Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)C(C)C)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To 3-iodo-4-methylaniline (500.0 mg, 2.145 mmol) was added dichloromethane (DCM) (10 mL) followed by N,N-diisopropylethylamine (DIPEA) (520 μL, 3.0 mmol) and 3-(trifluoromethyl)-benzoyl chloride (0.36 mL, 2.4 mmol). The reaction was stirred at 25° C. for 16 hours and was transferred to a separatory funnel and partitioned between water and dichloromethane (DCM). The organic phase was sequentially washed with 0.1N HCl, saturated aqueous NaHCO3, water, then saturated aqueous NaCl. The washed organic phase was then dried over MgSO4 and filtered and concentrated to leave the crude product. The crude product was triturated with hexanes to leave the product as an off-white solid, (797 mg, 92%). 1H NMR (400 MHz, CDCl3): δ 8.10 (m, 2H), 8.04 (d, 1H), 7.84 (bs, 1H), 7.81 (d, 1H), 7.63 (m, 1H), 7.58 (dd, 1H), 7.22 (d, 1H), 2.42 (s, 3H). MS (EI) m/z=274 (M+H).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:23][CH2:22]1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2)CC1
Yield: 71.7 %

Procedure:
A mixture of 0.07 mole (20.7 g) of 2,4'-dichloro-5-nitrobenzophenone, of 0.1 mole (11.4 ml) of 4-methyl-piperidine and of 10 g of K2CO3 in 100 ml of anhydrous ethanol is heated to reflux for 3 hours. After cooling of the reaction medium, the precipitate obtained is filtered, washed with water, dried then recrystallized from ethanol. 18 g (yield=71.7%) of the expected product are thus obtained. M.p.=136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Br:22])[CH:16]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[Br:22][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:30](=[O:33])[CH:31]=[CH2:32])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[Br:21]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)c(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a solution of 0.75 g (1.79 mmol) of 6-amino-4-[(3,4-dibromophenyl)amino]-3-quinolinecarbonitrile and 0.22 g (2.15 mmol) of triethylamine in 10 mL of tetrahydrofuran was added dropwise 0.195 g (2.15 mmol) of acryloyl chloride. After stirring overnight at 25° C., volatile material was removed and the residue was slurried in water and solid was collected. The crude product was washed with boiling ethyl acetate dried in vacuo (50° C.) to give 0.609 g of brown solid: high resolution mass spectrum (m/e): 470.9457.
Reaction SMILES: [Na].COS(O)(=O)=O.[CH2:8]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[NH:15])[CH2:9][CH3:10].C([O:23][CH:24]=[C:25]([C:31](OCC)=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])C.O>C(O)C.C(O)(=O)C>[O:23]=[C:24]1[NH:16][C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:8][CH2:9][CH3:10])=[N:15][CH:31]=[C:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCOc1ccccc1C(=N)N
Agent: COS(=O)(=O)O
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Yield: 78.5 %

Procedure:
To a warm solution of sodium (181.7 g., 7.9 g-atoms) in ethanol (5 l) was added with stirring a slurry of 2-n-propoxybenzamidine methyl sulfate (1146.7 g., 3.95 moles) in ethanol 1.6 l). After 2-3 minutes diethyl ethoxymethylenemalonate 854 g., 3.95 moles) was added and the mixture stirred and heated under reflux for 2.25 hours. The mixture was cooled and then added to cold water (13 l). The mixture was acidified to pH 5-6 with glacial acetic acid. The solid was collected by filtration, washed with water, and dried to give the title compound (937.8 g.), m.p. 102°-104°. An additional crop of product (101.6 g., m.p. 105°-107°, was obtained from the filtrate and washings. Total yield of product, 1039.4 g. (87%).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:22][C:21]4[C:16](=[C:17](I)[CH:18]=[C:19]([Cl:23])[CH:20]=4)[C:15]3=[O:25])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[Cu][C:28]#[N:29].ClCCl.C(O)C>CN(C)C=O>[Cl:23][C:19]1[CH:18]=[C:17]([C:28]#[N:29])[C:16]2[C:15](=[O:25])[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH:5]4[CH2:6][CH2:7][C:2]([F:26])([F:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)[CH2:22][C:21]=2[CH:20]=1
Reactant: N#C[Cu]
Reactant: O=C1c2c(I)cc(Cl)cc2CN1C1CCN(C2CCC(F)(F)CC2)CC1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc2c1C(=O)N(C1CCN(C3CCC(F)(F)CC3)CC1)C2
Yield: 73 %

