Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]=1[CH3:10].C(N(C(C)C)CC)(C)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([C:39](O)=[O:40])=[C:36]([CH3:42])[C:35]=2[CH:43]=1.CCCP(O)(O)=O.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:6]([CH3:19])=[N:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:39]([C:37]3[O:38][C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:43][C:35]=4[C:36]=3[CH3:42])=[O:40])=[CH:16][CH:17]=2)[C:9]=1[CH3:10]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2)c1C
Reactant: Cc1c(C(=O)O)oc2ccc(F)cc12
Agent: CCCP(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Cc1c(C)nn(Cc2ccc(NC(=O)c3oc4ccc(F)cc4c3C)cc2)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
To a solution of [1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (400 mg, 1.46 mmol) in 5 mL dichloromethane are added diisopropylethylamine (1.5 mL, 8.8 mmol) and 5-fluoro-3-methyl-1-benzofuran-2-carboxylic acid (369 mg, 1.9 mmol). After stiffing at room temperature for 10 minutes a 50% solution of 1-propylphosphonic acid cyclic anhydride in ethyl acetate (1.725 mL, 2.93 mmol) is added with cooling and the mixture is stirred at room temperature for 12 hours. The solvent is evaporated in vacuo and the residue is purified by MPLC (dichloromethane/methanol 98:2) to yield 410 mg of (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=450; TLC: Rf=0.56 (dichloromethane/methanol 95:5, silicagel 60 F254)). b) To a solution of (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (410 mg, 0.91 mmol) in dioxane/water (10 mL/10 mL) is added 1 M NaOH (2.3 mL) and the mixture is stirred at room temperature for 24 hours. The mixture is diluted with water and acidified with hydrochloric acid (1 M, 3.25 mL). The precipitate is filtered, washed with water and dried to yield 338 mg of the title compound (ESI mass spectrum: [M+H]+=436; Retention time HPLC: 0.85 min (method D).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=1)[C:33](Cl)=[O:34]>O1CCCC1>[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][N:38]=1)[C:33]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:34]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccnc(CCl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Temperature: 0 °C
Yield: 79.6 %

Procedure:
To a solution of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine (2.3 g, 8.7 mmol) in tetrahydrofurane (80 ml) is added N-ethyldiisopropylamine (6.0 ml, 35 mmol) and the solution cooled to 0° C. 2-chloromethyl-isonicotinoyl chloride (2.4 g, 10.5 mmol), dissolved in tetrahydrofurane (50 ml), is added over 15 minutes and the mixture heated to 70° C. for 1 h. After evaporation of the volatile components, the residue was disolved in ethyl acetate and water, filtered and the residue combined with the dryed and evaporated organic phase. Recrystallization from dichloromethane/ethyl acetate afforded the title compound as light brown solid (2.9 g, 81% yield). MS: m/e=420(M+H+).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11](Cl)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CN(C=O)C>O>[CH2:1]([C:8]1[S:12][C:11]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(-c2nc(Cl)sc2Cc2ccccc2)cc1
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(N3CCNCC3)sc2Cc2ccccc2)cc1
Temperature: 100 °C
Yield: 69.5 %

Procedure:
To 25 ml eggplant-shaped bottle were added 1.30 g (4.12 mmol) 5-benzyl-2-chloro-4-(4-methoxy-phenyl)-thiazole prepared in the step 1 of Example 70, 0.35 g (8.24 mmol) LiOH.H2O, 20 mg KI, 1.77 g (20.6 mmol) piperazine, 5 ml DMF and 0.5 ml water. The mixture was stirred until homogeneous, heated to 100° C., stirred for 12 hours, added 20 ml water, and extracted with ethyl acetate three 3×10 ml. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a thick crude product, which was purified under a reduced pressure by silica gel column chromatography eluted with dichloromethane and methanol at a ratio 10:1-5:1 (V:V) to give a 1.05 g oily and thick product in a yield of 69.5%, 1H-NMR (CDCl3, 400 MHz) δ: 2.99 (4H, t, J=5.2 Hz, 2×CH2), 3.46 (4H, t, J=5.2 Hz, 2×CH2), 3.82 (3H, s, OCH3), 4.12 (2H, s, CH2), 6.90 (2H, d, J=8.80 Hz, ArH), 7.18˜7.35 (5H, m, ArH), 7.53 (2H, d, J=8.80 Hz, ArH); EI-MS m/e (%): 365.0 (M+, 86), 323.0 (28), 309.0 (100), 296.0 (49); HREI-MS Calcd. for C21H23N3OS: 365.1562. found: 365.1564.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:22]1([C:2]2[CH:19]=[CH:18][C:17]3[C:16](=[O:20])[C:15]4[C:6](=[CH:7][C:8]5[C:13]([CH:14]=4)=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:5](=[O:21])[C:4]=3[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2ccc(N3CCCCC3)cc2C(=O)c2cc3ccccc3cc21

