Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1NC=CC=1)(OC(C)(C)C)=O.[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:27]([NH:29][C:30]2[CH:31]=[C:32]([C:36]([NH:38][C:39]3[CH:40]=[C:41]([C:45]([O:47]C)=[O:46])[N:42]([CH3:44])[CH:43]=3)=[O:37])[N:33]([CH3:35])[CH:34]=2)=[O:28])[N:24]([CH3:26])[CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>CO.CCOCC>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:27]([NH:29][C:30]2[CH:31]=[C:32]([C:36]([NH:38][C:39]3[CH:40]=[C:41]([C:45]([OH:47])=[O:46])[N:42]([CH3:44])[CH:43]=3)=[O:37])[N:33]([CH3:35])[CH:34]=2)=[O:28])[N:24]([CH3:26])[CH:25]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc(NC(=O)OC(C)(C)C)cn3C)cn2C)cn1C
Agent: CC(C)(C)OC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3cc(NC(=O)OC(C)(C)C)cn3C)cn2C)cc1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
The Boc pyrrole trimer (5) (0.6 g, 1.2 mmol) was dissolved in MeOH (5 mL) and treated with NaOH solution (0.1 g in 5 mL H2O). The reaction mixture was stirred overnight then heated at 60° C. for 2 hours. The MeOH was removed in vacuo and the aqueous fraction extracted with EtOAc (25 mL). The aqueous layer was adjusted to pH 2-3 with 1M HCl solution then extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4 then concentrated in vacuo to give an orange solid. The solid was suspended in Et2O (10 mL) and collected on a filter then dried in vacuo to give an orange solid 0.431 g (74%). 1H NMR d6-DMSO δ 12.11 (1H, s, OH), 9.89 (1H, s, N—H), 9.86 (1H, s, N—H), 9.09 (1H, s, Boc-N—H), 7.43 (1H, d, J=1.9 Hz, Py-H), 7.22 (1H, d, J=1.7 Hz, Py-H), 7.06 (1H, d, J=1.7 Hz, Py-H), 6.90 (1H, s, Py-H), 6.86 (1H, d, J=1.9 Hz, Py-H), 6.84 (1H, s, Py-H), 3.85 (3H, s, N—CH3), 3.83 (3H, s, N—CH3), 3.82 (3H, s, N—CH3), 1.46 (9H, s, Boc-H); 13C NMR d6-DMSO δ 161.9, 158.4, 158.4, 152.8, 122.8, 122.7, 122.5, 122.4, 122.3, 120.2 (CH), 119.5, 118.4 (CH), 117.0 (CH), 108.4 (CH), 104.7 (CH), 103.8 (CH), 78.2, 36.1 (CH3), 36.0 (CH3), 28.1 ([CH3]3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21].C(NC(C)C)(C)C>O1CCOCC1.[Cu](I)I.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:22]1([C:20]#[C:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Br)cc2)CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#Cc3ccccc3)cc2)CCC1
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclobutylcarbamate (1.53 g, 4.7 mmol), ethynylbenzene (2.5 mL, 22.6 mmol), copper iodide (36 mg, 0.24 mmol) and diisopropylamine (3.2 mL, 22.6 mmol) in dioxane (3 mL) was degassed for 30 min, followed by the addition of bis(tri-tert-butylphosphine)palladium (144 mg, 0.36 mmol). The resulting mixture was heated at 90° C. for 16 h, after cooled down to RT, concentrated to dryness. The crude residue was purified by column chromatography (eluting with 10% DCM in heptane) to give the title compound (0.85 g, 52%). 1H NMR (500 MHz, CDCl3): 7.58-7.54 (m, 4H), 7.48-7.43 (m, 2H), 7.39-7.20 (m, 3H), 2.55-2.40 (m, 4H), 2.15-2.10 (m, 1H), 1.93-1.84 (m, 1H), 1.45-1.20 (br s, 9H).
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15](N)=[CH:14][CH:13]=1.C(#[N:23])C>>[C:4]([CH:1]1[CH2:2][CH2:3][N:23]([C:14]2[CH:15]=[CH:17][CH:18]=[C:12]([C:11]([F:20])([F:19])[F:10])[CH:13]=2)[C:7]1=[O:9])([OH:6])=[O:5]
Reactant: CC#N
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C1(C(=O)O)CC1
Product: O=C(O)C1CCN(c2cccc(C(F)(F)F)c2)C1=O
Yield: 38.8 %