Procedure:
2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-5-chloro-7-iodo-2,3-dihydro-1H-isoindol-1-one (80 mg, 0.16 mmol) and copper(I) cyanide (22 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (1 mL) and the resulted solution was refluxed under nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with 15% ammonium hydroxide. Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (dichloromethane/ethanol:95/5) afforded title compound (46 mg, 72% yield).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][CH:20]2[OH:23])=[CH:16][CH:15]=1.CCOCC>C(Cl)Cl>[F:12][C:13]([F:24])([F:25])[C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][C:20]2=[O:23])=[CH:16][CH:15]=1
Reactant: OC1C=Cc2ccc(C(F)(F)F)cc21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1C=Cc2ccc(C(F)(F)F)cc21
Reaction time: 14 h
Yield: 40.4 %

Procedure:
To a solution of pyridinium chlorochromate (1.08 g, 5.0 mmol) in methylene chloride (15 mL) was added dropwise a solution of 6-(trifluoromethyl)-1H-inden-1-ol (500 mg, 2.498 mmol) in methylene chloride (10 mL). After being stirred for 14 h, ether (30 mL) was added, and the reaction mixture was filtered through silica gel. The filtrate was concentrated in vacuo. The crude material was chromatographed (10:1 hexane/EtOAc) to afford 200 mg (40%) of the product. LC-MS [M+1]=199.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([N:15]1[CH2:16][CH2:17][C:12]2([O:11][C:10]3[C:20]4[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=3[S:19][CH2:18]2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=4)[CH2:13][CH2:14]1)=[O:29]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C(=O)c4cccc(Cl)c4)CC3)O1)C(=O)C2=O

Procedure:
Compound 69 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.=125-127° C.; 400 MHz 1H NMR (CDCl3) δ: LCMS: 7.90 (d, 1H), 7.55-7.47 (m, 3H), 7.41 (m, 1H), 7.25 (d, 1H), 7.11 (dd, 1H), 3.94, (s, 3H), 3.55-3.40 (m, 2H), 3.11 (s, 2H), 2.18-1.92 (m, 4H), 1.89-1.82 (m, 2H); LCMS: 470 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9](=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(F)cc1Nc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 70 °C
Yield: 75.4 %

Procedure:
[(4-Fluoro-2-phenylaminophenylcarbamoyl)methyl]carbamic acid tert-butyl ester (0.37 g, 1.03 mmol) was taken up in AcOH (10 mL) and heated at 70° C. for 16 h. After cooling to RT, the volatiles were removed under reduced pressure, the resulting residue was partitioned between EtOAc and water and the mixture basified with Na2CO3. The organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting oil was purified by column chromatography (Si—PCC, gradient 0-60% EtOAc in cyclohexane) to afford the title compound as a white foam (0.265 g, 75%). LCMS (Method B): RT 3.35 min [M+H]+ 342.03
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[O:4].[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]([CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[O:4]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COC(=O)CNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COC(=O)CNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(methoxycarbonyl-methyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[CH:16]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.N1CCCC1.Cl>CO>[CH:16]1(/[CH:21]=[C:10]2/[C:11](=[O:15])[C:12]3[CH:13]=[CH:14][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=3[CH2:8][CH2:9]/2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Reactant: O=CC1CCCC1
Agent: Cl
Solvent: C1CCNC1
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)CC/C(=C\C1CCCC1)C2=O
Temperature: 55 °C
Yield: 72.4 %

Procedure:
A mixture of 6-acetamido-1-tetralone (200 mg, 0.98 mmol) and cyclopentanecarboxaldehyde (0.21 mL, 1.9 mmol) in methanol (2 mL) was treated with pyrrolidine (0.25 mL, 2.9 mmol) at room temperature for 1 hour then heated at 55° C. overnight. The mixture was cooled to room temperature, treated with 1N Hydrogen chloride (4 mL) was filtered thru a Chem Elute tube (CE101 1) eluting with 90% dichloromethane/10% ethyl acetate and condensed filtrate to give (E)-N-(6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (200 mg, 0.71 mmol, 72% n yield) as a tan foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.44 (m, 2H), 1.52-1.76 (m, 4H), 1.77-1.90 (m, 2H), 2.08 (s, 3H), 2.70-2.92 (m, 5H), 6.63 (d, J=9.67 Hz, 1H), 7.49 (dd, J=8.59, 2.15 Hz, 1H), 7.59-7.66 (m, 1H), 7.86 (d, J=8.59 Hz, 1H), 10.23 (s, 1H). ES-MS m/z 284 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:20][CH:19]=4)[S:17][C:10]=23)=[CH:6][CH:5]=1)([O-])=O.CN1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=S)=CC=3F)C=2C=C1>>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][O:22][C:21]2[CH:31]=[CH:32][C:18]([C:16]3[S:17][C:10]4[C:11](=[N:12][CH:13]=[CH:14][C:9]=4[O:8][C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:34][CH:33]=4)[CH:15]=3)=[CH:19][CH:20]=2)[CH2:26][CH2:27]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)cc1
Agent: Cn1ccc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc21
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)cc1
Yield: 69 %

