Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][N:19]([CH3:36])[C:20]3[CH:35]=[CH:34][C:23]([C:24]([NH:26][O:27]C4CCCCO4)=[O:25])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[ClH:37]>CO>[ClH:37].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][N:19]([CH3:36])[C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH:26][OH:27])=[O:25])=[CH:34][CH:35]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)CC1)c1ccc(C(=O)NOC2CCCCO2)cc1
Agent: Cl
Solvent: CO
Product: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)CC1)c1ccc(C(=O)NO)cc1

Procedure:
To a solution of the compound (0.60 g) obtained in Example 23 in methanol (20 mL) was added 10% hydrogen chloride in methanol (5.0 mL), followed by stirring. The solvent was removed under reduced pressure, the residue was dissolved in methanol, and the solvent was removed again under reduced pressure. The residue was solidified with ethyl acetate, the resulting solid was finely powdered and was collected by filtration. The powder was dissolved in water (60 mL), and the solvent was removed under reduced pressure. The residue was finely powdered and dried under reduced pressure to yield the titled compound (447 mg) as a powder.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=[O:11])[CH2:4][CH:3]=1.[H][H]>[Pd]>[CH3:8][C:6]1([CH3:7])[CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[CH2:9][CH:10]=[O:11]
Reactant: CC1=CCC(CC=O)C1(C)C
Reactant: [H][H]
Agent: [Pd]
Product: CC1CCC(CC=O)C1(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
A three liter autoclave with a stirrer is charged with 830 g of campholenic aldehyde and 56 g of catalyst Pd(5%)/C. Hydrogen is introduced until the pressure reaches 30 bars. The mixture is heated up to 80° C. with stirring for five hours. The calculated amount of hydrogen is now absorbed. The catalyst is separated by filtration and washed with ethanol. The solvent is removed by vacuum evaporation and 815 g of crude saturated aldehyde are obtained (purity: 95%, GC). The vacuum distillation of the crude through a Widmer column gives 763 g of pure product (purity 95%); bp20 85° C.; nD20 : 1,4553;
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]1([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=2)[CH2:31][CH2:30]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:24]=[C:23]3[C:22](=[CH:17][CH:16]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:32]([CH:29]2[CH2:31][CH2:30]2)[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=2)=[O:28])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: COc1ccc(CNC2CC2)cc1OC
Product: COc1ccc(CN(C(=O)CN(c2ccc3ncccc3c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc1OC

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with cyclopropyl-(3,4-dimethoxy-benzyl)-amine
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:9]=[C:8]([CH2:18][S:19][CH3:20])[CH:7]=1)([CH3:5])[C:3]#[N:4].I([O-])(=O)(=O)=[O:22].[Na+]>CO.O1CCCC1.O>[CH3:5][C:2]([C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:9]=[C:8]([CH2:18][S:19]([CH3:20])=[O:22])[CH:7]=1)([CH3:1])[C:3]#[N:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCc1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)Cc1cc(Cn2cncn2)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the product of Example 30 (0.16 g) in methanol (0.5 ml) and tetrahydrofuran (5 ml) was stirred while a solution of sodium periodate (0.15 g) in water (0.5 ml) was added, and was then stirred at room temperature for a further 18 h. Water (5 ml) was added and the mixture was extracted six times with dichloromethane. The extracts were combined, dried and evaporated to dryness, and the residue was purified by flash column chromatography, eluting with methanol:ethyl acetate (1:9 by volume) to give 2-methyl-2-[3-methylsulphinylmethyl-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-propiononitrile. Nmr in deuteriochloroform; δ 8.16(1H,s), 8.0(1H,s), 7.38(1H,m), 7.27(1H,m), 7.15(1H,m), 5.4(2H,s), 3.98(1H,d), 3.88(1H,d), 2.5(3H,s), 1.72(6H,s).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].CC1(C)CCCC(C)(C)N1.C([Li])CCC.[I:40]I.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[CH3:1][NH:2][C:3]([C:5]1[C:6]([I:40])=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: II