Procedure:
10.0 g of 1,1-cyclopropanedicarboxylic acid and 12.4 g of 4-trifluoromethylaniline were added to 15 ml of acetonitrile, followed by refluxing for 7 hours with heating and stirring. The subsequent operation was conducted in the same manner as in Example 2 to obtain 7.1 g of an intended compound at a yield of 38.8%.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[C:13]([O:17][K])(C)(C)[CH3:14].C(CCl)#[N:20].O>CN(C=O)C>[C:14]([CH2:13][O:17][C:8]1[CH:9]=[CH:10][CH:11]=[C:4]2[C:3]([NH:2][C:6](=[O:7])[C:5]=12)=[O:12])#[N:20]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: N#CCCl
Reactant: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1cccc2c1C(=O)NC2=O
Reaction time: 0.17 h
Yield: 49.5 %

Procedure:
To a mixture of 16.8 g (0.1 mol) N-hydroxyphthalimide and 12.7 g (0.11 mol) tert-BuOK in 150 mL DMF under stirring was added cyanomethyl chloride (7.8 g, 0.1 mol). Discoloration of the reaction mixture occurred in 10 min. After 24 h of stirring at room temperature the mixture was poured into 750 mL of cold H2O. Precipitate was filtered off and dried under vacuum in the presence of anhydrous CaSO4 to yield about 10 g (50%) of cyanomethoxyphthalimide. To a solution of 10 g (0.05 mol) cyanomethoxyphthalimide in 50 mL THF was added dropwise at room temperature during 2 h a solution of 2.5 mL (0.05 mol) hydrazine-hydrate (100%) in 10 mL MeOH. After additional stirring for 2 h the mixture was acidified under ice-cooling with 25 mL of 2M solution (0.05 mol) HCl and the resulting mixture was stirred at this temperature for 30 min. The insoluble material was filtered off, filtrate adjusted to pH 7 with 2M NaOH. The product was then extracted 4 times with EtOAc, the combined organics were washed with brine, and dried over anhydrous Na2SO4. The solution was concentrated in vacuo, the residue was dissolved in ether and treated with an excess of dry hydrogen chloride. The title compound, a precipitate, was filtered off and dried under vacuum in the presence of anhydrous CaSO4.
Reaction SMILES: [N+]([O-])([O-])=[O:2].[Ce+3:5].[N+]([O-])([O-])=[O:7].[N+]([O-])([O-])=[O:11].N[C:15](N)=[O:16].[OH2:18]>C(O)C>[C:15](=[O:16])([O-:11])[O-:18].[Ce+3:5].[C:15](=[O:16])([O-:7])[O-:18].[C:15](=[O:16])([O-:2])[O-:18].[Ce+3:5]
Reactant: O=[N+]([O-])[O-]
Reactant: NC(N)=O
Reactant: O
Agent: [Ce+3]
Solvent: CCO
Product: O=C([O-])[O-]

Procedure:
A cerium oxide powder was produced in the same manner as described in Embodiment 1 except 0.5 mol of cerium nitrate was dissolved in a solution of 10 mL of water and 90 mL of ethanol, and then mixed with a solution in which 1.5 mol of urea solution was dissolved in a solution of 10 mL of water and 90 mL of ethanol to obtain a cerium carbonate powder. 1.5 kg of the cerium carbonate powder was placed into an alumina crucible and the decomposed material was removed by thermal treatment in an oxygen atmosphere at 300° C. for 24 hours to obtain 1.2 kg of oxide, which was then calcinated in an oxygen atmosphere at 700° C. for one hour. A cerium oxide powder having a crystal size of 24 nm, a specific surface area of 44 m2/g, a pore distribution, of pores less than and over 3 nm, of 33:67, and an average particle diameter of 68-510 nm, was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][C:26]#[N:27])[C:5]2=3)[CH:14]=1>C1COCC1.CO.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH2:27])[C:5]2=3)[CH:14]=1
Reactant: Cc1cc2c3c(c1)c1c(OCC#N)cccc1n3C(c1ccccc1)CO2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2c3c(c1)c1c(OCCN)cccc1n3C(c1ccccc1)CO2
Temperature: 85 °C
Yield: 66.6 %

