Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:26][NH:25][C:8]2=[N:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].O=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]([O:4][CH:5]1[CH2:26][N:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:8]2=[N:9][C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=[C:7]2[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CNc2nc(-c3ccccc3)c(-c3ccccc3)nc2C1OC(C)=O
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC(OC(C)=O)C(OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine-7,8-diyl diacetate (Intermediate I) (69 mg, 0.171 mmol) in DCE (3 ml) was added ethyl 7-oxoheptanoate (88 mg, 0.513 mmol) followed by sodium triacetoxyborohydride (109 mg, 0.513 mmol). The reaction was left to stir overnight at room temperature under an atmosphere of nitrogen. To the reaction mixture was added further ethyl 7-oxoheptanoate (88 mg, 0.513 mmol) followed by sodium triacetoxyborohydride (109 mg, 0.513 mmol). The reaction mixture was left to stir at RT under an atmosphere of nitrogen for 4 days. The mixture was diluted with water and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-70% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.S(Cl)(Cl)=O.C([N:34]([CH:37]([CH3:39])[CH3:38])CC)(C)C.C1(N)CC1>C(OCC)(=O)C.O1CCOCC1>[CH:37]1([NH:34][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[N:16][N:15]=[CH:14]4)[CH:4]=2)[CH2:39][CH2:38]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(F)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: O=C(NC1CC1)c1ccc(F)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To 4-fluoro-3-(1-morpholinophthalazin-6-yl)benzoic acid (200 mg, 566 μmol) was added thionyl chloride (2.83 mL) before it was heated to 65° C. for 1 h. The reaction mixture was concentrated in vacuo and azeotropically dried with toluene. Dioxane (2.83 mL,), diisopropylethylamine (493 μl, 2830 μmol), and cyclopropylamine (323 μl, 5660 μmol) were added and the mixture was stirred at RT overnight. The reaction mixture was diluted with 50 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 20 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, concentrated in vacuo, and purified by HPLC to give the title compound. MS (ES+): 393 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:13])[CH:5]=[CH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+].CO>O1CCOCC1>[CH:7]1([CH:6]=[CH:5][C:4]([OH:13])=[O:3])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C=CC1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)C=CC1CCCCC1
Reaction time: 48 h
Yield: 34.1 %

Procedure:
to a solution of 3-Cyclohexyl-acrylic acid ethyl ester (7.00 g, 38.4 mmol) in dioxane (200 mL) was added lithium hydroxide (4.03 g, 96.1 mmol) dissolved-in-water (70 mL). Because LiOH fell out methanol (170 mL) was added to the reaction. After 4 hours at 70° C. ¾ of the solvent was removed in vacuo. 2 N HCl was added until the pH reached 3. The mixture was treated with ammonium chloride (150 mL) saturated solution. The product was extracted with dichloromethane (200 mL×3). The combined organic phases were washed with saturated sodium solution (50 mL) and dried with magnesium sulfate. After filtration the solvent was removed in vacuo. The liquid was left at room temperature for 48 hours for crystallization to occur. The colourless crystalline product (2.01 g, 13.1 mmol) was obtained in 34% yield. 1H NMR (300 MHz, [D6-DMSO]: δ=1.01-1.37 (m, 5H, cyclohexyl-CH2), 1.55-1.79 (m, 5H, cyclohexyl-CH2), 2.06-2.21 (m, 1H, cyclohexyl-CH); 5.69 (dd, J=15.7 Hz and J=1.5 Hz, 1H, C═C—H), 6.76 (dd, J=15.7 Hz and J=6.8 Hz, 1H, C═C—H), 12.01 (broad s, 1H, OH). 13C NMR (75 MHz, [D6-DMSO]: δ=25.1, 25.4, 31.1 (cyclohexyl-CH2), 39.4 (cyclohexyl-CH), 119.5 and 153.4 (C═C) 167.3 (COON). MS: m/z calcd for (C9H14O2) [M+H]+ 155; found 155.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14](OCC2C=CC=CC=2)=O)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1>CO>[S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=1)([OH:34])(=[O:33])=[O:32].[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[CH3:14])=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@H]1COc1ccc(F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CN1CC[C@H]1COc1ccc(F)nc1

Procedure:
