Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.[Cl:14]OC(C)(C)C>O1CCCC1>[NH2:1][C:2]1[C:3]([Cl:14])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1N)CCCC2=O
Reactant: CC(C)(C)OCl
Solvent: C1CCOC1
Product: Cc1cc2c(c(Cl)c1N)CCCC2=O
Yield: 90 %

Procedure:
The product from Example 105 (0.175 g) was dissolved in tetrahydrofuran (5 ml) and was treated with t-butyl hypochlorite (0.12 ml). Following the procedure of Example 95 the desired product was obtained in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[C:17]([CH2:18][S:19][C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)=[C:16]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:15]=[CH:14][C:3]=1[C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5].C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[Cl:33][C:7]1[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:6]=1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][C:16]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:17]([CH2:18][S:19][C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:2]=1[Cl:1]
Reactant: Cn1nnnc1SCc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CCCC2=O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nnnc1SCc1c(S(C)(=O)=O)ccc(C(=O)C2=C(Cl)CCCC2=O)c1Cl
Yield: 68.2 %

Procedure:
To a solution of 2-{2-chloro-4-methylsulfonyl-3-{[(1-methyl-1Htetrazol-5-yl)thio]-methyl}benzoyl}cyclohexane-1,3-dione (1.0 g) in dichloromethane (100 ml), oxalyl chloride (0.91 g) and 2 drops of N,N-dimethylformamide were added dropwise and the mixture was refluxed for 3 hours. The residue obtained by distilling off the solvent after the reaction was purified by silica gel column chromatography (eluant:ethyl acetate:hexane=7:3) to obtain the objective 3-chloro2-{2-chloro-4-methylsulfonyl-3-{[(1-methyl-1H-tetrazol-5-yl)thio]methyl}benzoyl}-2-cyclohexen-1-one (0.71 g). IR (NaCl):=1662,1310,1279, 1150 cm−1.
Reaction SMILES: C[O:2][C:3]1([O:35]C)[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[C:24](=[O:28])[C:23]([O:31]C)([O:29]C)[C:22]5=[O:33])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]1=[O:34].C(O)(=O)C.Br>O>[OH:31][C:23]1([OH:29])[C:22](=[O:33])[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:8]4[CH:9]=[C:10]5[C:5](=[CH:6][CH:7]=4)[C:4](=[O:34])[C:3]([OH:35])([OH:2])[C:11]5=[O:12])=[CH:18][CH:17]=3)[CH:20]=2)[C:24]1=[O:28]
Reactant: COC1(OC)C(=O)c2ccc(-c3ccc(-c4ccc5c(c4)C(=O)C(OC)(OC)C5=O)cc3)cc2C1=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(-c3ccc(-c4ccc5c(c4)C(=O)C(O)(O)C5=O)cc3)cc2C(=O)C1(O)O
Temperature: 25 °C
Yield: 91 %

Procedure:
1,4-bis(2,2-dimethoxy-1,3-dioxoindan-5-yl)benzene (20) (209 mg, 0.429 mmol) was suspended in a solvent mixture of 3 ml of acetic acid and 3 ml of water, and the suspension was mixed with 3 ml of 47% hydrobromic acid. The mixture was refluxed for 2 hours. It was then cooled to room temperature to deposit a solid, which was collected by filtration. The solid was washed with cold water and chloroform and vacuum dried to obtain 168 mg (91%) of 1,4-bis(2,2-dihydroxy-1,3-dioxoindan-5-yl)benzene (21) in the form of a light gray solid. The readings for this compound are as follows.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35]>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:35]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([Cl:30])[CH:32]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: NCc1cccc(Cl)c1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(Cc2cccc(Cl)c2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 3-chloro-benzylamine. MS (ESI): 453.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:64]([C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1)[CH3:65]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:64]([C:66]1[CH:72]=[CH:71][C:69]([NH:70][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])=[CH:68][CH:67]=1)[CH3:65]
Reactant: CCc1ccc(N)cc1
Reactant: COC(=S)c1cc(Br)c(C)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CCc1ccc(Nc2cc(C(=S)OC)sc2C)cc1
Temperature: 100 °C
Yield: 12.8 %