Procedure:
To a mixture of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile (0.66 g, 1.86 mmol) in dry THF (120 mL) is added borane-methylsulfide complex (0.53 mL, 5.6 mmol). The mixture is refluxed at 85° C. for 18 h. The mixture is removed from heat and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added and again removed. The residue is dissolved in CH2Cl2/CH3OH (1:2 15 mL). Conc. HCl (2 mL) is added and the mixture heated at 65° C. for 1 h. The mixture is removed from heat and neutralized with aqueous potassium carbonate then partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. Column chromatography (70 g silica get) using CH3OH/CH2Cl2 (4:96) as eluent gave 0.444 g (67%) of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>CO.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([O:32][CH3:31])[CH:34]=2)=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: COc1cccc(N=C=O)c1
Solvent: CC#N
Solvent: CO
Product: COc1cccc(NC(=O)Nc2nc3nc(NCCCN4CCN(C)CC4)ncc3cc2-c2c(Cl)cccc2Cl)c1
Yield: 69 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.334 g of 3-methoxyphenyl isocyanate according to the general procedure of Example 37 to give 0.920 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(3-methoxy-phenyl)-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=595; mp 87.5°-92.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[N:17]=[C:7]3[C:8](=[O:16])[CH:9]2[CH2:13][CH2:14][Cl:15])[CH:4]=[N:3]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[ClH:15].[ClH:15].[ClH:15].[CH3:27][C:2]1([CH3:1])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=4)[N:17]=[C:7]3[C:8](=[O:16])[CH:9]2[CH2:13][CH2:14][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH:4]=[N:3]1
Reactant: CN1CCNCC1
Reactant: CC1(C)N=CC2=C3N=C(c4ccc(Cl)cc4)N=C3C(=O)C(CCCl)C2C1=O
Product: CN1CCN(CCC2C(=O)C3=NC(c4ccc(Cl)cc4)=NC3=C3C=NC(C)(C)C(=O)C32)CC1
Product: Cl

Procedure:
A mixture consisting of 2.1 gm of 7,7-dimethyl-2-(4-chloro-phenyl)-5-(2-chloro-ethyl)-5H,7h-imidazo[4,5-h]isoquinoline-4,6-dione and the 10 ml of N-methyl-piperazine was heated at 130° C. for 2 hours. After distilling off the excess of N-methyl-piperazine in vacuo, the residue was purified on a silicagel column (eluant: chloroform/acetone 19:1). The trihydrochloride was precipitated from acetone by addition of ethereal hydrochloric acid and recrystallized from ethanol.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14](=[O:29])[CH2:15][C:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[N:17]2.ClC1C=C2C(C(=O)CC(C3C=CC(C)=CC=3)=N2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([O:29][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4])=[CH:15][C:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[N:17]2
Reactant: Cc1ccc(C2=Nc3cccc(Cl)c3C(=O)C2)cc1
Reactant: O=C(CBr)N1CCOCC1
Agent: Cc1ccc(C2=Nc3cc(Cl)ccc3C(=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3c(Cl)cccc3n2)cc1
Temperature: 20 °C
Yield: 13.6 %

Procedure:
4-(2-Bromoacetyl)morpholine (7.9 g) in 2-butanone (50 cc) is added to a stirred suspension of a mixture (10 g) of 5-chloro-2-(4-methylphenyl)-4-quinolone and 7-chloro-2-(4-methylphenyl)-4-quinolone and anhydrous potassium carbonate (10.2 g) in 2-butanone (250 cc). The mixture is heated to reflux for 15 hours and cooled to room temperature (approximately 20° C.), the insoluble matter is removed by filtration and the 2-butanone is evaporated off under reduced pressure. The residue is taken up with water (200 cc) and the aqueous phase is extracted with methylene chloride (3×100 cc). The organic phase is separated after settling has taken place, dried and evaporated under reduced pressure. After the residue has been chromatographed twice on silica gel, the first time using a chloroform/ethyl acetate mixture (70:30 by volume) and the second time using a chloroform/ethyl acetate mixture (80:20 by volume) as eluant, the solid obtained is recrystallized in ethyl acetate. 4-{[ 5-chloro-2-(4-methylphenyl)-4-quinolyl]oxyacetyl}morpholine (2 g), m.p. 170 ° is thereby obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([Cl:19])[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[ClH:19].[ClH:19].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: COc1ccc(OB(O)O)cc1
Reactant: CCN1CCN(c2nc(Cl)nc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1CCN(c2nc(-c3ccc(OC)cc3)nc3ccccc23)CC1
Product: Cl
Reaction time: 2 h
Yield: 136.1 %

