Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:25])=[CH:11][C:12]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:37])[C:27]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:25])=[CH:11][C:12]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:13]([CH:17]=1)[C:14]([NH:37][CH2:26][C:27]1[CH:36]=[CH:35][C:32]([O:33][CH3:34])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)cc1NC1CCOCC1
Reactant: COc1ccc(CN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)c(F)cc2NC2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A mixture of 14 g of the compound obtained in Step 4.4, 7.46 g of veratrylamine, 19.99 g of HBTU and 13.1 g of DIEA in 300 ml of DMF is stirred for 2 hours at room temperature. The solvent is evaporated off under reduced pressure and the residue is taken up in DCM. The resulting solution is washed twice with saturated aqueous NaHCO3 solution. The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (90/10, v/v) to (40/60, v/v) to give 16 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].IC.[C:16](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Yield: 92.8 %

Procedure:
A solution of 2-chloro-3-nitrobenzoic acid (20.16 g, 100 mmol), iodomethane (15.6 g, 110 mmol), and potassium carbonate (15.0 g, 108.5 mmol) in DMF (100 mL) was stirred at room temperature for 48 h. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford 20.0 g (93%) of the title compound 2-chloro-3-nitrobenzoic acid, methyl ester as a white solid (MW 215.59).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[CH3:41][C@@H:42]1[C@@H:47]([NH2:48])[CH2:46][C@H:45]2[CH2:49][C@@H:43]1[C:44]2([CH3:51])[CH3:50]>>[CH3:41][C@@H:42]1[C@@H:47]([NH:48][C:30]([CH:29]2[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]2[CH2:24][C:23]2[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=3[F:38])[C@H:10]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:22]=2)=[O:31])[CH2:46][C@H:45]2[CH2:49][C@@H:43]1[C:44]2([CH3:50])[CH3:51]
Reactant: C[C@@H]1[C@@H](N)C[C@H]2C[C@@H]1C2(C)C
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)N[C@H]4C[C@H]5C[C@@H]([C@@H]4C)C5(C)C)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 72.3 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7 (Epimer 1), 0.070 g, 0.117 mmol) was reacted with (1S,2S,3S,5R)-2,6,6-Trimethyl-bicyclo[3.1.1]hept-3-ylamine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 25 μL, 0.148 mmol) to form 2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (Epimer 1) (0.062 g, 72%). m/z=733 (M+1); HRMS: calcd for C39H59ClFN4O4S. Calc [M+H+] 1733.3924. found 733.3925.
Reaction SMILES: C(#N)C.[NH2:4][CH:5]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[C:6]([NH:8][CH:9]1[C:24](=[O:25])[N:11]2[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]12)=[O:7].C1OC1C.[O:37]=[C:38]1[N:42]([C:43](Cl)=[O:44])[C:41]2[CH:46]=[CH:47][CH:48]=[CH:49][C:40]=2[NH:39]1>C(Cl)Cl.CC(C)=O>[O:37]=[C:38]1[N:42]([C:43]([NH:4][CH:5]([C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)[C:6]([NH:8][CH:9]2[C:24](=[O:25])[N:11]3[C:12]([C:21]([OH:23])=[O:22])=[C:13]([CH2:16][O:17][C:18](=[O:20])[NH2:19])[CH2:14][S:15][C@H:10]23)=[O:7])=[O:44])[C:41]2[CH:46]=[CH:47][CH:48]=[CH:49][C:40]=2[NH:39]1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(O)cc3)[C@H]2SC1
Reactant: O=C(Cl)n1c(=O)[nH]c2ccccc21
Agent: CC1CO1
