Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([N:6]([CH2:38][CH3:39])[CH2:7]/[CH:8]=[CH:9]\[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([O:33]C)=[O:32])=[C:29]2[C:24]([C:25]3[CH:37]=[CH:36][O:35][C:26]=3[CH:27]=[N:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:5].C(O)=O>O1CCOCC1.O>[CH2:38]([N:6]([CH2:4][CH3:5])[CH2:7]/[CH:8]=[CH:9]\[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:30]([C:31]([OH:33])=[O:32])=[C:29]2[C:24]([C:25]3[CH:37]=[CH:36][O:35][C:26]=3[CH:27]=[N:28]2)=[CH:23][CH:22]=1)(=[O:19])=[O:18])[CH3:39]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)O
Temperature: 90 °C
Yield: 51.4 %

Procedure:
Lithium hydroxide monohydrate (0.107 g) was added to a solution of methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]-quinoline-6-carboxylate (Intermediate 6, 0.026 g) in a mixture of dioxane (1.7 mL) and water (0.8 mL). The resultant mixture was stirred and heated at 90° C. overnight. After cooling, the mixture was acidified by addition of formic acid and then evaporated to dryness. The residue was triturated with a mixture of methanol and DCM (10%) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-12%. The product was triturated with a mixture of DCM and diethyl ether (50%) and the solid was collected by filtration and dried in vacuo to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]quinoline-6-carboxylic acid (0.013 g) as a yellow solid.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[F-].C([N+:10]([CH2:19][CH2:20][CH2:21][CH3:22])(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N+:1]([CH2:4][C:21]1([CH2:20][C:19]#[N:10])[CH2:22][CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC1(C[N+](=O)[O-])CCCCC1
Yield: 91.1 %

Procedure:
The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[N:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][N:12]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[Cl:25])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([CH3:23])[C:17]=1[N:12]1[CH2:13][CH2:14][CH2:15][C:16]2=[C:8]([NH2:7])[N:9]([CH3:26])[N:10]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3NC(=O)OC(C)(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To a 0° C. solution of 287 mg of [7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]carbamic acid tert-butyl ester (Example 12) in 9 mL of dichloromethane, was added 3 mL of trifluoroacetic acid. After 15 min, the cooling bath was removed and the reaction mixture was allowed to stir and warm to room temperature over 3 h. The reaction mixture was then diluted with dichloromethane and washed with dilute aqueous sodium hydroxide. The aqueous phase was washed with additional dichloromethane, after which the combined organics were dried with magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a methanol/dichloromethane gradient to provide 182 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-45): mp 234-236° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH:18]1([S:23]([CH2:26][C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])(=[O:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([CH2:26][S:23]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)(=[O:25])=[O:24])[CH:28]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Nc1cccc(CS(=O)(=O)C2CCCC2)c1
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cc1cccc(Nc2ncnc(Cl)n2)c1)C1CCCC1
Yield: 205.7 %

Procedure:
To a stirred solution of 2,4-dichloro-1,3,5-triazine (150 mg, ABCR GmbH & CO. KG) in THF/i-PrOH (1:1; 1.9 mL) DIPEA (0.35 mL) was added at −40° C. Then a suspension of 3-[(cyclopentylsulfonyl)methyl]aniline (240 mg) in THF/2-PrOH (1:1, 0.94 mL) was added at this temperature. Under stirring the temperature of the reaction mixture was slowly raised over 2 hours to 0° C. The reaction mixture was then concentrated in vacuo to give the crude title compound (726 mg) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[O:34]=[C:35]([CH3:55])[CH2:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C.CO.ClCCl>C(#N)C>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][CH2:36][C:35](=[O:34])[CH3:55])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CC(=O)CCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4CCCC(C)=O)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 24 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.40 g, 0.72 mmol), 4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.30 g, 0.65 mmol), and N,N-diisopropylethylamine (0.52 mL, 3.02 mmol) in acetonitrile (10 mL). Heat to reflux. After 24 hours, cool and partition the reaction mixture between ethyl acetate and a half saturated aqueous sodium bicarbonate solution. Separate the organic layer extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia solution to give the title compound: Rf=0.45 (silica gel, 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia solution).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C[Si]([O:20][S:21](Cl)(=[O:23])=[O:22])(C)C.CO>ClC(Cl)C>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:21]([OH:23])(=[O:22])=[O:20])=[CH:8]1
Reactant: c1ccc2c(c1)ccn2CC1=NCCN1
Reactant: C[Si](C)(C)OS(=O)(=O)Cl
Solvent: CO
Solvent: CC(Cl)Cl
Product: O=S(=O)(O)c1cn(CC2=NCCN2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-1H-indole (1.0 g, 4.243 mmol) was dissolved/suspended in dichloroethane (120 ml) and cooled in ice under a nitrogen atmosphere. Trimethylsilylchlorosulfonate (0.654 ml, 0.801 g, 4.243 mmol) was added to the cooled solution dropwise with stirring. The mixture was allowed to warm up to room temperature with stirring, and stirring was continued overnight. Methanol (20 mL) was then added, followed by stirring at room temperature for 20 minutes. The mixture was then rotovapped to dryness. The crude product was recrystallized from MeOH/EtOAc as the hydrochloride salt of 1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-1H-indole-3-sulfonic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH:11]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[Br:24]N1C(=O)CCC1=O.O.C(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH:4]([C:10]1[CH:11]=[C:12]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:13]([NH2:16])=[C:14]([Br:24])[CH:15]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(CC1CCC1)c1ccc(N)c(OCC(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(CC1CCC1)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.6 %

