Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Br)#[C:2][CH2:3][CH3:4].[C:6]1([CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)[OH:7].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:7][C:6]1[CH:13]=[CH:12][C:10]([OH:11])=[CH:9][CH:8]=1)[C:2]#[C:3][CH3:4]
Reactant: CCC#CBr
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC#CCOc1ccc(O)cc1
Yield: 24.7 %

Procedure:
To a solution containing butynyl bromide (1 g, 7.5 mmol), hydroquinone (827 mg, 7.5 mmol), and K2CO3 (1.04 g, 7.5 mmol) was refluxed for 10 h. Solvent was removed in vacuo and the crude product was dissolved in EtOAc and partitioned with water. Organic layer was separated and washed with water and dried over anhydrous Na2SO4. The solvent was removed in vacuo to obtain the crude product (0.3 g, 25%), which was used for the next step without further purification; LCMS 99%, m/z 162.2 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=[CH2:15]>COCCOC>[Cl:12][CH2:13][C:14](=[CH2:15])[CH2:16][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: C=C(CCl)CCl
Reactant: N#Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=C(CCl)COc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of 4-cyanophenol (11.9 g; 0.1 mol) in 1,2-dimethoxyethane (100 mL) was slowly added to a stirred and cooled (0° C.) suspension of NaH (4.0 g; 0.1 mol; 55% dispersion) in 1,2-dimethoxyethane (250 mL). The reaction mixture was refluxed for 1 hour and then allowed to cool to room temperature. 3-Chloro-2-chloromethyl-propene (20 g; 0.16 mol) was added in one portion and the reaction mixture was stirred at 45° C. for 40 hours. The reaction mixture was partitioned between DCM and NaHCO3 (satd.) and the organic layer collected, dried, concentrated and purified using column chromatography (DCM:MeOH; 50:1) to give the sub-title ompound in a 66% yield.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH:10]=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.[Li]CCCC>>[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:10]([OH:11])[C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: c1cscn1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)c1nccs1

Procedure:
31 (1.0 g, 5.02 mmol), thiazole (0.39 ml, 5.52 mmol), n-BuLi (1.6 M) (3.45 ml 5.52 mmol).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH:26][CH2:27][C@H:28]([OH:30])[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([N:26]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1)[CH2:27][C@H:28]([OH:30])[CH3:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1Br
Reactant: C[C@@H](O)CNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H](O)CN(Cc1ccccc1)c1nc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.3 %

Procedure:
2,6-Dibromo-3-nitropyridine (2.59 g, 9.20 mmol) and triethylamine (2.70 mL, 19.37 mmol) were added to a solution of (R)-1-(benzylamino)propan-2-ol (1.6 g, 9.68 mmol) in ethanol (35 mL). The solution was stirred at rt for 17 h and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution (25 mL). The layers were separated, and the organic layer was washed with 5% aqueous sodium chloride solution (25 mL). The ethyl acetate layer was concentrated under reduced pressure to afford an orange syrup. The crude product was purified by column chromatography on silica gel (eluting with 5:1 hexanes-ethyl acetate followed by 3:1 hexanes-ethyl acetate) to afford (R)-1-(benzyl(6-bromo-3-nitropyridin-2-yl)amino)propan-2-ol (3.01 g, 85%) as a bright yellow syrup. MS (ESI, pos. ion) m/z 388, 390 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1>N.[Rh]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCC#N)CC1
Agent: [Rh]
Agent: N
Product: COc1ccccc1N1CCN(CCCN)CC1
Yield: 86.9 %

