Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.O>[Cl:15][C:2]([Cl:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([Cl:14])[C:9]([O:13][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:10]([Cl:12])[CH:11]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
A mixture of 0.5 gram (0.0017 mole) of 4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenol (known compound), 0.26 gram (0.0019 mole) of potassium carbonate and 0.26 gram (0.0017 mole) of tert-butyl chloroacetate in 0.12 mL of DMF was heated to 70° C. where it stirred for about 18 hours. After this time the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with 30 mL of water then extracted with three 30 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a yellow oil. The crude oil was purified with column chromatography on silica gel using a mixture of hexanes and ethyl acetate (93:7) as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.7 gram of the subject compound.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6](N[C@H](C2N(C3C=NC=C(F)C=3)C3C=C(F)C=CC=3N=2)C)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:31].[K+].[K+].OO.O>CS(C)=O>[N:5]1[CH:6]=[C:7]([C:8]([NH2:9])=[O:31])[CH:2]=[N:3][CH:4]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cncnc1
Reaction time: 2 h

Procedure:
To a solution of (S)-4-amino-6-(1-(6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethylamino)pyrimidine-5-carbonitrile (0.040 g, 0.10 mmol) in DMSO (1.02 mL) was added potassium carbonate (0.017 g, 0.122 mmol) followed by hydrogen peroxide (31% in water, 0.635 mL, 6.42 mmol). After stirring for 2 h the solution was poured into water and extracted with EtOAc. Organic extracts were concentrated and purified by MPLC (eluted with 0-100% (1:10:90 NH4OH:MeOH:DCM) in DCM) to afford 4-amino-6-4(1S)-1-(6-fluoro-1-(5-fluoro-3-pyridinyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.85 Hz, 3H) 5.34 (quin, J=6.94 Hz, 1H) 6.57 (s, 2H) 7.04-7.22 (m, 2H) 7.43 (br. s., 2H) 7.67-7.80 (m, 2H) 7.92 (d, J=7.63 Hz, 1H) 8.21 (dt, J=9.29, 2.10 Hz, 1H) 8.71 (s, 1H) 8.81 (d, J=2.74 Hz, 1H). LC-MS (ESI) m/z 411.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C)C=O.C(OCC)C>[CH2:16]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCc1ccccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCc1ccccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To an ice-bath cooled suspension of sodium hydride (60% dispersion in mineral oil, 0.40 g) in dimethylformamide (18 ml) were added dropwise methyl 3-(2-hydroxyphenyl)propionate (1.80 g) and benzyl bromide successively. After being stirred for 30 minutes, the mixture was poured into a mixture of diethyl ether (20 ml) and 1N hydrochloric acid solution (90 ml). The organic layer was separated and the aqueous layer was extracted by diethyl ether. The combined organic layer was washed with aqueous sodium bicarbonate solution, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography [eluting with ethyl acetate n-hexane (1:1)] to provide methyl 3-(2-benzyloxyphenyl)-propionate (2.33 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[O:14][C:13]([CH2:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:18])=[N:12][N:11]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][C:13]2[O:14][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:11][N:12]=2)[CH2:21][CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(CCc1nnc(Nc2ccc(F)cc2F)o1)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: O=C(CCc1nnc(Nc2ccc(F)cc2F)o1)NC1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-{5-[(2,4-difluorophenyl)amino]-1,3,4-oxadiazol-2-yl}-N-piperidin-4-ylpropanamide (200 mg) in N-methylpyrrolidinone (4 ml) was added benzaldehyde (115 μl) and glacial acetic acid (0.04 ml). The reaction mixture was then heated at 80° C. for 1 hour before being left to cool and sodium triacetoxyborohydride (242 mg) added. The mixture was then stirred at room temperature for 8 hours before being evaporated to dryness and the residue separated into basic and non-basic components using SCX chromatography. Basic fractions were combined and evaporated to dryness. The residue was purified by RPHPLC (MeCN with NH3 buffer). Fractions containing the desired product were combined and evaporated to dryness to give the title compound. (92 mg).
Reaction SMILES: COC([C:5]1[C:6]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:9][N:10]=1)=O.Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:6]3[CH:5]=[N:10][CH:9]=[CH:8][N:7]3[CH:11]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(-c2cn3ccncc3n2)cc1
Temperature: 105 °C
Yield: 93 %

