e (102 mg, 0.288 mmol), and the resulting solution was stirred for 5 h under Ar(g). Sat. aq. NaHCO3 (2 mL) was then added, and the mixture was stirred vigorously overnight. The mixture was then diluted with sat. aq. NaCl (15 mL) and extracted with CH2Cl2 (2×15 mL). The organic layers were combined, dried over Na2SO4(s), filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 20% EtOAc/hexanes, to give the diazo-compound 5f as a yellow oil (64 mg, 0.209 mmol, 76% yield).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]1([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31]O)[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:52]1[CH2:56][C:55](=[O:57])[NH:54][C:53]1=[O:58]>O1CCCC1>[C:15]1([N:25]2[CH2:26][CH2:27][CH:28]([CH2:31][N:54]3[C:55](=[O:57])[CH2:56][O:52][C:53]3=[O:58])[CH2:29][CH2:30]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1
Reactant: OCC1CCN(c2nccc3ccccc23)CC1
Reactant: O=C1COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1COC(=O)N1CC1CCN(c2nccc3ccccc23)CC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2.01 g (9.95 mmol) of diisopropyl azodicarboxylate (DIAD) in 5 ml of tetrahydrofuran is added dropwise, under an inert atmosphere, to a solution of 2.4 g (9.95 mmol) of [1-(1-isoquinolyl)-4-piperidyl]methanol, prepared in step 5.1, 2.87 g (10.94 mmol) of triphenylphosphine and 1.21 g (11.93 mmol) of 1,3-oxazolidine-2,4-dione in 40 ml of tetrahydrofuran, cooled to about −10° C., the temperature of the reaction medium being maintained throughout between −10° C. and 0° C. Stirring is then continued at 0° C. for 1 hour and then at 25° C. for 18 hours.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]([C:12](=[O:15])[CH2:13][CH3:14])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C(O)C>[I-].C[N+]1C(C)=C(CCO)SC=1.ClCCl>[O:15]=[C:12]([CH:7]([CH:6]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=1)[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:13][CH3:14]
Reactant: CCC(=O)C(=Cc1ccc(F)cc1)C(=O)OC
Reactant: O=Cc1ccccc1
Agent: Cc1c(CCO)sc[n+]1C
Agent: [I-]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)C(C(=O)OC)C(C(=O)c1ccccc1)c1ccc(F)cc1
Yield: 28.5 %

Procedure:
A mixture of methyl 2-(4-fluorobenzylidene)-3-oxopentanoate (52.0 g), benzaldehyde (25.4 g), triethylamine (22 g), 3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide (6.3 g) and ethanol (100 ml) was heated at reflux under nitrogen for 16 hours. The cooled mixture was diluted with dichloromethane, and washed with dilute hydrochloric acid (2N), with dilute aqueous sodium bicarbonate solution, and with water, and dried over magnesium sulphate. The solution was concentrated in vacuo and the residue was dissolved in hot methanol. The resulting off-white solid was filtered off, to give methyl 2-(1-oxopropyl)-3-(4-fluorophenyl)-4-phenyl-4-oxobutanoate (21.5 g), m.p. 104°-109° C. [Elemental analysis: C,70.1;H,5.42;F,5.58%; calculated: C,70.15;H,5.60; F,5.55%; I.R. 1749, 1738, 1716, 1708, 1679, 1508, 761, 697cm-1 [N.M.R. (in CDCl3): 0.81 and 1.08 (3H, two triplets, J=7 Hz), 1.80-2.04 and 2.46-2.80 (2H, two sets of multiplets), 3.53 and 3.68 (3H, two singlets), 4.58 and 4.62 (1H, two doublets, J=10 Hz), 5.39 and 5.42 (1H, two doublets, J=10 Hz), 6.96 (2H, t, J=8 Hz), 7.20- 7.60 (5H, m), 7.90-8.00 (2H, m)].
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]3[CH3:25])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:32]>CO.[OH-].[OH-].[Pd+2]>[ClH:32].[CH3:25][C:20]1[N:19]([C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[C:23]([CH3:24])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C)n1-c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1-c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 8-benzyl-3-(2,5-dimethyl-1H-pyrrol-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (60 mg) in methanol (4 mL) was added 20% Pd(OH)2/C (10 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (4 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (50 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered to give the title compound (28 mg, 56%) as a brown powder.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10](=[O:18])[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([CH3:23])([O-:22])=[O:21]>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([OH:18])([CH2:23][N+:20]([O-:22])=[O:21])[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccc(Cl)cc21
Reactant: C[N+](=O)[O-]
Solvent: O
Product: O=C1N(Cc2ccccc2)c2ccc(Cl)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 6 h