Procedure:
A solution of the product of Example 26 (4.4 g, 18 mmol) in concentrated ethanolic ammonia solution (150 ml) was hydrogenated over 5% rhodium on alumina powder (0.6 g) at 50 p.s.i. (about 3.4×105Pa) for 50 h to give the product (3.9 g) as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[F:14][C:15]([F:30])([F:29])[CH:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.C([BH3-])#N.[Na+]>CO>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:21]3[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:17][CH:16]3[C:15]([F:29])([F:14])[F:30])=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: CC(C)(C)OC(=O)N1CCNC(C(F)(F)F)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2)COC3=O)C(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (0.495 g, 2.8 mmol) and tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (0.65 g, 2.6 mmol) in methanol (5 ml) at 0° C. was added sodium cyanoborohydride (0.21 g, 3.3 mmol) and the reaction stirred 12 hours at RT. The reaction mixture was concentrated and diluted with water. The aqueous was extracted with dichloromethane and the combined organics washed with brine, dried (MgSO4), filtered and concentrated. MPLC chromatography (2→20% EtOAc:hexane) provided tert-butyl 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate. LC-MS (IE, m/z): 415.1 [M+1]+.
Reaction SMILES: C([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([Br:19])=[CH:11][C:10]=1[NH:20][C:21]([C:23]([O:25]CC)=O)=[O:22])(C(OCC)=O)=O>Cl.C(O)(=O)C>[Br:19][C:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:9]2[N:8]=[C:23]([OH:25])[C:21]([OH:22])=[N:20][C:10]=2[CH:11]=1
Reactant: CCOC(=O)C(=O)Nc1cc(Br)c2ccccc2c1NC(=O)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: Oc1nc2cc(Br)c3ccccc3c2nc1O
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A mixture of 2,0 g (4,6 mmol) 1,2-diethoxalylamino-4-bromonaphthalene in 50 ml 2N hydrochloric acid and 25 ml acetic acid was refluxed for 1,5 h. After cooling to 25° C., the precipitate was filtered off. The crude product was recrystallized (dimethylformamide-water) to give 1,2 g ( 90%) of pure 6-bromo-2,3-dihydroxybenzo(f)quinoxaline, m.p. > 300° C.1H NMR (DMSO-d6): 8,8 (1H,m), 8,3 (1H,m), 7,87 (1H,s), 7,7 (2H,m).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[C:3]=1[CH3:11].N.[H][H]>C(O)C.[Pd]>[CH3:10][C:4]1[C:3]([CH3:11])=[CH:2][C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1nc(Cl)c(C)c(Cl)c1C
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCO
Product: Cc1cnc(C)c(C)c1
Reaction time: 3 h

Procedure:
20 g 4,6-dichloro-2,3,5 trimethylpyridine was dissolved in 150 ml ethanol and 1 g 10% Pd/C and 10 ml conc. aqueous ammonia. The hydrogenation was performed at 3 bar for 3 hrs when the calculated amount of hydrogen had been adsorbed. Evaporation of solvent gave the 2,3,5-trimethylpyridine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[N:14]=[C:15]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=O)[NH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[C:7]1([C:13]2[N:14]=[C:15]([S:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[NH:16][C:17]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCCCCCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 0.5 h

Procedure:
Part D. To a solution of lithium aluminum hydride, (1.52 g, 0.04 mol) in dry tetrahydrofuran (50 mL) was added, dropwise, a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio) -N-heptylpentanamide (4.04 g, 0.009 mol) in tetrahydrofuran (25 mL) and the reaction mixture was stirred at reflux for 18 hours. The reaction mixture was cooled to 0°, quenched by the slow and careful sequential addition of water (1.52 mL), 15% sodium hydroxide (4.56 mL), and water (4.56 mL), and then stirred at 0° for 30 minutes. The solution was then dried over magnesium sulfate and concentrated under vacuum, and the residue was chromatographed with a gradient of 1:0 to 3:1 to 1:1 ethyl acetate-methanol . The resulting yellow oil was triturated with cold hexane to give N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine as a white solid. A solution of this amine (0.80 g, 0.0018 mol) in ether (20 mL) was treated with a sufficient amount of ethereal HCl (about 25 mL) to cause complete precipitation of the amine as the hydrochloride salt. The reaction mixture was stirred for 15 minutes, and the supernatant liquid was decanted to afford a gummy solid, which was triturated with hot acetonitrile and then with cold hexane to give N-[5-(4,5-diphenyl-1H-imidazol- 2-ylthio)pentyl]-1-heptanamine hydrochloride (0.82 g, 0.0017 mol) as a white solid, mp 187°-190°. 1H NMR (CDCl3) δ 9.3(s,2H), 7.7-7.3(m,10H), 3.7-3.5 (m,2H), 3.0-2.7 (m,4H), 2.0-1.2(m,16H), 0.9(t,3H,J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC1CCNCC1
Solvent: CCO
Product: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Yield: 99.1 %

Procedure:
The procedure of Example 4, step (a) was followed using 0.950 g (5.43 mmol) of 4-chloro-2-fluoronitrobenzene and 1.93 mL (16.3 mmol) of 4-methylpiperidine in 10 mL of EtOH to afford 1.37 g (99%) of the title compound as an orange oil which crystallized on standing: Mass spectrum (ESI, m/z): Calcd. for C12H15ClN2O2, 255.1 (M+H), found 255.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11]([OH:13])=O)=[O:5])[CH3:2].Cl.Cl.[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:27][CH2:28][NH2:29]>>[CH3:14][N:9]1[C:10]([C:11](=[O:13])[NH:29][CH2:28][CH2:27][C:19]2[N:18]([CH3:17])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Cn1c(CCN)nc2ccccc21
Agent: Cl
Product: CCOC(=O)c1cnn(C)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (150 mg, 757 μmol, prepared as described in US 2011/0071128) and 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine dihydrochloride (225 mg, 908 μmol) according to the method described in example 8, step 3 as red viscous oil (80 mg, 225 μmol, 29.7%).
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19]N=3)=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5].[CH3:28][CH:29](C)[C@H](N1CC2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C1=O)C(OC)=O.BrC1C=CC([N+]([O-])=O)=CC=1C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][CH:2]([CH3:27])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:28]=3[CH3:29])=[CH:13][CH:14]=2)[C:9]1=[O:26])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cn3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cc1cc([N+](=O)[O-])ccc1Br
Solvent: ClCCl
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3C)cc2C1=O
Yield: 75 %