Procedure:
A mixture of 4-(1-ethylpiperazin-4-yl)-2-chloroquinazoline (0.56 g), 4-methoxyphenylboric acid (0.46 g), tetrakistriphenylphosphinepalladium(0) (0.12 g), toluene (50 ml) and a 10% aqueous solution of sodium carbonate (30 ml) was vigorously stirred in nitrogen atmosphere at 100° C. for 1 hr. To the resulting mixture was additionally added 4-methoxyphenylboric acid (0.31 g), and the mixture was further stirred for 2 hr. To the resulting mixture was again added 4-methoxyphenylboric acid (0.31 g), and the mixture was further stirred for 1 hr. To the resulting mixture was further added 4-methoxyphenylboric acid (0.31 g), and the mixture was further stirred overnight. The resulting insoluble matters were filtered off, and then the organic layer was separated and extracted with 2N hydrochloric acid twice, followed by the addition of a 8N aqueous solution of sodium hydroxide to adjust the resulting mixture to pH 10. The resulting mixture was extracted with ethyl acetate twice. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.58 g of the free compound of the title compound as a pale yellow viscous oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[Br:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:15]3[CH:14]=[CH:13][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[CH:3]=2)[CH:8]=1
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Brc1ccc2cc(-c3ccc4ccccc4c3)ccc2c1
Reaction time: 16 h
Yield: 68.7 %

Procedure:
Under an argon gas atmosphere, 246 g (860 mmol) of 2,6-dibromonaphthalene, 163 g (950 mmol) of 2-naphthalene boronic acid, 20 g (17.0 mmol) of tetrakis(triphenylphosphine)palladium(0), 3 L of dimethoxyethane (DME) and 1.5 L of 2M sodium carbonate solution were mixed, and stirred for 16 hours while being refluxed. After the completion of the reaction, precipitated crystal was separated by filtration. Then, the obtained solid was cleansed with water, methanol and hexane. The obtained solid was dried under reduced pressure, and 197 g of 2-bromo-6-(2-naphthyl)naphthalene was obtained at an yield of 69%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[N:23]=[N:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]2[S:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[CH:31][C:19]=12.CCOC(C)=O>CN1C(=O)CCC1>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([O:1][C:18]2[N:23]=[N:22][C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:20]3[S:29][C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)=[CH:31][C:19]=23)[CH2:3]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: CCOC(=O)c1nnc(Cl)c2cc(-c3cccc(F)c3)sc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nnc(OC2CCCN(C(=O)OC(C)(C)C)C2)c2cc(-c3cccc(F)c3)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
tert-Butyl 3-hydroxypiperidine-1-carboxylate (100 mg, 0.5 mmol) was dissolved in dry NMP (5 mL) and NaH (20 mg, 60% in oil, 0.5 mmol) was added carefully. The mixture was stirred at room temperature for 10 min. Then, ethyl 4-chloro-2-(3-fluorophenyl)thieno[2,3-d]pyridazine-7-carboxylate (130 mg, 0.5 mmol) was added. The mixture was heated up to 80° C. and stirred for 30 min. After cooling to room temperature, EtOAc was added to dilute the reaction and washed with water and brine. The organics was dried over Na2SO4 and filtered, concentrated. The crude product was purified with column (silica gel) to give the product ethyl 4-(1-(tert-butoxycarbonyl)piperidin-3-yloxy)-2-(3-fluorophenyl)thieno[2,3-d]pyridazine-7-carboxylate (151 mg). HPLC-MS tR=2.17 min (UV254 nm); mass calculated for formula C25H28FN3O5S 501.2, observed LCMS m/z 502.2 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:18]([N:20]1[CH2:25][CH2:24][C@@:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)([OH:26])[C:22]([CH3:35])([CH3:34])[CH2:21]1)=[O:19])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C@@:23]2([OH:26])[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C@H:3]([NH:2][C:41]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:42])[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:21][C:22]2([CH3:35])[CH3:34])=[CH:32][CH:31]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC1(C)CN(C(=O)[C@H](N)CCCNC(=O)OCc2ccccc2)CC[C@]1(O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CN(C(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C2CCCC2)CC[C@]1(O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
Benzyl (R)-4-amino-5-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-5-oxopentylcarbamate hydrochloride (50.5 mg, 0.096 mmol) was dissolved in dichloromethane (0.5 mL) and added cyclopentane carbonylchloride (14 μL, 0.12 mmol) followed by DIPEA (42 μL, 0.24 mmol). The solution was stirred for 2 h, concentrated, and partitioned between EtOAc (2 mL) and aq NaHCO3 (0.5 mL). The EtOAc layer was separated, dried over magnesium sulfate, and concentrated to give benzyl (R)-5-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-4-(cyclopentanecarboxamido)-5-oxopentylcarbamate which was used without further purification.
Reaction SMILES: [Cl-].O[C:3]1[C:12]([N+]#N)=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=C[CH:4]=1.[C:15](=[O:18])(O)[O-:16].[Na+].[CH3:20]O>>[C:10]1([C:15]([O:16][CH3:20])=[O:18])[NH:9][CH:8]=[CH:7][C:6]2[C:11]=1[CH:12]=[CH:3][CH:4]=2
Reactant: N#[N+]c1c(O)ccc2ccncc12
Reactant: O=C([O-])O
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)c1[nH]ccc2cccc1-2
Yield: 50 %

