Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:31]=[CH:30][C:9]([O:10][C:11]2[C:16]([C:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[C:16]([CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:30][CH:31]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ncccc2C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc(Oc2ncccc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 4-(2-(4-(ethoxycarbonyl)phenoxy)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.89 g, 13.87 mmol) and palladium hydroxide on carbon (0.950 g, 1.353 mmol) in EtOH (50 mL) was evacuated/purged with hydrogen (1 atm, 3×). After stirring at rt overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness to give a light-yellow oil. MS m/z: 427.1 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19].[CH3:22][C:23]1[CH:27]=[C:26]([CH2:28][C:29](O)=[O:30])[O:25][N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[C:5]([C:9]2[CH:10]=[CH:11][C:12]([N:15]([CH3:16])[CH3:17])=[CH:13][CH:14]=2)=[CH:4][C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:26]2[O:25][N:24]=[C:23]([CH3:22])[CH:27]=2)[CH:7]=1
Reactant: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1N
Reactant: Cc1cc(CC(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccc(N(C)C)cc2)c(Cl)cc1NC(=O)Cc1cc(C)no1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.8 %

Procedure:
To a solution of methyl 4-amino-6-chloro-4′-(dimethylamino)-[1,1′-biphenyl]-3-carboxylate (Intermediate 47) (10.8 g, 35.4 mmol) in dichloromethane (525 mL) was added 2-(3-methylisoxazol-5-yl)acetic acid (Aldrich, 5 g, 35.4 mmol), HATU (17.52 g, 46.1 mmol) and triethylamine (11.85 mL, 85 mmol) and the reaction mixture was stirred at room temperature for 72 h. The mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with hot methanol, filtered and dried to give the title compound methyl 6-chloro-4′-(dimethylamino)-4-(2-(3-methylisoxazol-5-yl)acetamido)-[1,1′-biphenyl]-3-carboxylate (13.91 g, 32.5 mmol, 92% yield) as a beige solid. LCMS: (M+H)+=428; Rt=3.86 min.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.[Cl:15][C:16]1[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[CH2:25]C#N.[H-].[Na+].CN(C=[O:34])C>>[Cl:15][C:16]1[C:23]([CH3:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[C:25]([C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([O:11][CH3:12])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1)=[O:34]
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Reactant: Cc1cc(C#N)cc(CC#N)c1Cl
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C#N)cc(C)c2Cl)n1
Reaction time: 24 h
Yield: 11 %

Procedure:
To a solution of 4-chloro-5-isopropyl-2,6-dimethoxy-pyrimidine (0.442 g, 2.04 mmol) and 4-chloro-3-cyanomethyl-5-methyl-benzonitrile (0.3707 g, 1.94 mmol) in DMF at 0° C. was added NaH portionwise over 15 minutes to give an orange-red reaction mixture. After stirring for 24 hr, O2 was bubbled into the reaction mixture for 36 hr. The reaction mixture was quenched with saturated ammonium chloride solution and methanol, and diluted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, H2O, saturated ammonium chloride solution and dried (MgSO4), then concentrated and purified by flash column chromatography (silica gel, 5 to 50% ethyl acetate/hexane) to give title compound (0.0767 g, 11%). 1H NMR (300 MHz, CDCl3): 7.67 (s, 1H), 7.59 (s, 1H), 4.00 (s, 3H), 3.75 (s, 3H), 3.3-3.2 (m, 1H), 2.37 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H); 13C NMR (75 MHz, CDCl3): 192.8, 171.1, 162.2, 160.2, 139.1, 138.9, 137.3, 135.9, 132.3, 119.9, 117.4, 110.8, 54.7, 54.2, 26.5, 20.2, 20.2; Mass Spectrum: 360.2, 362.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:14])([CH3:13])[C:6]1[CH:10]=[C:9]([OH:11])[N:8]([CH3:12])[N:7]=1)([CH3:4])[CH3:3].Cl[C:16]1[N:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.N1C(C)=CC=CC=1C>C1(C)C(C)=CC=CC=1>[CH3:4][C:2]([Si:5]([CH3:14])([CH3:13])[C:6]1[CH:10]=[C:9]([O:11][C:16]2[N:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=2)[N:8]([CH3:12])[N:7]=1)([CH3:1])[CH3:3]
Reactant: Cn1nc([Si](C)(C)C(C)(C)C)cc1O
Reactant: COc1cnnc(Cl)c1
Solvent: Cc1ccccc1C
Solvent: Cc1cccc(C)n1
Product: COc1cnnc(Oc2cc([Si](C)(C)C(C)(C)C)nn2C)c1
Yield: 25.8 %

