Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:31][C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(F)ccc34)cnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3nn(CC(=O)N4CCOCC4)c4cc(F)ccc34)cnc21
Temperature: 100 °C
Yield: 68.2 %

Procedure:
A 5 ml microwave vial was charged with 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (300 mg, 0.73 mmol), 4-(2-chloroacetyl)morpholine (0.19 ml, 1.46 mmol), cesium carbonate (713 mg, 2.19 mmol) and DMF (3.3 ml). The vial was flushed with argon, sealed and heated in a microwave reactor at 100° C. for 2 h. The reaction mixture was quenched with water and extracted with diethyl ether (2×). The organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-70% EtOAc) to afford 268 mg (68%) of 2-[6-fluoro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH2:27])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH:27][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([OH:1])[N:7]=3)=[O:10])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=C(O)c1cccc(O)n1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cccc(O)n1
Yield: 21.8 %

Procedure:
Using the general method of Example 97 6-hydroxypicolinic acid (0.24 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.15 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-hydroxy-2-pyridinecarboxamide as a white powder, m.p. 258-260° C. Analysis: Calculated for C21H23N7O2+½CH3CN: % C, 62.03; % H, 5.80; % N, 24.66; Found: % C, 61.87; % H, 5.70; % N, 24.60.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CS(O[C:21]1[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][C:22]=1[C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([O:13][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][C:22]=2[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=CC(=O)Oc2ccc(C(=N)N)cc2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a mixture of 3.1 g of 4-acetyloxycinnamic acid and 50 ml of dried pyridine, while being cooled in ice, was added 3.7 g of DDC. To the mixture, after having been stirred for 30 minutes, was added 5.0 g of 4-amidino-2-benzoylphenol methanesulfonate. The mixture was stirred overnight at room temperature. The insolubles precipitated from the reaction mixture were collected by filtration and mixed with DMF. Ethyl ether was added to the supernatant to precipitate an insoluble substance which was recrystallized from ethanol, yielding 4.7 g of colorless crystals of 4-amidino-2-benzoylphenyl 4-acetyloxycinnamate methanesulfonate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[CH3:21]>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[C:23](=[O:29])[NH:22][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CCNC(=O)[C@@H]1CCCN1C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (S)-proline ethyl amide (0.108 g, 0.76 mmol) gives the title compound.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[N:9]([CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[O:15][C:14]([F:13])([F:24])[F:25])[C:4]=2[CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: FC(F)(F)Oc1ccccc1CBr
Product: O=C1CNc2ncc(I)cc2N1Cc1ccccc1OC(F)(F)F
Yield: 61 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (942 mg) was reacted with 2-(trifluoromethoxy)benzyl bromide as in General Procedure 1 to give the title compound as a light yellow solid (61% yield). m.p.=235° C., LCMS: m/z=449.92 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 4.29 (2H, s), 4.89 (1H, s), 5.16 (2H, s), 7.09 (2H, m), 7.24 (1H, m), 7.34 (2H, m), 7.92 (1H, s).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=O.Br[C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=1>CN1CCCC1>[CH2:10]([O:9][C:3]([C:4]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([Br:19])[N:18]=2)[NH:20][C:5]=1[CH3:7])=[O:8])[CH3:11]
Reactant: Nc1ncc(Br)nc1Br
Reactant: CCOC(=O)CC(C)=O
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(C)[nH]c2ncc(Br)nc12
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 9.5 %

