Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([NH2:16])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(CC(=O)C)C(C)=O.CO.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([N:16]3[C:4]([CH3:5])=[CH:3][CH:2]=[C:7]3[CH3:6])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: CC(=O)CCC(C)=O
Agent: O=[Si]=O
Agent: [Al+3]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (100 mg) and Montmorillonite KSF clay (100 mg) in acetonylacetone (1 ml) was heated at 120° C. (50 W) for 15 minutes in a CEM discover microwave synthesiser. The reaction mixture was diluted with 5% methanol/dichloromethane, filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1:2 ethyl acetate/hexane, and the product containing fractions were combined and evaporated to give 65 mg of the target molecule as a pale brown solid. (LC/MS: Rt 3.75 [M+H]+ 299).
Reaction SMILES: [NH2:1][C:2](=[O:51])[CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH2:23][CH2:24][N:25]([CH2:47][CH:48]([CH3:50])[CH3:49])[C:26]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=4)=[CH:29][C:27]=3[CH:28]=2)=[O:21])=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:60])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[NH2:1][C:2](=[O:51])[CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][S:12]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH2:23][CH2:24][N:25]([CH2:47][CH:48]([CH3:50])[CH3:49])[C:26]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=4)=[CH:29][C:27]=3[CH:28]=2)=[O:21])=[CH:15][CH:14]=1)=[O:60]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(N)=O)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(N)=O)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of N-[4-[[[1-(4-amino-4-oxobutyl)-1H-imidazol-2-yl]methyl]thio]phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (350 mg) in dichloromethane (30 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.18 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:19→1:9), to give N-[4-[[[1-(4-amino-4-oxobutyl)-1H-imidazol-2-yl]methyl]sulfinyl]phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 416) (259.9 mg) as yellow amorphous.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])(=O)=O)=CC=1>CN(C)C=O>[CH3:5][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH2:3][CH2:2][S:1][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44]
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOCCOCCSCCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (2.05 g, 8.1 mmol) in N,N-dimethylformamide (10 ml) was added cesium carbonate (2.27 g, 6.97 mmol) and 2-(2-(2-methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2.32 g, 7.29 mmol). The solution was heated to 60° C. for 2 hour, then 70° C. for 16 hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in 50 ml 5% NaHSO4, extracted with 3×50 ml ethyl acetate, dried on MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (10% to 60% ethyl acetate in hexanes) to give the title compound as a clear oil (1.24 g, 3.10 mmol, 60%). 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 6H), 1.99 (m, 2H), 2.53 (m, 2H), 2.73 (m, 2H), 3.39 (s, 3H), 3.5-3.7 (m, 10H), 4.8 (s, 1H), 5.05 (s, 2H), 7.3-7.4 (m, 5H). LRMS (ESI/APCI) m/z 422 [M+Na]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][NH:6][CH3:7])[CH3:2].Cl[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][N:6]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:7])[CH3:2]
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CCN(CC)CCNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN(C)Cc1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Into a 1000-mL round bottom flask, was placed a solution of N1,N1-diethyl-N2-methylethane-1,2-diamine (10 g, 69.23 mmol, 1.20 equiv, 90%) in N,N-dimethylformamide (500 mL), 4-(chloromethyl)benzoic acid (11.5 g, 67.65 mmol, 1.00 equiv), potassium carbonate (10 g, 71.94 mmol, 3.00 equiv), and potassium iodide (1.95 g, 11.75 mmol, 0.20 equiv). The resulting solution was stirred for 2 h at 90° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (10 g) was purified by reverse phase chromatography eluting with a water/methanol gradient. This resulted in 5 g (27%) of 4-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid as a white solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 8.00(d, J=8.4 Hz, 2H), 7.39(d, J=8.1 Hz, 2H), 3.68(s, 2H), 3.23-3.15(m, 6H), 2.91(m, 2H), 2.33(s, 3H), 1.33-1.27(m, 6H). MS (ES, m/z): 