Procedure:
1-benzyl-5-chloroindoline-2,3-dione (0.135 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 6 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([N+]1C=CN(C)C=1)CCC.C([N+]1C=CN(C)C=1)CCC.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Ni+2]>[CH2:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:7]=[CH:8][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: c1ccccc1
Agent: [Ni+2]
Agent: CCCC[n+]1ccn(C)c1
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C=CCCCCCC
Product: CCCCCCCCc1ccccc1

Procedure:
Nickel(II) bis-triflimide (0.06 g, 0.1 mmol) was dissolved in [bmim][NTf2] (1.0 g) in a round-bottomed flask equipped with a magnetic stirrer and reflux condenser. Benzene (3.90 g, 50 mmol) and oct-1-ene (1.12 g, 10 mmol) were added. The mixture was heated under reflux for 18 hours and was analysed by gas chromatographic analysis as in previous examples. The oct-1-ene peak disappeared and three isomers of octylbenzene were formed (70%, 20:26:54 2- to 3- to 4-isomer ratio) as well as octene dimer (30%). The less dense product phase was decanted from the ionic/catalyst phase and purified by Kugelrohr distillation. The ionic liquid and catalyst were prepared for reuse by heating at 60° C. under vacuum for 1 hour. The ionic liquid and catalyst were used for further reactions of benzene with oct-1-ene without loss of activity. This is an alkylation of benzene with an alkene using a metal bis-triflimide catalyst. Benzene and oct-1-ene react in the presence of 1% nickel(II) bis-triflimide in [bmim][NTf2] to form three isomers of octyl benzene and a small amount of hexadecene (unknown isomeric distribution). This is shown below: The Alkylation of Benzene with oct-1-ene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Mg].[CH2:11]1[O:27][C:14]2([CH2:19][CH2:18][CH:17]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[O:13][CH2:12]1>C1COCC1>[CH2:12]1[O:13][C:14]2([CH2:15][CH2:16][CH:17]([CH:20]3[CH2:25][CH2:24][C:23]([OH:26])([C:2]4[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=4)[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)[O:27][CH2:11]1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Reactant: Fc1ccc(Br)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)c(F)c2)CCC(C2CCC3(CC2)OCCO3)CC1