The title compound was prepared by the procedure of example 98c, except substituting 6-fluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine for the R enantiomer thereof. The product was obtained as a white solid: mp 124-126° C.; [α]D=+15.93 (c 0.5, MeOH); 1H NMR (300 MHz, D2O) δ7.92 (s, 1H), 7.68 (m, 3H), 7.38 (d, 2H, J=8.0 Hz), 7.11 (dd, 1H, J=2.5,8.5 Hz), 4.8 (br s, 1H), 4.45 (m, 2H), 4.27 (br s, 1H), 4.02 (br s, 1H), 2.99 (s, 3H), 2.68 (m, 2H), 2.40 (s, 3H); MS (CI/NH3); m/z 197 (M+H)+. Anal. Calcd for C10H13FN2O.TsOH: C, 55.42; H, 5.75; N, 7.60. Found: C, 55.33; H, 5.74; N, 7.59.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:39][CH2:40][NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1.O1CCCC1>[CH2:44]([O:43][C:42](=[O:51])[NH:41][CH2:40][CH2:39][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:17][CH:16]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Oc1ccc(-c2nc(-c3ccccc3)cs2)cc1
Reactant: O=C(NCCO)OCc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCOc1ccc(-c2nc(-c3ccccc3)cs2)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
4-(4-Phenyl-thiazol-2-yl)-phenol (516 mg, 2.03 mmol) was dissolved in toluene (6.8 ml), and triphenylphosphine (786 mg, 3.00 mmol) and benzyl N-(2-hydroxyethyl)-carbamate (585 mg, 3.00 mmol) were added. The solution was cooled to about 0° C. and 1,1-(azodicarbonyl)-dipiperidine (757 mg, 3.00 mmol) was added. The mixture was allowed to stir for about 10 minutes at about 0° C. and was then allowed to warm to room temperature. An additional 6.8 ml of toluene and 6.8 ml of tetrahydrofuran were added to the viscous solution. The reaction mixture was stirred for about forty-eight hours, and then the solids were filtered off and rinsed with a minimum volume of 1:1 toluene/tetrahydrofuran. The filtrate was concentrated in vacuo to a semisolid which was then purified by column chromatography (silica gel; methylene chloride to 2% methanol/methylene chloride) to give 396 mg of pure product (45% yield). LRMS ([M+H]+)=430.9.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O>[CH3:30][O:29][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:26](=[O:28])[CH3:27])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: C1CCNCC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCN1CCCCC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
1-{3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (41 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (268 mg) and piperidine (0.1 ml) were added to the solution, and the mixture was stirred at 80° C. for 2 days. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (24 mg, yield 53%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(4-aminophenyl)piperidine dihydrochloride (2.49 g) and triethylamine (5.6 g) in dichloroform (30 ml) was ice-cooled and to this was added dropwise acetyl chloride (1.42 ml). After stirred at room temperature for 30 minutes, water (10 ml) was added to the mixture and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off and then the residue was recrystallized from ethyl ether to obtain N(4-acetylaminophenyl)piperidine (2 g) as colorless crystals, m.p. 150°-152° C.
Reaction SMILES: [C:1](/[C:3](=[C:8]1/[C:9](=[O:19])[NH:10][C:11]2[C:16]/1=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)/[C:4]([O:6][CH3:7])=[O:5])#[N:2].[C-:20]#[N:21].[K+]>>[C:1]([CH:3]([C:8]1([C:20]#[N:21])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][C:9]1=[O:19])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(OC)cc21
Reactant: [C-]#N
Agent: [K+]
Product: COC(=O)C(C#N)C1(C#N)C(=O)Nc2ccc(OC)cc21
Yield: 90 %

Procedure:
Following the general method as outlined for Intermediate 5, starting from methyl (2Z)-cyano(5-methoxy-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetate (intermediate 2) and potassium cyanide, the title compound was isolated, after evaporation, as a pale brown solid in 90% yield. This was a mixture of diastereomers.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH2:23]([O:25][C@@H:26]([CH2:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][CH3:45])[CH:39]=2)=[CH:36][CH:37]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:24].O>ClCCl>[CH2:23]([O:25][C@@H:26]([CH2:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]([CH3:45])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH:39]=2)=[CH:36][CH:37]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:24]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(NC)c2)nc1)C(=O)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)nc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
