Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:16]=[CH:17]\[CH2:18]Cl)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:38].[Na+]>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:16]=[CH:17]/[CH2:18][I:38])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of diphenylmethyl 7-t-butoxycarbonylamino-3- [(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate (IIIa) (541 mg, 1 mmol) and sodium iodide (450 mg, 3 mmol) in acetone (5.4 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml), washed with aqueous sodium thiosulfate and water successively, dried with MgSO4 and concentrated to yield 632 mg of the title product.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrC1CCCC1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCCC1
Yield: 70.6 %

Procedure:
To a solution of 4.6 g (0.2 mol) sodium in 80 mL absolute ethanol was added 30.4 mL (0.2 mol) diethyl malonate. After briefly stirring, 21.4 mL (0.2 mol) cyclopentyl bromide was added, and the resulting solution refluxed for 12 hrs. Most of the ethanol was then removed by rotary evaporation, and the reaction was quenched with 250 mL of water and extracted 3×, each with 100 mL ether. The extracts were dried over MgSO4, filtered, and concentrated. Distillation through a 6" Vigreaux at 6 mm Hg provided 32.232 g of a clear colorless oil at bp 122-125 C.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH:3]=[C:4]([C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=1)[C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1>O1CCCC1.CO.[Pd]>[CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=1)[C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C(CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.8 %

Procedure:
A solution of 2-(3-methyl-1-m-tolylbut-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.30 g, 4.70 mmol) in tetrahydrofuran (20 mL) and methanol (40 mL) was treated with 10% palladium on carbon (260 mg). The reaction was stirred at 25° C. under hydrogen atmosphere for 2 d. The reaction mixture was filtered and washed with tetrahydrofuran (2×15 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 11% ethyl acetate/petroleum ether) afforded 2-(3-methyl-1-m-tolylbutyl)-1H-pyrrolo[2,3-b]pyridine (1.07 g, 81.3%) as light oil: 1H NMR (300 MHz, d6-DMSO): δ ppm 11.54 (s, 1H), 8.09 (d, 1H, J=3.6 Hz), 7.80 (d, 1H, J=7.5 Hz), 7.19-7.16 (m, 3H), 6.98-6.94 (m, 2H), 6.26 (d, 1H, J=1.5 Hz), 4.13 (t, 1H, J=8.1 Hz), 2.27 (s, 3H), 2.09-2.05 (m, 1H), 1.86-1.81 (m, 1H), 1.41-1.36 (m, 1H), 0.90 (s, 3H), 0.89 (s, 3H.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3]([N:5]=[C:6]=[S:7])=[O:4].[NH3:9]>C(Cl)Cl>[CH3:1][N:2]([CH3:8])[C:3]([NH:5][C:6]([NH2:9])=[S:7])=[O:4]
Reactant: N
Reactant: CN(C)C(=O)N=C=S
Solvent: ClCCl
Product: CN(C)C(=O)NC(N)=S
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 65 parts of dimethylcarbamoylisothiocyanate (a compound of formula VI) in 350 parts methylene chloride are added within 10 minutes at 0° C, 50 parts of conc. aqueous ammonia with good agitation. The resulting slurry of crystals is stirred for an additional 15 minutes at 0° C and then filtered to give 70 parts of 1,1-dimethyl-4-thiobiuret (a compound of formula VII), m.p. 184°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][O:10][CH:11]([C:17]([O-])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[CH:11]([O:10][CH3:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(OC)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(OC)C(=O)Nc1cccc(Cl)c1
Yield: 30 %