Procedure:
To a solution of the 2-[4-amino-3-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester (12.3 g, 31.8 mmol) in chloroform (150 mL) was added N-bromosuccinimide (7 g, 39.3 mmol). The reaction mixture was stirred at 25° C. for 16 h and a mixture of water and methylene chloride (100 mL/100 mL) was added. The reaction mixture was extracted with methylene chloride (2×50 mL) and the organic phases were separated. The combined organic phases were dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by a short silica gel column chromatography eluting with heptane-EtOAc (4:1) to give the product (13.9 g, 94%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.06 (d, J=1.1 Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 4.37 (q, J=8.0 Hz, 2H), 4.21 (br s, 2H), 3.64 (s, 3H), 3.31 (t, J=7.7 Hz, 1H), 2.20-1.89 (m, 4H), 1.81-1.75 (m, 3H), 1.67-1.51 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 174.2, 144.6, 134.4, 128.9, 125.7, 123.0 (d, 1JCF=277.6 Hz), 110.9, 108.7, 66.5 (q, 1JCF=36.0 Hz), 52.0, 48.6, 40.7, 33.9, 28.3, 28.0, 18.5.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([CH:14]=[O:15])[CH:3]=1.[Na].OO.Cl([O-])=[O:20].[Na+]>C(#N)C.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([OH:20])=[O:15])[CH:3]=1
Reactant: COc1c(C=O)cc(F)c2ccccc12
Reactant: [O-][Cl+][O-]
Agent: OO
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: COc1c(C(=O)O)cc(F)c2ccccc12
Reaction time: 2.5 h
Yield: 93.7 %

Procedure:
9.3 g of 4-fluoro-1-methoxynaphthalene-2-carbaldehyde were dissolved in 100 ml of acetonitrile. 2.1 g sodium dihydrogenphsophate monohydrate in 10 ml of water were added, followed by the addition of 9.5 ml hydrogen peroxide (30%). 8.9 g sodium chlorite, dissolved in 20 ml water were added drop wise while maintaining an internal temperature between 5° C. and 15° C. The reaction was then allowed to come to room temp over 2.5 h. The precipitated solid was filtered with suction, and the solid was washed with water, and dried in vacuo at 40° C. to yield 9.4 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid. The filtrate was treated with 60 ml of cold 10% aqueous sodium bisulfite solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was washed with 0.2 N NaOH twice. The washes were acidified with 6 N HCl to pH 3, whereupon crystallization occurred. The precipitating product was filtered, washed with water and dried in vacuo at 40° C. to yield a second batch of 1.0 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[S:7])=[O:4].[F:8][C:9]([F:32])([F:31])[C:10]1[CH:11]=[C:12]([S:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH:27][C:28]([NH2:30])=[O:29])=[C:24]([CH:26]=2)[NH2:25])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.C(OC(C)C)(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:25][C:24]1[CH:26]=[C:20]([O:19][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:8])([F:31])[F:32])[CH:11]=2)(=[O:18])=[O:17])[CH:21]=[CH:22][C:23]=1[NH:27][C:28]([NH2:30])=[O:29])=[S:7])=[O:4]
Reactant: COC(=O)N=C=S
Reactant: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: COC(=O)NC(=S)Nc1cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1NC(N)=O
Reaction time: 4 h

