Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11](N)[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].C(N1C2C(=CC(C3C=CC(S(C)(=O)=O)=CC=3)=C([Br:43])C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11]([Br:43])[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(Br)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2cc(Br)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
Isopropyl (S)-4-acetyl-6-bromo-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-6-bromo-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 238). MS (ESI, pos. ion) m/z 461, 463 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][SH:9].[CH3:10][O:11][C:12](=[O:44])[C:13](=[N:32]OS(C1C=CC(C)=CC=1)(=O)=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:28][N:29]=[CH:30][CH3:31])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12](=[O:44])[C:13](=[N:32][S:9][CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:28][N:29]=[CH:30][CH3:31])[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1
Reactant: CC=NOC(c1ccc(Cl)cc1)c1ccccc1C(=NOS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Reactant: CS
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC=NOC(c1ccc(Cl)cc1)c1ccccc1C(=NSC)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2 ml triethylamine in 15 ml chloroform saturated with methanethiol are added 5.15 g (10 mmol) 2-{2-[1-(4-chloro-phenyl)-ethylideneaminooxymethyl]-phenyl}-tosyloxyimino-acetic acid methyl ester. The mixture was stirred at room temperature for 48 hours. After evaporation the residue is purified by silicagel chromatography (ethyl acetate 1, hexanes 5) to give—after elution of 2-[1-(4-chloro-phenyl)-ethylideneaminooxymethyl]-benzonitrile as by-product—1.0 g (28%) of the 2-{2-[1-(4-chloro-phenyl)-ethylideneamino-oxymethyl]-phenyl}-methylthioimino-acetic acid methyl ester. Melting point of 112-113° C.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([Sn:7](Cl)(Cl)[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].[Cl].[Cl].[Cl].C([Sn])CCC>C1(C)C=CC=CC=1>[CH2:3]([Sn:7](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6]
Reactant: [OH-]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: CCCC[Sn]
Agent: [Cl]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCC[Sn](=O)CCCC
Temperature: 75 °C
Yield: 97 %

Procedure:
The same apparatus as used in Example 1 was employed. To the flask were continuously fed 1,300 g of 16% aqueous sodium hydroxide solution and 5,504 g of a toluene solution which had been prepared by dissolving, in 3,592 g of toluene, 1,912 g of di-n-butyltin dichloride containing 1.5% tri-n-butyltin chloride and 1.0% mono-n-butyltin trichlorine. The above feeding was performed with stirring and heating at 75° C., to conduct hydrolysis for 60 minutes. The resulting reaction mixture overflowed was allowed to stand, thereby splitting into three distinct phases. The specific gravities of the upper, intermediate and lower phases were 00.6, 1.1 and 1.2, respectively. These three phases were separated from one another and then subjected to the same treatments as in Example 4. As a result, the lower phase gave 1,520 g of di-n-butyltin oxide having a purity of 99.8% and an average particle diameter of 80 μm; the intermediate phase gave 2.6 g of mono-n-butyltin oxide having a purity of 95.9%; and the upper phase gave 5.9 g of bis(tri-n-butyltin) oxide having a purity of 95.6%. The total yield based on the starting material was 99.2%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[OH:18])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:9])[N:6]=1.Br[CH:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:17]/[O:18][CH:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:28])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])=[O:9])[N:6]=1
Reactant: CS(=O)(=O)CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(O/N=C(\C(=O)OCCS(C)(=O)=O)c1csc(N)n1)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 75.4 %

Procedure:
In 100 ml of acetone was suspended 5 g (0.017 mole) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate and 5.33 g (0.0255 mole) of t-butyl 2-bromopropionate was added. After a serial addition of 0.3 ml of water and 9.4 g of anhydrous potassium carbonate, the mixture was stirred at 40° C. for about 2.5 hours. After completion of the reaction, the insoluble matter was filtered off. To the filtrate was added 100 ml of water and the mixture was extracted with 150 ml of ethyl acetate. The organic layer was washed with 50 ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated to dryness under reduced pressure. The concentrate was crystallized from ethyl acetate-isopropyl ether (1:5, v/v). After cooling to 0° C. or below, the crystalline precipitate was collected by filtration and dried under reduced pressrue to give 5.4 g (yield, 75.4%) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxyimino)acetate as white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[C:9](=[N:15]O)[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C.S(=O)(=O)(O)O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH2:15])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(=NO)C2=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2c(c1)CC(N)C2
Yield: 34.4 %

