Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[N:29]1[CH:33]=[C:32]([Sn](CCCC)(CCCC)CCCC)[N:31]=[CH:30]1>CN(C=O)C.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.[Cu]I>[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[N:29]1[CH:33]=[C:32]([C:2]2[N:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]3=[N:6][CH:7]=2)[N:31]=[CH:30]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(F)ccc2F)cn1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3cn(-c4cc(F)ccc4F)cn3)cnc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
A pressure tube was charged with 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.110 g, 0.31 mmol), Pd(PPh3)4 (0.020 g, 0.017 mmol), CuI (0.012 g, 0.063 mmol) and the above-prepared crude 1-(2,5-difluorophenyl)-4-(tributylstannyl)-1H-imidazole (0.198 g) in 3 mL of DMF. The tube was capped under Ar and the orange yellow mixture stirred at 80° C. for 1.5 h, then allowed to cool. The mixture was partitioned between 20 mL of ethyl acetate and 20 mL of water+20 mL of a sat. aq. NH4Cl solution. The organic layer was washed with 20 mL of a sat. aq. NaCl solution, dried over Na2SO4, filtered and concentrated. Column chromatography (20-100% EtOAc/hexanes) of the residue afforded 0.087 g (62%) of 2-[1-(2,5-difluoro-phenyl)-1H-imidazol-4-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a slightly impure yellow oil, which was used without further purification. MS: (M+Na)+=478.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1>>[NH2:28][CH2:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)=[CH:7][C:6]([C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:21])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cccnc1
Product: NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (S)-tert-butyl ((1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)carbamate (Stage 108.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) tR=0.8 min, m/z=458.0 [M+H]+.
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:15])[C@H:11]\1[CH2:10][CH:9]=[C:8]2[C:12](=[O:14])[CH3:13].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.CSC.B.[H][H]>C1(C)C=CC=CC=1.O.C(OCC)C.CO>[Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:15])[C@H:11]\1[CH2:10][CH:9]=[C:8]2[C@@H:12]([OH:14])[CH3:13]
Reactant: CC(=O)C1=CC[C@H]2/C(=C/Br)CCC[C@]12C
Reactant: [H][H]
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[C@H](O)C1=CC[C@H]2/C(=C/Br)CCC[C@]12C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
1-{(3aS,7E,7aR)-7-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-3a-methyl-1H-indene-3-yl}ethanone (Compound 13: 24.7 mg, 0.0918 mmol) was dissolved in toluene (200 μl), and (R)-2-methyl-CBS-oxazaborolidine (18 μl, 0.018 mmol, 1.0 M in toluene) and borane dimethyl sulfide (26 μl, 0.274 mmol) were added thereto at −20° C., followed by stirring the resulting mixture for 1 hour. Methanol (100 μl) was added to the reaction solution, and when generation of hydrogen gas stopped, diethyl ether and water were added thereto. After separating the organic layer, the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with saturated brine, dried over sodium sulfate, and evaporated. The obtained crude product was purified by flash column chromatography to obtain (S)-1-{(3aS,7E,7aR)-7-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-3a-methyl-1H-indene-3-yl}ethanol (23.6 mg, 94.8%) as a white solid. The spectrum data thereof agreed with the data described in Example 4.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([Li])[CH3:12]>O1CCCC1>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:11][CH3:12]
Reactant: Cc1cccc(C=O)c1C
Reactant: [Li]CC
Solvent: C1CCOC1
Product: CCC(O)c1cccc(C)c1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 2,3-dimethylbenzaldehyde (1.0 g, 7.5 mmol) in anhydrous tetrahydrofuran (50 ml), at −78° C. and under nitrogen, was added ethyllithium (0.5M in benzene:cyclohexane 9:1, 14.9 ml, 7.5 mmol), dropwise via syringe. The reaction mixture was stirred at −78° C. for 30 min and then poured into ice cold hydrochloric acid (2N, 20 ml). The mixture was extracted with ethyl acetate (2×50 ml) and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (1.22 g).
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O-])=O>C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:20])[CH3:21])[N:10]=[C:9]2[C:23]#[C:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1nc(C#Cc2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(C#Cc2ccccc2)c2cc(N)ccc21
Temperature: 20 °C
Yield: 14.2 %

