Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1)(=O)=O.[NH:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][N:21]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][N:32]3[CH:36]=[CH:35][N:34]=[C:33]3[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:8][N:9]=1)=[CH:20]2
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: CN(c1cccc2cc(C3=NCC(COS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nccn1CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 83.2 %

Procedure:
A mixture of (2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)methyl methanesulfonate (250 mg), ethyl 1H-imidazole-2-carboxylate (146 mg), potassium carbonate (144 mg) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 4.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=15:85-100:0) to give the title compound (227 mg, yield 83%) as a orange oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.Br[CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:10]3)=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Product: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Yield: 57.8 %

Procedure:
The title compound (66 mg yield) was prepared in analogy to the procedure described in Preparation 4 and Preparation 5 starting from (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (97 mg, 0.4 mmol), and [(3-bromopropyl)oxy](1,1-dimethylethyl) dimethylsilane (152 mg, 0.6 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:12]([O:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(Br)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5.22 g (23.9 mmol) of 2-bromo-6-nitrophenol, 3.0 ml (25.1 mmol) of benzyl bromide and 3.64 g (26.3 mmol) of potassium carbonate in 50 ml of acetonitrile was heated under reflux for 2 h. After cooling to RT, the solid was filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue obtained was dissolved in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the filtrate was concentrated on a rotary evaporator. The residue that remained was dried under high vacuum. This gave 7.53 g (99% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@@H:10]1[OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]2)[C:11](=[O:27])[C@@H:10]1[O:28][S:37]([CH3:36])(=[O:39])=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@@H](O)C2=O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2C[C@H](OCc3ccccc3)[C@@H](OS(C)(=O)=O)C2=O)CC1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
tert-Butyl 4-((3R,4S)-4-(benzyloxy)-3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (525 mg, 1.34 mmol) was dissolved in THF (10 mL) and triethylamine (375 μL, 2.69 mmol) and methanesulfonyl chloride (126 μL, 1.61 mmol) were added to the reaction and stirred for 1 hour. The reaction was partitioned between saturated aqueous NaHCO3 and EtOAc, dried over Na2SO4, filtered and concentrated to afford tert-butyl 4-((3R,4S)-4-(benzyloxy)-3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (623 mg, 1.33 mmol, 98.9% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:21][Si:20]([C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][CH:14]=1)([CH3:22])[CH3:23]
Reactant: C#Cc1ccc(OC)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.5 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.72 g (0.0054 mole) of p-methoxyphenylacetylene, 1.51 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.0102 g (0.0053 mmole) of CuI, 0.102 g (0.146 mmole) of bis(triphenylphosphine)palladium(II)dichloride in 10 ml of THF and 10 ml of triethylamine. The light orange brown mixture was stirred at room temperature under nitrogen for 3 days. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 10 ml of chloroform and the solution was washed two times with water (10 ml each) and then dried over anhydrous MgSO4, filtered and concentrated. 1.5 g (98.7% yield) of solid was obtained. 1HNMR: 0.28 ppm (s, 9H); 3.85 ppm (s, 3H); 6.90 ppm (d, 2H); 7.45 ppm (s, 4H); 7.48 ppm (d, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11](=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.CS(C)=O>O>[CH3:21][C:22]1[N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11](=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=2)[CH:24]=[CH:25][N:26]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CCC(=O)CCC(=O)c1ccc(-n2ccnc2C)cc1
Temperature: 180 °C
Yield: 27.1 %

