Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]([C:24]([OH:26])=O)[CH3:23])[C:7]=2[C:6]=1[CH3:28])=[O:4].[NH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>>[CH3:1][O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]([C:24](=[O:26])[NH:29][CH2:30][CH2:31][NH:32][C:33]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:39])[CH3:23])[C:7]=2[C:6]=1[CH3:28])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)O)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)NCCNC(=O)OC(C)(C)C)c2c1C

Procedure:
Prepared analogously to example 56.1 using the product from 55 (170 mg) and tert-butyl N-(2-aminoethyl)carbamate (90 μl).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[CH3:20])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C.Cl>ClCCl>[CH2:25]([O:24][C:22]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])/[C:7]1=[O:11])=[O:23])[CH3:26]
Reactant: Cc1ccc(F)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)/C(=C\c2cc(F)ccc2C)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1,3-dihydro-indol-2-one prepared in example 145a (0.20 g, 0.71 mmol) in dichloromethane (3 mL) at 0° C. was added ethyl chloroformate (0.10 mL, 1.1 mmol), followed by the addition of triethylamine (0.14 g, 1.4 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. The mixture was then poured into aqueous HCl solution (1 N). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, and concentrated to give E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid. The crude product was purified by chromatography to obtain 75 mg yellow solid (Yield 1.7 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:42]/[O:43]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2/[C:25](=[O:41])[N:26]([C@@H:29]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[CH2:27][CH2:28]/2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:42]/[OH:43])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15](/[CH:23]=[C:24]2/[C:25](=[O:41])[N:26]([C@@H:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)[CH2:27][CH2:28]/2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN([C@@H]5CCNC5)C4=O)CS[C@H]23)ns1
Yield: 97.3 %

Procedure:
5.2 (large scale): A suspension of 5.785 g of (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-[(E)-(R)-1′-tert.-butoxycarbonyl-2-oxo-[1,3′]bipyrrolidinyl-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1.69 ml of triethylsilane in 25 ml of dichloromethane was treated at −15° with 7.21 ml of trifluoroacetic acid and the solution was heated to 30° for 30 min after which time HPLC indicated completion of the reaction. The mixture was evaporated to dryness, the residue was digested with 60 ml of ethyl acetate, the suspension was filtered and the residue dried to give 3.43 g of the crude title compound as a brown solid, containing about 1.4 equivalents of ethylacetate. 1H-NMR (d6-DMSO): 13.9 (s, br., 1H, COOH); 11.94 (s, 1H, OH); 9.50 (d, J=8.4, 1H, NH—C(7)); 8.96 (s, br., 2H, NH2); 8.07 (s, br., 2H, NH2); 7.26 (s, br., 1H, CH—C(3)); 5.88 (dd, J=8.4 and 4.9, 1H, H—C(7)); 5.18 (d, J=4.9, 1H, H—C(6)); 4.64 (m, 1H); 3.87 (s, br., 2H H2C(4)); 3.9-2.7 (m, 8H); 2.2-2.0 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.N1C=CC=CC=1[N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[SH:38].O>C(O)(C)C>[CH3:9][C:8]1[C:3]([CH:2]([S:38][C:34]2[NH:35][CH:36]=[CH:37][N:33]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: Sc1nccn1-c1ccccn1
Solvent: CC(C)O
Solvent: O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1C(Sc1ncc[nH]1)c1ccccn1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