Procedure:
5-Amino-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: 18 ml of water, 0.2 ml of an aqueous 12N hydrochloric acid solution and 0.36 g of powdered iron are added to a solution of 0.84 g of 5-nitro-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 15 ml of absolute ethanol, at the reflux temperature of the solvent. The reaction mixture is then stirred at the reflux of the solvent for 4 hours, and is then cooled to a temperature in the region of 20° C. After filtration through Celite® and washing with absolute ethanol, the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a column of 60 g of silica (particle size 40-63 μm), eluting successively with cyclohexane/ethyl acetate (95/5; 90/10; 80/20; 70/30; 60/40; 50/50; 30/70 by volume) mixtures, and then with pure ethyl acetate and, finally, with pure ethanol. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 0.11 g of 5-amino-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of a brown oil (Rf=0.47, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (60/40 by volume)). 0.2 g of 5-amino-3-phenylethynyl-1H-indazole is also obtained in the form of a brown oil (Rf=0.17, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (60/40 by volume)).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][CH:16]=[CH:17][C:18]2[CH:70]=[C:21]3[N:22]=[C:23]([CH3:69])[C:24]([C@H:58]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[C:59]([O:61][CH2:62][CH3:63])=[O:60])=[C:25]([N:26]4[CH2:31][CH2:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]([O:40][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH3:39])([CH3:32])[CH2:28][CH2:27]4)[N:20]3[N:19]=2)=[C:13]([F:71])[C:12]([F:72])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(O)C.C1COCC1.[Pd]>[C:65]([O:64][C@@H:58]([C:24]1[C:23]([CH3:69])=[N:22][C:21]2[N:20]([N:19]=[C:18]([CH2:17][CH2:16][CH2:15][C:14]3[C:9]([OH:8])=[CH:10][CH:11]=[C:12]([F:72])[C:13]=3[F:71])[CH:70]=2)[C:25]=1[N:26]1[CH2:31][CH2:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]([OH:40])[CH3:39])([CH3:32])[CH2:28][CH2:27]1)[C:59]([O:61][CH2:62][CH3:63])=[O:60])([CH3:66])([CH3:67])[CH3:68]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3c(OCc4ccccc4)ccc(F)c3F)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3c(O)ccc(F)c3F)nn2c1N1CCC(C)(OCCCC[C@@H](C)O)CC1
Yield: 45.6 %

Procedure:
To a solution of (S)-ethyl 2-(2-(3-(6-(benzyloxy)-2,3-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (114 mg, 0.114 mmol) in Ethanol (4 mL) was added 10% Pd—C (24 mg, 0.022 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vac. The residue was then treated with 1M TBAF (0.849 mL, 0.849 mmol) in THF (4 mL) for 16 h. Mixture was then concentrated and purified by Biotage (5-70% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(2,3-difluoro-6-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (35 mg, 0.052 mmol, 30% yield) as thick paste. 1H NMR (400 MHz, CDCl3) δ 6.90 (q, J=9.0 Hz, 1H), 6.59 (d, J=10.0 Hz, 1H), 6.36 (s, 1H), 5.91 (br. s., 1H), 4.32-4.15 (m, 2H), 3.85 (d, J=6.3 Hz, 2H), 3.44 (br. s., 3H), 2.94 (br. s., 1H), 2.89-2.71 (m, 4H), 2.63 (s, 3H), 2.15-2.04 (m, 2H), 2.04-1.94 (m, 2H), 1.90 (d, J=6.8 Hz, 2H), 1.75 (d, J=7.3 Hz, 1H), 1.57-1.44 (m, 6H), 1.38-1.27 (m, 12H), 0.94-0.87 (m, 6H). LCMS (M+H)=675.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:28]=1[CH2:29][NH:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C@H:9]1[C:10]([N:33]1[CH2:34][CH2:35][CH2:36][C@H:32]1[C:31]([NH:30][CH2:29][C:28]1[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:27]=1[CH2:26][NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:24])=[O:37])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C)C1C(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)OC(C)(C)C)CCC1(C)C