Procedure:
Starting from the compound 201 and following the procedure described above for the compound 162 (scheme 31), title compound 202 was obtained in 69% yield. LRMS (M+1) 448.2 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:33]([O-])(O)=O.[Na+].CCOC(C)=O>C1(C)C=CC=CC=1.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:22][CH3:33])[CH:24]=[CH2:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C[C@H](CC)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Tebbe reagent (Bis(cyclopentadienyl)-μ-chloro(dimethylaluminum)-μ-methylenetitanium, 0.5 M solution in toluene, 1.7 mL, 0.85 mmol) was added dropwise over 5 minutes to a stirred solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetate (Example 415, Step A, 360 mg, 0.756 mmol) in toluene (4.7 mL) at 0° C. The reaction was stirred at 0° C. for 20 minutes and at rt for 30 minutes. The reaction was recooled to 0° C. and an additional portion of Tebbe reagent (0.5 M solution in toluene, 1 mL, 0.5 mmol) was added. The reaction was allowed to warm to rt for 20 minutes. The reaction was recooled to 0° C. and treated with sat. aq. NaHCO3 solution (40 mL) and EtOAc (100 mL). The separated aqueous layer was extracted with EtOAc (2×60 mL) and the combined organic extracts were washed with brine (80 ml), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Column chromatography on silica gel (24 g, SiO2, eluent: hexanes:EtOAc, 1:0 to 3:1, gradient elution) gave the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CS(C)=O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
12.0 g (74.9 mmol) diethyl malonate were dissolved in 50 ml DMSO and 8.6 g (76.6 mmol) potassium t-butoxide were added. A solution of 7.9 g (50.1 mmol) 1-chloro-4-nitrobenzene in 50 ml DMSO was added via a dropping funnel. The mixture was heated at 100° C. for 4 h and poured on to crushed ice. It was extracted twice with ethyl acetate, the combined organic layers washed with brine, dried over sodium sulfate, and evaporated in vacuo to afford a brown oil, which contained the title compound in an amount of about 75% and which was used in the reaction of the next step.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:24]([CH2:26][NH2:27])[OH:25]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][CH2:26][CH2:24][OH:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Reactant: NCCO
Product: CCOC(=O)C(=CNCCO)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (7.0 g) and ethanol amine (1.33 ml), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetraflurobenzoyl)-3-(2-hydroxyethyl)aminoacrylate. To the product are added pyridine (70 ml) and acetic anhydride (2.57 ml) and the mixture is stirred at room temperature over-night. After concentration, the resultant is diluted with water, subjected to extraction with dichloromethane, and the extract is washed with water and then with a saturated saline solution and dried to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2-acetyloxyethyl) aminoacrylate, which is then treated with 60% sodium hydride (1.09 g) as in Reference Example 22 to give ethyl 1-(2-acetyloxyethyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4 -oxoquinoline-3carboxylate (6.15 g), as colorless prisms (recrystallized from ethyl acetate), m.p. 192°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N1CCCCC1CCl
Reactant: Sc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N1CCCCC1CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 280 g (1.94 mole) of p-chlorothiophenol and 120 ml of 50% sodium hydroxide in 1 liter of dimethylformamide was stirred for 15 min at 25° C. One mole of 2-chloromethyl-1-(phenylsulfonyl)piperidine was added and the solution was stirred at 60° C. for 65 hr. The mixture was quenched in water and the aqueous mixture was extracted with methylene chloride. The methylene chloride solution was extracted with several portions of dilute sodium hydroxide and evaporated in vacuo to give an oil. The oil was crystallized from methanol to give solid product, m.p. 78.5°-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:26])[CH2:14][NH:15][C:16]3[CH:25]=[CH:24][C:19]4[NH:20][C:21](=[O:23])[O:22][C:18]=4[CH:17]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.N[C:30]1C=CC2NC(=O)COC=2C=1>CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:26])[CH2:14][NH:15][C:16]3[CH:25]=[CH:24][C:19]4[NH:20][C:21](=[O:23])[CH2:30][O:22][C:18]=4[CH:17]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(CNc1ccc2[nH]c(=O)oc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Solvent: CO
Product: O=C1COc2cc(NCC(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 2-chloro-1-[4-(4-chloro-phenoxy)-piperidin-1-yl]-ethanone (Example 233) and 7-amino-4H-benzo[1,4]oxazin-3-one according to the method described in Example 206. Melting Point:207-210° C. (methanol)
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21]C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([OH:21])=[C:6]([C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[CH:8][CH:9]=1)[O:20][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC(F)F)c2O)cc1
Temperature: 80 °C
Yield: 47.3 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (100 mg, 0.310 mmol) in acetonitrile (20 mL), was added potassium carbonate (128.3 mg, 0.930 mmol) and 4-bromomethyl-benzenesulfonamide (155.2 mg, 0.620 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford title compound as a solid (70 mg, 46%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([NH2:11])=O)=[N:4]1)[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]#[N:11])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(N)=O)cc1C
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1nc(C#N)cc1C
Yield: 90.6 %