Procedure:
1 g (3.62 mmol) of 2-fluoro-naphthacene-5,12-dione, 0.92 g (10.86 mmol) of piperidine, 1.50 g (10.86 mmol) of potassium carbonate and 10 ml of DMSO are stirred at a bath temperature of 60° C. for 45 minutes. After cooling, the mixture is poured onto water and the orange product is filtered off. The crystals are dissolved in tetrahydrofuran (THF)/toluene and the solution is dried over sodium sulfate and evaporated. The residue is recrystallized from toluene/pentane. Yield: 1.11 g (90%); melting point 230°-233° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:20])[C:9]1C=CC=C[CH:10]=1.C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C=C>CO.C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:15][C:16](=[O:32])[CH2:17][C@@H:18]([NH2:31])[C:19]([NH:21][C@H:22]([C:27](=[O:30])[NH:28][CH3:29])[C:23]([CH3:24])([CH3:25])[CH3:26])=[O:20])[CH:9]=[CH2:10]
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Agent: C=CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C=CCOC(=O)C[C@@H](N)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Reaction time: 2 h
Yield: 87 %

Procedure:
As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester trifluoroacetate salt, crude 3(R)-(t-butoxycarbonylamino)-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester was deprotected after 2 hours. Flash column chromatography with 0.5% TFA17% MeOH/CHCl3 gave 2.46 g (87%) of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester trifluoroacetate salt as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[Br-:12].[K+].BrBr>O>[Br:12][C:8]1[CH:9]=[C:2]([F:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1F
Reactant: [Br-]
Agent: BrBr
Agent: [K+]
Solvent: O
Product: COc1cc(C=O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
A solution of 4-fluoro-3-methoxybenzaldehyde (4.3 g, 27.9 mmol), potassium bromide (16.6 g, 139.5 mmol), bromine (3.6 mL, 69.8 mmol), and water (45 mL) were stirred at room temperature for 24 hours. More bromine (1.43 mL, 27.9 mmol) was added and the reaction was stirred at room temperature overnight. The product precipitated out of solution and was collected via filtration and dried under reduced pressure to give 2-bromo-4-fluoro-5-methoxybenzaldehyde (6.01 g, 92% yield).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25](=O)([O-])[O-].[K+].[K+].[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>CN(C)C=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:25])[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1Cn1c(=O)c(C(=O)NCC(=O)O)c(O)n(C2CCCCC2)c1=O
Reaction time: 8 h
Yield: 2.9 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (740 mg, 5.35 mmoles) and 2-methylbenzene (268 uL, 2.0 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Preparative HPLC (20-90% acetonitrile-water-0.1% TFA) gave the title compound (12 mg, 3.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 10.15 (br. s., 1 H), 7.00-7.29 (m, 3 H), 6.89 (d, J=6.82 Hz, 1 H), 4.96 (s, 2 H), 4.65 (t, J=12.25 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.35 (s, 3 H), 2.26 (q, 2 H), 1.78 (d, J=12.13 Hz, 2 H), 1.51-1.72 (m, 3 H), 1.28 (q, 2 H), 1.10 (q, 1 H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(C(=O)O)C1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C1CCC(=O)C1
Temperature: 0 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-oxocyclopentane-1-carboxylic acid (1.0 g, 7.80 mmol, 1.00 equiv), potassium carbonate (1.62 g, 11.72 mmol, 1.50 equiv), Acetone (20 mL). This was followed by the addition of iodomethane (11.1 g, 78.20 mmol, 10.02 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 60° C. in an oil bath. The reaction progress was monitored by GCMS. The solids were collected by filtration. The filtrate was concentrate. The resulting mixture was diluted with 10 mL of H2O. The resulting solution was extracted with 3×10 mL of ether and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. This resulted in 1.0 g (crude) of methyl 3-oxocyclopentane-1-carboxylate as yellow oil. The crude could be used for the next step directly.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19]Br)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(O)C>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:22]
Reactant: BrCCCc1ccc(-c2ccc(CCCBr)cc2)cc1
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCCc1ccc(-c2ccc(CCCN(CC)CC)cc2)cc1
Yield: 84.9 %