Procedure:
7-Hydroxy-8-isoquinolinediazonium chloride (0.50 g, 2.4 mmol) and sodium bicarbonate (302 mg, 3.6 mmol) in anhydrous methanol (650 ml) is irradiated with a 275 watt sunlamp at 0° C. for 3 hours. The reaction mixture is evaporated to dryness under vacuum. The crude residue is dissolved in water and the product is extracted in methylene chloride. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the product as an orange solid (210 mg) in 50% yield.
Reaction SMILES: C[N:2]1[CH2:7]COCC1.ClC(OCC)=[O:10].[C:14]([CH2:16][CH2:17][O:18][C:19]([CH2:21][C:22]1([CH2:28]C(O)=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20])#[N:15].[N-]=[N+]=[N-].[Na+]>C1COCC1>[N:2]([CH2:28][C:22]1([CH2:21][C:19]([O:18][CH2:17][CH2:16][C:14]#[N:15])=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[C:7]=[O:10]
Reactant: N#CCCOC(=O)CC1(CC(=O)O)CCCCC1
Reactant: CCOC(=O)Cl
Reactant: CN1CCOCC1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCCOC(=O)CC1(CN=C=O)CCCCC1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 64.1 %

Procedure:
1.5 mL of N-methyl morpholine (13.62 mmol) and 1.3 mL of ethyl chloroformate (13.03 mmol) was added to a solution of 1-[(2-cyanoethoxycarbonyl)-methyl]-1-cyclohexane acetic acid (5) (11.84 mmol) in 30 mL of anhydrous THF at −20° C. under nitrogen atmosphere. The reaction mixture was stirred at −20° C. for 20 minutes, warmed to −5° C., an aqueous solution of NaN3 (29.61 mmol, in 3.5 mL of H2O) was added and then stirred for 30 minutes at −5° C. to −10° C. Then, THF was removed under reduced pressure and the residue was extracted with CH2Cl2 and dried over Na2SO4. After concentration in vacuo the crude product was dissolved in 20 mL of anhydrous toluene and refluxed for 20 minutes. The mixture was cooled to room temperature and toluene was removed under reduced pressure. The residue was purified on silica gel (15% ethyl acetate in hexane) to afford 1.9 g (64%) of the title compound. 1H NMR (CDCl3): δ 4.29 (2H, t, J=6.0 Hz); 3.42 (2H, s); 2.73 (2H, t, J=6.0 Hz); 2.44 (2H, s); 1.49-1.39 (10H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:23])[C:7]=2[N:6]=[C:5]1[CH2:24][O:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37]>>[NH2:23][C:8]1[C:7]2[N:6]=[C:5]([CH2:24][O:25][CH2:26][CH3:27])[N:4]([CH2:3][CH2:2][NH:1][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:16]=2[C:15]2[CH:14]=[CH:13][C:12]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCNC(=O)C(C)C
Yield: 32.8 %

Procedure:
1-(2-Aminoethyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.50 mmol) was treated with triethylamine (1.00 mL, 7.20 mmol) and isobutyryl chloride (0.64 mL, 6.10 mmol) according to the method described in Part B of Examples 372–376. The crude product was recrystallized from 93:7 acetonitrile:water and then from isopropanol (7.3 mL/g) and dried for two hours in a drying oven to provide 0.78 g of N-{2-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-2-methylpropanamide as a white solid, mp 213–215° C.