Reactant: CNC(=O)c1ccc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cnc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
To a solution of 500 mg (1.43 mmol) 4-(tert-butyl-dimethyl-silanyloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid methylamide, 1.7 ml (11 mmol) N,N,′,′-tetramethyl-ethylenediamine and 1.0 ml (5.7 mmol) 2,2,6,6-tetramethylpiperidine in 9.5 ml dry tetrahydrofuran 7.2 ml (11 mmol) of a 1.6 M solution of n-butyllithium in hexanes were added dropwise during 10 min. at −78° C. under argon. The resulting solution was stirred at −78° C. for 30 min., warmed to −20 C. and stirred at this temperature for 3 h. After cooling the reaction mixture to −78° C. a solution of 2.92 g (11.5 mmol) iodine in 7 ml dry tetrahydrofuran was added dropwise under argon. The resulting suspension was kept at −78° C for 2 h and subsequently allowed to warm to room temperature over 1 h. The suspension was poured into a solution of 12.4 g (50.0 mmol) sodium thiosulfate pentahydrate in 50 ml ice-water. The resulting yellow suspension was extracted with two 250-ml portions of tert-butyl methyl ether. The combined organic extracts were washed with 2 portions of a saturated aqueous ammonium chloride solution, dried with sodium sulfate and concentrated. Flash chromatography afforded 495 mg (72.8%) of the title compound as an off-white amorphous mass. MS m/e (%): 476 (M+H+, 100).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17]([C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])Cl)=[CH:16][CH:15]=[C:14]1[C:9]=3[CH:10]=[CH:11][CH:12]=[CH:13]1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>CCCCCC>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17]([C:4]=2[CH:3]=[C:2]1[Si:18]([CH3:21])([CH3:20])[NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:15]=[C:14]1[C:9]=3[CH:10]=[CH:11][CH:12]=[CH:13]1
Reactant: CC(C)(C)N
Reactant: C[Si](C)(Cl)C1=Cc2c(ccc3c2ccc2ccccc23)C1
Solvent: CCCCCC
Product: CC(C)(C)N[Si](C)(C)C1=Cc2c(ccc3c2ccc2ccccc23)C1

Procedure:
To a 500 ml round bottom flask containing 1.98 g (0.0064 mole) of (1H-cyclopenta[I] phenanthrene-2-yl) dimethylchlorosilane and 250 ml of hexane was added 2.00 ml (0.0160 mole) of t-butylamine. The reaction mixture was allowed to stir for several days, then filtered using diatomaceous earth filter aid (CeliteTM), washed twice with hexane. The product was isolated by removing residual solvent under reduced pressure. The isolated yield was 1.98 g (88.9 percent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[CH3:23][N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:14]=1
Reactant: CI
Reactant: COc1ccc(Nc2nc(-c3ccncc3)cs2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(-c3ccncc3)cs2)cc1
Reaction time: 0.03 h

Procedure:
N-(4-methoxyphenyl)-4-pyridin-4-yl-1,3-thiazol-2-amine (7-2, 0.1 g, 0.36 mmol) was dissolved in 1 mL DMF. NaH (0.02 g, 0.7 mmol) was added and the suspension was allowed to stir for 2 min. MeI (0.02 mL, 0.36 mmol) was added and the reaction was allowed to stir for 1 h. The reaction was quenched with water and the products extracted with EtOAc. The organic layer was concentrated to 0.5 mL then purified on a Gilson automated system affixed with a YMC Combiflash 50×20 mm column eluted at 30 mL/min with 5-65% CH3CN in H2O (both containing 0.1% TFA) over 10.5 min to yield N-methyl-N-(4-methoxyphenyl)-4-pyridin-4-yl-1,3-thiazol-2-amine (8-1): 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=1 Hz, 2H), 7.72 (d, J=1 Hz, 2H), 7.3 (d, J=3 Hz, 2H), 6.97 (d, J=3 Hz, 2H), 6.88 (s, 1H), 3.85 (s, 3H), 3.57 (s, 3H): MS 298.3 found 298.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)[CH3:13])=[CH:7][CH:6]=1)=[O:4].Cl>ClCCl>[CH3:13][N:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][NH:16]1
Reactant: COC(=O)c1ccc(CN(C)CC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(C)CC2CCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1,1-dimethylethyl 2-[[[[4-(methoxycarbonyl)phenyl]methyl]methylamino]methyl]-1-pyrrolidinecarboxylate in dichloromethane was treated with 4 N HCl (2 mL) and stirred at ambient temperature for 4 hours. The reaction was concentrated to give methyl 4-[[methyl(2-pyrrolidinylmethyl)amino]methyl]benzoate as a hydrochloride salt.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([S:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:12]=1[CH:23]=O>C1(O)CCCCC1>[Cl:10][C:11]1[C:12]2[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[S:17][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COC(=O)CSc1ncnc(Cl)c1C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: OC1CCCCC1