Procedure:
A solution of 515 mg of 4,4'-bis(3-bromopropyl)biphenyl and 0.95 g of diethylamine in 1.3 ml of ethanol was refluxed in a flask equipped with a balloon for 2 hours, cooled, and concentrated under a reduced pressure. To the concentrate was added 5% sodium bicarbonate aqueous solution, the mixture was extracted three times with 50 ml benzene. The extract was washed with 5% sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, concentrated under a reduced pressure to and dried in vacuo obtain 420 mg of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24].[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)O
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1
Product: CCC(=O)[O-]
Yield: 38.4 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 55 mg (0.23 mmol) of 4-tert-butyl-benzenesulfonyl chloride. After recrystallization from acetonitrile/dichloromethane mixture, 36 mg (40%) of 8-(4-tert-butyl-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8](=O)([O:11][CH3:12])[O:9][CH3:10])([O-:3])=[O:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31]>>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[Cl:29])=[CH:14][C:5]=1[O:6][CH2:7][P:8](=[S:31])([O:11][CH3:12])[O:9][CH3:10])([O-:3])=[O:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COP(=O)(COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC
Product: COP(=S)(COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])OC

Procedure:
In the same way, dimethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonate and phosphorus pentasulfide are reacted together to yield O,O'-dimethyl 2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphonothioate
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:12]=O)[CH:10]=O)=[CH:5][CH:4]=1.[NH2:14][NH2:15]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:12]=[N:14][NH:15][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(C=O)C=O)cc1
Solvent: CCO
Product: COc1ccc(-c2cn[nH]c2)cc1
Temperature: 0 °C

Procedure:
The (4-methoxyphenyl)malonaldehyde (1.5 g, 8.42 mmol) was dissolved in ethanol (10 mL), followed by addition of hydrazine (540 mg g, 16.8 mmol). The pale yellow solution was heated in a microwave sealed tube at 110° C. overnight. Large amount of white crystalline solid formed. The reaction mixture was cooled to 0° C. The white solid was collected by filtration and was washed with 5 mL of ice-cold ethanol to give the desired product, which was further dried under high vacuum pump.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([CH:8]([CH2:36][CH2:37][C:38]([F:41])([CH3:40])[CH3:39])[CH2:9][CH:10]([O:32][C:33](=[O:35])[CH3:34])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)C.[NH2:42]N.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:41][C:38]([CH3:39])([CH3:40])[CH2:37][CH2:36][CH:8]([C:6]1[NH:5][CH:4]=[N:2][N:42]=1)[CH2:9][CH:10]([O:32][C:33](=[O:35])[CH3:34])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(=O)N=CN(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC(CC(CCC(C)(C)F)c1nnc[nH]1)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 50 °C
Yield: 100 %

Procedure:
To a solution of acetic acid 3-(dimethylaminomethylene-carbamoyl)-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptyl ester (580 mg, 1.03 mmol) in acetic acid (2.5 mL) was added hydrazine (35 wt. % in water, 0.040 mL). The resulting solution was heated to 50° C. for 4 hours, cooled to ambient temperature, diluted with ethyl acetate, and neutralized with saturated aqueous sodium bicarbonate. The organic later was dried over sodium sulfate, filtered, and concentrated to give the title compound as a white foam (580 mg, >100%).
Reaction SMILES: [CH2:1]([CH:7]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([OH:25])=[O:24])[N:12]=[CH:11]1)[C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Sn]([N:40]=[N+:41]=[N-:42])(CCCC)CCCC)CCC.Cl>CO>[OH2:24].[NH:40]1[C:8]([CH:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([OH:25])=[O:24])=[O:26])[N:12]=[CH:11]2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9][N:42]=[N:41]1.[NH:40]1[C:8]([CH:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([OH:25])=[O:24])=[O:26])[N:12]=[CH:11]2)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9][N:42]=[N:41]1
Reactant: CCCCCCC(C#N)n1cnc(NC(=O)c2ccccc2C(=O)O)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: CO
Product: CCCCCCC(c1nnn[nH]1)n1cnc(NC(=O)c2ccccc2C(=O)O)c1
Product: O
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 28 %