Procedure:
Ethyl 7-(4-fluorophenyl)-4,7-dioxoheptanoate (2.00 g, 7.1 mmol) and 2-methyl-1H-imidazole (7.0 g, 86 mmol) were taken up into DMSO (4 mL). The mixture was heated to 180° C. under microwave for 72 min. Water (100 mL) was added and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (DCM to DCM:MeOH=25:1) to afford the title compound as a dark brown solid (660 mg, yield 25%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:5]([CH2:24][CH3:25])[CH:4]=1)=O.[O:26]=[C:27]([CH3:37])[CH2:28]P(=O)(OCC)OCC>>[CH2:24]([C:5]1[CH:4]=[C:3](/[CH:1]=[CH:28]/[C:27](=[O:26])[CH3:37])[CH:8]=[CH:7][C:6]=1[N:9]=[C:10]1[S:14][CH2:13][C:12]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[N:11]1[CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:25]
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reactant: CCOP(=O)(CC(C)=O)OCC
Product: CCc1cc(/C=C/C(C)=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method D11a to give 2-(4-formyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with diethyl (2-oxopropyl)phosphonate according to Method D12a according to afford 2-(2-ethyl-4-((1E)-2-acetylvinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]2[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:14]=12)C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>[Pd].CO>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:15]2[C:14]3[C:9](=[O:8])[NH:10][N:11]=[CH:12][C:13]=3[CH:17]=[C:16]2[CH3:18])=[CH:25][CH:24]=1
Reactant: COc1ccc(Cn2c(C)cc3c(Cl)nnc(OCc4ccccc4)c32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(Cn2c(C)cc3cn[nH]c(=O)c32)cc1
Yield: 69 %

Procedure:
38.3 g (97 mmol) of 7-benzyloxy-4-chloro-1-(4-methoxybenzyl)-2-methylpyrrolo[2,3-d]pyridazine (contaminated with about 5% of the isomeric 4-benzyloxy compound), 15 ml of triethylamine and 3.0 g of palladium (5%)/carbon catalyst are hydrogenated with hydrogen for 10 h in 3 1 of methanol. Purification: crystallization from methanol. Yield: 69%, m.p.: 212°-213° C.
Reaction SMILES: C(OC(N[C@@H](CC1N=CNC=1)C(N(CC(NCC(C)(C1C=CC=CC=1)C)=O)CCC(OC)=O)=O)=O)C1C=CC=CC=1.Cl.[CH3:43][O:44][C:45](=[O:49])[CH2:46][CH2:47][NH2:48].Br[CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53].C(N(CC)CC)C>C(Cl)Cl>[CH3:43][O:44][C:45](=[O:49])[CH2:46][CH2:47][NH:48][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)CCN
Agent: COC(=O)CCN(CC(=O)NCC(C)(C)c1ccccc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNCC(=O)OC(C)(C)C

Procedure:
Scheme 2 shows a method by which the compounds of the present invention can be prepared, by illustrating the synthesis of Example 4, methyl 3-([(2S)-2-[(benzyloxy)carbonyl]amino-3-(1H-4-imidazolyl)propanoyl]-2-[(2-methyl-2-phenylpropyl)amino]-2-oxoethylamino)propanoate. Reaction of β-alanine methyl ester hydrochloride with t-butyl bromoacetate was carried out in methylene chloride in the presence of triethylamine as the base to give 3-(tert-butoxycarbonylmethyl-amino)-propionic acid methyl ester which was then coupled to Cbz-His(trityl) in methylene chloride/acetonitrile with HBTU as coupling agent, and triethylamine as the base. The resulting product was treated with 95% aqueous TFA, to remove the trityl and the t-butyl groups, followed by coupling with β,β-dimethylphenethylamine in methylene chloride/dimethylformamide, with HBTU as coupling agent, and diisopropylethylamine as the base to give the desired product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:15]#[N:16])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[C:15]#[N:16])=[CH:7][CH:8]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(C#N)n1-c1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C#N)n1-c1ccc(COS(C)(=O)=O)cc1
Temperature: 0 °C