Product: COC(=O)c1cc2c(Cl)ncnc2s1
Temperature: 120 °C
Yield: 53.9 %

Procedure:
DIPEA (2.1 mL) was added to methyl [(6chloro-5-formylpyrimidin-4-yl)thio]acetate (intermediate 9) (2.9 g) in cyclohexanol (50 mL) under an inert atmosphere. The reaction mixture was heated at 120° C. for 90 minutes. The solvent was evaporated and the product purified by flash chromatography on silica eluting with hexane:diethyl ether (4:1) to afford the title compound as a pale yellow solid (1.45 g, 53%);
Reaction SMILES: Cl[C:2]1[C:3]([CH3:20])=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:21][O-:22].[Na+]>CN(C=O)C.O>[CH3:18][CH:17]([N:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:22][CH3:21])[C:3]=2[CH3:20])[CH2:12][CH2:13]1)[CH3:19]
Reactant: Cc1c(N2CCN(C(C)C)CC2)ccc([N+](=O)[O-])c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c([N+](=O)[O-])ccc(N2CCN(C(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 175.3 %

Procedure:
To a solution of 1-(3-chloro-2-methyl-4-nitrophenyl)-4-(1-methylethyl)piperazine (12.6 g, 42.4 mmol, 1 equiv) in 120 mL of DMF was added sodium methoxide (1.12 g, 21 mmol, 0.5 equiv) at 0° C. After stirring for 1 hour at room temperature, additional sodium methoxide was added (4.61 g, 85 mmol, 2 equiv, ×2) at 0° C. The mixture was warmed to 35° C. overnight. The next morning, the mixture was diluted with water, dried, and taken to a residue under reduced pressure. Recrystallization from ethyl acetate afforded 1-(1-methylethyl)-4-[2-methyl-3-(methyloxy)-4-nitrophenyl]piperazine (10.8 g, yield 87.1%) of sufficient purity for use in subsequent chemical transformations. 1H NMR (400 MHz, CDCl3) δ ppm 1.12 (d, J=6.53 Hz, 6H), 2.27 (s, 3H), 2.68-2.74 (m, 4H), 2.98-3.09 (m, 4H), 3.89 (s, 3H), 6.78 (d, J=9.2 Hz, 1H), 7.74 (d, J=9.2 Hz, 1H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:81][O:82][C:83](=[O:93])[C@@H:84]([C:86]1[CH:91]=[CH:90][CH:89]=[C:88](Cl)[CH:87]=1)[OH:85]>C1(C)C=CC=CC=1.O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:81][O:82][C:83](=[O:93])[C@@H:84]([C:86]1[CH:87]=[C:88]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])[CH:89]=[CH:90][CH:91]=1)[OH:85]
Reactant: COC(=O)[C@H](O)c1cccc(Cl)c1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)OC)c2)c(C)c1
Reaction time: 0.05 h
Yield: 70.8 %

Procedure:
Degassed toluene (0.17 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 46.5 mg, 0.0766 mmol), palladium (II) acetate (2.8 mg, 0.013 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (10.5 mg, 0.0256 mmol) and potassium phosphate (39.8 mg, 0.187 mmol), and the mixture was stirred in a nitrogen atmosphere for three minutes. Then, a solution of (R)-(3-chloro-phenyl)hydroxy-acetic acid methyl ester (Example 156-(1); 18.8 mg, 0.0937 mmol) in toluene (0.17 mL) and water (0.033 mL) were added, and the mixture was heated while stirring at an external temperature of 95 to 105° C. for one hour. The reaction mixture was diluted with diethyl ether and filtered through cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=8/1) to give the title compound (35 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]#[N:6].[N:15]([O-])=O.[Na+]>Cl.O>[OH:14][CH2:13][CH2:12][CH2:11][N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[N:15]1
Reactant: N#Cc1ccc(NCCCO)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2c(c1)nnn2CCCO
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a vigorously stirred solution of 3-amino-4-[(3-hydroxypropyl)amino]benzonitrile (Intermediate 96, 11.5 g, 0.06 mol) in aqueous HCl (105 mL of a 5N HCl solution) was added, dropwise an 0° C., a solution of sodium nitrite (6.2 g, 0.09 mol) in water (47 mL). After 3.5 hours of vigorously stirring at 0° C., water was added (200 mL) and the reaction mixture extracted with AcOEt (3×150 mL). The combined organic extracts were washed with water (3×100 mL) and brine, and the resulting organic phase was evaporated to dryness to deliver the title compound as a brownish solid (10.8 g, 86%) which was used without further purification.