265 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:38][C:39]1[CH:44]=[CH:43][C:42]([O:1][C@@H:2]2[CH2:3][CH2:4][C@H:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[CH:41][CH:40]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reactant: Oc1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](Oc2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of trans-2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione 3 (1.0 g, 4.1 mmol), triphenylphosphine (1.3 g, 4.9 mmol), and 4-fluorophenol (0.55 g, 4.9 mmol) in 40 mL of THF was added dropwise at room temperature diisopropyl azodicarboxylate (0.99 g, 4.9 mmol). The reaction mixture was stirred overnight. The solvent was evaporated after 12 h, and the resulting solid was purified by recrystallization from methanol. Yield: 1.1 g (80% of theory). 1H NMR (300 MHz, CDCl3): δ 7.84-7.80 (m, 2H), 7.71-7.67 (m, 2H), 6.98-6.94 (m, 4H), 4.51 (s, 1H), 4.26-4.12 (m, 1H), 2.76-2.60 (m, 2H), 2.18 (d, J=13 Hz, 2H), 1.79-1.49 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([O:29]C)=[O:28])[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([OH:29])=[O:28])[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a methanol solution (7 ml) of methyl 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}benzoate (1.15 g) was added 1N aqueous sodium hydroxide solution (4 ml). The solution was stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with brine. After dried over MgSO4, the organic solvent was evaporated in vacuo to afford 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}-benzoic acid (1.02 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:6]=O.[C:12]([CH2:14]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:13]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:12]#[N:13])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: N#CC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1C
Product: COc1cc(C=CC#N)ccc1C
Yield: 77 %

Procedure:
Wittig reaction of 3-methoxy-4-methylbenzaldehyde with cyanomethyl triphenylphosphorane gave 3-(3-methoxy-4-methylphenyl)acrylonitrile in 77% yield which was further transformed to 3-(3-methoxy-4-methylphenyl)propan-1-amine using the above described procedures.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[C:9]2[C:10]([CH3:28])=[CH:11][C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[F:14][C:13]1[C:8]2[S:7][CH:6]=[C:5]([CH2:4][C:3]([OH:29])=[O:2])[C:9]=2[C:10]([CH3:28])=[CH:11][C:12]=1[O:15][CH2:16][C:17]1[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1csc2c(F)c(OCc3ccc(C(F)(F)F)nc3C)cc(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)ccc1COc1cc(C)c2c(CC(=O)O)csc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a mixture of methyl(7-fluoro-4-methyl-6-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (159.8 mg), THF (dry) (2.0 mL) and MeOH (2.0 mL) was added 1N NaOH (1.122 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl and concentrated in vacuo. The precipitate was collected by filtration to give a solid. The solid was crystallized from EtOAc-hexane to give the title compound (134 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[S:17][C:16]2([CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:15][N:14]=1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClCCl>[CH3:12][C:13]1[S:17][C:16]2([CH2:22][CH2:21][N+:20]([O-:9])([CH3:23])[CH2:19][CH2:18]2)[CH2:15][N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=NCC2(CCN(C)CC2)S1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Product: CC1=NCC2(CC[N+](C)([O-])CC2)S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of m-chloroperbenzoic acid, mCPBA, (1.40 gr, 8.11 mmol) in dichloromethane (30 ml) was added gradually to a solution of AF150(S) (1.45 gr, 7.88 mmol) in dichloromethane (10 ml). The reaction was stirred at room temperature overnight. Chromatography of the reaction mixture was on a column of natural aluminum oxide (Merck)(metanol:chloroform 1/49) gave AF406 (0.75 gr) as a crystalline solid. A sample was crystallized from ethylacetate. A very hygroscopic solid was obtained. mp. 130–132° C. (145–159° C. dec.); 1H NMR (300 MHz, CDCl3) δ 1.89 (m, 2H), 2.2 (t, j=1.5 Hz, CH3C═N), 2.82 (m, 2H), 3.24 (m, 2H), 3.25 (s, CH3N+O−), 3.35 (m, 2H), 4.03 (q, j=1.5 Hz, CH2N═C) ppm; IR(CHCl3) 2947, 1636, 1448, 1153, 931, 664 cm−1; MS(EI) 200 (M+), 184, 182, 149, 141, 140, 126, 110, 109, 108, 96, 82, 70.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:13][CH2:12][C:14](=[O:15])[CH3:16])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: C=CC(C)=O