70 mg (0.3 mmol) of 4-nitrophenyl chloroformate and then 60 μl (0.3 mmol) of diisopropylethylamine are added to a solution of 70 mg (0.25 mmol) of methyl 2(S)-ethoxy-3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoate in 3 ml of dichloromethane. The reaction medium is stirred at room temperature for 2 hours. After addition of water, the reaction medium is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. 110 mg (100%) of methyl 2(S)-ethoxy-3-(6-{3-[methyl(4-nitrophenoxycarbonyl)amino]phenyl}pyrid-3-yl)propanoate are obtained.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:17]([N:19]2[CH:23]([CH:24]([CH3:26])[CH3:25])[CH2:22][O:21][C:20]2=[O:27])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:7][CH:8]([C:17]([N:19]2[CH:23]([CH:24]([CH3:25])[CH3:26])[CH2:22][O:21][C:20]2=[O:27])=[O:18])[CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C1COC(=O)N1C(=O)C(CC(=O)OC(C)(C)C)CC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1COC(=O)N1C(=O)C(CC(=O)O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A solution of tert-butyl 3-cyclohexylmethyl-4-(4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutyrate (2.90 g, 7.6 mmol) in methylene chloride (10 mL) was treated with trifluoroacetic acid (4.83 g, 42.5 mmol) and the mixture was stirred at ambient temperature for 3 hours. The solvent and excess acid were removed by evaporation at reduced pressure. The residue was dissolved in ether/hexane and product was crystallized out to provide 3-cyclohexylmethyl-4-(4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutyric acid (2 g, 81%). MS (M+1): 326.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/B2OC(C)(C)C(C)(C)O2)[CH:11]=[CH:12][CH:13]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]2[N:38]([CH3:48])[C:39]([C:41]3[CH:46]=[CH:45][N:44]=[C:43](I)[N:42]=3)=[CH:40][C:34]=2[C:33]1=[O:49])=[O:31])([CH3:28])([CH3:27])[CH3:26]>O1CCOCC1.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:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35]2[N:38]([CH3:48])[C:39]([C:41]3[CH:46]=[CH:45][N:44]=[C:43](/[CH:15]=[CH:14]/[C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([Cl:7])[CH:9]=4)[N:42]=3)=[CH:40][C:34]=2[C:33]1=[O:49])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC1(C)OB(/C=C/c2cccc(Cl)c2)OC1(C)C
Reactant: Cn1c(-c2ccnc(I)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
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: [Cs+]
Solvent: C1COCCO1
Product: Cn1c(-c2ccnc(/C=C/c3cccc(Cl)c3)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 50 %

Procedure:
Cesium carbonate (0.143 g, 0.438 mmol), palladium tetrakis (0.051 g, 0.042 mmol) and 2-[(E)-2-(3-Chloro-phenyl)-vinyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.116 g, 0.440 mmol) were added to a solution of 2-(2-Iodo-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (synthesised as reported in Example 9) (0.100 g, 0.22 mmol) in dioxane (5.0 ml) under argon atmosphere. Argon was bubbled for 5 minutes, the vial was closed and the reaction mixture was heated by microwave irradiation for 30 minute at 100° C. for two cycles. In order to affect completion, a refresh of the catalyst and the base and two more cycles at the microwaves were carried on. The solvent was removed under vacuum, the residue was taken into DCM (5.0 ml), which was washed with a saturated solution of NaHCO3 (1×5.0 ml), brine (1×5.0 ml), and it was dried over Na2SO4. The filtrate was evaporated to dryness to give the crude product, which was purified by flash chromatography, over silica gel, using DCM/MeOH (9.9:0.1) as eluent, to afford 2-{2-[(E)-2-(3-Chloro-phenyl)-vinyl]-pyrimidin-4-yl}-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester yellow solid (0.051 g, 0.110 mmol, 50%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16]Cl)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:8]2[CH2:16][C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cccc1N1Cc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
A solution of 3-bromo-2-methylaniline (10 g, 53.7 mmol) in DCM (200 mL) at 0° C. was treated with TEA (14.98 mL, 107 mmol), followed by dropwise addition of 2-(chloromethyl)benzoyl chloride (10.16 g, 53.7 mmol) in DCM (50 mL) over 1 h. The mixture was diluted with DCM (ca. 1 L), washed with NaHCO3 (aq) and water, and concentrated to remove most of the solvent. The precipitate was collected by filtration and washed with DCM (2×10 mL) to provide N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (8.0 g). The filtrate was concentrated further, resulting in additional precipitate which was collected by filtration and washed with DCM (2×10 mL) to provide additional N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (3.06 g), for a combined yield of 61%. Mass spectrum 338, 340, 342 The filtrate was concentrated and purified by column chromatography (hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (2.0 g, 12%). A solution of the N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide (11.06 g, 32.7 mmol) in DMF (50 mL) was cooled to 0° C. and treated with a mixture of sodium hydride (60% oil dispersion, pre-washed with hexane, 1.70 g, 42.5 mmol) and DMF (10 mL). The mixture was stirred at 0° C. for 1.5 h, then was treated with water. The precipitate was collected by filtration, dried and combined with the material purified by column chromatography (see above) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (9.41 g, 95%). 