Procedure:
To 700 mg of α-hexyl-4-[(2-carboxybenzoyl)-amino]-1H-imidazole-1-acetonitrile were added 2.0 g of tributyl tin azide. The mixture was heated at 85° C. for 2 days, cooled, and added to 50 ml of methanol previously saturated with hydrogen chloride gas. After stirring for 20 minutes, the solvent was removed in vacuo. The residue was triturated with diethyl ether. The remaining solid was diluted with 100 ml of absolute ethanol and 100 ml of 4N sodium hydroxide. After stirring for two hours, the solution was concentrated in vacuo. The residue was taken up in water and the pH adjusted to 3.7. The aqueous solution was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting solid was slurried with diethyl ether and filtered to provide 150 mg of the desired titled product, m.p. 120°-121° C.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23][O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.Cl.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[CH3:23][O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-CBZ-D-phenylalanine (47.3 g, 0.158 mmol) in DMF (300 mL) at 0° C., was added L-proline-methylester.HCl (25.0 g, 0.151 mmol), 1-hydroxybenzotriazole hydrate (20.28 g, 0.166 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.8 g, 0.166 mmol) and 4-methylmorpholine (16.0 g, 0.159 mmol). The reaction mixture was stirred for 8 h while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (1.2 L) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed as follows: KHSO4 (0.25M, 2×200 mL), water (1×200 mL), saturated aqueous NaHCO3 (2×200 mL) and saturated NaCl (1×200 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo to give title compound, 60.9 g (98 %), as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].CCN(CC)CC.FC(F)(F)S(O[Si:22]([CH3:25])([CH3:24])[CH3:23])(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH3:23][Si:22]([CH3:25])([CH3:24])[O:8][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[CH2:7]
Reactant: CC(=O)c1ccc[nH]1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C)c1ccc[nH]1
Reaction time: 0.5 h

Procedure:
1-(1H-pyrrol-2-yl)-ethanone (2.67 mmol, 0.29 g) in CH2Cl2 (10 ml) and Et3N (13.3 mmol, 1.90 ml) was cooled to 0° C. and treated with trimethylsilyl trifluoromethanesulfonate (5.34 mmol, 1.00 ml). The solution was held at 0° C. for 30 minutes, then diluted with ethyl acetate (75 ml) and washed with saturated aqueous sodium bicarbonate (2×20 ml) then brine (30 ml). The solution was concentrated under reduced pressure to provide crude 2-[1-(trimethyl-silanyloxy)-vinyl]-1H-pyrrole. 1H NMR (CDCl3) δ6.77 (1H, dd, J=2.7, 1.6), 6.34 (1H, dd, J=3.2, 1.6), 6.15 (1H, t, J=2.8), 4.56 (1H, d, J=1.0), 4.31 (1H, d, J=1.0), 0.45 (9H, s), 0.25 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:13])([CH3:14])[C:7](=[O:15])[C:6]([C:16]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:17])=[C:5]2[OH:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)c(F)cc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)c(F)cc2C(C)(C)C1=O
Yield: 68.5 %

Procedure:
A solution of ethyl 6-chloro-7-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.350 g, 1.12 mmol), glycine tert-butyl ester hydrochloride (0.244 g, 1.45 mmol), and Hunig's base (0.390 mL, 2.24 mmol) in 1,4-dioxane (15 mL) was heated at 120° C. for 2 hours in a sealed vessel. The solution was diluted with water (50 mL), extracted with EtOAc (2×50 mL), washed with water (50 mL), and then washed with brine (50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 0-75% DCM in hexane) to give the title compound (0.305 g). MS m/e=396.5 (M−H)−.