Procedure:
1-(tert-Butoxycarbonyl)-3,3-dimethylprolyl-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-L-prolinamide was prepared as a mixture of diastereomers from 1-(tert-butoxycarbonyl)-3,3-dimethyl-D,L-proline (73 mg, 0.30 mmol) and L-prolin-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)amide (111 mg, 0.30 mmol) essentially according to the EDC coupling procedure described in Step 3 of Example 46. The diastereomeric products were separated by reverse phase HPLC as described in Step 3 of Example 46. Diastereomer A: LCMS RT=2.44 min. LCMS (M+H)=593.4. Diastereomer B: LCMS RT=2.58 min. LCMS (M+H)=593.5.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1)=[O:4].Cl[CH2:12][C:13]([NH:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[Cl:24])=[O:14].C(N(CC)CC)C>COCCO>[CH3:1][NH:2][C:3]([CH:5]1[NH:6][CH2:7][CH2:8][N:9]([CH2:12][C:13]([NH:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[O:14])[CH2:10]1)=[O:4]
Reactant: O=C(CCl)Nc1c(Cl)cc(Cl)cc1Cl
Reactant: CNC(=O)C1CNCCN1
Solvent: COCCO
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(Cl)cc2Cl)CCN1
Temperature: 60 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
A mixture of 15.33 parts of N-methyl-2-piperazinecarboxamide, 27.2 parts of 2-chloro-N-(2,4,6-trichlorophenyl)acetamide, 9.8 parts of N,N-diethylethanamine and 300 parts of 2-methoxyethanol was stirred for 3 hours at 60° C. The reaction mixture was evaporated. The residue was taken up in a small amount of water and treated with sodium carbonate. The product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off (the filtrate was set aside) and dried, yielding a first fraction of 9.27 parts (24.4%) of 3-[(methylamino)carbonyl]-N-(2,4,6-trichlorophenyl)-1-piperazineacetamide.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]2[CH:11]=[C:10]([CH2:12][OH:13])[NH:9][C:6]2=[N:7][CH:8]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:1][S:2][C:3]1[N:4]=[C:5]2[CH:11]=[C:10]([CH:12]=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CSc1cnc2[nH]c(CO)cc2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CSc1cnc2[nH]c(C=O)cc2n1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of the compound obtained in Example 34 (4) (123 mg) in acetone (40 ml), manganese dioxide (1.86 g) was added and the mixture was stirred at 15 to 30° C. for 1 hour. The reaction solution was filtered through Celite and concentrated under reduced pressure to obtain 60 mg (49.3%) of the desired product as a yellow powder.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:9][CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)[N:17]=2)=[CH:14][N:15]=1)[CH3:8]>O.CO>[CH2:7]([S:9]([CH2:10][C:11]1[N:12]([CH2:38][CH2:39][CH3:40])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29](=[O:37])(=[O:36])[NH:30][CH2:31][CH2:32][O:33][CH2:34][CH3:35])=[CH:27][CH:28]=3)[N:17]=2)=[CH:14][N:15]=1)=[O:2])[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CSCC
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOCC)cc3)n2)cnc1CS(=O)CC
Reaction time: 18 h
Yield: 50.8 %

Procedure:
A solution of sodium periodate (43 mg, 0.2 mmol) in water (0.5 ml) was added to a stirred solution of 4-[2-(ethylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Example 82; 70 mg, 0.14 mmol) in MeOH (2 ml) and the solution was stirred for 18 hours. The MeOH was removed by evaporation and the aqueous residue was extracted with EtOAc. The extracts were combined, washed with brine, dried and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (95:5 increasing in polarity to 90:10) and the purified product triturated with ether to give the title compound (37 mg, 51%). NMR: 0.68 (t, 3H), 1.05 (t, 3H), 1.22 (t, 3H), 1.52 (m, 2H), 2.85 (m, 4H), 3.33 (m, 4H), 4.31 (d of d, 2H), 4.63 (m, 2H), 7.23 (d, 1H), 7.46 (t, 1H), 7.70 (d, 2H), 7.78 (s, 1H), 7.86 (d, 2H), 8.48 (d, 1H), 9.90 (s, 1H); m/z 521.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCOC(=O)c1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 80.7 %

Procedure:
A mixture of methyl thiosalicylate (2.0 g, 11.9 mmol), ethyl 6-cyano-2-pyridinecarboxylate (2.1 g, 11.9 mmol), triethylamine (3.0 ml, 21.5 mmol) and toluene (6 ml) was refluxed for 12 hrs as described in Example 1. The precipitated crystals were collected by filtration and recrystallized from diisopropylether-tetrahydrofuran to give the titled compound (3.0 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)[N:5]=[C:4]([CH3:24])[N:3]=1.Cl[CH2:26][CH:27]=O>CN(C=O)C>[F:23][C:19]1[N:18]=[C:17]([C:13]2[N:12]([CH2:11][C:6]3[N:5]=[C:4]([CH3:24])[N:3]4[CH:26]=[CH:27][N:1]=[C:2]4[C:7]=3[CH2:8][CH2:9][CH3:10])[CH:16]=[CH:15][N:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCCc1c(N)nc(C)nc1Cn1ccnc1-c1cccc(F)n1
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)nc(C)n2ccnc12