Procedure:
To an oven-dried glass vial with stir bar was added a mixture of 100 mg (0.374 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a)), 5.8 mg (6.9 mol %) of palladium (II) acetate, 21.7 mg (9.3 mol %) of racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 171.5 mg (0.526 mmol) of cesium carbonate and 59 mg (0.487 mmol) of 4-ethylaniline. The vial was transferred to a glove bag, flushed with dry argon and anhydrous toluene (749 μL) was added. The vial was capped with a Teflon-lined screw cap and heated at 100° C. for 48 h. The cooled suspension was filtered (Celite) washing with ethyl acetate (2×2 mL), and the solvents removed in vacuo. The resulting residue was purified on 1 mm silica prep plates eluting with 40% methylene chloride-hexanes to afford 14 mg (12%) of methyl 4-[(4-ethylphenyl)amino]-5-methylthiothiophene-2-carboxylate as a pale yellow resin which was used directly in the following step.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(N(CC)CC)C.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(OCC)(=O)C.O>CN(C=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Temperature: 78 °C
Yield: 96.8 %

Procedure:
To a solution of 4-chloromethyl-1-methyl-2-nitro-benzene (2 g) and triethylamine (3 ml) in DMF (10 ml) was added piperazine-1-carboxylic acid tert-butyl ester (2.01 g) and the stirred reaction heated at 78° C. for 15 hr. After cooling to room temperature, the reaction was poured into ethyl acetate/water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water, aqueous KHSO4, aqueous K2CO3 and brine, dried (Na2SO4) and concentrated to leave the sub-title compound as a brown oil (3.5 g).
Reaction SMILES: [C:1]1([N:7]=[C:8]([S:15][CH:16]([CH3:22])[CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>CO>[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36][CH:10]=[CH:9][C:8](=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:15][CH:16]([CH3:22])[CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:32][CH:31]=1
Reactant: Fc1ccc(S)cc1
Reactant: CCC(CC)C(C)SC(C#C[Si](C)(C)C)=Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(CC)C(C)SC(C=CSc1ccc(F)cc1)=Nc1ccccc1
Reaction time: 1 h

Procedure:
Etynyltrimethylsilane (0.7 mL) was dissolved to dry THF (15 mL), hexane solution of n-butyl lithium (1.58 moL/L; 3.2 mL) was added dropwise to the solution at −78° C., and then the mixture was allowed to warm to 0° C. After that, THF (2 mL) solution of phenyl isotiocyanate (0.61 mL) was added dropwise to the mixture, and then it was stirred for 30 minutes under ice-cooling. THF (1 mL) solution of 2-ethyl-1-methylbutyl methanesulfonate (1.01 g) was added to the solution and heated under reflux for 6.5 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to Florisil column chromatography(hexane/ethyl acetate=20/1) to obtain 2-ethyl-1-methylbutyl N-phenyl-3-(trimethylsilyl)thiopropynimidate (0.74 g). Obtained 2-ethyl-1-methylbutyl N-phenyl-3-(trimethylsilyl)thiopropynimidate was dissolved to methanol (15 mL), and then small amount of potassium carbonate was added to the solution at room temperature, and then it was stirred for 1 hour. After that, 4-fluorothiophenol (0.19 mL) was added to the mixture at room temperature and stirred for 2.7 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane/ethyl acetate=20/1) and medium pressure HPLC (hexane/ethyl acetate=99/1) to obtain 2-ethyl-1-methylbutyl 3-(4-fluorophenylthio)-N-(phenyl)thioacrylimidate (0.43 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17](=[O:27])[N:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[CH3:19])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:27])[N:18]([C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:24][CH2:25]1)[CH3:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Oc2cc(F)ccc2[N+](=O)[O-])CC1