Procedure:
A Grignard reagent was prepared from 1-bromo-3,4-difluorobenzene and magnesium in THF, and a THF solution of bicyclohexane-4,4'-dione monoethyleneacetal was added thereto dropwise while cooling with ice. After allowing the mixture to react at room temperature for 1 hour, the reaction mixture was worked-up in a conventional manner to obtain crude crystals of 4-[4-hydroxy-4-(3,4-difluorophenyl) cyclohexyl]cyclohexanone ethyleneacetal. The crude crystals were dissolved in toluene, and a small amount of potassium bisulfate was added thereto, followed by refluxing for 10 hours while removing water. After cooling to room temperature, water was added to the reaction mixture, and the product was extracted with toluene. The solvent was removed by distillation to obtain white crystals of 4-[4-(3, 4-difluorophenyl)-3-cyclohexyl]cyclohexanone ethyleneacetal. Triethylamine and a catalytic amount of palladium-on-carbon were added to a toluene solution of the product, and the mixture was allowed to react in an autoclave at a hydrogen pressure of 5 kg/cm2 for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated. The resulting crude product were recrystallized from ethanol to obtain white crystals of 4-[trans-4-(3,4-difluorophenyl) cyclohexyl]cyclohexanone ethyleneacetal. Formic acid was added to a toluene solution of the product, followed by stirring at room temperature for 4 hours. Water was added thereto, and the organic layer was separated, washed with a sodium bicarbonate aqueous solution, and dried. The solvent was removed by distillation, and the residue was recrystallized from ethanol to obtain white crystals of 4-[trans-4-(3, 4-difluorophenyl)cyclohexyl]cyclohexanone. The resulting product was deuterated in the same manner as in (1-a) to obtain 4-[trans-4-(3,4-difluorophenyl)cyclohexyl]cyclohexanone-2,2,6,6-d4. (16-b) Synthesis of 4-[trans-4-(3,4-difluorophenyl) cyclohexyl]cyclohexane-2,2,6,6-d4 carbaldehyde:
Reaction SMILES: CO[CH:3]([O:14]C)[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([N+:11]([O-])=O)[CH:5]=1.[C:16]1([NH:22][C:23](=O)[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:24][C:23]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:14])=[CH:5][C:6]=2[N:11]=1
Reactant: COC(OC)c1ccc(I)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccccc1
Product: Cc1nc2cc(C=O)ccc2n1-c1ccccc1
Yield: 25.4 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 4-Dimethoxymethyl-1-iodo-2-nitrobenzene (155 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as pale yellow oil (30 mg, 25% yield). 1H NMR (DMSO) δ 2.50 (s, 3 H), 7.31 (d, J=8.3 Hz, 1 H), 7.61-7.68 (m, 5 H), 7.82 (d, J=8.3 Hz, 1 H), 8.25 (s, 1 H), 10.10 (s, 1 H); 13C NMR δ 13.6, 111.4, 120.1, 124.2, 127.0, 129.8, 130.2, 132.3, 139.1, 154.7, 158.3, 192.4. HRMS (FAB): cal. for C15H13N2O [M+H+]: 237.1028; found: 237.1024.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:24]=1.C(ON=O)CC(C)C.C(Br)(Br)[Br:34]>>[Br:34][C:2]1[S:3][C:4]2[C:9]([NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:24]=1
Reactant: CC(C)(CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Reactant: BrC(Br)Br
Agent: CC(C)CCON=O
Product: CC(C)(CO)Nc1nc(SCc2ccccc2)nc2nc(Br)sc12
Temperature: 60 °C

Procedure:
To a solution of the product from example 1 step d) (0.1 g) in bromoform (5 ml) was added isoamylnitrite (0.13 ml) and the mixture heated at 60° C. for 10 mins. The mixture was evaporated to dryness and purified (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to give the subtitle compound as a colourless solid (0.043 g).
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[Al+3].[Cl-].[Cl-].[Cl-].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([P:1]([Cl:4])[Cl:2])=[CH:12][CH:11]=1
Reactant: Fc1ccccc1
Reactant: ClP(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Product: Fc1ccc(P(Cl)Cl)cc1
Temperature: 73 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
A mixture of 3.4 mol of PCl3 and 1.2 mol of AlCl3 (98% pure) was placed under an argon atmosphere in a 1 l flask which was provided with a thermostated jacket, mechanical stirring, thermometer and reflux condenser at 73° C. 0.8 mol of fluorobenzene was subsequently added over a period of 30 minutes, with a gentle stream of argon being passed through the reaction flask. The reaction mixture was stirred for 3 hours, cooled to 60° C. and 1.25 mol of pyridine were slowly added over a period of 45 minutes. The reaction was exothermic and mist was formed. The mixture was subsequently stirred for another 30 minutes at 60° C. A nonuniform solid in the form of large lumps precipitated, and this could not be separated off via a suction filter but only by filtration. The filtration residue was washed with petroleum ether. The filtrate and the washings were combined and distilled, giving 73.3 g of p-fluorophenyldichlorophosphine in a yield of 47% of theory.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:16]=[O:17].O>CO.C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:16][OH:17])[C:11](=[O:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: C=O
Reactant: CSc1cccc(-n2oc(=O)[nH]c2=O)c1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CSc1cccc(-n2oc(=O)n(CO)c2=O)c1
Reaction time: 2 h