Procedure:
to a solution of 1-(4-hydroxymethylphenyl)-5-methylpyrrole-2-carbonitrile (890 mg) in dichloromethane (9 ml) was added triethylamine (794 μl) and methanesulfonyl chloride (343 μl) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for an hour and then dichloromethane was added therein. The mixture was stirred and washed with water twice and brine, dried over magnesium sulfates and concentrated in vacuo to give 1-(4-methanesulfonyloxymethylphenyl)-5-methylpyrrole-2-carbonitrile (1.19 g).
Reaction SMILES: [I:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:19]=[CH:18][N:17](C(OC(C)(C)C)=O)[N:16]=4)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[OH-].[Na+]>O1CCCC1.C(O)C.Cl>[I:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:19]=[CH:18][NH:17][N:16]=4)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ccc(-c3nc4ccc(I)cc4o3)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Ic1ccc2nc(-c3ccc(-c4cc[nH]n4)cc3)oc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
Subsequently, tert-butyl 3-[4-(6-iodo-1,3-benzoxazol-2-yl)phenyl]-1H-1-pyrazolecarboxylate (49 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) and ethanol (2 mL), and 6N hydrochloric acid (500 μL) was added to the solution, followed by stirring at 80° C. for 2 hours. The reaction mixture was alkalified with 1N sodium hydroxide, followed by stirring at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by drying. The thus-obtained white solid was recovered through filtration, and washed sequentially with water and ethanol, followed by drying under reduced pressure, to thereby yield the title compound (26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([CH:10]2[CH2:12][CH2:11]2)[CH3:9])=[C:4]([F:25])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:37])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([CH:10]2[CH2:12][CH2:11]2)[CH3:9])=[C:4]([F:25])[CH:3]=1
Reactant: CSCc1cccc2c(C(C)(c3ccc(Cl)cc3F)C3CC3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(C)(c3ccc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.27 mmol) of the compound from Example 97 were introduced into 18 ml of dichloromethane at 0° C., 66 mg (0.27 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solvents were removed in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 86 mg (83% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:28](Cl)(=O)[CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:29]([C:28]1[N:12]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2cnc3ccccc3c2n1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 52 %

