Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile in a manner analogous to Example 1221d. Product was isolated as an off-white solid (298 mg, 36%), MP=99-100, LCMS 479.23 (M+H), HPLC purity 99%, 1H-NMR (CDCl3, 400 MHz) δ 8.45 (d, J=7.6 Hz, 1H), 8.08 (s, 1H), 7.62 (s, 1H), 7.38-7.33 (m, 2H), 7.21 (d, 8.0 Hz, 1H) 7.13-7.72 (m, 4H), 4.87 (s, 2H), 3.56 (t, J=5.7 Hz, 2H), 3.39 (s, 3H), 2.97-2.90 (m, 4H), 2.79-2.2.73 (m, 6H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:3]=1
Reactant: Ic1cccnc1
Reactant: c1ccc2[nH]ccc2c1
Product: c1cncc(-n2ccc3ccccc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 3-iodopyridine and 1H-indole: ESMS m/e: 195.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][O:9][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCOc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of 2-(4-bromophenoxy)ethanol (10.94 g, 50.4 mmol), in dry DMF (50 mL), was added t-butyldimethylsilyl chloride (7.6 g , 50.4 mmol) and imidazole (3.77 g , 55.5 mmol). The reaction was stirred at ambient temperature for 18 h, then partitioned with hexane (300 mL) and water (300 mL). The aqueous layer was extracted with hexane (3×100 mL). The combined organic extracts were dried (MgSO4) and the solvent removed under reduced pressure to give the desired product as an oil (16.6 g, 99%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([C:31](=[O:33])[CH3:32])[CH:17]2[C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([C:31](=[O:33])[CH3:32])[CH:17]2[C:21]([OH:23])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)N1CSC2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CSC2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a cooled solution of benzyl 7-phenoxyacetamido-8-oxo-3-acetyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (300 mg.) in tetrahydrofuran (9 ml.) was added an aqueous solution (8 ml.) of sodium carbonate (107 mg.). The mixture was stirred at 0° C. for 75 minutes and at room temperature for additional 30 minutes. After removal of the tetrahydrofuran, the remaining aqueous layer was washed with ethyl acetate, acidified to pH 2 with 1N hydrochloric acid and extracted three times with methylene chloride. Drying over magnesium sulfate and removal of the solvent gave an amorphous solid (235 mg) of 7-phenoxyacetamido-8-oxo-3-acetyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylic acid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.Cl.[F:21][C:22]([F:32])([F:31])[C@H:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[NH2:24]>>[F:32][C:22]([F:21])([F:31])[C@@H:23]([NH:24][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Agent: Cl
Product: CC(C)CS(=O)(=O)c1nc(C(=O)N[C@@H](c2cccnc2)C(F)(F)F)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and (S)-2,2,2-trifluoro-1-(pyridin-3-yl)ethanamine hydrochloride (CAN 336105-46-5) as starting materials. MS (EI): m/e=442.4 [M+H]+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:28][C:29]([F:32])([F:31])[F:30])[S:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:19])=[C:12]([F:33])[CH:11]=1.IC>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:28][C:29]([F:30])([F:31])[F:32])[S:18]([CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:1])(=[O:20])=[O:19])=[C:12]([F:33])[CH:11]=1
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: CC(c1ccccc1)S(=O)(=O)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a solution of lithium diisopropylamine (2.0 M in THF/heptane/ethylbenzene) (1.2 mL, 2.5 mmol) at −78° C. was slowly added a solution of N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide (1 g, 2.3 mmol) in tetrahydrofuran (11 mL) and the reaction was stirred at −78° C. for 1 hour. Iodomethane (0.16 mL, 2.5 mmol) was then added and the reaction was warmed to ambient temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc, washed with 1 N aqueous HCl, and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-30% EtOAc in heptane) to give N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)ethanesulfonamide (614 mg, 60% yield). LCMS (m/z) ES+ 471 [M+18]+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@H:7]([C:22](=[O:32])[NH:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:6]1)=[O:4].O.[OH-].[Li+]>CO.O>[CH2:25]([O:24][NH:23][C:22]([C@H:7]1[CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][N:8]1[S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)(=[O:13])=[O:12])=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2CC[C@@H](C(=O)O)C[C@@H]2C(=O)NOCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred cold (0° C.) solution of (2R,4R)-2-benzyloxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (4.0 g, 8.6 mmol) in 10 mL of 9:1 methanol/water was added lithium hydroxide monohydrate (1.8 g, 43 mmol). The mixture was stirred for 2 hours before Amberlite IR-120 resin (96 g) was added. After 15 minutes, the mixture was filtered and the filtrate was concentrated to give (2R,4R)-2-benzyloxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylicacid, which was used in the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1)[CH3:2].[Br:14]Br>C(Cl)Cl>[Br:14][C:4]1[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:7][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(-c2ccccc2)n[nH]1