Solvent: CC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)n3c(=O)[nH]c4ccccc43)c3ccc(O)cc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To 8 ml. of dry acetonitrile were added 422 mg. (1 mmole) of 7-(α-amino-4-hydroxyphenylacetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid. The mixture was stirred in a bath comprising acetone and wet ice, and 1.62 grams (8 mmoles) of N,O-bis-trimethylsilylacetamide were added. Solution was complete within about 5 minutes. The mixture was stirred for an additional 5 minutes, and 0.7 ml. of propylene oxide was added followed, after an additional 5 minutes, by 197 mg. (1 mmole) of 2,3-dihydro-2-oxo-1H-benzimidazol-1-ylcarbonyl chloride. The mixture was stirred for 105 minutes and then was rotary evaporated to about one-half volume. The concentrated reaction mixture was slowly added to rapidly-stirred ice water, and the pH of the resulting mixture, containing a percipitated gum, was adjusted from 3.8 to 1.6. The resulting mixture then was sonicated, with hardening of the gum. The resulting hard lumps were broken, sonicated, filtered, washed with dilute hydrochloric acid (pH 1.8), and air-dried to give 251 mg. of a buff powder. The filtrate was concentrated to remove acetonitrile and was filtered to afford an additional 20 mg. of a buff-colored powder. The solids were combined and added to 40 ml. of methylene chloride. The mixture was sonicated and filtered to recover 210 mg. of solid. The solid was added to 100 ml. of methylene chloride, sonicated, and filtered to obtain 200 mg. of the title compound.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(C(C)=O)C>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:1][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Under a nitrogen atmosphere, p-aminophenol (109 g) was suspended in methyl ethyl ketone (2000 ml). To this suspension was added triethylamine (253 g) and then was added nonadecanoyl chloride (331 g), followed by refluxing with heating for 2 hours. The reaction mixture was cooled to room temperature to precipitate a white crystal. This crystal was filtered off under reduced pressure and recrystallized from methyl ethyl ketone to obtain 323 g of the desired product. Yield 80%; m.p. 138° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[CH:7]=[C:8]3[C:15]4[N:16]=[N:17][NH:18][C:19](=[O:20])[C:14]=4[S:13][C:9]3=[N:10][C:11]=2[CH:12]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[CH:7]=[C:8]3[C:15]4[N:16]=[N:17][N:18]([CH3:23])[C:19](=[O:20])[C:14]=4[S:13][C:9]3=[N:10][C:11]=2[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2cc3c(nc2cc1OC)sc1c(=O)[nH]nnc13
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2cc3c(nc2cc1OC)sc1c(=O)n(C)nnc13
Reaction time: 3 h

Procedure:
To a mixture of 8.8 g of 8,9-dimethoxy-1,2,3-triazino[4',5':4,5]thieno[2,3-b]quinolin-4(3H)-one and 12 g of potassium carbonate in 50 ml of dimethylformamide at 75° C. is added 6 ml of methyl iodide. Stirring at this temperature is continued for 3 hours. The mixture is then diluted with water and the precipitate which forms is separated by filtration to give 8,9-dimethoxy-3-methyl-1,2,3-triazino[4',5':4,5]thieno[2,3-b]quinolin-4(3H)-one.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][C:8]=1[Cl:22])(=O)=O.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CO.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:17][C:15]([NH:14][C:10]1[CH:11]=[C:12]([Cl:13])[C:7]([C:15]([O:17][CH3:18])=[O:16])=[C:8]([Cl:22])[CH:9]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cc(NC(=O)OC(C)(C)C)cc1Cl
Yield: 119.4 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino)-2,6-dichlorophenyl trifluoromethanesulfonate (14 g, 34 mmol), dppp (1.4 g, 3.4 mmol), Pd(OAc)2 (0.84 g, 3.4 mol) and Et3N (19.6 mL) in MeOH (112 mL) and DMF (224 mL) was refluxed under an atmosphere of carbon monoxide (10 atm) overnight. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/EtOAc 80:1) to give methyl 4-(tert-butoxy carbonylamino)-2,6-dichlorobenzoate (6.5 g, yield: 60%). 1H NMR (CDCl3, 400 MHz) δ 7.40 (s, 2H), 6.56 (brs, 1H), 3.94 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: C1=COCCC1