Procedure:
Prepared analogously to example III.1 from 1.11 ml 2,4-difluoronitrobenzene and 1.56 g trans-(4-hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1]Br.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[N:14]3[CH:23]=2)=[CH:7][CH:6]=1)#[N:4]>C(Cl)Cl.CC(O)=O>[Br:1][C:23]1[N:14]2[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)cn12
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nc(-c3ccc(C#N)cc3)c(Br)n12
Yield: 88 %

Procedure:
Br2 (1.0 eq.) was added, dropwise, to a solution of (A2) in DCM/AcOH=1:1 (0.05 M) at RT and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched by the addition of sat. aq. NaHCO3. The aqueous phase was separated and extracted several times with DCM. The combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent gave a residue which was purified by flash column chromatography on silica using a gradient of EtOAc/Petroleum ether from 30:70 to 50:50 to yield (88%) the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.24 (2H, d, J=8.4 Hz), 8.00 (2H, d, J=8.6 Hz), 7.93 (1H, d, J=8.6 Hz), 7.55-7.45 (2H, m), 4.02 (3H, s). MS (ES+) C16H10BrN3O2 requires: 355/357, found: 356/358 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[C:5]([F:27])=[C:6]([C:19]([N+:24]([O-:26])=[O:25])=[C:20]([F:23])[C:21]=1[F:22])[C:7]([C:9](=[CH:15]OCC)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[CH:29]1([NH2:32])[CH2:31][CH2:30]1>C(Cl)Cl>[CH:29]1([NH:32][CH:15]=[C:9]([C:7](=[O:8])[C:6]2[C:19]([N+:24]([O-:26])=[O:25])=[C:20]([F:23])[C:21]([F:22])=[C:4]([O:3][CH:2]([F:28])[F:1])[C:5]=2[F:27])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:31][CH2:30]1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Reactant: NC1CC1
Solvent: ClCCl
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
The whole of the ethyl 2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)-3-ethoxyacrylate [(XVI), R1 =--OCHF2, R3' =NO2, R17 =C2H5, X=X'=F]obtained as described in step (c) above was dissolved in 500 ml of methylene chloride, and 3.5 g (0.06 moles) of cyclopropylamine were added dropwise to the resulting solution, whilst stirring and ice-cooling. The mixture was then stirred for 1 hour, whilst ice-cooling, and then for an additional 1 hour at room temperature, after which the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography using a 9:1 by volume mixture of toluene and ethyl acetate as the eluent, to give 19.8 g of ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)acrylate as an yellow powder, melting at 105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.CSC1C2C(=CN=CC=2)NN=1.[CH3:31][S:32]([C:35]1[C:43]2[C:38](=[CH:39][N:40]=[CH:41][CH:42]=2)[NH:37][N:36]=1)(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]3)[C:7]([CH2:9][N:37]3[C:38]4=[CH:39][N:40]=[CH:41][CH:42]=[C:43]4[C:35]([S:32]([CH3:31])(=[O:33])=[O:34])=[N:36]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: O=C1CC(n2c(CCl)nc3cc(Cl)ccc32)CCN1
Agent: CSc1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCNC(=O)C2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 4-(5-chloro-2-(chloromethyl)-1H-benzo[d]imidazol-1-yl)piperidin-2-one and 3-(methylthio)-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: CNCCNC.Br[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[Cl:14][C:15]1[C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN(C)C=O>[Cl:14][C:15]1[C:19]([NH:20][C:21](=[O:23])[CH3:22])=[CH:18][N:17]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:16]=1
Reactant: CC(=O)Nc1c[nH]nc1Cl
Reactant: Brc1cccnc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Temperature: 97.5 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A 4-neck round bottom flask was charged with N,N-dimethylformamide (250 mL) and then degassed 2-3 times. Copper(I) iodide (17.9 g, 94.0 mmol) was added, followed by N,N′-dimethylethane-1,2-diamine (16.2 g, 188 mmol) at 25-30° C. The mixture was purged with nitrogen for 30 minutes. 3-Bromopyridine (59.4 g, 376 mmol) was added, followed by N-(3-chloro-1H-pyrazol-4-yl)acetamide (50.0 g, 313 mmol) and potassium carbonate (87.0 g, 188 mmol) at 25-30° C. The reaction mixture was purged with nitrogen for 30 minutes and heated at 95-100° C. for 3 hours, at which point HPLC analysis indicated that the reaction was complete. It was cooled to 25-30° C. and water (1 L) was added over 30-45 minutes. The resulting suspension was stirred at 25-30° C. for 30 minutes and cooled to 0-10° C. It was stirred for 12 hours at 0-10° C. and then filtered. The filter cake was rinsed with water (2×250 mL) and dried to afford an off-white solid (55 g, 74%). Characterization matched sample prepared by previous method.
Reaction SMILES: Br[C:2]1[C:3]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:12][C:4]=2[N:5]([CH:7]([O:9][CH2:10][CH3:11])[CH3:8])[N:6]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[CH2:10]([O:9][CH:7]([N:5]1[C:4]2[S:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:3]=2[C:2]([NH:33][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([N:24]3[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]3)=[CH:35][CH:34]=2)=[N:6]1)[CH3:8])[CH3:11]
Reactant: CCOC(=O)c1cc2c(Br)nn(C(C)OCC)c2s1
Reactant: CN1CCN(c2ccc(C(N)=O)cc2)CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(NC(=O)c3ccc(N4CCN(C)CC4)cc3)nn(C(C)OCC)c2s1
Temperature: 110 °C
Yield: 26.9 %