Procedure:
12 ml of methoxycarbonyl isothiocyanate are added dropwise, with stirring, to 18.7 g of 5-(3-trifluoromethylphenylsulfonyloxy)-2-ureidoaniline in 300 ml of dioxane, the temperature rising to about 40° C. The mixture is stirred for a further four hours without cooling, 60 ml of diisopropyl ether are added and the precipitate is filtered off with suction. After washing with diisopropyl ether, recrystallization is carried out from methanol/diisopropyl ether with the addition of active charcoal, melting point 190° C., decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[C:28](C2C=CC(OC)=CC=2)[CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:15][CH2:14]1>>[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[C:28]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:15][CH2:14]1
Reactant: CCOc1ccc(B(O)O)cc1
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cc1
Product: CCOc1ccc(-c2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cc1

Procedure:
This compound has been synthesized from 4-ethoxy-phenyl-boronic acid analogously to the method described in the synthesis of 178 (see example 141).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[C:17]([C:22]1([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23]1)[N:16]=2.C1COCC1.CO.O>[Zn].C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][C:3]=1[C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[C:17]([C:22]1([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][CH2:24]1)[N:16]=2
Reactant: O=[N+]([O-])C=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 65 °C

Procedure:
To 2-(2-fluoro-4-(2-nitrovinyl)phenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.788 g, 1.89 mmol) was added THF (9.44 mL), methanol (9.44 mL), water (9.44 mL), and acetic acid (9.44 mL) before zinc (0.987 g, 15.1 mmol) was added. The reaction mixture was heated to 65° C. for 18 h. The reaction mixture was concentrated, neutralized with aq NaHCO3, and extracted with DCM. The organic layer was concentrated, filtered, washed with water, and dried in a vacuum oven to give the title compound after purification via preparatory LC. MS (ESI) m/z: Calculated: 389.1; Observed: 380.1 (M++H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:21])[CH:17]=2)[CH:12]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C=CC=CC=1>[Br:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=2)[CH:17]=1
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc2cc(-c3ccccc3)ccc2c1
Temperature: 78 °C
Reaction time: 24 h
Yield: 36.4 %

Procedure:
Under an argon gas atmosphere, 128.0 g (1.049 mol) of phenylboronic acid, 300.0 g (1.163 mol) of 2,6-dibromonaphthalene, 24.2 g (21.0 mmol) of tetrakis(triphenylphosphine) palladium(0), 4.3L of dimethoxyethane and 1.60L of 2M sodium carbonate solution were mixed, and stirred for 24 hours at 78 degrees C. The reaction mixture was further added with toluene and water, and then aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. By refining residue thereof by silica-gel column chromatography and by recrystallizing the residue by hexane, 108 g of 2-bromo-6-phenyl naphthalene was obtained with an yield of 36%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]([CH3:16])=[C:14]3[N:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OC(C)C)(C)C.CCCCCC>C1COCC1>[Br:17][C:9]1[N:10]2[C:14](=[C:15]([CH3:16])[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:13][CH2:12][CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(F)cc2)cn2c1CCC2
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: Cc1c(-c2ccc(F)cc2)c(Br)n2c1CCC2
Yield: 62.2 %