Reaction SMILES: CB1OB(C)OB(C)O1.Br[C:11]1[C:12]2[C:13](=[CH:18][N:19]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])[N:20]=2)[CH:14]=[N+:15]([O-:17])[CH:16]=1.[C:29](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:21]=1[N:19]1[CH:18]=[C:13]2[CH:14]=[N+:15]([O-:17])[CH:16]=[C:11]([CH3:29])[C:12]2=[N:20]1
Reactant: O=C([O-])[O-]
Reactant: [O-][n+]1cc(Br)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c[n+]([O-])cc2cn(-c3c(Cl)cccc3Cl)nc12
Temperature: 80 °C
Yield: 68.8 %

Procedure:
Trimethylboroxine (0.348 mL, 2.5 mmol) was added to a suspension of 7-bromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-5-oxide (720 mg, 2.0 mmol), potassium carbonate (829 mg, 6.0 mmol) and Pd(PPh3)4 (228 mg, 0.2 mmol) in dioxane (11 mL) and the reaction mixture was heated at 80° C., under an atmosphere of nitrogen overnight. Additional trimethylboroxine (0.278 mL) was added and the reaction mixture was heated at 80° C. for another 2 hours. The resultant mixture was cooled to room temperature and filtered. The solid was washed with ethyl acetate and methanol (9:1). The filtrate was concentrated under reduced pressure to give a brown solid. This was purified by silica gel flash chromatography (0-20% methanol in ethyl acetate) to afford the title compound as a pale yellow solid (405 mg, 69% yield). LCMS (Method F): RT=2.30 min, m/z: 294 [M+H+].
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:10])=[CH:6][C:7]=1[O:8][CH3:9].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[N:3]=[N:4][C:5]([Cl:10])=[CH:6][C:7]=2[O:8][CH3:9])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1cc(Cl)nnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc(Cl)nnc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
To a stirred solution of 3,6-dichloro-4-methoxy-pyridazine (0.73 g, 4.08 mmol) (prepared by a procedure similar to that described in Eichenberger, K.; Rometsch, R.; Druey, J. Australian Journal of Chemistry 1956, 9, 1755-1764), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.98 g, 4.90 mmol) and cesium carbonate (2.66 g, 8.16 mmol) in toluene (15 ml) in a sealed tube under nitrogen, were added (R)-(+)-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl (0.38 g, 0.61 mmol) and palladium(II) acetate (0.046 g, 0.20 mmol). The reactiom mixture was stirred at 110° C. for 18 h. After cooling to room temperature, the reaction mixture was filtered though Celite and the filtrate was evaporated. The crude product was purified by flash column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. to yield D1 (0.44 g, 32%) as a yellow solid. C15H23ClN4O3 requires 342; Found 343 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.CC1C=CC(C2[O:21]C=CN=2)=CC=1>>[O:10]1[CH:11]=[N:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH:1]=[O:21])=[CH:7][CH:6]=2)=[N:9]1
Reactant: Cc1ccc(-c2ncco2)cc1
Reactant: Cc1ccc(-c2ncon2)cc1
Product: O=Cc1ccc(-c2ncon2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Step B of Reference Example 73 by substituting 3-(4-methylphenyl)-1,2,4-oxadiazole (prepared as described in Bull. Chem. Soc. Jpn. 1978, 51,1484) for the 2-(4-methylphenyl)oxazole of Step B of Reference Example 73. MS 175 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)CCBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCN(CCC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