Procedure:
3-[(1,1-Dimethylethyl)dimethylsilyl]-1-methyl-1H-pyrazol-5-ol (0.48 g, 0.0023 mole), 3-chloro-5-methoxypyridazine (0.36 g, 0.00249 mole) and 2,6-lutidine (0.396 mL, 0.003396 moles) were refluxed under N2 in xylene (20 mL) for 18 hours. The mixture was then filtered through silica gel with ethyl acetate and evaporated in vacuo. The crude compound was purified by reverse phase chromatography to give 3-[[3-[(1,1-dimethylethyl)dimethylsilyl]-1-methyl-1H-pyrazol-5-yl]oxy]-5-methoxypyridazine (0.19 g, 26% yield) as a brown solid.
Reaction SMILES: [C@@H:1]12[O:8][CH2:7][C@@H:5]([O:6]1)[CH:4]=[CH:3][C:2]2=O.S(=O)(=O)(O)O.C(=O)([O-])[OH:16].[Na+].[C:20]([O:24][C:25](=[O:28])[CH2:26][CH3:27])(=[O:23])[CH2:21][CH3:22]>>[C:20]([O:24][C@H:25]1[O:28][C@H:5]([CH2:7][O:8][C:1](=[O:6])[CH2:2][CH3:3])[CH:4]=[CH:27][C:26]1=[O:16])(=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C([O-])O
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCC(=O)OC[C@@H]1C=CC(=O)[C@@H](OC(=O)CC)O1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 1,6-anhydro-3,4-dideoxy-β-D-glycero-hex-3-enopyranos-2-ulose was dissolved in 3 ml of propionic anhydride, and the solution was cooled to -20° C. Then, 0.06 ml of concentrated sulfuric acid was added thereto, and the mixture was stirred for 30 minutes. Then, the reaction mixture was added to 100 ml of an ice-cooled saturated sodium hydrogencarbonate aqueous solution. The mixture was stirred for 30 minutes and then extracted with 100 ml of ethyl acetate. The extract was washed three times with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane=1:2) to obtain 100 mg of the desired product (Intermediate No. 19) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][N:17](C)[C:18](=O)OCC2C=CC=CC=2)[CH2:12][CH2:11]1>C(O)C.[Pd]>[CH3:18][NH:17][CH2:16][C@H:13]1[CH2:14][CH2:15][C@H:10]([C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:11][CH2:12]1
Reactant: CN(C[C@H]1CC[C@H](c2nc3ccccc3[nH]2)CC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNC[C@H]1CC[C@H](c2nc3ccccc3[nH]2)CC1

Procedure:
6.0 g of benzyl [[trans-4-(2-benzimidazolyl)cyclohexyl]methyl]methylcarbamate are dissolved in 600 ml of ethanol and hydrogenated at room temperature and normal pressure after the addition of 1 g of 5% palladium-on-active charcoal. The product, isolated in the usual manner, is recrystallized from methylene chloride/ether. There are obtained 3.0 g (78%) of 2-[trans-4-[(methylamino)methyl]cyclohexyl]benzimidazole, m.p. 232°-235°, as a colourless crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH:7][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH3:12])=[CH:14][CH:15]=1)=[O:5]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NNC(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)NNC(=O)c2ccccc2Cl)cc1
Yield: 45.7 %

Procedure:
2-Chlorobenzhydrazide (38.8 g) was dissolved in sodium hydroxide solution (9.18 g in 125 ml water). The solution was stirred and 4-methylbenzoyl chloride (35.2 g) added dropwise. The mixture was then stirred for 2 hours and the solid which precipitated was filtered off, washed with water and recrystallised from ethanol to give 30.0 g of the desired product, mp 204°-206° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][C:11](=[O:13])[CH:10]([C:14](=O)[CH2:15][CH3:16])[C:9](=[O:18])[CH2:8]2)[CH:4]=[N:3]1.[Cl:19]/[CH:20]=[CH:21]/[CH2:22][O:23][NH2:24]>>[Cl:19][CH:20]=[CH:21][CH2:22][O:23]/[N:24]=[C:14](/[CH:10]1[C:11](=[O:13])[CH2:12][CH:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH2:8][C:9]1=[O:18])\[CH2:15][CH3:16]
Reactant: NOC/C=C/Cl
Reactant: CCC(=O)C1C(=O)CC(c2cnn(C)c2)CC1=O
Product: CC/C(=N\OCC=CCl)C1C(=O)CC(c2cnn(C)c2)CC1=O

