Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:57][CH2:58]C=O)[N:45]=[C:46]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)[C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:57][CH2:58][CH2:6][N:8]3[CH2:9][CH2:10][N:11]([C:14]4[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:23])[CH2:12][CH2:13]3)[N:45]=[C:46]([C:47]3[CH:48]=[CH:49][C:50]([C:53]([F:55])([F:56])[F:54])=[CH:51][CH:52]=3)[C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2[N+](=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
4-(2-Chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (940 mg, 2.75 mmol) in 10 mL of CH2Cl2 was treated with 5 mL of trifluoroacetic acid and stirred at 25° C. for 1 h. The volatiles were then removed. The residue was taken up in CH2Cl2 (60 mL) and KOH (4 N, 20 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The yellow oil was dissolved in CH2Cl2 and added into the 996 mg (2.35 mmol) of 1-(3-oxo-propyl)-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester. The yellow solution was treated with glacial acetic acid (0.8 mL, 6 eq) and stirred at 25° C. for 1 h. NaBH(OAc)3 (1.5 g, 7.05 mmol) was added and stirred under nitrogen for 2 h. Then saturated NaHCO3 (20 mL) was added and stirred for 30 min, and the layers were separated. The organic extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Column chromatography (silica, 2-5% MeOH/CH2Cl2) afforded 1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester as a white solid (1.40 g, 92%). TLC (silica, 5% MeOH/CH2Cl2): Rf=0.3. MS (electrospray): exact mass calculated for C31H36ClF3N6O4, 648.24; m/z found 649.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.69 (d, J=8.2 Hz, 1H), 7.60-7.50 (m, 1H), 7.45-7.37 (m, 4H), 7.02 (t, J=8.2 Hz, 1H), 4.58 (br s, 2H), 4.04 (t, J=6.7 Hz, 2H), 3.73-3.65 (m, 2H), 3.05-2.95 (m, 4H), 2.71 (t, J=5.6 Hz, 2H), 2.50-2.35 (m, 4H), 2.30 (t, J=6.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)=[CH:32][CH:31]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.4 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (451 mg) synthesized in Example 4 and 4′-fluorobiphenyl-4-ol (280 mg) were dissolved in tetrahydrofuran (10 mL), triphenylphosphine (430 mg) and diisopropyl azodicarboxylate (40% toluene solution, 0.88 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 17 hr. The reaction mixture was concentrated under reduced pressure, and hexane (about 10 mL) was added. The precipitated crystals were removed by filtration, and the solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (390 mg) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=2)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:28])=[CH:22][CH:21]=1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(Cl)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:17]1(B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20][CH2:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:17]1([C:2]2[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)[CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(C2=CCCC2)c1
Temperature: 80 °C
Yield: 43.6 %

Procedure:
To a stirred solution of 3-bromo-5-nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (Example 1a) (6 g, 19.9 mmol) in DMF (30 mL) was added 2-(1-cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 287944-10-9) (4.64 g, 23.9 mmol) and K2CO3 (8.2 g, 59.8 mmol) at 25° C. and the reaction mixture was degassed with argon over 30 min. To this was added PdCl2 (dppf)2 dichloromethane complex (814 mg, 1.1 mmol) and the reaction mixture was heated to 80° C. for 20 h. The reaction mixture cooled to 25° C., water (50 mL) was added, the mixture was extracted with ethyl acetate (4×50 mL), washed with water (200 mL), brine, dried with Na2SO4 and concentrated. The crude material was purified by column chromatography (Combi-Flash, 40 g, 2% dichloromethane/hexane) to get the title compound (2.5 g, 43.51%) as pale white solid; NMR complies.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=[S:4].CO[CH:14](OC)[CH2:15]Cl>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[S:4][CH:14]=[CH:15][N:5]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C(N)=S)c1ccccc1
Reactant: COC(CCl)OC
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1nccs1