Reactant: BrBr
Solvent: ClCCl
Product: CCc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a solution of 5-ethyl-3-phenyl-1H-pyrazole (10.0 g, 58.1 mmol) in DCM (150 mL) was added dropwise bromine (9.28 g, 58.1 mmol) at 0° C. The reaction was stirred at that temperature for 30 min and continued for 2 h at room temperature before quenched with aqueous Na2SO3 solution (10% wt, 10 mL). DCM was removed and the residue was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow liquid (9.5 g). LCMS m/z=250.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.58 Hz, 3H), 2.66 (q, J=7.58 Hz, 2H), 7.40-7.56 (m, 3H), 7.82 (d, J=7.58 Hz, 2H), 13.15 (s, 1H).
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][C:2]=12.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[CH:5]=[CH:6][N:1]=[C:2]2[CH2:9][CH2:8][CH2:7][C:3]=12
Reactant: [O-][n+]1cccc2c1CCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2c1CCC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
6,7-Dihydro-5H-cyclopenta[b]pyridine 1-oxide (2.5 g, 18 mmol) was mixed with POCl3 (20 mL). The reaction mixture was stirred at 120° C. for 3 h. The excess POCl3 was removed under reduced pressure. The residue was diluted in EtOAc (80 mL) and neutralized with aq. Na2CO3. After filtration, the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the sub-title compound (2.6 g, 93%). LCMS calc. for C8H9ClN (M+H)+: m/z=154.0. Found: 154.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:27])[C@@H:8]([NH:19]C(OC(C)(C)C)=O)[CH2:9][CH2:10][CH2:11][NH:12][CH2:13][N:14]=[N:15][N+:16]([O-:18])=[O:17].Cl.[Cl:29]CCl>C1COCC1.O1CCOCC1>[ClH:29].[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:27])[C@@H:8]([NH2:19])[CH2:9][CH2:10][CH2:11][NH:12][CH2:13][N:14]=[N:15][N+:16]([O-:18])=[O:17]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1
Reaction time: 3 h

Procedure:
(2S)-2-tert-Butoxycarbonylamino-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide (2.28 g, 5.68 mmol) is dissolved in 5 mL THF and 5 mL 4 N HCl in dioxane. After 3 h, dichloromethane is added and the mixture is filtered. The semisolid is collected and is treated with methanol—toluene and concentrated in vacuo; this process is repeated several times to afford 1.63 g of (2S)-2-amino-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide hydrochloride as a solid.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:11][C@@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9][C:8](=[O:20])[O:7]1)(=O)C>CO.C1COCC1>[Si:13]([O:12][C@@H:10]1[CH2:11][C@@H:6]([CH2:5][OH:4])[O:7][C:8](=[O:20])[CH2:9]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)O[C@H](CO)C1
Temperature: 24 °C
Reaction time: 27 h
Yield: 54.2 %

Procedure:
((2S,4R)-4-(tert-Butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-yl)methyl acetate (8.36 g, 27.64 mmol) and [tBu2SnOH(Cl)]2 (1.577 g, 2.764 mmol) are dissolved in MeOH/THF mixture (280 mL). The reaction mixture is stirred at 23-25° C. for 27 h. After the solvent is removed under reduced pressure, the remained residue is purified by silica gel chromatography (elution with tBuMeO/hexane mixture) to afford a crude product as white solid (5.59 g, 78%). Recrystallization from n-hexane affords (3.90 g, 54%) of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)-tetrahydro-pyran-2-one as white needles. M.p.=102° C. (DSC peak).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([Cl:10])=[CH:4][CH:3]=1.[CH3:11][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:9])[CH3:11])[C:5]([Cl:10])=[CH:4][CH:3]=1
Reactant: O=Cc1nc(Br)ccc1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Br)ccc1Cl
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a solution of 6-bromo-3-chloropicolinaldehyde (10.0 g, 45.45 mmol) in 200 mL THF stirring at −78° C. under N2 was slowly added methylmagnesium bromide (3.0 M in diethyl ether, 16.63 mL, 50 mmol). The reaction was stirred at this temperature for 3 hours, and then saturated ammonium chloride was added. The mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% EtOAc/hexanes over 20 minutes) to provide 1-(6-bromo-3-chloropyridin-2-yl)ethanol (8.4 g, 78%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[NH:4][C:3]1=O.[H-].[Na+].C(O)(=O)C>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C:3]2[NH:4][C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=3[C:7](=[O:11])[C:8]=2[CH2:9][O:10]1