Procedure:
To 200 ml of an ethanolic solution of 20.0 g (81 mmols) of 5-(1-methyl-1H-pyrazol-4-yl)-2-propionylcyclohexane-1,3-dione was added 210 ml (84 mmols) of 0.4 mol ethanolic solution of (E)-3-chloro-2-propenyloxyamine. The mixture was reacted for 8 hours with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to give 12.5 g of the product.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:28])[CH2:24][N:25]([CH3:27])[CH3:26])=[CH:19][C:18]=1[C:29]([F:32])([F:31])[F:30]>>[CH3:26][N:25]([CH3:27])[CH2:24][C@@H:23]([NH:28][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:20]1[CH:21]=[CH:22][C:17]([F:16])=[C:18]([C:29]([F:30])([F:31])[F:32])[CH:19]=1
Reactant: CN(C)C[C@@H](N)c1ccc(F)c(C(F)(F)F)c1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CN(C)C[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C(F)(F)F)c1

Procedure:
Compound 50 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-1-(4-Fluoro-3-trifluoromethyl-phenyl)-N2,N2-dimethyl-ethane-1,2-diamine hydrochloride to give the title compound as a white solid. LC/MS [423 (M+H)]; 1H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s, 1H), 8.96 (d, 1H), 8.55-8.42 (m, 3H), 7.90-7.73 (m, 2H), 7.33 (t, 1H), 6.63 (s, 1H), 5.55 (s, 1H), 3.20 (s, 1H), 2.81 (s, 1H), 2.17 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][N:13]([C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)[C:12](=[O:21])[C:11]1([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32].[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][N:13]([C:15]2[C:19]([N+:31]([O-:33])=[O:32])=[CH:18][N:17]([CH3:20])[N:16]=2)[C:12](=[O:21])[C:11]1([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1ccc(N2CC(COCc3ccccc3)C(C)(C)C2=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])c(N2CC(COCc3ccccc3)C(C)(C)C2=O)n1

Procedure:
To a mixture of 4-((benzyloxy)methyl)-3,3-dimethyl-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (459 mg) and acetic anhydride (3.0 mL) was added fuming nitric acid (0.12 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hr, water was added thereto, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (343 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C)[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:14]=1.Cl>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:14]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nc(N)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 65 °C
Yield: 91.8 %

Procedure:
A solution of N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (3.88 g, 12.00 mmol) in THF (30 mL) was treated with 2M HCl (30 mL, 60 mmol), heated at 65° C. for 6 h, cooled to RT and concentrated to dryness. The mixture was treated with H2O, neutralized with solid NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was suspended in 3:2 EtOAc/Hex, sonicated and the resulting solid collected via filtration and dried to afford 6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (3.1 g, 92%) as a white solid. MS (ESI) m/z: 282.1 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:31][CH2:30]2)[S:27][CH:28]=1
Reactant: Clc1cccc(-c2csc(N3CCNCC3)n2)c1Cl
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccc(Cl)c3Cl)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 24.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (94.3 mg, 0.350 mmol), 1-[4-(2,3-dichlorophenyl)-1,3-thiazol-2-yl]piperazine (100 mg, 0.318 mmol) and diisopropylethylamine (0.111 ml, 0.636 mmol) in dimethyl sulfoxide (1.0 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 34.3 mg (24.8%) of the desired product as a solid. mp 132-133° C.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[N:9]=[CH:8]1.C[Si](C)(C)CCOCN1C(NC(=O)C)=CN=C1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[N:9]=[CH:8]1
Reactant: CC(=O)Nc1cn(COCC[Si](C)(C)C)cn1
Agent: CC(=O)Nc1cncn1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1c[nH]cn1