1H NMR (400 MHz, chloroform-d) δ 7.96 (1H, d, J=7.5 Hz), 7.58-7.67 (2H, m), 7.49-7.57 (2H, m), 7.20-7.25 (1H, m), 7.15 (1H, t, J=7.9 Hz), 4.72 (2H, s), 2.31 (3H, s). Mass spectrum m/z 302, 304 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](Cl)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][O:17][C:10]([C:6]1[C:5]2[S:1][N:2]=[N:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)=[O:11]
Reactant: O=C(Cl)c1cccc2nnsc12
Reactant: C[Si](C)(C)CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.99 g (0.01 mol) of 7-benzothiadiazolecarboxylic acid chloride in 18 ml of toluene are added dropwise over a period of 25 minutes to a solution of 1.9 ml (0.013 mol) of 2-trimethylsilylethanol, 2.4 ml (0.017 mol) of triethylamine and 18 ml of toluene. The reaction mixture is then stirred for 16 hours at room temperature and afterwards poured onto ice/water and extracted twice with ethyl acetate. The extracts are combined, washed with water, dried over magnesium sulfate, filtered and concentrated and the same amount of hexane is added and the batch is filtered through silica gel. Concentration gives 2.0 g (71% of the theoretical yield) of product; m.p. 37°-39° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH2:36][CH:37]=[O:38])[CH:31]([NH:39][C:40](=[O:79])[C:41](=[N:67][O:68][C:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])([CH3:71])[CH3:70])[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[S:45][CH:46]=1)[C:30]2=[O:80])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH:31]([NH:39][C:40](=[O:79])[C:41](=[N:67][O:68][C:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])([CH3:70])[CH3:71])[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[S:45][CH:46]=1)[C:30]2=[O:80])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C3SC2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
p-Toluenesulphonyl chloride (1.31 g) is added to a solution, cooled to 5° C., of the syn isomer of 2-benzhydryloxycarbonyl-7-{2-[(2-t-butoxycarbonylprop-2-yl)-oxyimino]-2-(2-tritylaminothiazol-4-yl)-acetamido}-3-formylmethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (product 5e) (4.45 g) in pyridine (50 cc). The temperature is left to rise to 20° C. in the course of 30 minutes, the mixture is stirred for 1 hour at 20° C. and poured into iced water (300 cc), the water is decanted and the insoluble pasty product is taken up in ethyl acetate (300 cc). The solution is washed with 1 N hydrochloric acid (100 cc), a saturated solution of sodium bicarbonate (100 cc) and a saturated solution of sodium chloride (100 cc), dried over sodium sulphate and filtered and the filtrate is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The product thus obtained is used as such for the remainder of the synthesis. This product (1 g) is purified by chromatography on a column of silica gel (0.05-0.2) (20 g) (diameter of the column: 1.7 cm), elution being carried out with an 80/20 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 4 to 12, containing the pure product, are evaporated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give a product (5d) (0.43 g), which is a mixture of the E and Z forms (in proportions--determined by NMR--of 75% of the E form and 25% of the Z form), in the form of a pale yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.S1C=NN=C1NC(=O)C1C=CC=CC=1.[CH3:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([NH:35][C:36]2[S:37][CH:38]=[N:39][N:40]=2)=[O:34])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[S:37]1[CH:38]=[N:39][N:40]=[C:36]1[NH:35][C:33]([C:32]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][CH:3]=2)[C:29]([CH3:28])=[CH:42][CH:41]=1)=[O:34]
Reactant: Cc1ccc(C(=O)Nc2nncs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Agent: O=C(Nc1nncs1)c1ccccc1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4nncs4)ccc3C)cc2)o1

Procedure:
Example 33 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and 4-methyl-3-4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-([1,3,4]thiadiazol-2-yl)-benzamide (Intermediate 23) with propan-2-ol as the solvent.