Reactant: CC1(C)OCCC(=O)c2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)OCc2c1[nH]c1ccccc1c2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound of formula V, 5,6-dihydro-3,3-dimethyl-4,1-benzoxazonine-2,7(1H,3H)-dione (11.66 g, described in Example 1), in tetrahydrofuran (250 ml) is added to a stirred mixture of sodium hydride (4.8 g, 55% dispersion) in tetrahydrofuran (220 ml). The mixture is stirred at room temperature for 30 minutes and acetic acid is added until the mixture is neutral. The precipitate is collected and washed with a small amount of tetrahydrofuran and water. The precipitate is dried and crystallized from methanol to give the title compound, mp 335°-340° C. (dec.).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 36 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=1.60 min, m/z=459.0 [M+H]+, m/z=457.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.73 (dd, J=8.07, 3.91 Hz, 1H) 1.77-1.89 (m, 1H) 2.55 (s, 3H) 2.88 (d, J=11.74 Hz, 1H) 3.17-3.27 (m, 2H) 3.42 (br. s, 1H) 4.19 (br. s, 1H) 4.84 (br. s, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.39 (d, J=7.83 Hz, 1H) 7.75 (dd, J=7.95, 1.83 Hz, 1H) 7.85 (d, 2H) 8.00 (d, J=2.45 Hz, 1H) 8.52 (d, J=1.96 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: C(C1C(=O)[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH:13]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=2)C.O=[C:24]([CH2:28][CH3:29])[C:25](O)=[O:26]>>[CH2:28]([C:24]1[C:25](=[O:26])[NH:12][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([CH:13]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH:14]([CH3:15])[CH3:16])[CH:10]=2)[CH3:29]
Reactant: CCc1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]c1=O
Reactant: CCC(=O)C(=O)O
Product: CCc1nc2ccc(C(C(C)C)n3ccnc3)cc2[nH]c1=O

Procedure:
3-ethyl-6-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2(1H)-quinoxalinone; mp. 203.7° C. (comp. 104) and 3-ethyl-7-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2(1H)-quinoxalinone (comp. 314) were prepared following substantially the same procedures as in example 23a were used except that 2-oxobutanoic acid was used in place of 2-oxopentanoic acid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][C:36](=[O:37])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCCI)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Yield: 83.4 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.30 g, 0.585 mmol), 4-iodobutyrophenone (0.17 g, 0.585 mmol), and potassium carbonate (0.12 g, 0.878 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.28 g, 82%); MS for C35H47N3O4 m/z 574 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]([CH:11]([CH3:15])[C:12]([OH:14])=O)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>FC(F)(F)S(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:16][CH:17]=1)[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:11]([CH3:15])=[C:12]2[OH:14]
Reactant: CC(C(=O)O)C(=Cc1ccc(Cl)cc1)C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c(C(=O)O)cc2ccc(Cl)cc2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a flask containing trifluoromethanesulfonic acid (40 mL), 2-(4-chloro-benzylidene)-3-methyl-succinic acid (14.0 g, 55 mmol) was added in portions. After being stirred at room temperature for 18 hours, the resulting mixture was poured onto ice-water, and stirred for 15 minutes. The formed precipitate was collected by filtration, and dissolved in ethyl acetate (150 mL). The solution was dried over sodium sulfate, and concentrated in vacuo. The residue was precipitated from ethyl acetate/petroleum ether (1:10) to afford 6-chloro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid (12.7 g, 98%) as a pink solid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]([CH:29]=[CH:30][N:31]=3)[C:24]([O:26]CC)=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+]>CO.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]([CH:29]=[CH:30][N:31]=3)[C:24]([OH:26])=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccnc(-c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(-c2cc(C(=O)O)ccn2)no1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.9 %

Procedure:
To a solution of the title compound of Example 24 (0.44 g, 1.0 mmol) in methanol (20 mL) was added a solution of lithium hydroxide (0.09 g, 2.0 mmol) in water (7 mL) and the reaction was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was diluted with water (20 mL) and dichloromethane (20 mL). The layers were separated, the organic layer was discarded and the aqueous layer was acidified to pH 4 with 2M aqueous hydrochloric acid and then extracted with dichloromethane (2×20 mL). The combined organic layers were dried (MgSO4) and the solvent was removed in vacuo to give the title compound as a white solid (0.04 g).