Procedure:
3-Chloroaniline (2.82 grams, 0.02 mole), monoethyl methoxymalonate (3.58 grams, 0.02 mole), prepared in Example LIII Part B, and 1,3-dicyclohexylcarbodiimide (4.50 grams, 0.02 mole) were reacted in a manner similar to that described in Example LVII to give 1.60 grams (0.006 mole) of ethyl 3-[(3-chlorophenyl)amino]-2-methoxy-3-oxopropanoate having melting point of 43.5° C.-46.5° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=1[S:48](Cl)(=[O:50])=[O:49].[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[Cl:37][C:38]1[CH:43]=[C:42]([C:44]([F:46])([F:45])[F:47])[CH:41]=[CH:40][C:39]=1[S:48]([N:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:14][CH:13]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:19][CH:18]=1)(=[O:50])=[O:49]
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1Cl)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.060 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 2-chloro-4-trifluoromethyl benzenesulfonyl chloride (0.084 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 6 days. PS-isocyanate resin (Argonaut Technologies, Foster City, Calif.; 0.050 g) and PS-trisamine resin (Argonaut Technologies; 0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off and was washed with methylene chloride. The filtrate was concentrated to give the title compound of Step A. MS 639.4 (M+1)+
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:8]([O:21][CH2:22][CH3:23])[CH:7]=2.[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1>C(#N)C>[CH2:22]([O:21][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][N:34]3[CH2:39][CH2:38][CH:37]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH2:36][CH2:35]3)[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[N:5]2)=[CH:10][C:9]=1[S:17]([CH3:20])(=[O:19])=[O:18])[CH3:23]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(C)(=O)=O
Solvent: CC#N
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(C)(=O)=O
Yield: 77.6 %

Procedure:
A suspension of methyl 3-(bromomethyl)-7-(ethyloxy)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.705 g, 3.12 mmol) and -(4-piperidinyl)morpholine (0.691 g, 4.06 mmol) in acetonitrile (30 mL) was stirred for 3 h. The solvent was removed under reduced pressure, and the residue was dissolved in DMSO and purified via HPLC (Biotage RP, 0-50% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and were extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.54 g, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ8.40 (s, 1H), 7.98 (s, 1H), 7.87-7.94 (m, 2H), 7.76-7.81 (m, 2H), 4.40 (q, J=6.94 Hz, 2H), 4.01 (s, 3H), 3.61 (s, 2H), 3.53 (br. s., 4H), 3.42 (s, 3H), 2.62 (d, J=11.29 Hz, 2H), 2.38 (br. s., 4H), 1.93-2.05 (m, 1H), 1.81 (t, J=11.04 Hz, 2H), 1.62 (d, J=12.05 Hz, 2H), 1.47 (t, J=6.90 Hz, 3H), 1.18-1.30 (m, 2H); MS (m/z) 636.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:14]([CH2:15][CH2:16][OH:17])[CH3:13])(=[O:11])=[O:10]
Reactant: CNCCO
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO)S(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
2,4-Difluorobenzenesulfonyl chloride (4 g, 18.81 mmol) in DCM (10 mL) was added slowly to a solution of 2-(methylamino)ethanol (1.66 mL, 20.70 mmol) in DCM (200 mL) and 10% sodium hydroxide solution (200 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 20 hours. The DCM layer was separated and the aqueous re-extracted into DCM (2×50 mL). The combined organics were washed with brine, dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a colourless oil (4.7 g).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:15]([C:19]1([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[O:24][C:23](=[O:25])[CH:22](Cl)[C:21](=[O:27])[CH2:20]1)[CH2:16][C:17]#[CH:18]>CN(C=O)C>[CH2:15]([C:19]1([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[O:24][C:23](=[O:25])[CH:22]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21](=[O:27])[CH2:20]1)[CH2:16][C:17]#[CH:18]
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Reactant: Sc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCCC1(C2CCCC2)CC(=O)C(Sc2ccccc2)C(=O)O1
Yield: 35.8 %