Product: CC(=O)CCOCc1ccc([N+](=O)[O-])cc1

Procedure:
Treat 4-nitrobenzyl alcohol with methyl vinyl ketone in a manner similar to Preparation 2 to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21].[CH2:22]([CH:24]1[O:26][CH2:25]1)Br>>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21]
Reactant: BrCC1CO1
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)CC2
Product: CCCc1c(OCC2CO2)ccc2c1OC(CCC(=O)OCC)CC2

Procedure:
The title compound was prepared by the method of Example 11 using 3.0 g (10.3 mmole) of the product of Example 27 and 1.3 ml (15 mmole) of epibromohydrin as starting materials. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:17][CH:16]=1)[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[OH:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([B:21]2[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:19][CH:20]=1
Reactant: COC(=O)[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (9.50 g, 0.0234 mol) was dissolved in tetrahydrofuran (30 mL, 0.37 mol) and cooled to 0° C. 2 M lithium tetrahydroborate in tetrahydrofuran (12.0 mL) was added over 3 minutes. The reaction was allowed to stir in the ice bath for 21 minutes. The bath was removed and the reaction continued stirring for additional 3 hours. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. The solution was filtered through a glass frit and the solvent concentrated to give a white solid (8.80 g, 100%). 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 4.73 (br s, 1H), 3.86 (br s, 1H), 3.66 (m, 1H), 3.54 (m, 1H), 2.87 (m, 2H), 1.42 (s, 9H), 1.34 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.[Br:19]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([Br:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(ccc(N)c2Br)C1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (Q1, 683 mg, 2.75 mmol) in methylene chloride (40 mL) was added N-bromosuccinimide (NBS) (490 mg, 2.75 mmol) at 0° C. The reaction mixture was stirred for 30 min and then diluted with methylene chloride (200 mL). The resulting solution was washed with water (50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 12% to 30% ethyl acetate/hexanes to afford compound Q2 as a white solid (743 mg, 83%): 1H NMR (500 MHz, CDCl3) δ 6.86 (d, J=8.2 Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 4.47 (s, 2H), 4.07 (s, 2H), 3.63 (t, J=5.8 Hz, 2H), 2.82 (t, J=5.8 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: CC(C)=O.[N-:5]=[N+:6]=[N-:7].[Na+].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>O>[N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CBr
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CN=[N+]=[N-]
Temperature: 65 °C
Yield: 67 %

Procedure:
A mixture of 6:4 acetone:water (20 ml) to was added to sodium azide (1.30 grams, 20 mmol, 2 molequivalents) followed by addition of ethyl bromoacetate (1.67 grams, 10 mmol, 1 molequivalent). The resulting mixture was refluxed overnight at 65° C. The acetone was thereafter evaporated under reduced pressure and the mixture was extracted with dichloromethane. The aqueous phase was washed with dichloromethane and the combined organic phase was washed with water, dried over sodium sulfate and evaporated to give 865 mg (76% yield) of ethyl azidoacetate as colorless oil having purity higher than 98% (as determined by NMR).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:15][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[C:16]1([C:22]2[C:23]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)=[N:24][C:25]3[N:26]([N:28]=[CH:29][CH:30]=3)[CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1COCC1>C(O)(=O)C>[C:16]1([C:22]2[C:23]([C:31]3[CH:32]=[CH:33][C:34]([CH2:35][N:1]4[CH2:2][CH2:3][CH:4]([C:7]5[NH:15][C:10]6[CH:11]=[N:12][CH:13]=[CH:14][C:9]=6[N:8]=5)[CH2:5][CH2:6]4)=[CH:37][CH:38]=3)=[N:24][C:25]3[N:26]([N:28]=[CH:29][CH:30]=3)[CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1cc2nc(C3CCNCC3)[nH]c2cn1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(-c2cn3nccc3nc2-c2ccc(CN3CCC(c4nc5ccncc5[nH]4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