Procedure:
2-(3-methylthiophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(3-methylthiophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [C:1](O)(=O)C.Cl.[NH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][CH:10]=1.C(=O)C>CO>[CH2:1]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:9]=2[CH2:8][CH2:7][NH:6]1
Reactant: CC(=O)O
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: CC=O
Agent: Cl
Solvent: CO
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3
Temperature: 75 °C

Procedure:
Acetic acid was added dropwise to a solution of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (200 mg) in 7 mL of methanol until the pH=4. Acetaldehyde (0.2 mL) was added and the mixture was heated at 75° C. in a sealed tube for 1 h. The tube was cooled to rt and unsealed. The solvent was evaporated yielding 160 mg of 2,3,4,9-tetrahydro-1H-β-carbolin-6-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[Li]CCCC.C([O:27]B(OC(C)C)OC(C)C)(C)C.OO>C1COCC1.CCCCCC.CCOCC.[Na+].[Cl-].[O-]S([O-])(=S)=O.[Na+].[Na+].CC(O)=O.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([OH:27])=[C:10]([F:11])[CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1cc2c(ccn2-c2ccc(Cl)cc2)cc1Br
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Oc1cc2ccn(-c3ccc(Cl)cc3)c2cc1F
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A solution of 1.05 g (3.2 mmol) 5-Bromo-1-(4-chloro-phenyl)-6-fluoro-1H-indole in THF at −78° C. was treated dropwise with 3 ml (4.8 mmol) 1.6 M BuLi in hexane, stirred during around 30 min, treated with 1.5 ml (6.5 mmol) triisopropylborate, stirred for 10 min at −78° C. and then for 30 min at 0° C. A mixture of 0.8 ml H2O and 0.8 ml AcOH was added dropwise, the resulting mixture treated within 15 min with 0.5 ml of H2O2 (35% in H2O ), stirred for 30 min at 0° C., and 1 h at room temperature. The mixture was diluted with 50 ml of Et2O, 40 ml of saturated aqueous NaCl, and 10 ml of 1M aqueous Na2S2O3 and stirred during 2 hours at room temperature. The organic layer was dried with MgSO4 and the solvent evaporated. Column chromatography on silica gel with (Et2O/hexane 1:2) gave 594 mg (70%) 1-(4-Chloro-phenyl)-6-fluoro-1H-indol-5-ol as a light brown solid. The solid was dissolved in 1.5 ml DMF and treated with grinded 740 mg K2CO3 and 900 mg 1,4-dibromobutane and stirred during 2 hours at 80° C. The mixture was poured into saturated aqueous NaCl and extracted three times with Et2O. Drying of the combined organic layers with Na2SO4, evaporation of the solvent, and column chromatography on silica gel with hexane/Et2O 3:1 gave 180 mg (14%) 5-(4-Bromo-butoxy)-1-(4-chloro-phenyl)-6-fluoro-1H-indole as a light brown solid, MS: 395 (M, 1Cl, 1Br).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH:21][S:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(=[O:24])=[O:23])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH:10]1[C:11]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:23])=[O:24])[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:8][N:9]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(NS(=O)(=O)c2ccccc2)CC4)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NC1CCc2c(cnc3[nH]ncc23)C1)c1ccccc1
Temperature: 65 °C