Procedure:
A solution of 10 g (60 mmol) of N-methyl-N-phenylthiourea in 100 mL of toluene was treated with 7.2 mL (63 mmol) of chloroacetaldehyde dimethylacetal and heated at reflux for 12 h. The solvent was removed in vacuo and the residue purified by flash chromatography eluting with a linear gradient of 30% EtOAc in hexane to 80% EtOAc in hexane to deliver the title compound. MS (M+H)+ 191.
Reaction SMILES: O.[Cl:2][C:3]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[N:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8]>[Zn].C(O)(=O)C>[Cl:2][C:3]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:7](=[O:8])[NH:9][C:10](=[O:11])[CH2:12][NH:13]1
Reactant: O=c1cnn(Cc2ccc(Cl)cc2Cl)c(=O)[nH]1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CNN(Cc2ccc(Cl)cc2Cl)C(=O)N1
Yield: 50 %

Procedure:
Into a three-necked flask equipped with a mechanical stirrer and a condenser were placed 300 ml of water, and stirring was commenced. 3 g of 1-(2',4'-dichlorobenzyl)-6-aza uracil were added and after a fine suspension had been obtained, of 60 ml of glacial acetic acid was added to this suspension. 3.3 g of fine zinc powder was then added in small portions. After all materials had been added the mixture was vigorously stirred and refluxed for 24 hours. The completion of the reduction was verified by thin layer chromatography. The mixture was cooled and the precipitate thus formed was filtered off and redissolved in hot methanol. The undissolved material was filtered off and the methanol solution was cooled to yield 2-(2',4'-dichlorobenzyl)hexahydro-1,2,4-triazine-3,5 dione; m.p. 230°; yield 1.4 g (60%).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2csc3c2OC(C)CN(C(=O)OC(C)(C)C)C3)c1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (348 mg), (3-methoxyphenyl)boronic acid (198 mg), dichlorobis(triphenylphosphine)palladium (35 mg) and potassium carbonate (415 mg) in DME-water (1:1, 10 mL) was stirred at 85° C. for 1.5 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (294 mg, 78%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:24]([O:26][CH3:27])=[O:25])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)=[N:11][CH:10]=1>C(O)(=O)C.C1COCC1.[Pt]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]2[S:13][C:9]([S:8][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:24]([O:26][CH3:27])=[O:25])[C:2]=3[F:1])=[CH:10][N:11]=2)=[N:16][CH:17]=1
Reactant: COC(=O)c1nccc(Sc2cnc(Nc3ccc([N+](=O)[O-])cn3)s2)c1F
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1nccc(Sc2cnc(Nc3ccc(N)cn3)s2)c1F
Reaction time: 8 h

Procedure:
A stirring solution of methyl 3-fluoro-4-(2-(5-nitropyridin-2-ylamino)thiazol-5-ylthio)picolinate (1.77 g, 4.34 mmol), 10% Pt/C (366 mg) in acetic acid (5 mL) and THF (20 mL) was purged 4× with H2, then pressurized to 140 psi in a steel bomb reactor and stirred overnight. The reaction was depressurized, and LCMS showed intermediate nitroso as predominant product. Pt/C (270 mg) was added and the reaction repressurized to 140 psi and stirred overnight. The reaction was depressurized, LCMS showed complete reaction. The reaction was filtered through Celite, washed with THF and DCM, the filtrate was concentrated. The residue was recrystallized from EtOAc and hexane, the solid was collected by filtration and washed with hexane. The product was obtained (828 mg, 51%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.43 (1H, s), 8.31 (1H, d, J=5.05 Hz), 7.72 (1H, s), 7.66 (1H, d, J=2.27 Hz), 7.11 (1H, t, J=5.31 Hz), 7.06 (1H, dd, J=8.59, 2.78 Hz), 6.87 (1H, d, J=8.59 Hz), 4.99 (2H, s), 3.89 (3H, s); LC/MS (M+H)+: 378. HPLC ret. time (Condition E): 1.45 min.
Reaction SMILES: [C:1]([S:5](/[N:7]=[C:8](/[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)\[CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Mg]Br.C(OCC)C>C(Cl)Cl>[C:1]([S:5]([NH:7][C@@:8]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)([CH3:26])[CH2:9][CH2:10][C:11]([CH3:16])([CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(C)CC/C(=N\S(=O)C(C)(C)C)c1cc(F)cc(F)c1
Reactant: C[Mg]Br
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C)(C)CC[C@](C)(NS(=O)C(C)(C)C)c1cc(F)cc(F)c1
Reaction time: 0.25 h