Procedure:
Ethyl 3-bromo-1-(1-ethoxyethyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate (10.9 g, 31 mmol), 4-(4-methylpiperazin-1-yl)benzamide (9 g, 41 mmol, 1.3 eq.), copper(I)iodide (0.601 g, 3.1 mmol, 0.1 eq.), preground tripotassium phosphate (20.1 g, 94 mmol, 3 eq.) and 70 mL of anhydrous dioxane degassed beforehand with argon are placed in a 500 mL round-bottomed flask under argon. N,N′-Dimethylethylenediamine (0.336 mL, 3.16 mmol, 0.1 eq.) is added to this suspension by syringe. The reaction mixture is then heated at a temperature in the region of 110° C. for a period of 24 hours. The dioxane is then evaporated off under vacuum and the residue is diluted with ethyl acetate (300 mL) and 150 mL of water. The organic phase is washed with 100 mL of water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel, eluting at the start with a dichloromethane/methanol mixture (90/10 by volume). Ethyl 1-(1-ethoxyethyl)-3-[4-(4-methylpiperazin-1-yl)benzoylamino]-1H-thieno[2,3-c]pyrazole-5-carboxylate (4.05 g, 27%) is thus obtained in the form of a pale yellow oil, which product is used directly in the following step.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1[SH:9].Br[C:12]1[S:13][C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>>[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1[S:9][C:12]1[S:13][C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(Br)s1
Reactant: Sc1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 9 %

Procedure:
3,5-dichloropyridine-4-thiol sodium salt prepared as in example 17 (0.160 g, 0.39 mmol) and 2-bromo-5-methylsulfonyl-3-nitro-thiophene (0.1 g, 0.36 mmol) were dissolved in N,N-dimethylformide (3 mL). To the above mixture, potassium carbonate (0.192 g, 1.39 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 5 hours. After this time, the reaction mixture was quenched with ice water and stirred at ambient temperature for 20 minutes and the resulting precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo at 40° C. overnight. The solid was triturated with dichloromethane and diethyl ether to afford the title product as an off-white solid (35 mg, 9% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.03 (1H, s), 8.66 (1H, s), 3.56 (3H, s). MS m/z: 383.09 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3]Cl.COCCO.C(=O)([O-])[O-].[K+].[K+].[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:17]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:16]([O:24][CH2:25][CH3:26])=[O:23])[CH2:3][CH2:2]1
Reactant: ClCCCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: COCCO
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CC1
Yield: 85 %