2.3 g (5.6 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine and 1.0 g (5.6 mmol) of 1-pyridin-2-yl-1H-imidazole-2-thiol in 100 ml of isopropanol are heated under reflux for 2 h under a nitrogen atmosphere. The mixture is then cooled to room temperature, treated with 1 l of water and extracted with 4×200 ml of ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia=19:1:0.6). The fractions of Rf =0.35 are concentrated and crystallized from methanol. 0.45 g of the title compound is isolated as a pale beige solid. M.p. 146-149° C.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC(C)C)(=O)C.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH2:35][CH2:36][C:37](=O)[C:38]#[C:39][Si](C)(C)C)[C:31]([O:33]C)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].FC(F)(F)C(O)=O>>[C:22]([O:26][C:27]([N:29]1[C@@H:37]([C:38]#[C:39][CH3:1])[CH2:36][CH2:35][C@H:30]1[C:31]([OH:33])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@H](CCC(=O)C#C[Si](C)(C)C)NC(=O)OC(C)(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: CC#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Temperature: -10 °C

Procedure:
A 2-L, 3-neck jacketed round-bottomed flask equipped with an overhead mechanical stirrer, N2-inlet, temperature probe and addition funnel was charged with sodium triacetoxyborohydride (93.0 g, 0.44 mol), isopropyl acetate (100 g) and an isopropyl acetate solution obtained from Example 1 (27.8 wt %, 410 g, 0.33 mol). The resulting mixture was chilled to −10° C. (internal temperature). Trifluoroacetic acid (170 g, 1.5 mol) was added dropwise by addition funnel over a 2-hour period. The internal temperature was adjusted to 10° C. and the mixture was stirred until HPLC analysis indicated complete consumption of starting material (about 15 hours). The reaction was poured into 750 g of 25% K2HPO4 (prepared by dissolving 250 g of K2HPO4 in 750 g of water). The pH of the mixture was adjusted to 6.6 using 20% KOH (prepared by dissolving 100 g of KOH in 400 g of water). The layers were separated. The organic layer was washed with 25% K2HPO4 (250 g) and with water (250 g). The organic layer was distilled to remove isopropyl acetate, which was chased with ethanol to a final volume of about 250 mL. The solution was cooled to 0° C. and 3.5 M LiOH solution (prepared by dissolving 37 g of LiOH—H2O in 250 g of water) was added such that the temperature remained below 20° C. The reaction progress was followed by HPLC until no ester remained (typically about 2 hours). The ethanol was removed by distillation under vacuum and the resulting aqueous layer was extracted with methyl tert-butyl ether (190 g). The methyl tert-butyl ether layer was extracted with water (100 g) and discarded. The combined aqueous layers was cooled to 0° C. and neutralized to pH 7 with concentrated HCl. Isopropyl acetate (220 g) was added and the pH was adjusted to 3 with concentrated HCl. The layers were separated and the aqueous layer was extracted with isopropyl acetate (220 g). The combined organic layers were washed with water (100 g). The organic solution was distilled under vacuum to a total volume of about 180 mL, and cooled to 0° C. Crystals formed over a 30-minute period. Heptanes (50 g) was added dropwise over a 2-hour period and the resulting mixture was stirred for 2 hours at 0° C. The mixture was filtered and the solid was washed with cold 1:1 isopropyl acetate/heptanes (50 mL) and dried under vacuum to afford the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.24 (s, 9H) 1.45 (s, 9H) 1.87-2.04 (m, 1H) 2.11-2.28 (m, 1H) 2.57-2.81 (m, 2H) 3.75 (s, 3H) 4.23-4.40 (m, 1H) 4.99-5.14 (m, 1H).