Procedure:
A solution of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (2.18 g, 7.96 mmol) in 80 mL of anhydrous CH2Cl2 was cooled to 0° C. and treated with triethylamine (1.12 mL, 8.00 mmol) and valeryl chloride (0.95 mL, 8.00 mmol) under an atmosphere of nitrogen. After stirring for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was treated with Et2O and filtered. The filtrate was concentrated and the resulting black tar was dissolved in 80 mL of ethanol and treated with 3 mL of triethylamine and the mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure. Chromatography (SiO2, 1–5% methanol (MeOH)/CHCl3) gave tert-butyl N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (1.41 g) as a mauve foam.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:23]=[C:24]([CH2:25][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(OC(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.7 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (935 mg, 3.85 mM), 3-trifluoromethoxybenzyl bromide (1.0 g, 3.93 mM), and potassium carbonate (531 mg, 3.85 mM) in 20 mL DMF was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.6 g (100%) of the 9-[(3-trifluoromethoxyphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a foam. 1H NMR (DMSO-d6) δ7.7 (dd, 1H, J=1 and 8 Hz), 7.45 (t, 1H, J=8 Hz), 7.3-7.1 (m, 4H), 7.05 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), and 2.1 (m, 2H). IR (CDCl3, cm−1) 1729, 1647, 1439, 1259, 1176, and 1116. MS (ES) m/e 418.
Reaction SMILES: O.[PH2]([O-])=O.[Na+].[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#N)=[CH:18][CH:17]=1)([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1.C(O)(=[O:35])C>O.[Ni]>[C:6]([O:10][C:11](=[O:26])[NH:12][C:13]([CH3:25])([CH3:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:35])=[CH:18][CH:17]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)O
Reactant: CC(C)(COc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
The title compound was synthesized by referring to J. Chem. Soc., 1962, 3961. To a solution of sodium hypophosphite monohydrate (1.5 g) in water (3 ml) were sequentially added tert-butyl[2-(4-cyanophenoxy)-1,1-dimethylethyl]carbamate (500 mg), pyridine (10 ml) and acetic acid (5 ml). While stirring at room temperature, Raney nickel (50% suspension in water) (2 ml) was added dropwise to the reaction mixture and the solution was stirred for 15 minutes at room temperature and for 1 hour at 40° C. After filtration through celite pad and several wash with tetrahydrofuran and methanol, the solvent was evaporated in vacuo, and the residue was neutralized by adding a saturated aqueous solution of sodium bicarbonate. After extraction with ethyl acetate, the solution was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (443 mg).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[CH3:17][N:18](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:16][C:13]1[O:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][CH:3]=[C:2]([C:17]#[N:18])[C:6]=3[CH:7]=2)=[N:15][N:14]=1
Reactant: CN(C)C=O
Reactant: Cc1nnc(-c2ccc3occ(Br)c3c2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occ(C#N)c3c2)o1
Temperature: 80 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
A suspension of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole (5.58 g, 20.0 mmol), zinc cyanide (1.41 g, 12.0 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.16 g, 1.00 mmol) in N,N-dimethylformamide (50 mL) was stirred at 80° C. for 10 hr under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from hexane/tetrahydrofuran to give the title compound (3.74 g, yield 83%) as colorless crystals.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.O.CCO[C:24]([CH3:26])=[O:25]>CN1C(=O)CCC1>[N:11]1([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:11][C@H:15]3[CH2:16][CH2:26][C@H:24]([OH:25])[CH2:19][CH2:14]3)[N:10]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)c1nccc(-n2nnc3ccccc32)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: O[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-methanesulfonyl-pyrimidin-4-yl)-1H-benzotriazole (1.59 g, 6 mmol) in 15 mL of NMP was added trans-4-aminocyclohexane (3.11 g, 27 mmol) and the resulting mixture was stirred at 120° C. for 2 hours. It was then cooled, poured onto 100 mL of water, stirred and allowed to stand overnight. The resulting suspension was filtered, the collected solids were washed with water and dissolved with CH2Cl2; the solvent was removed under reduced pressure. The solid residue formed was taken up with EtOAc, filtered and dried to give trans-4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexanol as a white solid (910 mg, 51% yield), mp=224.8-228.1° C.; MS=311 (M+H)+.
Reaction SMILES: Br[C:2]1C=CO[C:3]=1C(O)=O.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14]([OH:16])=[O:15]>>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:14]([O:16][CH2:2][CH3:3])=[O:15]
Reactant: O=C(O)c1occc1Br
Reactant: COc1ccc(C(=O)O)cc1Br
Product: CCOC(=O)c1ccc(OC)c(Br)c1

Procedure:
A reaction was carried out in the same manner as in Reference Example 1 except that the 3-bromo-2-furancarboxylic acid used in Reference Example 1 was replaced with 3-bromo-4-methoxybenzoic acid (4.62 g). The crude product was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10), thereby giving 4.65 g of ethyl 3-bromo-4-methoxybenzoate.
Reaction SMILES: Cl.[NH2:2]/[C:3](/[C:8]#[N:9])=[C:4](\[NH2:7])/[C:5]#[N:6].[C:10]([CH2:18][C:19](=O)[CH3:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[C:5]([C:4]1[CH:3]([C:8]#[N:9])[NH:2][C:10]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=[C:19]([CH3:20])[N:7]=1)#[N:6]
Reactant: N#C/C(N)=C(/N)C#N
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Product: CC1=CC(O)(c2ccccc2)NC(C#N)C(C#N)=N1

Procedure:
In the presence of a catalytic amount of HCl (4N=4 mol/l), 1 mol of diaminomaleonitrile was reacted with 1 mol of benzoylacetone in a solvent (benzene) at 45° C. for 6 hours to give 2,3-dicyano-5-hydroxy-5-phenyl-7-methyl-4H-1,4-diazepine (compound 1a). The diazepine compound (1a) thus obtained was reacted with 4-methoxybenzaldehyde in the presence of piperidine to give the object compound 2,3-dicyano-5-hydroxy-5-phenyl-6-(4-methoxyphenylmethylidene)-7-methyl-4H-1,4-diazepine (compound 1).