Reactant: CC(=O)c1ccc(O)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(OC2CCCCO2)cc1F
Yield: 74 %

Procedure:
A solution of 1-(2-fluoro-4-hydroxy-phenyl)-ethanone (130 mmol), 3,4-dihydro-2H-pyran (260 mmol) and a catalytic amount of pyridinium p-toluenesulfonate in CH2Cl2 (200 mL) was left overnight at room temperature. The organic phase was washed with 1 N NaOH (aq) (1×50 mL) and dried (K2CO3). Evaporation in vacuo gave a brown oil, that was purified by vacuumdistillation. The desired product was isolated as clear oil in 74% yield:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[C@@H:14]3[C:20](=O)[CH2:21][CH2:22][N:13]3[C:12]2=[O:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.Cl.[NH2:32][OH:33]>CO.O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:17])([F:18])[F:19])[C@@H:14]3[C:20](=[N:32][OH:33])[CH2:21][CH2:22][N:13]3[C:12]2=[O:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NO
Reactant: Cc1c(N2C(=O)N3CCC(=O)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Agent: Cl
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(N2C(=O)N3CCC(=NO)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To 68A (96.0 mg, 0.269 mmol) in MeOH (2.7 mL) and water (5 drops) was added pyridine (109 μL) and hydroxylamine hydrochloride (93.0 mg, 1.34 mmol) and the whole was stirred overnight at rt. The reaction was concentrated then diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-18, 30×100 mm, eluting with 60-100% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 10 min; Flow rate at 40 mL/min; UV detection at 220 nm) to provide a solid which was re-purified via preparative HPLC (YMC ODS C-18, 30×100 mm, eluting with 40-70% solvent B (A=90% H2O—10% CH3CN and B=10% H2O—90% CH3CN) over 12 min; Flow rate at 40 mL/min; UV detection at 220 nm) to provide the title compound (48.0 mg) as a white solid. MS: m/z 371 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]2[CH2:18][CH2:17][CH2:16][C:15]2([F:20])[F:19])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:14]2[CH2:18][CH2:17][CH2:16][C:15]2([F:19])[F:20])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1ccc(Cl)cc1)C1CCCC1(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(c1ccc(Cl)cc1)C1CCCC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.70 g (8.92 mmol) of ethyl (4-chlorophenyl)(2,2-difluorocyclopentyl)acetate (diastereomer mixture) were dissolved in 10 ml of methanol, 10 ml of THF and 5 ml of water, and 7.13 g (89.18 mmol) of 50% strength aqueous sodium hydroxide solution were added at RT. The reaction mixture was stirred at RT overnight. The mixture was then diluted with water and acidified with hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate, the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure and the residue was dried under high vacuum. This gave 2.39 g of the target compound (97.6% of theory, diastereomer ratio about 1:1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:18])=[C:11]([F:17])[C:12]=3[C:14]#[C:15][CH3:16])[C:7](=[O:19])[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:18])=[C:11]([F:17])[C:12]=3[C:14]#[C:15][CH3:16])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 81.9 %

Procedure:
1.4 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propin-1-yl)-3-quinolinecarboxylate are refluxed for 1 hour in a mixture of 20 ml of glacial acetic acid, 1.5 ml of water and 0.5 ml of concentrated sulphuric acid. The mixture is treated with approx. 10 ml of water, and the solid which has precipitated is then isolated and dried. In this manner, 1.05 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(propin-1-yl)-3-quinolinecarboxylic acid are obtained (82% of theory).