Reaction SMILES: C(O[C:6]([C:8]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=1>>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:6]([C:8]2[CH:18]=[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:29]1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(CO)C2
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)c3c(c2)OC(CO)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-benzyloxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (204a) and 3-amino-1-methyl-pyrazole to give a white solid. 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1 H) 7.33-7.45 (m, 5 H) 7.30 (d, J=2.27 Hz, 1 H) 7.09 (d, J=1.26 Hz, 1 H) 6.89 (d, J=1.01 Hz, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.12 (s, 2 H) 4.95-5.03 (m, 1 H) 3.81 (s, 3 H) 3.73-3.79 (m, 1 H) 3.27 (dd, J=16.17, 9.60 Hz, 1 H) 3.03 (dd, J=16.29, 7.20 Hz, 1 H) 2.13 (t, J=6.44 Hz, 1 H); LCMS for C21H21N3O4 m/z 380.00 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1[nH]c(=O)c(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cl)cc(Br)c(=O)n1Cc1ccc(OC)cc1

Procedure:
A solution of ethyl 5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (3.0 g, 10.7 mmol), 4-methoxybenzyl chloride (4.19, 26.74 mmol) and potassium carbonate (4.43 g, 32.09 mmol) in dimethylformamide (40 ml) was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (3×30 mL). The organic layer was again washed with brine, separated, dried over Sodium sulfate, filtered and concentrated under reduced pressure. The residue was finally purified by flash column chromatography to afford ethyl 5-bromo-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate (2) as off white solid. Yield: 1.2 g, 28%; MS (ESI) m/z 399.99 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 7.11 (d, J=8.64 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 5.11 (s, 2H), 4.27 (q, J=7.12 Hz, 2H), 3.72 (s, 3H), 1.13 (t, J=7.12 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:25])[C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:26](OC(=N)C(Cl)(Cl)Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.C(S(O)(=O)=O)(F)(F)F.[Cl-].[Na+].O>[CH2:26]([O:25][CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:18]([CH3:23])([CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(OCc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 14.7 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2-dimethylpropanoate (282 mg, 0.82 mmol) was dissolved in 10 mL DCM and benzyl-2,2,2-trichloroacetimidate (0.185 mL, 1.0 mmol) was added followed by 3 drops of CF3SO3H. The reaction was stirred for 2 h. Reaction was incomplete so added more benzyl-2,2,2-trichloroacetimidate (0.185 mL, 1.0 mmol). After 12 h, diluted with brine and extracted with DCM×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with EtOAc/hexane gradient. Obtained 52 mg (15% yield) of methyl 3-(benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoate. MS found: (M+H)+=433.
Reaction SMILES: [C:1](/[C:4](=[CH:7]/N(C)C)/[C:5]#[N:6])(=O)[CH3:2].[C:11]([O:15][C:16]([NH:18][C:19]([NH2:21])=[NH:20])=[O:17])([CH3:14])([CH3:13])[CH3:12].CC1CCCO1>>[C:11]([O:15][C:16](=[O:17])[NH:18][C:19]1[N:21]=[C:1]([CH3:2])[C:4]([C:5]#[N:6])=[CH:7][N:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: CC(=O)/C(C#N)=C/N(C)C
Solvent: CC1CCCO1
Product: Cc1nc(NC(=O)OC(C)(C)C)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 250 ml 3-neck flask was equipped with an overhead stirrer, thermocouple, reflux condenser and heating mantle. The flask was charged with (E)-2-acetyl-3-dimethylamino-acrylonitrile (8.93 g, 63.34 mmol), N-tert-butyloxycarbonyl-guanidine (10 g, 61.56 mmol) and 2-methyltetrahydrofuran (98.76 g). The resultant suspension was stirred and heated to reflux, whereupon the solids were observed to dissolve. The resultant mixture was stirred for about 6 hours, then concentrated by rotary evaporation to yield a solid which was triturated with water (120.00 g) to complete precipitation of the desired product. The resultant suspension was stirred for ˜30 minutes at ambient temperature, then filtered and the wet solid washed twice with water (120.00 g) and dried in a vacuum oven at 75-80° C. under a N2 bleed overnight to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH2:24](O)[CH2:25][CH2:26][CH3:27].C1CCN2C(=NCCC2)CC1>COCCOC>[CH2:24]([O:8][C:6]1[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCO
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCOc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester, butanol and DBU in DME. EI-MS m/e (%): 278 (M+, 24), 249 ([M—C2H5]+, 28), 193 (70), 177 (100), 150 (48), 108 (86), 94 (62), 70 (48), 69 (46), 43 (68), 41 (62), 29 (45).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[C:7]([CH3:9])[N:8]=1.F[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].O>CN(C)C=O>[CH3:3][C:4]1[N:5]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: N#Cc1ccccc1F
Reactant: Cc1c[nH]c(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2ccccc2C#N)c(C)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Sodium hydride (8.65 grams 60%, 0.216 mol) was stirred in 75 mL of anhydrous dimethylformamide. To this was added dropwise a solution of 2,4-dimethylimidazole (20.75 grams, 0.216 mol) in 100 mL of DMF. After stirring at ambient temperature for 1 hour a solution of 2-fluorobenzonitrile (23.0 mL, 0.216 mol) in 75 mL of DMF was added dropwise. This was stirred at 50° C. for 2 hours and then at ambient temperature for 16 hours. The mixture was then poured into water and the product extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The crude product was chromatographed (silica gel) and eluted with 19:1 dichloromethane-methanol then 9:1 dichloromethane-methanol to afford the product as a solid. LCMS data confirmed structure.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:34])/[C:6](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:7]/[C:8]1[S:9][CH:10]=[CH:11][N:12]=1>O1CCCC1.CO>[Br:32][C:16]1[CH:17]=[C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])[CH:19]=[CH:20][C:15]=1[C:14]([NH:13]/[C:6](=[CH:7]\[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)/[C:5]([OH:34])=[O:4])=[O:33]
Reactant: COC(=O)/C(=C/c1nccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C(=C/c1nccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
A solution of 1N sodium hydroxide (0.16 mL, 0.16 mmol) was added to a solution of (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(thiazol-2-yl)propenoic acid methyl ester (Example 153; 39.3 mg, 0.076 mmol) in tetrahydrofuran/methanol (2:1; 0.25 mL). After the solution had been allowed to stir at room temperature for 16 h, a second portion of 1N sodium hydroxide solution (0.05 mL) was added and the reaction was allowed to proceed for another 24 h at ambient temperature. The solvent was evaporated using a rotary evaporator then high vacuum. The de-esterification had not gone to completion, so the residue was re-dissolved in tetrahydrofuran/methanol (2:1; 0.25 mL) and treated with a solution of 1N sodium hydroxide (0.16 mL, 0.16 mmol). The reaction mixture was stirred for 16 h and after the solvents were removed in vacuo, the residue was purified by HPLC to give (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(thiazol-2-yl)propenoic acid (14.8 mg, 39%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC(Cl)=CC=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccc(Cl)cc1)c1cc(Br)ccc1OCc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (164 mg, 6.86 mmol) in water (20.00 mL) was added dropwise to a stirred solution of (4-chlorophenyl)methyl 5-bromo-2-{[(4-chlorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 15; 320 mg, 0.69 mmol) in THF (20 ml) over 5 min. The reaction mixture was then stirred at 20° C. for 16 h. The organic phase was evaporated and the residual aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml) and was extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to give the title compound as a light yellow solid. 