Procedure:
To a solution of methyl (5E)-5-[(tert-butylsulfinyl)imino]-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate (342 mg, 0.920 mmol) in CH2Cl2 (6 mL) at 0° C., was added dropwise over five minutes methyl magnesium bromide as a 3M solution in diethyl ether (0.61 mL, 1.83 mmol). After 15 minutes the reaction was determined to be complete by LCMS analysis. The reaction was quenched by the dropwise addition of 1M HCl (5 mL), followed by 5 mL of water. The aqueous layer was extracted once with CH2Cl2 (10 mL) and the organics were combined and washed once with brine (15 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 55:45, to give the title compound. MS: m/z=390 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[F:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([N:23]3[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH2:25][CH2:24]3)=[CH:21][S:20][C:19]=2[CH:35]=1>N1C=CC=CC=1.C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]2[C:22]([N:23]3[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)=[O:12])[CH2:25][CH2:24]3)=[CH:21][S:20][C:19]=2[CH:35]=1
Reactant: NCCCCN1CCCN(c2csc3cc(F)ccc23)CC1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCCCN1CCCN(c2csc3cc(F)ccc23)CC1)c1ccc2ccccc2c1
Yield: 91.9 %

Procedure:
Add slowly a solution of 2-naphthoyl chloride (600 mg, 3.15 mmol) to a solution of 4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazapan-1-yl]butylamine (Example 6) (920 mg, 2.86 mmol), in pyridine-methylene chloride (10 mL,1:1), and stir the solution at room temperature overnight. Evaporate the solvent under vacuum, dissolve the residue in EtOAc and wash the organic layer with water and saturated sodium chloride solution. Combine the organic phases, dry over MgSO4 and evaporate the solvent under vacuum. Purify the crude product by column chromatography (EtOAc/MeOH 7:3) to obtain 1.25 g of a solid LC/MS (LiChrospher 5μ, RP-18, 250 mm CH3CN/Water-gradient 20%→100% (25 min), Flow: 1.5 mL/min) tR=21.11 min, m/z=475.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[CH:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:19]1[S:20][CH:21]=[CH:22][C:23]=1[S:24]([CH3:27])(=[O:26])=[O:25].C(N(CC)CC)C.CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]#[C:17][C:19]3[S:20][CH:21]=[CH:22][C:23]=3[S:24]([CH3:27])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: C#CC1CCN(Cc2cccnc2OC)CC1
Reactant: CS(=O)(=O)c1ccsc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncccc1CN1CCC(C#Cc2sccc2S(C)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
500 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-(1-ethynyl)piperidine, 530 mg of 2-bromo-3-(methylsulfonyl)thiophene, 21 mg of anhydrous cupric iodide and 127 mg of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent of 2.2 ml of triethylamine and 2.2 ml of N,N-dimethylformamide, and the mixture was stirred at 100° C. for 2 hours under nitrogen flow. Ethyl acetate was added to the reaction solution, and the resulting precipitates were filtered off. Then, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and then the crude product was purified by silica gel column chromatography (ethyl acetate), to give 450 mg of the title compound as a colorless oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11]([CH3:13])[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl>ClC1C=CC=CC=1>[CH:11]([C:5]1[CH:10]=[CH:9][C:8]([C:21]([C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:25][CH:24]=2)=[O:22])=[CH:7][CH:6]=1)([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CC(C)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
710 parts of chlorobenzene and 160 parts of AlCl3 are initially introduced. A mixture of 120 parts of cumene, 185.6 parts of p-nitrobenzoyl chloride and 410 parts of chlorobenzene is added dropwise in the course of 1 hour at 20° to 25° C., HCl gas being liberated. The mixture is then heated in the course of 1 hour to 60° C. and stirred for 1 hour at 60° C., 1,400 parts of ice are added, the aqueous phase is separated off in a separating funnel and the organic phase is concentrated in vacuo. 247.6 parts of 4-isopropyl-4'-nitrobenzophenone having a melting point of 95° C. are obtained. Yield: 92% of theory.
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(O)=[O:2].S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[Cl:26][C:1](/[CH:4]=[CH:5]/[C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: Cc1c(-c2ccccc2)oc2c(/C=C/C(=O)O)cccc2c1=O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2)oc2c(/C=C/C(=O)Cl)cccc2c1=O
Yield: 69.7 %