Reaction SMILES: B(Br)(Br)[Br:2].Cl.[CH3:6][N:7]([CH2:9][C:10]1[S:25][C:13]2[NH:14][C:15](=[O:24])[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:22]C)[C:21]=3[C:12]=2[CH:11]=1)[CH3:8]>ClCCl>[BrH:2].[CH3:8][N:7]([CH2:9][C:10]1[S:25][C:13]2[NH:14][C:15](=[O:24])[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([OH:22])[C:21]=3[C:12]=2[CH:11]=1)[CH3:6]
Reactant: BrB(Br)Br
Reactant: COc1cccc2c(=O)[nH]c3sc(CN(C)C)cc3c12
Agent: Cl
Solvent: ClCCl
Product: Br
Product: CN(C)Cc1cc2c([nH]c(=O)c3cccc(O)c32)s1
Temperature: 23 °C
Yield: 54 %

Procedure:
Boron tribromide, 1 M CH2Cl2 solution, (0.1 ml, 0.41 mmol) was added to a solution of 2-dimethylaminomethyl-9-methoxythieno[2,3-c]isoquinolin-5(4H)-one hydrochloride (0.03 g, 0.09 mmol) in dichloromethane (2 ml) and the reaction mixture was refluxed for 24 hours. The mixture was cooled to 23° C., poured on to ice and the resulting mixture was evaporated under reduced pressure. The mixture was purified by crystallization with 96% ethanol to obtain the title compound (54% yield) as pure solid.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[F:20][CH2:21][C:22]([CH2:26][F:27])([OH:25])[C:23]#[CH:24]>>[F:19][C:18]1[C:2]([C:24]#[C:23][C:22]([CH2:26][F:27])([OH:25])[CH2:21][F:20])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(O)(CF)CF
Product: NC(=O)c1nc2c(s1)CCOc1cc(F)c(C#CC(O)(CF)CF)cc1-2
Yield: 32 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 1-fluoro-2-(fluoromethyl)but-3-yn-2-ol to give the titled compound as an off-white solid (73 mg, 32%).
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[NH2:27][C@@H:28]1[CH2:32][C@H:31]([CH2:33][OH:34])[CH:30]=[CH:29]1.[Cl:35][C:36]1[C:41]([NH:42][CH:43]=[O:44])=[C:40](Cl)[N:39]=[C:38]([NH:46][C:47](=[O:49])[CH3:48])[N:37]=1.C(N(CC)CC)C>O.C(O)C>[Cl:35][C:36]1[C:41]([NH:42][CH:43]=[O:44])=[C:40]([NH:27][C@H:28]2[CH2:32][C@@H:31]([CH2:33][OH:34])[CH:30]=[CH:29]2)[N:39]=[C:38]([NH:46][C:47](=[O:49])[CH3:48])[N:37]=1
Reactant: CC(=O)Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: N[C@H]1C=C[C@@H](CO)C1
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(Cl)c(NC=O)c(N[C@@H]2C=C[C@H](CO)C2)n1

Procedure:
(1S,4R)-4-Amino-2-cyclopentene-1-methanol dibenzoyl-D-tartrate prepared as described in Example 13 (2.76 g, 9.02 mmol) was dissolved in water (20 ml) and applied to a column of 65 ml of Amberlite IA-400 (OH- form) anion exchange resin. The column was washed with water. Basic fractions were combined and evaporated to a residual oil which was dried by evaporation of absolute ethanol and then at 0.5 mm to give oil (darkens rapidly in air) which was used immediately. This oil was dissolved in ethanol (5 ml) and added to a solution of N-(4,6-dichloro-5-formamido-2-pyrimidinyl)acetamide (2.07 g, 8.31 mmol), prepared as described in Example 15, and triethylamine (2.50 g, 24.8 mmol). The resulting dark solution was heated (oil bath 75°-80° C.) under nitrogen for 50 minutes. The solution was evaporated to a syrup which was applied to a silica gel column. Title compound was eluted with 3 to 5% methanol-chloroform as a pale yellow solid foam (1.59 g, 54%); 1H-NMR identical with that of crystallized sample. Such a sample was crystallized from ethanol to give white granules, m.p. 194°-195° C.; 1H-NMR (DMSO-d6) identical with that of the title compound of Example 15; [α]20D +2.7°, [α]54620 +2.9°, [α]43620 -2.5°, [α]36520 -41.2° (c=0.238, methanol).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[S:13]([CH3:16])(=[O:15])=[O:14])([CH3:3])[CH3:2].CC1C([N+:24]([O-:26])=[O:25])=C(C)C(S(C)(=O)=O)=CC=1[N+]([O-])=O.OS(O)(=O)=O.O=S(=O)=O.[N+:44]([O-])([OH:46])=[O:45]>C(OCC)(=O)C>[CH:10]([C:8]1[C:9]([N+:24]([O-:26])=[O:25])=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:6][C:7]=1[N+:44]([O-:46])=[O:45])([CH3:11])[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccc(S(C)(=O)=O)c(C(C)C)c1