Procedure:
To a flask charged with 20 mL of anhydrous N-methylpyrrolidine at 0° C. was added 60% NaH (840 mg, 21 mmol). After stirring 15 min, ethyl acetoacetate (2.73 g, 10.8 mmol) was added slowly. After stirring an additional 20 min 3,5-Dibromo-pyrazin-2-ylamine (5.04 g, 20 mmol). The reaction vessel was then removed from the ice bath and heated to 140° C. for 3 days. The dark mixture was cooled to rt and diluted with diethyl ether and water. The mixture was filtered and then partitioned. The organic layer was washed with water and then brine, dried over Na2SO4, filtered, and concentrated to afford a dark red oil. This was purified by silica gel chromatography (4:1 Hexanes:EtOAc) to afford 290 mg of 2-Bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O1CCOCC1>C(OCC)(=O)C>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(NCc2ccc(Cl)cc2Cl)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (0.30 g), 2,4-dichlorobenzyl amine (818 μL), and 1,4-dioxane (3 mL) was stirred at room temperature for 21 hours. To the reaction liquid was added ethyl acetate (30 mL), washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain methyl 2-(2,4-dichlorobenzylamino)-4-(trifluoromethyl)pyrimidine-5-carboxylate (446 mg) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>CN(C=O)C.C1COCC1.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>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:12]=[CH2:13])=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 1324.9 %

Procedure:
2 g of 5-bromo-2-(trifluoromethyl)pyridine was dissolved in DMF:THF (3:1, 12 mL). vinyltributyltin (3 g) and tetrakis(triphenylphosphine)palladium (135 mg) were added to this solution. The reaction mixture was degassed and purged with nitrogen for 5 min and then heated at 100° C. for 2 h. at which point the reaction was found complete (monitored by TLC). The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure (Caution: product may be volatile) and the residue was purified by SiO2 chromatography (100-200 mesh, eluent:hexane-ethyl acetate gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 20.3 g of 2-(trifluoromethyl)-5-vinylpyridine as oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:31])[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(CCCCCNC(=O)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-(4-tert-Butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (2.00 g) was dissolved in methylene chloride (80 ml) and a solution of 4-chlorophenyl isocyanate (1.13 g) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 15 hr, and the reaction mixture was concentrated under reduced pressure to give 4-tert-butoxycarbonylaminomethyl-1-(5-(3-(4-chlorophenyl)ureido)pentyl)piperidine.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[K+]>O>[C:1]1([C:7]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 62.5 g. of ethyl 3-phenyl-3-(4-nitrophenyl)propenoate, 100 ml. of ethanol and 300 ml. of 1.5 N potassium hydroxide was heated on a steam bath for 1 hour. To the cooled reaction mixture was added 800 ml. of water and 500 ml. of ethyl acetate, and then the ethyl acetate layer was removed. The aqueous layer was acidified, and the solid which precipitated was collected by filtration. This solid was recrystallized from toluene and then from carbon tetrachloride to give 22 g. of the title compound, m.p. 188°-189° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4].[CH3:31][NH:32][CH3:33]>O1CCOCC1.C(O)C>[CH3:31][N:32]([CH3:33])[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4]
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CNC(=O)CCl)c3)cc12)c1ccccc1
Reactant: CNC
Solvent: C1COCCO1
Solvent: CCO
Product: C[C@@H](Nc1ncnc2[nH]c(-c3cccc(CNC(=O)CN(C)C)c3)cc12)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 210 mg (0.5 mmol) 2-chloro-N-{3-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide in 3 ml dry dioxane is treated with 268 μl (1.5 mmol) of a 5.6 N dimethylamine solution in ethanol (Fluka, Buchs, Switzerland) and then heated to 100 ° C. for 6 h. The clear yellow solution is cooled and the solvent evaporated. The residue is purified by flash chromatography using a mixture of dichloromethane/methanol with gradually increasing concentrations of methanol starting with 100:2.5 and ending with 100:5 and then switching to dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 and ending with 100:10:0.5. The title compound is obtained as a colorless foam; Rf (dichloromethane/methanol/conc. ammonia 90:10:1)=0.41; MS-ES+: (M+H)+=429.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([C:10]([OH:12])=O)=[N:8][S:9][C:5]=2[CH:4]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=2[C:30]([F:33])([F:32])[F:31])[CH2:18][CH2:17]1.CCN(CC)CC.CCCP(=O)=O>CN(C=O)C>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:29]=[CH:28][C:26]([NH:27][C:10]([C:7]3[C:6]4[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[S:9][N:8]=3)=[O:12])=[CH:25][C:24]=2[C:30]([F:33])([F:31])[F:32])[CH2:18][CH2:17]1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: COc1ccc2c(C(=O)O)nsc2c1
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)Nc3ccc(CN4CCN(C)CC4)c(C(F)(F)F)c3)nsc2c1