Procedure:
A solution of 9.2 g of Intermediate III and 7.8 g of thionyl chloride in 75 ml of toluene was refluxed for 3 hours. After cooling to 20°-25° C. the resultant crystal was collected by suction filtration, washed with acetone and dried in vacuo to give 6.8 g of the title compound, m.p. (190) 196°-198° C. after recrystallization from toluene.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](SC)=[N:17][C:16]3=[O:22])[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH2:34])[CH3:24].CCN(C(C)C)C(C)C>>[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][NH:34][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][CH:5]=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=1)[CH3:24]
Reactant: CCOc1ccccc1CCN
Reactant: CCOc1ccnc2ccc(C=C3SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccccc1CCNC1=NC(=O)/C(=C/c2ccc3nccc(OCC)c3c2)S1

Procedure:
Similar procedure as described in example 40c was used, starting from 5-(4-ethoxy-quinolin-6-ylmethylene)-2-methylsulfanyl-thiazol-4-one (example 40b), 2-(2-ethoxy-phenyl)-ethylamine and DIEA to give 2-[2-(2-ethoxy-phenyl)-ethylamino]-5-[1-(4-ethoxy-quinolin-6-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 448 (MH+).
Reaction SMILES: [Br:1][C:2]1(O)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.[C:9](=O)([O-])[O-:10].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:10][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: OC1(Br)C=CC=CN1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccnc1Br
Temperature: 70 °C
Yield: 76.7 %

Procedure:
2-Bromo-2-pyridinol (15 g, 86 mmol) in acetone (500 ml) was treated with potassium carbonate (23.8 g, 172 mmol) and iodomethane (8.1 ml, 130 mmol) and the suspension was refluxed at 70° C. for 16 hours. Once cooled, the mixture was filtered and the filtrate concentrated in vacuo. The residue was then purified by silica wet flash chromatography to give the product as yellow crystals (12.4 g, 66 mmol, 77% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[O:3]1.[H-].[Na+].[CH3:26]I>C1COCC1>[CH3:26][N:15]([C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:23])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under N2, to a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (500 mg, 1.57 mmol) in anhydrous THF (4 mL), was slowly added sodium hydride (94 mg, 2.35 mmol) at 0° C. The mixture was stirred at room temperature for 20 minutes, then cooled to 0° C. CH3I (445 mg, 3.13 mmol) was slowly added. After the completion of the addition, the reaction mixture was stirred at room temperature overnight, quenched with H2O, and extracted with EtOAc. The combined extracts were concentrated, and the residue was purified by flash chromatography to give the title compound. MS (m/z): 278 (M−56)+.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[CH3:19][O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=2[CH2:4][N:5]2[CH2:9][CH2:8][O:7][C:6]2=[O:10])[C:26]([O:29][CH3:30])=[CH:27][CH:28]=1
Reactant: O=C1OCCN1Cc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2CCOC2=O)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
3-(2-Bromo-5-trifluoromethyl-benzyl)-oxazolidin-2-one (0.234 g, 0.71 mmol), [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester (0.181 g, 0.59 mmol), and potassium carbonate (0.209 g, 1.48 mmol) were combined in DME (2.5 mL) and H2O (1.2 mL) and purged with N2 for 30 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.069 g, 0.06 mmol) was added, and the reaction was stirred at 90° C. for 4 hours. After cooling to room temperature, the mixture was diluted with CH2Cl2 and H2O. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.