252 mg (1.06 mmol) 2-piperidine-4-yl-3H-imidazo[4,5-c]pyridine and 250 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde were reacted as described in example 12.0. Additional NaBH(OAc)3 has been added after one, three and five hours (two equivalents each) and the reaction mixture has been stirred overnight at room temperature. Since the reaction has not been complete, 20 mL THF and 10 mL acetic acid were added. Another two equivalents of NaBH(OAc)3 were added. Because after one hour stirring at room temperature the reaction has not changed additional 126 mg 2-piperidine-4-yl-3H-imidazo[4,5-c]pyridine and another two equivalents of NaBH(OAc)3 were added. The reaction has been worked up after stirring at room temperature for 70 hours. After purification 28 mg of the desired material has been obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C:10]([CH3:25])([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:14]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][CH:31]=1)([CH3:29])[CH3:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:26])[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:37](=[O:38])[CH2:36][C:33]3[CH:34]=[CH:35][C:30]([CH:27]([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[CH2:20]2)[CH:14]=1)([CH3:11])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1cccc(C2CCCNC2)c1)C(=O)OCc1ccccc1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1ccc(CC(=O)N2CCCC(c3cccc(OC(C)(C)C(=O)OCc4ccccc4)c3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
To a solution of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester (Preparation 2, Method C; 0.54 g, 1.52 mmol) in 5 mL methylene chloride was added 4-isopropylphenyl acetic acid (0.33 g, 1.83 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.58 g, 3.04 mmol) and allowed to stir 18 h at ambient temperature. The reaction was concentrated under reduced pressure and the resultant oil flash chromatographed with 30% ethyl acetate/hexanes to yield 0.696 g (89%) of 2-(3-{1-[(4-Isopropyl-phenyl)-acetyl]-piperidin-3-yl}-phenoxy)-2-methyl-propionic acid benzyl ester as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nccc2c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
A suspension of 6-Methoxy-2H-isoquinolin-1-one (900 mgs, 5.1 mmol) in POCl3 (4 mL) was heated at 110° C. for 3 h (clear solution obtained upon heating). After 3 h, the reaction mixture was concentrated under reduced pressure. The residue was poured into iced water (10 mL), pH was then adjusted to 10 with 3N NaOH and extracted with CHCl3 (3×25 mL). The combined CHCl3 layers were washed with brine and dried (MgSO4). The organic layer was then filtered, concentrated and purified by flash chromatography (50% ethyl acetate/hexane) to give 1-chloro-6-methoxy-isoquinoline (720 mgs, 3.7 mmol, 73% yield) as white solid. 1H NMR (CD3OD): 8.23 (d, 1 H, J=8.8 Hz); 8.11 (d, 1 H, J=6.0 Hz); 7.69 (d, 1 H, J=6.0 Hz); 7.37-7.33 (m, 2H); 3.97 (s, 3H). MS m/z 194 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](N)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-].[Na+].C([OH:35])CCC>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:35])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCCO
Reactant: CCN(Cc1cc(Br)ccc1NCc1ccccc1)c1ccc(C(N)=O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(Cc1cc(Br)ccc1NCc1ccccc1)c1ccc(C(=O)O)nn1

Procedure:
A mixture of 6-[N-(5-bromo-2-benzylaminobenzyl)-N-ethylamino]pyridazine-3-carboxamide (700 mg, 1.59 mmol), sodium hydroxide pellets (200 mg, 5.0 mmol) and butanol was stirred at reflux for 3 hours. The mixture was cooled, diluted with water (100 ml) and washed with hexane (2×100 ml). The aqueous layer was acidified with formic acid and extracted with dichloromethane (2×200 ml). The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated to give a white solid, which was triturated with ether and filtered to give the title compound (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH:18](=[O:23])[CH2:19][CH2:20][CH:21]=O.Cl>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:9]2[C:10]3=[C:14]([N+:15]([O-:17])=[O:16])[CH:21]4[O:23][CH:18]([N:11]3[CH2:12][CH2:13]2)[CH2:19][CH2:20]4)=[CH:6][CH:7]=1
Reactant: O=CCCC=O
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])C1=C2N(Cc3ccc(Cl)nc3)CCN2C2CCC1O2
Temperature: 25 °C
Yield: 71 %

Procedure:
To a 50 ml round bottom flask was added 1.27 g (0.005 mol) 2-chloro-5-((2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine, 30 ml dry acetonitrile, 0.860 g (0.01 mol) succinaldehyde and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 71% yield.