Procedure:
A solution of 126 (1.2 mmol) and chloroacetaldehyde (1 mL) in DMF (10 ml) is heated at 70° C. in a sealed tube overnight. The solvent is removed in vacuo and water (15 ml) and EtOAc (15 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (15 ml). The combined extracts are washed with brine (15 ml), dried (Na2SO4) and evaporated. PTLC separation of the residue with 10% MeOH in CH2Cl2 provides the title compound (119) as a white solid; LC-MS, M+1 351.1; 1H-NMR (CDCl3) δ: 8.10 (dd, 1H), 7.85 (q, 1H), 7.66 (d, 1H), 7.44 (d, 1H), 7.20 (d, 1H), 7.12 (d, 1H), 6.86 (dd, 1H), 6.02 (s, 2H), 3.01–3.07 (m, 2H), 2.69 (s, 3H), 1.60–1.67 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>ClCCCl>[C:20]1([CH3:24])[CH:21]=[CH:22][CH:23]=[C:18]([C:11]2([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:10]3[CH:15]([CH2:16][N:8]([C:33]([O:35][CH:36]=[CH2:37])=[O:34])[CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:19]=1
Reactant: C=COC(=O)Cl
Reactant: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CN(Cc4ccccc4)CC32)c1
Solvent: ClCCCl
Product: C=COC(=O)N1CC2C(=O)CCC(c3cccc(C)c3)(c3cccc(C)c3)C2C1

Procedure:
A solution of (3aRS,7aRS)-2-benzyl-7,7-bis(3-tolyl)perhydro-4-isoindolone (13.7 g) in 1,2-dichloroethane (150 cc) is treated with vinyl chloroformate (3.7 cc) and heated to reflux for 3 hours, then concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on silica gel (particle size 0.04-0.063 mm, column 5.4 cm in diameter and 39 cm high), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80:20). Fractions 23 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis(3-tolyl)-2-vinyloxycarbonylperhydro-4-isoindolone (7.4 g) in the form of a white meringue-like product.
Reaction SMILES: C(/[O-])=C(\[N+]([O-])=O)/C=O.O.[Na+].C(O)C.[Cl:14][C:15]1[CH:16]=[C:17]([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[N:22]1.O>C(O)(=O)C.[Fe]>[Cl:14][C:15]1[CH:16]=[C:17]([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22]1
Reactant: CC(C(=O)O)c1ccc(-n2cc([N+](=O)[O-])cn2)c(Cl)c1
Agent: [Fe]
Agent: O=C/C(=C\[O-])[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(-n2cc(N)cn2)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The starting compound is obtained in the following manner: 22.8 g (59 mmoles) of 2-(3-chloro-4-hydraziniumphenyl)propionic acid p-toluenesulphonate and 9.8 g (64 mmoles) of sodium nitromalondialdehyde monohydrate are heated under reflux for 30 minutes in 180 ml of 80% strength ethanol. Concentration is then effected, followed by taking up with sodium bicarbonate and extraction with ether. The aqueous solution is acidified and extracted with ether. Through concentration of the ethereal phase there is obtained, after recrystallisation from ethanol, 2-[3-chloro-4-(4-nitropyrazol-1-yl)phenyl]propionic acid (m.p. 173°-173.5° C.). 5 g (16.9 mmoles) of 2-[3-chloro-4-(4-nitropyrazol-1-yl)phenyl]propionic acid are dissolved in 30 ml of glacial acetic acid, heated to 80° C.; portionwise, 3.8 g of iron powder and then 7 ml of water are added. After one hour, pouring on to ice is effected, followed by extraction with ether. The ether phase is dried, clarified with Tonsil, and concentrated. 2-[3-chloro-4-(4-aminopyrazol-1-yl)phenyl]propionic acid is obtained as oil [RF =0.25 (silica gel; CHCl3 /ethanol 4:1)].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=4)[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: NCc1cccc(Cl)c1
Product: CCOC(=O)c1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
This compound is synthesized following an analogous procedure as described in Example 1, step 1.1 starting from 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester (WO 97/02266) and 3-chloro-benzylamine; m.p. 305-306° C.; MS-ES+: (M+H)+=407.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: OCCN1CCCC1
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(OCCN3CCCC3)ccc2o1
Reaction time: 48 h
Yield: 58.2 %

Procedure:
Anhydrous tetrahydrofuran (15 ml) was added to a mixture of 5-hydroxybenzofuran-2-carboxylic acid methyl ester (1.10 g, 5.7 mmol), triphenylphosphine (1.50 g, 5.7 mmol), and 1-(2-hydroxyethyl)-pyrrolidine (0.66 g, 5.7 mmol) under a nitrogen atmosphere. Diisopropyl azodicarboxylate (1.15 ml, 5.8 mmol) was slowly added to the solution at room temperature. After 2 days, the solvent was removed and the residue was dissolved in a 2:1 mixture of Et2O:EtOAc (150 ml). The solution was washed with 1.0M aqueous NaOH. The product was extracted into 1.0 M hydrochloric acid and the combined acid extracts were washed with Et2O. The extracts were cooled and the pH of the extracts was adjusted to pH 12 with 50% aqueous NaOH. The basic solution was extracted with CH2Cl2 and the organic layer was dried over anhydrous MgSO4, and concentrated to give 5-(2-pyrrolidin-1-yl-ethoxy)benzofuran-2-carboxylic acid methyl ester (0.96 g) as an amber colored solid.