Procedure:
A mixture of 2-(4-fluorophenyl)imidazo[1,2-a]pyrazine-8-carboxylic acid methyl ester (Preparation #1, 6.30 g, 23.2 mmol) in DCM (66 mL) was treated with 1.0 M HCl in water (200 mL). The mixture was heated at about 105° C. open to the air for about 16 h. The solution was allowed to cool and was treated with saturated aqueous NaHCO3 and DCM. The mixture was sonicated to dissolve all solids and the layers were separated. The aqueous layer was washed with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound (4.60 g, 93%): LC/MS (Table 1, Method b) Rt=1.6 min; MS m/z: 214.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(#N)C.C(=O)([O-])O.[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>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][OH:18])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: OCc1ccccc1B(O)O
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: CC#N
Solvent: Cc1ccccc1
Product: OCc1ccccc1-c1ccc2nc(-c3ccc(Cl)cc3)cn2c1
Yield: 58.3 %

Procedure:
Under a stream of nitrogen, 200 mg of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (prepared as described in 5.1), 148 mg of 2-(hydroxymethyl)phenyl boronic acid and 22.5 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube containing a mixture of 3 ml of acetonitrile, 3 ml of toluene and 3 ml of a 2M solution of sodium hydrogen carbonate. The tube is placed in a microwave apparatus and irradiated at 150° C. for 15 min. The organic phase is separated, dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a 98/2 dichloromethane/methanol mixture. The solid obtained is triturated in diisopropyl ether and recovered by filtration and then dried in a dessicator under reduced pressure. 127 mg of compound are obtained. Mp=164-166° C. 1H NMR (DMSO-d6, δ in ppm): 4.44 (d, J=5.6 Hz, 2H); 5.19 (t, J=5.4 Hz, 1H); from 7.25 to 7.64 (m, 8H); 7.98 (m, J=8.3 Hz, 2H); 8.41 (s, 1H); 8.54 (m, 1H). M+H=335.
Reaction SMILES: [H-].[Al+3].[H-].[H-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:17](=O)[C:16]=23)=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CO>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[CH:14][N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH2:17][C:16]=23)=[CH:10][CH:11]=1
Reactant: O=c1[nH]c2ccccc2n2cnc(-c3ccc(F)cc3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Product: Fc1ccc(-c2ncn3c2CNc2ccccc2-3)cc1
Reaction time: 24 h

Procedure:
Aluminum hydride (0.6 M in THF, 80 ml) is added to 3-(4-fluorophenyl)-4,5-dihydroimidazo[1,5-a]quinoxalin-4-one (XXXV, EXAMPLE 246, 3.21 g) and the resulting solution is heated at reflux for 36 hr. After 24 hr, lithium aluminum hydride (600 mg) is added as starting material is still present. After cooling to 20°-25°, methanol (12.1 ml) and sodium hydroxide (6N, 50.0 ml) are added successively and the resultant solution stirred for 30 min at 20°-25°. Aqueous workup (ethyl acetate, magnesium sulfate) and purification by flash chromatography eluting with hexane/ethyl acetate (2/1), pooling the appropriate fractions and concentration gives the title compound, IR (mineral oil) 3381, 2924, 1511, 1492, 1290, 1231, 838 and 741 cm-1 ; NMR (CDCl3) 8.04, 7.58, 7.42, 7.0-7.2, 6.8-6.95, 4.66 and 4.07 δ; MS (m/z) 265, 264, 237, 144 and 118.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Cs+].[Cs+].[C:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]>CN1C(=O)CCC1.O>[C:14]([C:8]1([C:4]2[CH:3]=[C:2]([S:38][C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:28](=[O:30])[CH3:29])=[CH:37][CH:36]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:15]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: N#CC1(c2cccc(Br)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1ccc(Sc2cccc(C3(C#N)CCOCC3)c2)cc1
Temperature: 130 °C
Yield: 79.5 %