4-methyl piperazine (7.68 mL, 70 mmol, 4 equiv) was added to a stirred solution of tert-butyl 3-bromopropionate (3.0 mL, 18 mmol) in ethyl acetate (15 mL) at 0° C. The solution was stirred at 25° C. for 1 h with evolution of a white precipitate, then heated on an oil bath to 55° C. for 2 h. TLC analysis (20% EtOAc in Hexanes, Rf=0.9 (starting material), 0.1 (product)) indicated complete consumption of the bromide reagent. The reaction was diluted with EtOAc (100 mL) and transferred to a separatory funnel, and the organic phase was washed with water (100 mL), NaHCO3 (sat'd, 2×100 mL), and brine (100 mL), dried over MgSO4 and concentrated to give a slightly yellow oil. The oil was dissolved in methylene chloride (20 mL), loaded on to a pre-equilibrated plug of silica gel (20% EtOAc in Hexanes, 150 mL SiO2) and the desired product was eluted from the silica with increasingly polar eluent (EtOAc in hexanes, starting at 20%, 200 mL volumes increasing in 15% increments to 100%). Fractions containing the desired material were concentrated to give tert-butyl 3-(4-methylpiperazin-1-yl)propanoate (4.1 g, quantitative). 1H NMR (400 MHz, CDCl3) δ (ppm)=3.45 (d, J=3 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.47 (br s, 6H), 2.38 (t, J=7.3 Hz, 2H), 2.25 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:29])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:27][CH3:28])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:30]([F:33])([F:32])[F:31])=[N:10]2)=[CH:5][CH:4]=1.C=O.[CH3:36]C(O)=O.[BH3-]C#N.[Na+].[OH-].[Na+]>CC#N.CC(C)=O>[CH3:28][N:27]([CH3:36])[C:24]1([C:21]2[CH:22]=[CH:23][C:18]([N:15]3[CH2:16][CH2:17][C:12]4[C:11]([C:30]([F:32])([F:33])[F:31])=[N:10][N:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[C:13]=4[C:14]3=[O:29])=[CH:19][CH:20]=2)[CH2:26][CH2:25]1
Reactant: CC(=O)O
Reactant: CNC1(c2ccc(N3CCc4c(C(F)(F)F)nn(-c5ccc(OC)cc5)c4C3=O)cc2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(N(C)C)CC4)cc2)CC3)cc1
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
The product from Example 130 (30 mg, 0.066 mmol) was stirred in CH3CN (0.2 mL) at rt under N2. Aqueous formaldehyde (0.07 mL, 7 mmol, 10 eq) was added followed by the addition of HOAc (0.012 mL, 0.21 mmol, 3.2 eq). The mixture was stirred for 15 min, and then NaBH3CN (12 mg, 0.198 mmol) was added. The mixture was stirred at rt for 2 h. Several drops of acetone were added followed by 1N NaOH. The mixture was extracted with CH2Cl2, washed with H2O and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by FCC (silica gel, EtOAc, than EtOAc:MeOH=10:1) to yield the title compound (15.7 mg, 51%). 1H NMR (CDCl3) δ 7.46 (d, J=8.8 Hz, 2H), 7.29 (m, 4H), 6.92 (d, J=9.2 Hz, 2H), 4.15 (t, J=6.6 Hz, 2H), 3.81 (s, 3H), 3.16 (t, J=6.6 Hz, 2H), 2.28 (s, 6H), 1.02 (m, 2H), 0.81 (m, 2H) ppm. LC/MS (ESI+) 471.4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[C:19][Si](C)(C)C)=[CH:13][CH:12]=2.C(OCC)(=O)C>CO>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[CH:19])=[CH:13][CH:12]=2
Reactant: C[Si](C)(C)C#Cc1ccc2cnc(Cl)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc2cnc(Cl)cc2c1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Potassium carbonate (9 mg, 0.0654 mmol) was added to a solution of 3-chloro-6-((trimethylsilyl)ethynyl)isoquinoline (Preparation 51, 170 mg, 0.654 mmol) in methanol (1 mL) and the reaction was stirred for 1 hour. Ethyl acetate (20 mL) was added and the organic solution was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50% hexane in dichloromethane to afford the title compound as a white powder (110 mg, 90%).