Procedure:
The compound of example 465 was prepared analogous to the compound of example 391 by reaction of the compound of example 390, 1-bromo-2-methyl-4-nitro benzene and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: [F:1][CH2:2][C:3](=[O:34])[CH:4]([NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([N:20]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:27][C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[O:11])[CH2:5][C:6]([OH:8])=O.N=C=N.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>C(Cl)Cl>[CH2:38]([N:40]([CH2:41][CH3:42])[C:6](=[O:8])[CH2:5][CH:4]([NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([N:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[S:27][C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])=[O:11])[C:3](=[O:34])[CH2:2][F:1])[CH3:39]
Reactant: CCNCC
Reactant: O=C(O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Agent: N=C=N
Solvent: ClCCl
Product: CCN(CC)C(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
To a stirred mixture of [3S/R, (2S)]-5-fluoro-4-oxo-3-{[1-(phenothiazine-10-carbonyl)piperidine-2-carbonyl]amino}-pentanoic acid (200 mg, 0.4 mmol), prepared as in Example 1, in anhydrous DCM (4 ml), was added carbodiimide (74 mg, 0.44 mmol) and a diethylamine (0.62 ml, 6 mmol). The mixture was stirred at room temperature for 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (2.5% Methanol in dichloromethane) to afford the title compound as a white solid (25.3 mg, 11%): 1H NMR (400 MHz, CDCl3) δ 1.00-1.23 (6H, m), 1.45-1.67 (6H, m), 2.18 (1H, m), 2.74 (1H, m), 2.92 (1H, m), 3.21-3.33 (4H,m), 3.65 (1H, m), 4.68 (1H, m), 4.85 (1H, m), 4.98-5.36 (2H, m) and 7.12-7.95 (8H, m). 19F NMR (376 MHz, CDCl3) δ −232.37 and −232.72.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].B(Br)(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: COc1cccc(-c2ccc3c(C(=O)Nc4ccccc4)c(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: O=C(Nc1ccccc1)c1c(O)ccc2cc(-c3cccc(O)c3)ccc12
Yield: 23 %

Procedure:
The compound is prepared by reaction of 2-methoxy-6-(3-methoxyphenyl)-N-phenyl-1-naphthamide (217 mg, 0.57 mmol, 1 eq) with boron tribromide solution (3.39 mmol, 6 eq) according to method G. Purification by column chromatography with dichloromethane/methanol 95/5 as the eluent yielded the desired product in a yield of 23%, 47 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB([C:44]2[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=2)O1.O1CCOCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([C:44]2[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[CH:46][CH:45]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Temperature: 90 °C
Yield: 86.8 %