Procedure:
4-(3-Bromo-phenyl)-tetrahydro-pyran-4-carbonitrile (1.33 g) was mixed with Na2CO3 (1.59 g), Cs2CO3 (0.651 g) and 4-acetamidothiophenol (1 g) in N-methyl pyrrolidinone (15 mL). The reaction mixture was heated at 130° C. overnight. After cooling, the mixture was poured into iced water. The product precipitated out as a solid, was collected by suction filtration. The solid was recrystallized from a mixture of EtOAc and hexanes to provide N-{4-[3-(4-Cyano-tetrahydro-pyran-4-yl)-phenyl sulfanyl]-phenyl}acetamide(1.4 g, 80% yield).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[N+:16]([O-])=O)[CH2:2][CH2:3][CH3:4].[C:19](O)(=O)[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:19]1[CH2:20][OH:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: O=C(O)CO
Product: CCCCn1c(CO)nc2cnc3ccccc3c21
Yield: 78.3 %

Procedure:
Using the general method of Example 1, N-butyl-3-nitro-4-quinolinamine (9.8 g, 0.04 mole, Example 122) was hydrogenated then reacted with glycolic acid (9.1 g, 0.12 mole) to provide 8.0 g of the desired product as a solid. A small sample was recrystallized from ethyl acetate to provide pure material, m.p. 146-149° C. Analysis: Calculated: %C, 70.6; %H, 6.7; %N, 16.5; Found: %C, 70.3; %H, 6.7; %N, 16.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.[OH-].[Na+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(Cl)ccc2NC1C(F)(F)F
Reaction time: 8 h
Yield: 41.5 %

Procedure:
The ester from Step 2 (1.7 g, 5.6 mmol) and 2.5 N sodium hydroxide (4.4 mL, 11 mmol) were mixed in tetrahydrofuran (25 mL), methanol (10 mL), and water (25 mL). After stirring overnight, contents were concentrated in vacuo to remove the THF and methanol. The aqueous solution remaining was extracted with diethyl ether (2×100 mL). The resulting aqueous layer was acidified with 2 N HCl causing the precipitation of an oil. The oil was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1). Fractions containing the desired product were combined, and concentrated in vacuo. The residue was triturated with dichloromethane, and filtered to afford the 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid as a yellow solid (0.645 g, 41%): mp 187.8-188.8° C. 1H NMR (acetone-d6, 300 MHz) 7.69 (s, 1H), 7.36 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 6.60 (brs, 1H), 5.20 (m, 1H). ESHRMS m/z 276.0040 (M−H, Calc'd 276.0039). Anal. Calc'd for C11H7NO2F3Cl+2.6% H2O: C, 46.39; H, 2.98; N, 4.92. Found: C, 45.99; H, 2.54; N, 4.85.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(#N)C>[N:14]1([C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:6][CH:7]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Clc1ccc(-c2ccccn2)nn1
Reactant: C1CNCCN1
Solvent: CC#N
Product: c1ccc(-c2ccc(N3CCNCC3)nn2)nc1
Yield: 77 %

Procedure:
To a solution of 3-chloro-6-pyridin-2-ylpyridazine (0.250 g, 1.300 mmol) in acetonitrile (15 mL) was added piperazine (0.335 g, 3.900 mmol) and the mixture was stirred at reflux for 4 hours. The solvent was removed in vacuo. The residue was purified by column chromatography to afford the title compound in 77% yield (0.240 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:13][CH2:12][CH2:11]2)[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6][C:5]=1[N+:18]([O-])=O>O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH2:13]2)[C:7]([C:14]([F:16])([F:17])[F:15])=[CH:6][C:5]=1[NH2:18]
Reactant: COC(=O)c1cc(N2CCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCC2)c(C(F)(F)F)cc1N
Yield: 99.8 %