Procedure:
The solution of 6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine (9.0 g, 42 mmol) in abs. THF (50 ml) is cooled to −15° C. N-Bromosuccinimide (3.46 g, 19.4 mmol) is added in portions; the mixture is stirred until no more starting material is detectable (TLC SiO2, diisopropyl ether-hexane 2:1). The black-purple-coloured reaction mixture is chromatographed on a column (20 cm×3 cm) packed with Al2O3 (ICI, for dry packing). The column is subsequently washed with n-hexane (80 ml), and the filtrates are concentrated. 3.55 g (28.9%) of a black-brown oil are obtained, which rapidly decomposes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][CH:8]=1.Cl>CO.O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[CH2:26]2)=[N:5][C:6]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-n2ncc3cnc(-c4cncc(C)n4)cc32)nc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-methoxy-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.2758 mmol; 142.5 mg) in Methanol (10 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 186 as an off-white solid (105.6 mg, 91%). 1H NMR (400 MHz, DMSO) δ 9.66-9.62 (s, 1H), 9.48-9.44 (s, 1H), 9.33-9.28 (s, 1H), 8.65-8.61 (d, J=3.5 Hz, 2H), 7.54-7.45 (dd, J=21.6, 8.5 Hz, 2H), 4.02-3.96 (d, J=10.3 Hz, 1H), 3.90-3.84 (d, J=11.7 Hz, 4H), 3.03-2.96 (d, J=9.0 Hz, 1H), 2.89-2.82 (m, 1H), 2.65-2.61 (s, 3H), 1.98-1.86 (t, J=10.6 Hz, 2H), 1.78-1.67 (d, J=10.2 Hz, 1H), 1.45-1.35 (dd, J=19.2, 8.9 Hz, 1H); MS (ESI) m/z: 417.2 [M+H]+
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([N:15]([CH2:26][CH3:27])[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:14]>>[CH2:24]([N:21]([CH2:22][CH3:23])[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][N:15]([CH2:26][CH3:27])[CH2:13][CH3:14])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:25]
Reactant: CCN(CC)CCNCCN(CC)CC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(CCN(CC)CC)CCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N-(2-(diethylamino)ethyl)-N′,N′ diethylethane-1,2-diamine as starting materials to give the aimed compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](OCC)=[O:21])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.[OH-].[Na+]>C1COCC1.O>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
1.42 g (0.0375 mol) of lithium aluminium hydride were suspended in 20 ml of THF. 1.548 g (0.00623 mol) of ethyl 1-benzylpiperidine-4-carboxylate were slowly added dropwise at 0°. The mixture was heated to 70° and boiled at reflux for 16 hrs. The reaction mixture was treated with 70 ml of ethyl acetate, 6.5 ml of water and 1.5 ml of 2N aqueous NaOH. The mixture was stirred for 1 hr., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed on silica gel with methanol/dichloromethane (1:9) as the eluent. 1.16 g (91%) of 1-benzyl-4-hydroxymethylpiperidine were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(B(CC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)C.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.CO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1cccnc1
Yield: 40.9 %

Procedure:
To a mixture consisting of 1-bromo-2-nitrobenzene (2.12 g, 8.7 mmol), diethyl (3-pyridyl) borane (1.47 g, 10.0 mmol), and bis (triphenylphosphine) palladium (II) chloride (913 mg, 1.3 mmol) in tetrahydrofuran (40 ml), sodium carbonate (4.24 g, 40.0 mmol) was added, and the resulting reaction mixture was heated at reflux for 4 hours. Water (40 ml) was added to the cooled reaction mixture which was then extracted with three 25 ml portions of ethyl acetate. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to afford a tacky residue. Flash chromatography of the entire sample (silica gel, 47-61 micron mesh; elution initially with methylene chloride and finally with methylene chloride/methanol=98:2 in volume) afforded the title compound as a viscous amber oil (713 mg, 41% yield). Subsequent eluent contained less pure product which was further purified by a similar flash chromatography, eluting with methylene chloride/methanol=99:1 in volume, thus affording an additional 488 mg (28% yield) of the purified title compound, again as a viscous amber oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][OH:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:15](#[N:19])[CH2:16][C:17]#[N:18].C(NCC)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([NH2:19])[O:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)CO)cc1
Reactant: N#CCC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CC(=O)Nc1ccc(-c2coc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of 4′-acetamido-2-hydroxyacetophenone 4 (7.17 g, 39 mmol) in DMF (65 mL), malononitrile (2.84 g, 43 mmol) was added. With cooling in an ice-water bath, diethylamine (6.05 mL 59 mmol) was gradually added within 20 min. The mixture was stirred at room temperature for 2 h and then diluted with ethyl acetate (400 mL). The mixture was washed with brine (3×200 mL), dried over sodium sulfate, and then evaporated in vacuo. Residual material was treated with dichloromethane and n-hexane, concentrated in vacuo, and precipiated in the concentrated mixture. The precipitated material was filtrated and washed with n-hexane to give 5 (7.64 g) as a brown solid. MS(ES) m/e 242 [M+H].