Procedure:
296.9 g of 1,2-dichloroethane (3 mol), 5 g of polyethylene glycol monomethyl ether (mean molar mass 550 g/mol) and 177.1 g of potassium carbonate (1.265 mol) were initially introduced, and the reaction mixture was heated until the 1,2-dichloroethane refluxes. 152.2 g of diethyl malonate (0.95 mol) and 1.25 g of tetrabutylammonium bromide (3.88 mmol) were then added at the boil. The mixture was stirred using a paddle stirrer for 8 hours. Water formed during the reaction was removed by azeotropic distillation with 1,2-dichloroethane throughout the reaction. Further work-up was carried out analogously to Comparative Example 2. The yield was 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:36]([SH:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([S:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Reactant: SCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2SCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added benzyl mercaptan (0.04 mL, 0.33 mmol) and TEA (0.046 mL, 0.33 mmol). The resulting solution was stirred at room temperature under nitrogen for 1 hour. The mixture was poured into H2O and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified using flash chromatography (SiO2, 2:1 hexanes:ethyl acetate) to provide the desired product (yield: 0.136 g 85%). mp 142-145° C. 1H NMR (300 MHz, DMSO d6) δ 3.31 (s, 3H), 4.36 (s, 2H), 7.17 (m, 2H), 7.21-7.33 (m, 3H), 7.51 (m, 2H), 7.57-7.64 (m, 3H), 7.74 (m, 1H), 8.01 (m, 2H). MS (DCI/NH3) m/z 483 (M+H)+, 500 (M+NH4)+. Anal. calc. for C24H19ClN2O3S2: C, 59.68; H, 3.96; N, 5.80. Found: C, 59.40; H, 4.11; N, 5.71.
Reaction SMILES: C[N:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([C:5]1[C:6](=[O:17])[N:7]([CH3:16])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[F:24]C1C=CC(N)=CC=1.CCCCCCC>C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([NH:2][C:3]([C:5]2[C:6](=[O:17])[N:7]([CH3:16])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:4])=[CH:19][CH:20]=1
Reactant: CN(C(=O)c1c(O)c2ccccc2n(C)c1=O)c1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cn1c(=O)c(C(=O)Nc2ccc(F)cc2)c(O)c2ccccc21
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A solution of N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (15 mg, 0.050 mmol) and 4-fluoro-aniline (0.100 mmol) in toluene (0.5 mL) was stirred at 100° C. for 1 h. Heptane (1.5 mL) was added and the solution was allowed to cool to room temperature. The crystallized product was separated from the solution and washed with heptane to give the title compound (12 mg, 79%).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:29])[C@@H:16]([S:18][C:19]3[C:24](OCOC)=[CH:23][CH:22]=[CH:21][N:20]=3)[CH3:17])=[CH:11][CH:10]=2)=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[CH3:17][C@H:16]1[C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[O:29][C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[S:18]1
Reactant: COCOc1cccnc1S[C@@H](C)C(O)c1ccc(OCc2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C[C@@H]1Sc2ncccc2O[C@H]1c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
The compound synthesized in the above (6) was mixed with anisole (8.52 mL, 78.8 mmol) and trifluoroacetic acid (20 mL, 0.26 mol) under cooling with ice, and stirred for 15 minutes under cooling with ice. Aqueous saturated sodium hydrogencarbonate solution was added, then the reaction solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, water and saturated saline in that order, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane/ethyl acetate=1/1), and further recrystallized (ethyl acetate/n-heptane) to obtain the entitled compound (1.9 g, 35% in 2 steps) as a white solid.