Procedure:
1.10 g of 5-azetidin-1-yl-2-nitro-4-trifluoromethyl-benzoic acid methyl ester in 12 ml of tetrahydrofuran are hydrogenated in presence of 200 mg of palladium on carbon. After 20 filtration of the catalyst the solution is evaporated to dryness yielding 0.99 g of 2-amino-5-azetidin-1-yl-4-trifluoromethyl-benzoic acid methyl ester as yellow powder, m.p. 80-86° C.
Reaction SMILES: Cl.[C:2]1(/[C:8](/[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9]/[C:10]([OH:12])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH2:26]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[CH2:24][CH2:25][NH:26][C:10](=[O:12])/[CH:9]=[C:8](/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)\[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)/C=C(/c1ccccc1)c1cccnc1
Agent: Cl
Product: COc1cccc(CCNC(=O)/C=C(/c2ccccc2)c2cccnc2)c1
Yield: 97.1 %

Procedure:
Starting from (Z)-3-phenyl-3-(3-pyridyl)-2-propenoic acid hydrochloride (1.00 g) and 3-methoxyphenethylamine (0.60 g), the titled compound (1.33 g, 98%) was obtained according to the method similar to that of Example 9.
Reaction SMILES: S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(O)=O)N=1)CC2)=O.[NH2:39][C:40]1[N:44](C(OC(C)(C)C)=O)[N:43]=[C:42]([C:52]2[CH:53]=[C:54]([CH:96]=[CH:97][CH:98]=2)[O:55][CH2:56][C:57]2[S:61][C:60]([N:62]3[CH2:71][CH2:70][C:69]4[C:64](=[C:65]([C:72](=[O:91])/[N:73]=[C:74]5/[S:75][C:76]6[CH:90]=[CH:89][CH:88]=[CH:87][C:77]=6[N:78]/5COCC[Si](C)(C)C)[CH:66]=[CH:67][CH:68]=4)[CH2:63]3)=[N:59][C:58]=2[C:92]([O:94]C)=[O:93])[C:41]=1[C:99]#[N:100]>>[NH2:39][C:40]1[NH:44][N:43]=[C:42]([C:52]2[CH:53]=[C:54]([CH:96]=[CH:97][CH:98]=2)[O:55][CH2:56][C:57]2[S:61][C:60]([N:62]3[CH2:71][CH2:70][C:69]4[C:64](=[C:65]([C:72](=[O:91])[NH:73][C:74]5[S:75][C:76]6[CH:90]=[CH:89][CH:88]=[CH:87][C:77]=6[N:78]=5)[CH:66]=[CH:67][CH:68]=4)[CH2:63]3)=[N:59][C:58]=2[C:92]([OH:94])=[O:93])[C:41]=1[C:99]#[N:100]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1COc1cccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)c1
Agent: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(-c3ccc(CO)cc3)s1)CC2
Product: N#Cc1c(-c2cccc(OCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2)n[nH]c1N

Procedure:
The title compound 46 was prepared in a similar manner to the synthesis of compound 34 by substituting compound 34D with compound 46A in step 5 of Example 34: 1H NMR (DMSO-d6): δ 12.83 (s, 1H), 7.96 (d, J=7.93 Hz, 1H), 7.72 (d, J=7.93 Hz, 1H), 7.61 (d, J=7.32 Hz, 1H), 7.27-7.42 (m, 7H), 6.95 (d, J=7.93 Hz, 1H), 5.47 (s, 2H), 4.72-4.81 (m, 4H), 3.74 (t, J=5.68 Hz, 2H), 2.98 (t, J=5.65 Hz, 2H). MS (ESI(+)): m/z 649 (M+H).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH2:11][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C:8]1=[O:18])=O)C.[NH3:19]>CO>[C:4]([CH2:6][N:7]1[CH2:11][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C:8]1=[O:18])(=[O:3])[NH2:19]
Reactant: N
Reactant: CCOC(=O)CN1C[C@@H](c2ccccc2)CC1=O
Solvent: CO
Product: NC(=O)CN1C[C@@H](c2ccccc2)CC1=O
Yield: 85 %