Procedure:
5-tert-Butyl-indan-1,2-dione 2-oxime (11.67 g) was hydrogenated over 10% palladium on carbon catalyst (2.95 g) using a mixture of 233 ml acetic acid and 15.6 ml concentrated sulfuric acid as solvent. The reaction was run at ambient temperature for 17 hours, under 60 psi hydrogen. After removal of catalyst by filtration, the filtrate was quenched by dropwise addition of 30 ml conc. ammonium hydroxide. The quenched mixture was then extracted with ethyl ether, the organic extracts dried with magnesium sulfate, and the solvent removed under vacuum to give 3.50 g of the product which was used without further purification. 1H NMR (300 MHz, CDCl3) 7.17 (m, 3H), 3.84 (m, 1H), 3.14 (m, 2H), 2.67 (m, 2H), 1.31 (s, 9H). MS (CSI) m/e 190 (M+H)+.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].O>CCCCCC>[C:2]1([CH:1]([OH:8])[C:10]([F:12])([F:11])[F:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: OC(c1ccccc1)C(F)(F)F
Temperature: 80 °C
Yield: 88 %

Procedure:
Benzaldehyde was reacted with trifluoromethyltrimethylsilane as in Example 10. After a reaction time of 5 hours, 20 ml of water were added, and the reaction mixture was heated briefly to 80° C. 50 ml of hexane were then added. The reaction mixture was then extracted twice with 100 ml of water, and the resultant organic phase was dried over Na2SO4. On distillation of the crude product, 15.4 g (88% yield) of 1-phenyl-2,2,2-trifluoroethanol (boiling point 68°-69° C./6 mbar) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([O:19][CH3:20])[C:15]([NH:17][NH2:18])=[O:16])=[C:4]([CH3:23])[CH:3]=1.[CH:24]([O-])([O-])OCC.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([C:15]2[O:16][CH:24]=[N:18][N:17]=2)[O:19][CH3:20])=[C:4]([CH3:23])[CH:3]=1
Reactant: CCOC([O-])[O-]
Reactant: COC(C(=O)NN)c1ccccc1COc1ccc(Cl)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(c1nnco1)c1ccccc1COc1ccc(Cl)cc1C
Yield: 13.5 %

Procedure:
To 0.50 g (1.5 mmol) of 2-(4-chloro-2-methylphenoxymethyl)phenyl-2-methoxyacetic acid hydrazide was added 1.5 ml of ethyl orthoformate, stirred under reflux for 3 hours, and thereafter concentrated under reduced pressure. To the residue thus obtained, 4.5 ml of benzene and 0.03 g (0.15 mmol) of p-toluenesulfonic acid monohydrate were added and stirred under reflux for an hour. After completion of the reaction, 100 ml of water was added and extracted twice with 50 ml of dichloromethane. The dichloromethane layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-[2-(4-chloro-2-methylphenoxymethyl)-α-methoxybenzyl]-1,3,4-oxadiazole (0.07 g, 13.5%) as colorless crystals. mp. 68-70° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>CN(C=O)C>[Cl:25][CH2:26][CH2:27][CH2:28][S:29]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:31])=[O:30]
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 38a. Thus, 3-(4-piperidinyl)-5-(2-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 17) (25 mg, 0.076 mmol) was reacted with 3-chloropropane sulfonyl chloride (30 uL, 0.242 mmol) in DMF (4 mL) to give 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indazole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:18])[CH:16]=[CH2:17])[CH:12]=[CH:13][CH:14]=1.Br[C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Li+].[Cl-].[Li]OC(C)=O.O.O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:18])[CH2:16][CH2:17][C:27]2[CH:28]=[CH:29][CH:30]=[CH:20][C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=CC(O)c1cccc(COC2CCCCO2)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]OC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccccc1CCC(=O)c1cccc(COC2CCCCO2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
The allylic alcohol of Step 11 (24.8 g, 100 mmol) and ethyl 2-bromobenzoate (25.2 g, 110 mmol) were dissolved in DMF (200 mL). LiCl (4.2 g, 100 mmol), LiOAc.2H2O(25.5 g, 250 mmol) and n-BU4N+Cl-(55 g, 200 mmol) were added and the resulting mixture was degassed three times. Pd(OAc)2 (1 g) was then added and the mixture was degassed three more times before heating it at 100° C. with stirring for 1 hr. After cooling to r.t., the reaction mixture was poured onto H2O(600 mL), 10% aq. NaHCO3 (200 mL) and Et2O. The crude product was extracted with Et2O(2×), washed with H2O and brine, and dried over Na2SO4 before concentrating in vacuo. Purification on a short silica gel column (20% EtOAc in hexanes) gave 34 g (86%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.C[O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17]>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:22]=[CH:23][C:18]([C:16]([OH:17])=[O:15])=[CH:19][CH:20]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1