Procedure:
1-Ethyl-5-methyl-1H-pyrazole-3-carboxamide (10.2 g, 66.7 mmol) was treated with phosphorus oxychloride (41 mL) according to the method described in Part C of Example 8. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 1-21% ethyl acetate/hexanes followed by 2-25% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure to yield 8.17 g of 1-ethyl-5-methyl-1H-pyrazole-3-carbonitrile as clear colorless crystals.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10]/[C:9](=[C:12](/[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)\[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)/[C:8]1=[O:30])(=O)C.[OH-].[Na+]>C(O)C.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23](/[C:12](=[C:9]2\[C:8](=[O:30])[N:7]([CH2:6][CH2:5][OH:4])[CH2:11][CH2:10]\2)/[C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)=[CH:28][CH:27]=1
Reactant: CC(=O)OCCN1CC/C(=C(/c2ccc(Cl)cc2)c2ccc(S(C)(=O)=O)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C2\CCN(CCO)C2=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
1 g (0.0022 mole) of (Z)-2-[3-[1-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]methylene]-2-oxo-pyrrolidin-1-yl]ethyl acetate are placed in solution in a mixture of 13 ml of ethanol and 11 ml of water and treated with 0.1 g (1.1 eq.) of sodium hydroxide. The medium is stirred at ambient temperature for 4 h, then the ethanol is evaporated off. The aqueous phase is extracted with dichloromethane. The organic phase is washed with water, dried and concentrated. The residue is taken up into t-butyl methyl ether. 0.7 g of (Z)-3-[1-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]methylene]-1-(2-hydroxyethyl)-pyrrolidin-2-one are thus obtained as a yellow solid of melting point 187-188° C.
Reaction SMILES: C([N:6]1[CH:12]([CH3:13])[C:11]2[CH:14]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:16][C:10]=2[S:9](=[O:22])(=[O:21])[CH2:8][CH2:7]1)(=O)C(C)C.C(O)C.C([O-])(O)=O.[Na+].[ClH:31]>O>[ClH:31].[CH3:13][CH:12]1[C:11]2[CH:14]=[C:15]([S:17](=[O:19])(=[O:20])[NH2:18])[S:16][C:10]=2[S:9](=[O:22])(=[O:21])[CH2:8][CH2:7][NH:6]1
Reactant: CC(C)C(=O)N1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1NCCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 100 °C
Yield: 80 %

Procedure:
A suspension of 4-isobutyryl-5(R,S)-methyl-7-sulfamoyl-2,3,4,5-tetrahydrothieno[3,2-f]-1,4-thiazepine-1,1-dioxide (500 mg, 1.5 mmol) in water (8 mL) and concentrated HCl (4 mL) containing ethanol (3 mL) was warmed at 100° C. for 2 days. The cooled solution was made weakly basic with NaHCO3 and the product was extracted into ethyl acetate. The extract was dried (Na2SO4), filtered through a pad of charcoal and the solvent evaporated. Trituration of this residue afforded 361 mg (80%) of title compound, mp 236°-238° C. dec.