Procedure:
A solution of thiophenol (0.23 mL, 2.2 mmol), triethyl amine (0.156 mL, 1.1 mmol), and 6-but-3-ynyl-3-chloro-6-cyclopentyl-dihydro-pyran-2,4-dione (0.30 g, 1.1 mmol; prepared as described in step 1 above) in DMF (3 mL) was stirred at room temperature for 2 hours. The reaction was then concentrated by rotary evaporation, and then chromatographed (40 g silica gel, gradient elution from 40% EtOAc/Hexanes to 75% EtOAc/Hexanes) to yield the title compound (135 mg, 36%). 1H NMR (CDCl3): δ1.31-1.80 (m, 9H); δ1.96-2.00 (m, 2 H); δ2.03-2.11 (3H, m); δ2.85 (2H, dd, J1=17.94, J2=27.03); δ7.13-7.36 (5H, m). Anal. Calcd. for C20H22O3S.0.1 MeOH.0.15 CH2Cl2: C, 67.86; H, 6.38; S, 8.95. Found C, 68.08; H, 6.48; S, 8.52. ESIMS (M+Na+): 365.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br>ClCCCl>[Br:21][C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[C:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: ClCCCl
Product: BrC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Into a reactor were introduced 12.5 g (48.8 mmol) of the 1,1,2-triphenylethylene and 50 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to 0° C., and 7.80 g (48.8 mmol) of bromine was gradually added dropwise thereto. This mixture was stirred at room temperature for 1 hour. The resultant reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium thiosulfate solution, and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The resultant concentrate was recrystallized from ethanol and ethyl acetate to obtain 11.3 g (69%) of the target compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH3:15][O-:16].[Na+]>CO.O.[Cl-].[Na+].O>[Br:1][C:2]1[C:3]([O:16][CH3:15])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2ncc(OC)c(Br)c2n1
Temperature: 50 °C
Yield: 95 %

Procedure:
8-Bromo-7-fluoro-2-(methoxy)-1,5-naphthyridine (for a synthesis see WO2004058144, example 53(g) (11.215 g, 43.64 mmol) was stirred in methanol (100 mL) at rt under argon and a solution of sodium methoxide in methanol (94 ml of a ca. 25% solution, 10 eq.) was added. The mixture was heated at 50° C. for 1 h. The mixture was allowed to cool to rt, then was diluted with water (500 ml) and brine (500 ml), and extracted with DCM (2×300 ml). The DCM extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 8-bromo-2,7-bis(methoxy)-1,5-naphthyridine as a cream solid (11.21 g, 95%).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)[CH:3]=1.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:1][C:2]1[S:6][CH:5]=[C:4]([CH2:7][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: O=C(c1csc(Br)c1)N1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Product: Brc1cc(CN2CCCCC2)cs1
Yield: 35.1 %

Procedure:
To a solution of (5-bromothiophen-3-yl)-piperidin-1-yl-methanone (907 mg, 3.30 mmol) in DCM (33 mL) was added tetrabutylammonium borohydride (2.54 g, 9.90 mmol) portionwise over 10 minutes. The reaction mixture was heated under reflux for 19 h then further tetrabutylammonium borohydride (2.54 mg, 9.90 mmol) was added to the reaction mixture, in four portions over 6 h. and then the reaction mixture was heated under reflux for 18 h. After this time the reaction mixture was partitioned between DCM (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, the solvent was removed in vacuo and the residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-50% ethyl acetate in cyclohexane) to afford an oil which solidified on standing to afford the title compound as a white solid (301 mg, 35%). 1H NMR (CDCl3, 300 MHz): 7.23 (d, J=1.7 Hz, 1H), 7.15 (d, J=1.7 Hz, 1H), 3.91 (s, 2H), 2.97-2.87 (m, 2H), 2.72-2.62 (m, 2H), 2.15-2.06 (m, 2H), 1.70-1.52 (m, 2H), 1.41-1.25 (m, 2H); LCMS (Method B): RT=4.0 min, M+H+=260.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])=[C:16]([C:25]([F:27])([F:28])[F:26])[CH:15]=2)[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: CCS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 18 step (iv) and the product from step (i).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:34]1([NH:40]O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:40][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: ONC1CCCCC1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(ONC1CCCCC1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (300 mg, 1.03 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (251 mg, 1.55 mmol) in N,N-dimethylformamide (12 mL) was stirred for 1 hour. In one portion N-cyclohexylhydroxylamine hydrochloride (469 mg, 3.09 mmol) was added and the solution was stirred for 2 hours at room temperature. To the resulting solution was added water (15 mL). The insoluble material was filtered and dried to give the title compound (286 mg, 72% yield, m.p. 220° C.).
Reaction SMILES: [C:1]([NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([Cl:18])=[CH:11][C:10]=1[C:19]([F:22])([F:21])[F:20])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[CH3:23]I.[H-].[Na+]>CN(C)C=O>[C:1]([N:8]([CH3:23])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([Cl:18])=[CH:11][C:10]=1[C:19]([F:20])([F:21])[F:22])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N(C)c1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Reaction time: 3 h