Procedure:
Followed Scheme 2, A conditions: Starting materials: 2-chloro-6-methoxyquinoline (Intermediate 1) (100 mg, 0.52 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid. 1H NMR (DMSO-d6, 400 MHz): δ 13.06-12.90 (bs, 1H), 10.14 (s, 1H), 8.36-8.33 (d, 2H), 8.30-8.27 (d, 1H), 8.11-8.06 (m, 3H), 7.97-7.94 (d, 1H), 7.38-7.34 (dd, 1H), 7.20 (s, 1H). MS (ESI): m/z 266.08 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:6][CH2:5]2.C(N(CC)CC)C.[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][BH:31][O:30]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][C:29]1([CH3:36])[C:33]([CH3:35])([CH3:34])[O:32][B:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][C@@H:7]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:6][CH2:5]3)[O:30]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2cc(I)ccc2O1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc3c(c2)CC[C@H](CO[Si](C)(C)C(C)(C)C)O3)OC1(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Argon was bubbled through a solution of tert-butyl(dimethyl)silyl [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl ether (Example 59, 11.1 mmol, 1.0 eq.) in dioxane (45 mL) for 10 minutes before Pd(dppf)Cl2 (0.306 mmol, 0.03 eq.), triethylamine (33.4 mmol, 3.0 eq.), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.8 mmol, 1.6 eq.) were added. The resulting reaction mixture was stirred at 80° C. overnight. The resulting reaction mixture was filtered through a Celite pad. The filtrate was concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=10:1). The product was obtained as a pale brown waxy solid in 94% yield. MH+=405.3, retention time (LC-MS) =4.79 min.
Reaction SMILES: I.[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[NH:8][C:9](SC)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CCOCC>CC(O)(C)C>[CH3:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[NH:8][C:9]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CSC(=Nc1ccccc1)Nc1nccn1C
Reactant: C1COCCN1
Agent: I
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: Cn1ccnc1NC(=Nc1ccccc1)N1CCOCC1

Procedure:
A solution of 1.5 g (0.004 mole) of methyl N-(1-methylimidazol-2-yl)-N'-phenylcarbamimidothioate hydroiodide and 0.73 g (0.0084 mole) of morpholine in 30 ml of t-BuOH is refluxed overnight. Upon cooling, ether is added and morpholine hydroiodide is removed by filtration. The filtrate is taken to dryness and the residue is taken up in CH2Cl2 and converted to the free base with 3 N NaOH. The organic layer is separated, dried over K2CO3, filtered and the solvent is removed in vacuo to give a residue of N-(1-methylimidazol-2-yl)-N'-phenyl-4-morpholine carboximidamide, which is taken up in acetone and converted to the hydrochloride salt with ethereal HCl.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:42])[C@@H:13]([NH:24]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(S)CCCCCCC.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:42])[C@@H:13]([NH2:24])[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCNC(=O)OC(C)(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: CCCCCCCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCNC(=O)OC(C)(C)C)CC1

Procedure:
A solution of 1.71 g 4-[(S)-4-tert-butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 30 ml THF was stirred in the presence of 8.9 ml 1-octanethiol and 101 μl DBU. After 12 h the mixture was concentrated, the residue dissolved in dichloromethane and extracted with 0.1 M HCl. The aqueous phase was brought to pH 9 by adding aqueous NaHCO3 before being extracted with dichloromethane. The product was obtained after evaporation of the solvent and was used in the subsequent reaction. Yield: 2.27 g colorless foam.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH2:8]1[O:11][CH:9]1[CH3:10]>C(O)(C)C>[OH:11][CH:9]([CH3:8])[CH2:10][S:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH:9]([OH:11])[CH3:10])=[N:5][N:6]=1
Reactant: Sc1nnc(S)s1
Reactant: CC1CO1
Solvent: CC(C)O
Product: CC(O)CSc1nnc(SCC(C)O)s1

Procedure:
2,5-Dimercapto-1,3,4-thiadiazole(276.21 grams, 1.84 moles) and isopropanol (400 ml) were charged into a reaction flask. Propylene oxide(222.8 grams, 3.84 moles) was added at a rate sufficient to maintain reflux condition. The mixture was refluxed for 15 minutes. The solvent was stripped off by using a rotary evaporator at approximately 20 mm Hg and 100° C. The product is characterized by infrared absorption bands at 3350, 2900, 1680, 1450, 1380, 1250, 1120, 1040, 930, 740, and 705 cm-1.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[C:17](=[O:25])[C:16]([C:26]([OH:28])=[O:27])=[CH:15]1>N1C=CC=CC=1>[CH:1]([O:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[C:17](=[O:25])[C:16]([C:26]([OH:28])=[O:27])=[CH:15]1)=[O:2]
Reactant: O=CO
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(CCO)c2n1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Temperature: 25 °C