Procedure:
The solution of N-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone (3) (250 mg, 1.01 mM) in methanol (30 ml) saturated by stream of gaseous ammonia for 5 hours. Reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography with ethylacetate-hexane mixture 1:1 silicagel giving N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (4a) (187 mg, 85%). M.p. 107.5-108° C. [α]D20=+8.5° (c=3, MeOH). 1H NMR (CDCl3), δ: 2.61 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (1H and 1H, br.s and br.s, NH2); 7.20-7.40 (5H, m, C6H5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at −75° C. 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried (MgSO4) to yield 4.95 g (94%) of (1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester as a white foam.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[CH:19]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(O)C>[Br:20][C:19]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(OC(C)(C)C)c1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Product: COC(=O)C(OC(C)(C)C)c1nc2ccccn2c1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
To a solution of methyl 2-(tert-butoxy)-2-{imidazo[1,2-a]pyridin-2-yl}acetate (25c) (108 mg, 0.41 mmol) in ethanol (5 mL) at 0° C. was added N-bromosuccinimide (76 mg, 0.43 mmol) portionwise. The mixture was stirred at 0° C. for 15 minutes and concentrated in vacuo. The residue was dissolved in ethyl acetate (5 mL) and washed with a saturated solution of sodium hydrogencarbonate (2×5 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired product (25d) (127 mg, 0.37 mmol, 90%) as a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.C=O.S(Cl)(Cl)=O.ClCN1C(C)=NC(C)=N1.[OH:23][C:24]1C2C(=CC=CC=2)C(O)=CC=1C(NCCCOC1C=CC(C(CC)(C)C)=CC=1C(CC)(C)C)=O.[O-]CC.[Na+]>CN(C=O)C>[OH:23][CH2:24][N:3]1[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[N:4]1
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(O)c3ccccc3c2O)c(C(C)(C)CC)c1
Reactant: Cc1n[nH]c(C)n1
Agent: C=O
Agent: CC[O-]
Agent: Cc1nc(C)n(CCl)n1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(C)n(CO)n1

Procedure:
1-Hydroxymethyl-3,5-dimethyl-1,2,4-triazole which was prepared from 3,5-dimethyl-1,2,4-triazole and formaldehyde was reacted with 1.5 to 5 times on a molar basis of thionyl chloride to prepare 1-chloromethyl-3,5-dimethyl-1,2,4-triazole. This was reacted with an equimolar amount of 1,4-dihydroxy-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide in DMF in the presence of 1.5 to 3 times on a molar basis of sodium ethoxide to obtain Coupler (36).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3c(Cl)cccc3Cl)c(=O)c12
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1c(Cl)cccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 17.4 %

Procedure:
A mixture of (4S,7R)-2-(2,6-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 15; 1.2 g, 3.6 mmol) and iodomethane (0.45 mL, 8.0 mmol) in N,N-dimethylformamide (20 mL) was heated to 80° C. and stirred for 4.5 h. The reaction mixture was allowed to cool and water (200 mL) was added. A solid precipitated. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered, concentrated and purified by chromatography, eluting with 5-80% ethyl acetate/dichloromethane. Fractions containing the product were combined, evaporated, and recrystallized from ethyl acetate/hexanes to give (4S,7R)-2-(2,6-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (220 mg 18%) as a light tan solid. ES(+)-MS (M+H) 351