Procedure:
The mixture of regioisomers N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)acetamide and N-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)acetamide (170 mg, 0.7 mmol) from Step 1 of this Example was stirred in 70% TFA in CH2Cl2 (10 mL) at rt for 4 h. The mixture was concentrated under reduced pressure to afford N-(1H-imidazol-4-yl)acetamide (147 mg) as a yellow film which was used in the next step without further purification. LCMS (ESI) m/z 126 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:42])[CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)cc1
Yield: 28.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (800 mg, 4.84 mmol) was reacted with tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (1.5 g, 4.16 mmol) to afford the desired product (550 mg, 46%) as a brown solid: ESI MS m/z 465 [C26H28N2O4S+H]+.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([O:12]C)=[O:11].Cl>O.C1COCC1>[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([OH:12])=[O:11]
Reactant: C=CCC(C(=O)OC)N1CCCC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(C(=O)O)N1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
Step A (2): A solution of LiOH (2 M, 0.73 g, 30.4 mmol) in 15 mL H2O was added to a solution of methyl 2-(2-oxopyrrolidin-1-yl)pent-4-enoate (2.0 g, 10.1 mmol) from step A(1) in THF (15 mL) at room temperature. The mixture was stirred at room temperature for 16 h. Poured into 1 N HCl. Extracted with EtOAc (3×250 mL). Washed combined organics with brine, dried with Na2SO4 After concentration in vacuo, dried on high-vacuum for ˜3 h to give 1.5 g (81%) of 2-(2-oxopyrrolidin-1-yl)pent-4-enoic acid as a beige solid: LC-MS (M+H)+=184.1; 1H NMR (300 MHz, CDCl3) δ 11.85 (s, 1H), 5.47-5.81 (m, 1H), 4.91-5.25 (m, 2H), 4.81 (dd, J=11.14, 4.73 Hz, 1H), 3.45-3.59 (m, 1H), 3.25-3.40 (m, 1H), 2.59-2.83 (m, 1H), 2.30-2.52 (m, 3H), 1.80-2.12 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].[C:8]([C:10]1[CH:38]=[CH:37][C:13]([CH2:14][C@@:15]2([CH3:36])[N:19]3[C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][N:22]=[C:18]3[N:17]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[C:16]2=[O:35])=[CH:12][CH:11]=1)#[N:9]>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH2:14][C@@:15]2([CH3:36])[N:19]3[C:20]([S:23]([NH:2][C@@H:3]([CH3:4])[C:5]([NH2:7])=[O:6])(=[O:25])=[O:24])=[CH:21][N:22]=[C:18]3[N:17]([C:27]3[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:16]2=[O:35])=[CH:37][CH:38]=1)#[N:9]
Reactant: C[C@H](N)C(N)=O
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)Cl)n21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
L-Alaninamide hydrochloride (0.151 g, 1.209 mmol) was dissolved in anhydrous DMF and DMAP (0.197 g, 1.612 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 1 h. Then, (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl chloride (0.24 g, 0.484 mmol) in anhydrous DMF was added to the reaction mixture and stirred for additional 10 min. The reaction solution was diluted with EtOAc and washed with water, 1 N HCl and then water. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford 0.211 g of the title compound as a white scaly solid (M+1, 547.2).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][N:6]1[CH:10]=[C:9]([CH2:11]O)[N:8]=[N:7]1)([CH3:4])[CH3:3].[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25]([NH:28][CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1)(=[O:27])=[O:26])([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CCOC(C)=O.C1C=CC=CC=1>[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25]([N:28]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=1)[CH2:11][C:9]1[N:8]=[N:7][N:6]([CH2:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[CH:10]=1)(=[O:26])=[O:27])([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reactant: C[Si](C)(C)Cn1cc(CO)nn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CN(Cc2cn(C[Si](C)(C)C)nn2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
A solution of {1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methanol (241 mg, 1.30 mmol), methyl 4-({[(2,4-dinitrophenyl)sulfonyl]amino}methyl)benzoate (514 mg, 1.30 mmol), triphenylphosphine (409 mg, 1.56 mmol) and benzene (4.34 mL) was treated with diethylazodicarboxylate (247 uL, 1.56 mmol). After one hour additional portions of triphenylphosphine (204 mg, 0.780 mmol) and diethylazodicarboxylate (124 uL, 0.780 mmol) The reaction was diluted with EtOAc and washed with 2M aq. HCl 2×, water, brine, dried (MgSO4) and concentrated to afford a brown oil used crude in the next reaction. MS: cal'd 563 (MH+), exp 563 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12](=[O:13])[CH2:11][N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: c1cc2[nH]ccc2cn1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1ccc2cnccc21

Procedure:
The title compound is prepared from 1H-pyrrolo[3,2-c]pyridine as described in EXAMPLES 18 and 19, Part A using tert-butyl bromoacetate in place of methyl iodide. The crude product is purified by column chromatography eluting with a gradient of 3% MeOH/CH2Cl2 to 6% MeOH/CH2Cl2 to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:16](OC)(=[O:19])[C:17]#[CH:18]>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:18]=[CH:17][C:16]([OH:19])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C#CC(=O)OC
Reactant: NNc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Oc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of 57.5 g of 4-chlorophenylhydrazine hydrosulfate in 1,000 ml of tert-butanol was first treated in portions with 100.8 g of potassium tert-butoxide and then (after stirring for 10 min) in the course of 45 min at 45° C.-50° C. with a solution of 27.7 g of methyl propiolate in 90 ml of tertbutanol. After 1 h at boiling point, the mixture was allowed to cool and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in 1,200 ml of water. The aqueous phase was first washed with methylene chloride and then acidified, the product being deposited as a solid. 47.6 g of the title compound were obtained, m.p.: 185°-187° C.