Procedure:
Formic acid (1.1 ml) was added to acetic anhydride (2.2 ml) which was cooled to 0°-5°. The mixture was heated at 50° for 15 minutes, cooled to 0° and added to 1,4-dihydro-1(2-hydroxyethyl)-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.5 g) in pyridine (12 ml), also cooled to 0°. The mixture warmed to room temperature and after 1 hour the solid was collected, washed with pyridine and dried, m.p. 213°-214° (85 %).
Reaction SMILES: C(O)(=O)C.CO[CH:7]1[CH2:11][CH2:10][CH:9](OC)O1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:36]=[CH:37][CH:38]=1)[C:18]([NH:20][C:21]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])=[O:19].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:30]1([C:28]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[C:21]([NH:20][C:18](=[O:19])[C:17]3[CH:36]=[CH:37][CH:38]=[C:15]([N:14]4[CH:7]=[CH:11][CH:10]=[CH:9]4)[CH:16]=3)[CH:29]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1
Reactant: COC1CCC(OC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cccc(-n2cccc2)c1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
0.25 mL of acetic acid and 4.3 μL of 2,5-dimethoxytetrahydrofuran were added sequentially to 10 mg of 2-(3-aminobenzamido)-4-phenylbenzoic acid at room temperature and stirred at 90° C. for 5 minutes. Ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure to obtain 8.3 mg of 4-phenyl-2-(3-(1H-pyrrol-1-yl)benzamido) benzoic acid as brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:44]1([S:47]([NH2:50])(=[O:49])=[O:48])[CH2:46][CH2:45]1>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:50][S:47]([CH:44]3[CH2:46][CH2:45]3)(=[O:49])=[O:48])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Reactant: NS(=O)(=O)C1CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 52.7 %

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid etherate (100 mg, 0.15 mmol) and cyclopropylsulfonamide (24 mg, 0.20 mmol) as described in the general procedure above. Flash chromatography (2% methanol/methylene chloride) gave 55 mg (53%) of [4-cyclopropanesulfonylaminocarbonyl-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo-[14.3.0.04,6]-nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: 1H NMR (500 MHz, CD3Cl3) δ 0.89–0.95 (m, 1H), 1.03–1.16 (m, 3H), 1.22 (s, 9H), 1.18–1.48 (m, 8H), 1.78 (m, 1H), 1.87 (m, 1H), 1.94 (m, 1H), 2.29 (q, J=9.0 Hz, 1H), 2.56 (m, 1H), 2.67 (dd, J=7.9 Hz, 2.7 Hz, 2H), 2.90 (m, 1H), 4.04 (dd, J=11.3 Hz, 4.0 Hz, 1H), 4.29 (m, 1H), 4.61 (m, 2H), 4.97–5.03 (m, 2H), 5.70 (m, 1H), 5.94 (s, 1H), 6.67 (s, 1H), 7.25 (m, 1H), 7.47 (t, J=7.3 Hz, 1H), 7.64 (t, J=7.3 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.97 (d, J=5.8 Hz, 1H), 8.17 (d, J=8.5 Hz, 1H), 10.20 (s, 1H). LC-MS (Method A, retention time: 3.67 min), MS m/z 696 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[F:38]>CN(C=O)C.CC#N>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=3[F:38])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Yield: 40.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 7-Benzyloxy-6-methoxy-1H-quinolin-4-one (12.2 g, 43.3 mmol, 1.0 eq.), acetonitrile (150 ml), DMF (150 ml) and cesium carbonate (28.2 g, 86.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 1,2-difluoro-4-nitro-benzene (7.57 g, 47.6 mmol, 1.1 eq) was added over a 10 minute period. After 2 hours the reaction was complete at which time 75% of the MeCN and DMF was removed and the resulting solution was poured over into ice water. The solid was filtered and dried and further columned with a biotage system. The eluent was 1:3 ethyl acetate/hexane. Removal of the solvent afforded 7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline as a pale green solid (7.4 g, 41% yield). 1H NMR (400 MHz, CDCl3): 8.53 (d, 1H), 8.42 (dd, 1H), 8.16 (m, 1H), 7.5 (m, 8H), 6.76 (d, 1H), 5.31 (s, 2H), 3.92 (s, 3H); MS (EI) for C23H27FN2O5: 421 (MH+).