Procedure:
To N-[3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl]-benzenesulfonamide (0.082 g, 0.18 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was heated at 65° C. for 5 h. On the completion of the reaction, toluene (5 mL) was added. The solvent was the removed under reduced pressure to give the crude product as a dark brown solid. The crude product was purified using reverse phase HPLC to give the desired product, N-(6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl)benzenesulfonamide was obtained as a white solid (0.038 g, 63%). M.p.=228-229° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.28 (s, 1H), 7.96 (s, 1H), 7.94-7.84 (m, 3H), 7.78 (s, 1H), 7.69-7.58 (m, 3H), 3.48 (br s, 1H), 3.04-2.72 (m, 4H), 1.95-1.7 (m, 2H); LCMS [M+H]: 329.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[H-].[Na+].C([N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1Cl)C1C=CC=CC=1>CN(C=O)C>[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][C:27]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: Clc1nc2ccccc2n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCOc2nc3ccccc3[nH]2)CC1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
To a solution of tert-butyl 4-(2-hydroxyethyl)-1-piperazinecarboxylate (230 mg, 1.00 mmol) in DMF (2 ml) was added sodium hydride (55%, 52 mg, 1.19 mmol) with ice-cooling and stirred at 75° C. for 30 minutes, and then added 1-benzyl-2-chlorobenzimidazole (243 mg, 1.00 mmol) and stirred at 75° C. for 24 hours. The reaction solution was concentrated in vacuo, and the resulting residue was dissolved in chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (silica gel 25 g, developing solvent; hexane:ethyl acetate=5:1 1:1) to provide 369 mg (yield 85%) of tert-butyl [4-[2-(benzimidazol-2-yloxy)ethyl]piperazin-1-yl]carboxylate as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([Cl:22])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)Cl
Temperature: 25 °C

Procedure:
To a mixture of 3.3 g 5-(benzyloxy)-2-methylbenzoic acid (compound F1) in 80 ml DCM are added 1.4 ml of oxaloylchloride, and the reaction is stirred at RT over night under a blanket of nitrogen. The solvent is removed under reduced pressure yielding the title compound, which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17](C(OC(C)(C)C)=O)[CH:16]=1)(=O)[C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].C(=O)(O)O.[NH2:35][C:36]([NH2:38])=[NH:37]>COCCO>[CH2:10]([C:9]1[CH:8]=[C:7]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[N:37]=[C:36]([NH2:38])[N:35]=1)[CH2:11][CH2:12][CH3:13]
Reactant: N=C(N)N
Reactant: CCCCC#CC(=O)c1cn(C(=O)OC(C)(C)C)c2ncccc12
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCCCc1cc(-c2c[nH]c3ncccc23)nc(N)n1

Procedure:
1.2 278 mg (2.0 mmol) of sodium carbonate are added to a solution of 314 mg (0.96 mmol) of tert-butyl 3-hept-2-inoylpyrrolo[2,3-b]pyridine-1-carboxylate and 130 mg (0.72 mmol) of guanidine carbonate in 2 ml of ethylene glycol monomethyl ether, and the mixture is heated at the boil for 24 hours. After cooling, the mixture is partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated, and the residue is chromatographed using preparative HPLC, giving 4-butyl-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-ylamine (“A1”) as colourless solid; ESI 269;
Reaction SMILES: [CH2:1](Br)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].CS(C)=O.[CH3:29][O:30][C:31]1[CH:38]=[C:37]([O:39][CH3:40])[C:34]([CH:35]=O)=[C:33]([OH:41])[CH:32]=1>>[CH3:40][O:39][C:37]1[C:34]([CH2:35][CH2:1][CH3:2])=[C:33]([OH:41])[CH:32]=[C:31]([O:30][CH3:29])[CH:38]=1
Reactant: CCBr
Reactant: COc1cc(O)c(C=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: CCCc1c(O)cc(OC)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
Triphenylphosphine ethylbromide (4.1 g) was added to 2N sodium hydroxide/dimethyl sulfoxide solution (11 ml), prior to stirring at 50° C. for 30 minutes. To the mixture was added 4,6-dimethoxy-2-hydroxybenzaldehyde (1 g), for stirring at 50° C. overnight. The resulting solution was partitioned between ethyl acetate and dilute hydrochloric acid, and the resulting ethyl acetate phase was washed in water and subsequently in an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:hexane:ethyl acetate=3:1), followed by addition of a catalytic amount of platinum dioxide for hydrogenation, to recover 3,5-dimethoxy-2-propylphenol (0.5 g; yield of 46%). By 2H-NMR (90 HMz, CDCl3), the compound has the peaks shown below.