180 mg.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][N:11]([CH2:29][C:30]#[CH:31])[S:12]([C:15]1[CH:24]=[CH:23][C:22]2[NH:21][C:20](=[O:25])[C:19]3[NH:26][CH:27]=[CH:28][C:18]=3[C:17]=2[CH:16]=1)(=[O:14])=[O:13])=O)(C)(C)C.[CH2:33]([C:36]([O-:38])=[O:37])[CH2:34][CH3:35].[ClH:39]>C(OCC)C>[CH3:6][NH:8][CH2:9][CH2:10][N:11]([CH2:29][C:30]#[CH:31])[S:12]([C:15]1[CH:24]=[CH:23][C:22]2[NH:21][C:20](=[O:25])[C:19]3[NH:26][CH:27]=[CH:28][C:18]=3[C:17]=2[CH:16]=1)(=[O:14])=[O:13].[ClH:39].[CH2:33]([C:36]([OH:38])=[O:37])[CH2:34][CH3:35]
Reactant: CCCC(=O)[O-]
Reactant: C#CCN(CCN(C)C(=O)OC(C)(C)C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: Cl
Solvent: CCOCC
Product: C#CCN(CCNC)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Product: CCCC(=O)O

Procedure:
This compound is prepared according to synthesis 139, from 54 mg (0.1 mmol) of 8-{[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-prop-2-ynyl-sulfamoyl}-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate and 2.5 mL (5 mmol) of a 2M solution of hydrochloric acid in diethyl ether to give, after filtration, 42 mg (87%) of 8-[(2-methylamino-ethyl)-prop-2-ynyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate hydrochloride in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23]C(C2CC(=C)C2)=O)[C:16]2[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:32]([O:39]C1C=C(C(N)C2C(Cl)=NC=CN=2)C=CC=1)[C:33]1[CH:38]=[CH:37][CH:36]=C[CH:34]=1.CC[N:57](C(C)C)C(C)C.C=C1CC(C(O)=O)C1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(OCC)(=O)C>[NH2:57][C:21]1[C:16]2[N:17]([C:36]([CH:37]3[CH2:34][CH:33]([CH2:32][OH:39])[CH2:38]3)=[N:23][C:15]=2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[CH:18]=[CH:19][N:20]=1
Reactant: C=C1CC(C(=O)NC(c2cccc(OCc3ccccc3)c2)c2nccnc2Cl)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Agent: C=C1CC(C(=O)O)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Nc1nccn2c(C3CC(CO)C3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylenecyclobutanecarboxylic acid [(3-benzyloxyphenyl)-(3-chloropyrazin-2-yl)methyl]amide: To a suspension of C-(3-benzyloxyphenyl)-C-(3-chloropyrazin-2-yl)methylamine hydrochloride (724 mg, 2.0 mol) in methylene dichloride (10 mL) was added iPr2NEt (1.7 mL, 10.0 mmol), at which time the solid dissolved. The reaction was charged with 3-methylenecyclobutanecarboxylic acid (560 mg, 5.0 mmol), EDC (1.15 g, 6.0 mmol) and HOBt (270 mg, 2.0 mmol) and the resulting mixture was stirred at rt overnight. The mixture was diluted with ethyl acetate (50 mL), washed with sat. aq. NaHCO3 (2×20 mL) and brine (2×20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with hexanes:EtOAc=80:20→60:40), yielding the title product as a light-yellow viscous oil; MS (ES, Pos.): m/z 420/422 (3/1) [MH+]; 1H NMR (CDCl3, 400 MHz) δ 2.85-3.09 (m, 5H), 4.78 (m, 2H), 5.03 (s, 2H), 6.55 (d, J=7.9 Hz, 1H), 6.87-6.95 (m, 3H), 7.08 (br d, 1H, NH), 7.21-7.41 (m, 6H), 8.33 (d, J=2.5 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH2:39][C:40]1[O:41][C:42]([CH3:46])=[C:43]([CH3:45])[CH:44]=1>CN(C)C=O.C(Cl)Cl>[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH2:39][C:40]1[O:41][C:42]([CH3:46])=[C:43]([CH3:45])[C:44]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: Cc1cc(Cc2ccc3ccccc3c2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc4ccccc4c3)oc(C)c2C)cc1C(C)C
Yield: 19.9 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (0.93 g, 3.95 mmol, RN-117439-59-5), oxalyl chloride (0.377 mL, 4.33 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.507 mL, 4.33 mmol) and 2-naphthalen-2-ylmethyl-4,5-dimethylfuran (0.93 g, 3.94 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2 & 4% EtOAc/pet ether step gradient gave 0.357 g (20%) of the title compound. 1H NMR (DMSO-d6) δ1.14 (d, 12H), 1.82 (s, 3H), 2.20 (s, 3H), 3.27 (septet, 2H), 3.74 (s, 3H), 4.02 (s, 2H), 7.19 (dd, 1H), 7.45-7.52 (m, 5H), 7.76-7.79 (m, 3H).