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][CH:17]([CH3:28])[CH2:18][NH:19][C:20]1[N:21]=[CH:22][NH:23][C:24]=1C(N)=O.CO>ClCCl>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][CH:17]([CH3:28])[CH2:18][N:19]1[C:20]2[N:21]=[CH:22][NH:23][C:24]=2[C:4](=[O:5])[NH:6][C:7]1=[S:8]
Reactant: CC(CNc1nc[nH]c1C(N)=O)OCc1ccccn1
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Solvent: CO
Product: CC(Cn1c(=S)[nH]c(=O)c2[nH]cnc21)OCc1ccccn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.246 mL, 2.18 mmol) was added to a suspension of 4-{[2-(pyridin-2-ylmethoxy)propyl]amino}-1H-imidazole-5-carboxamide (0.500 g, 1.82 mmol, obtained from Example 20(c)) in dichloromethane (10 mL). After 0.5 h, methanol (2 mL) was added. The solvent was removed in vacuo and acetone (5 mL) and another portion of ethoxycarbonyl isothiocyanate (0.246 mL, 2.18 mmol) were added. After o.n. stirring, the reaction was concentrated in vacuo. To the residue was added 1 N NaOH (10 mL) and the resulting solution was heated for 4 h at 100° C. After cooling to r.t., 2 N HCl was added until pH˜6. The mixture was concentrated in vacuo. The product was purified by preparative HPLC resulting in 54.3 mg (9% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=O)[C:8]2[CH:7]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[CH:5]=[CH:4][C:3]1=2.[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[CH3:16][O:15][C:13]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:17])([CH3:1])[CH2:11][CH:10]=[C:9]([S:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:7]=1)=[O:14]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Reactant: Sc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)=CCC2(C)C
Reaction time: 6 h

Procedure:
To a solution of methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (Compound E2, 835.0 mg, 3.60 mmol) in 25.0 mL of THF at room temperature was added TiCl4 (670.0 mg, 3.55 mmol). Thereafter a solution of thiophenol (430.0 mg, 3.90 mmol) and Et3N (730.0 mg, 7.20 mmol) in 10 mL THF was added. The resulting brown mixture was stirred for 6 h before H2 0 was carefully added to quench the reaction. The product was extracted into Et2O and the combined organic layers washed with saturated aqueous NaCl and dried over MgSO4. Removal of the solvents under reduced pressure afforded a solid from which the title compound was isolated as a yellow solid by column chromatography (5% EtOAc-hexanes).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C:18]([NH:17][C:8]3[S:9][C:10]([C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[N:7]=3)=[O:19])[CH2:21][CH2:22]2)=[N:28][CH:29]=1)#[N:34]
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)C1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N2CCC(C(=O)Nc3nc(-c4ccco4)c(-c4ccncc4)s3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
Compound 15 (177 mg, 0.50 mmol), 2-chloro-5-cyanopyridine (104 mg, 0.75 mmol) and potassium carbonate (207 mg, 1.50 mmol) were dissolved in NMP (4 mL), followed by stirring overnight under heating and reflux. The reaction mixture was allowed to cool down to room temperature, then poured into water, and the deposited precipitate was collected by filtration. The resulting precipitate was purified through silica gel column chromatography (chloroform:methanol=17:3) to afford the entitled Compound 16 (114 mg, 50%).