Procedure:
Under Ar, compound, 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine, (430 mg, 1.0 mmol) was mixed with Pd(dppf)Cl2 (82 mg, 0.1 mmol, K3PO4 (636 mg, 3.0 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (200 mg, 1.1 mmol) and dioxane (20 mL with 1 ml water). The resulting mixture was heated at 90° C. and stirred over night. After cooled to room temperature, the mixture was diluted with EtOAc (60 mL) and filtered through celite. After concentration, the crude was purified with column (silica gel, 0-30% EtOAc/Hexane) gave the product, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate (459 mg). HPLC-MS tR=2.89 min (UV254 nm); mass calculated for formula C26H40N4O4Si2 528.3, observed LCMS m/z 529.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]3[C:16]([CH2:17][OH:18])=[C:15]([CH3:19])[N:14]([CH2:20][C@H:21]4[CH2:23][C@@H:22]4[CH3:24])[C:13]=23)=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]3[C:16]([CH:17]=[O:18])=[C:15]([CH3:19])[N:14]([CH2:20][C@H:21]4[CH2:23][C@@H:22]4[CH3:24])[C:13]=23)=[CH:25][CH:26]=1
Reactant: Cc1c(CO)c2cnnc(OCc3ccc(F)cc3)c2n1C[C@H]1C[C@@H]1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1c(C=O)c2cnnc(OCc3ccc(F)cc3)c2n1C[C@H]1C[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
To a solution of 7-(4-fluorobenzyloxy)-3-hydroxymethyl-2-methyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (64.3 g, 181 mmol) in methylene chloride (900 ml) was added activated manganese dioxide (472 g, 5.43 mol) at room temperature. The mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through celite (trade mark) and the filtrate was concentrated in vacuo. The crude crystals (45.7 g) were washed with ethyl acetate and hexane to give the title compound (44.3 g, 69%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([S:16][CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=O)[CH:26]=[CH:27][CH:28]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:30]([CH2:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)=[N:20][C:18](=[O:19])[C:3]2=[C:4]([S:16][CH3:17])[NH:5]1
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(SC)c-3c(=O)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a stirred solution of 176 mg (0.5 mmol) of 5-amino-3-(methylthio)-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 220 mg (92%) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 245-248° C. Mass spec. Calc'd for C20H16N4O2SCl3: 481.0060. Found: 481.0076 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[CH:13]=[C:12]([NH:18][CH2:19][C:20]4([C:23]([F:26])([F:25])[F:24])[CH2:22][O:21]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>ClCCl>[F:24][C:23]([F:26])([F:25])[C:20]([CH2:22][NH:30][CH2:27][CH2:28][CH3:29])([OH:21])[CH2:19][NH:18][C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][N:8]2[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: Cc1cc(NCC2(C(F)(F)F)CO2)c2cnn(-c3ccc(F)cc3)c2c1
Reactant: CCCN
Solvent: ClCCl
Product: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-6-methyl-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-indazol-4-amine (1.4 g, 3.84 mmol) in dichloromethane (50 ml) was added n-propylamine (20 ml, 243 mmol). The reaction was stirred at room temperature overnight and then evaporated in vacuo. The crude product was purified on a 70 g silica Bond Elut cartridge using a 0-50% ethyl acetate in dichloromethane gradient over 60 minutes to give the title compound (0.4 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[F:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([CH:20]2[CH2:23][NH:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([CH:20]2[CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=3)[CH2:21]2)=[O:19])=[CH:24][CH:25]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=C(c1ccc(F)cc1)C1CNC1
Product: O=C(c1ccc(F)cc1)C1CN(Cc2ccc3ccccc3c2)C1

Procedure:
Following the procedure of Preparation 9, the title compound is prepared from 2-bromomethylnaphthalene and 3-(4-fluorobenzoyl)azetidine.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[I-].[K+].C(=O)([O-])O.[Na+]>CO.C(#N)C>[C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)N2CCCC2)cc1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
Chlorodiphenylmethane (0.50 g, 2.47 mmol) (Wako Pure Chemical Industries, Ltd.), pyrrolidine (0.53 g, 7.45 mmol) (Tokyo Chemical Industry Co., Ltd.), and potassium iodide (0.10 g, 0.60 mmol) (Wako Pure Chemical Industries, Ltd.) were added to acetonitrile (20 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was refluxed for 2 hours. The mixture was allowed to cool to room temperature. After that, a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=99:1 as an eluent), to thereby obtain the title compound (0.36 g, 61% yield).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:21])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:22][C@H:23]1[CH2:28][CH2:27][C@@H:26]([NH2:29])[CH2:25][CH2:24]1>CO>[NH2:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:2]2[C:3]([CH3:21])=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:25][CH2:24]1
Reactant: CCOc1ccc(Nc2c(C)c(Cl)nn3ccnc23)cc1
Reactant: N[C@H]1CC[C@@H](N)CC1
Solvent: CO
Product: CCOc1ccc(Nc2c(C)c(N[C@H]3CC[C@@H](N)CC3)nn3ccnc23)cc1
Temperature: 165 °C

Procedure:
To 6-chloro-N-(4-ethoxyphenyl)-7-methylimidazo[1,2-b]pyridazin-8-amine (40 mg, 0.14 mmol) from Example III(1), step 1d was added cis-1,4-diaminocyclohexane (250 mg, 2.19 mmol). The mixture was allowed to heat at 165° C. for 48 hrs. The reaction mixture then cooled, diluted with methanol and purified by preparative HPLC. The eluent was then concentrated in vacuo, diluted with methanol (2 mL), purified and neutralized by passing through a 500 mg SCX (Cation exchange column). The eluent was concentrated to give 6.0 mg (11.3%) of the titled compound. 1H NMR (500 MHz, MeOH) δ ppm 7.65 (1H, s), 7.25 (1H, s), 6.85 (4 H, m), 3.95 (2H, d, J=7.2 Hz), 3.95 (1H, m), 3.05 (1H, m), 1.95 (2H, m), 1.85 (3H, s), 1.80 (4H, m), 1.65 (2H, m), 1.35 (3H, t, J=7.2 Hz). LC/MS m/e 381 (M+1). HPLC, 1.91 min. Waters Sunfire C18 4.6×50.0%-100% B. B: 90% MeOH, 10% H2O, 0.1% TFA. A: 10% MeOH, 90% H2O, 0.1% TFA, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.