Reactant: Cc1c([N+](=O)[O-])cc(S(C)(=O)=O)c(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: CCOC(C)=O
Product: CC(C)c1c([N+](=O)[O-])cc(S(C)(=O)=O)c(C(C)C)c1[N+](=O)[O-]

Procedure:
2,4-Diisopropyl-1-methylsulfonylbenzene was dinitrated analogously to (a). To ensure complete dinitration, 20% oleum (1.6 mol of SO3 per mol of sulfone) was added after the addition of nitric acid and the after-stirring time was increased to 60 hours. The crude product was boiled with ethyl acetate to remove small quantities of mononitro compounds.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C([Li])CCC.[CH2:16]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH:17]=[CH2:18]>O1CCCC1.[Cl-].[Na+].O>[OH:25][C:22]1([C:3]2[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])[CH2:23][CH2:24][N:19]([CH2:16][CH:17]=[CH2:18])[CH2:20][CH2:21]1
Reactant: Cc1csc2ccccc12
Reactant: C=CCN1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN1CCC(O)(c2sc3ccccc3c2C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
Scheme IA, step A: To a solution of 3-methylbenzothiophene (2.863 g, 19.3 mmol) in tetrahydrofuran (80 mL) at −78° C. was added a solution of n-butyllithium (13.3 mL, 21.2 mmol, 1.6 M in hexanes). The solution was warmed to 0° C. for one hour then recooled to −78° C. A solution of 1-(2-propenyl)-4-piperidone (2.957 g, 21.2 mmol) in tetrahydrofuran was added dropwise and the mixture was warmed to 20° C. After stirring for 18 hours at 20° C. the mixture was diluted with brine and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate then filtered and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent) to give 4.61 g (83%) of the intermediate title compound as a white amorphous solid. FDMS m/e=288 (M++1).
Reaction SMILES: [C:1]12[CH2:8][CH2:7][C:6]=1[CH:5]=[CH:4][CH:3]=[CH:2]2.[Br:9]Br.S([O-])([O-])=O.[Na+].[Na+]>O.CCCCCC>[Br:9][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][C:1]=2[CH:2]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)CC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: Brc1ccc2c(c1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bicyclo[4.2.0]octa-1(6),2,4-triene 5a (7.9 g, 76 mmol) was dissolved in 80 mL of water at room temperature. Upon cooling by an ice-water, 3.9 mL of bromine was added dropwise. Upon completion of the addition, the ice-water bath was removed and the reaction mixture was warmed up to room temperature and stirred overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 50 mL of n-hexane and sodium sulfite (3 g, 23.8 mmol) was added. Upon completion of the addition, the mixture was stirred at room temperature for 30 minutes. Then the separated organic layer was dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 3-bromo-bicyclo[4.2.0]octa-1(6),2,4-triene 5b (13.53 g) as a colourless oil, which was directly used in the next step.
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO>[CH3:1][N:2]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:27])[F:28])(=[O:18])=[O:19])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3ccccc3C(F)(F)F)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
Ethyl 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carboxylate (3.7 g) was dissolved in a mixed solvent of tetrahydrofuran (25 ml)-methanol (25 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (1.5 g) in water (20 mL)) was added to this solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless crystals were washed with ethyl acetate-hexane to give the title compound (2.7 g, yield: 63%) as colorless crystals. MS: 399 (MH+). melting point: 211-212° C.