Procedure:
To a stirred solution of N-ethoxalyl-4-chloro-6-nitro-2-trifluoromethylaniline (11 g. 32.3 mmol) and methyl iodide (3.0 ml, 48 mmol) in dry dimethylformamide (DMF, 50 ml) was added in portions sodium hydride (total 1.7 g, 39 mmol). External cooling was used to keep the reaction temperature below 25° C. Stirring was continued at room temperature for 3 h, whereafter the solvent was removed by evaporation in vacuo. The residue was then partitioned between ether and water. The organic phase was washed twice with water, dried over Na2SO4 and evaporated. This treatment left the title compound as an oil, which was processed without further purification.
Reaction SMILES: [I:1][CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([Mg]Br)#[CH:12].[Cl-].[NH4+]>O1CCCC1>[C:11]([C:4]([OH:10])([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH:2][I:1])#[CH:12]
Reactant: C#C[Mg]Br
Reactant: CCCCCC(=O)C=CI
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)(C=CI)CCCCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7.9 g. of 1-iodo-1-octen-3-one in 30 ml. of tetrahydrofuran is added dropwise over 10 minutes to an ice-cooled solution of ethynyl magnesium bromide (prepared from 21 ml. of 3M methyl magnesium bromide in ether and excess acetylene) in 170 ml. of tetrahydrofuran. After stirring at 0° for 1 hour under nitrogen, the mixture is added to ammonium chloride solution and extracted with ether. The extract is washed, dried, evaporated and the residue distilled to obtain the title product, 5.05 g., b.p. 55°-65°/.005 mm.
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[Br:11][C:12]1[CH:13]=[C:14]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.8 %

Procedure:
To a solution of 534 mg (4.30 mmol) of orcinol monohydrate and 1.00 g (3.91 mmol) of 3-bromobenzenesulfonyl chloride in 25 mL of diethyl ether was added 25 mL of saturated aqueous NaHCO3 and the biphasic mixture was stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to 1.4 g of an amber-colored resin. Chromatography on 65 g of silica gel with 3% ethyl acetate-dichloromethane afforded 870 mg (65%) of the desired product as a colorless syrup: 1H-NMR (300 MHz; CDCl3) δ 8.02 (t, 1H, J=1.8 Hz), 7.79 (m, 2H), 7.41 (t, 1H, J=7.9 Hz), 6.57 (m, 1H), 6.40 (m, 1H), 6.33 (t, 1H, J=2.2 Hz) and 2.24 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=2.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([S:31]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1>>[C:35]([NH:34][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=3)[C:10]([CH3:11])=[C:2]2[CH3:1])=[CH:20][CH:21]=1)(=[O:33])=[O:32])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 6, Example 1, using the ethyl 2,3-dimethyl-1H-indole-5-carboxylate and 4′-(bromomethyl)-N-(tert-butyl)-[1,1′-biphenyl]-2-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[C:12]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:14])[CH3:13]
Reactant: NNC(=O)c1ccc(Cl)nc1
Reactant: CC(=O)Cl
Product: CC(=O)NNC(=O)c1ccc(Cl)nc1
Yield: 64 %

Procedure:
The title compound was prepared from 6-chloronicotinic acid hydrazide and acetyl chloride, using the method of preparation 33, as a white solid in 64% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].C([SiH](CC)CC)C.[C:33](=O)([O-])[O-:34].[Na+].[Na+]>CN(C=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:33]=[O:34])=[C:3]([CH3:25])[CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Temperature: 65 °C
Yield: 76.2 %

Procedure:
A mixture of 3-(4-bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (14.20 g, 31.34 mmol), triethyl silane (10.3 mL, 7.53 g, 62.8 mmol), sodium carbonate (5.43 g, 39.3 mmol), palladium bis(diphenylphosphine)-ferrocene dichloride CH2Cl2-complex (1.28 g, 1.57 mmol) and DMF (250 mL) were stirred under an atmosphere of carbon monoxide at 65° C. over night. After cooling to room temperature, the solvent was evaporated and the residue taken up in MTBE (methyl-tert-butyl ether), filtered and the filtrate was concentrated in vacuum. Purification of the residue on silica gel afforded the title compound (9.60 g, 76%).