Procedure:
Prepared analogousely to step 6.1 from 2.0 g (9.57 mMol) 6-methoxy-benzo[d]isothiazole-3-carboxylic acid, 3.9 g (14.3 mMol) 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-aniline, 13.3 ml (95.7 mMol) Et3N and 11.17 ml (50% in DMF; 19.1 mMol) propylphosphonic anhydride in 100 ml of dry DMF: m.p.: 156° C.; MS: [M+1]+=465.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([C:13]1[C:14](=[O:29])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[CH3:28])[CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH2:12].[OH-].[Na+].OO.S(=O)(O)[O-:35].[Na+]>C1COCC1.O.C(OCC)(=O)C>[OH:35][CH2:12][CH2:11][CH2:10][C:13]1[C:14](=[O:29])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[CH3:28])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S([O-])O
Reactant: C=CCc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCCO)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 18.5 ml (9.25 mmol) of a 0.5 molar solution of 9-borabicyclo[3.3.1]nonane in THF are slowly added dropwise to 1.00 g (3.70 mmol) of the compound from Example 35A in 4 ml THF. After one hour at room temperature, the mixture is again cooled to 0° C., and 18.5 ml (18.5 mmol) of a 1 molar solution of sodium hydroxide in water are added dropwise. The mixture is stirred at 0° C. for a further 30 min, and 3.24 ml of a 30% strength hydrogen peroxide solution are then added such that the temperature does not exceed 30° C. The mixture is stirred with ice-cooling for 30 min, and ethyl acetate and then 11 g (40 mmol) of sodium bisulphite solution are then added. The organic phase is separated off, and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and then evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:4). This gives 1.03 g (83% of theory) of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH2:19])=O)=[C:4]2[CH2:3]1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]#[N:19])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O

Procedure:
0.5 g of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxamide is heated to reflux while stirring for 40 hours together with 0.5 g of Sicapent in 150 ml of toluene. The mixture is treated with a 0.5 g portion of Sicapent after 16 hours, 19 hours and 24 hours. The mixture is subsequently cooled and treated with water. The mixture is adjusted to pH 9 with 28 percent sodium hydroxide. After separation of the organic phase, the alkaline-aqueous phase is extracted twice with 250 ml of ethyl acetate each time. The organic extracts are washed twice with saturated sodium chloride solution, dried and evaporated. After crystallisation of the residue from methylene chloride/hexane, there is recovered a portion of unreacted starting material. The mother liquor is evaporated and chromatographed on 100 g of silica gel while eluting with ethyl acetate and alcohol. After recrystallisation of the thus-obtained substance from acetone, there is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[ 1,5-a][1,4]benzodiazepine-3-carbonitrile of melting point 184°-185° C.
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O>C1COCC1>[CH:1](=[C:8]1[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1CCC(=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
To a solution of 8-benzylidene-1,4-dioxaspiro[4.5]decane (5.79 g, 25.1 mmol) in THF (126 mL) a solution of H2SO4 (10% in water, 67 mL) was added and the result mixture was stirred at room temperature for 3 days. THF was removed under reduce pressure and water was added. The aqueous phase was extracted with DCM and the organic layers were combined, washed with brine, dried with Na2SO4, filtered and concentrated to give 4-Benzylidenecyclohexanone (4.35 g 84%) as a yellowish oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23-7.33 (m, 2 H), 7.13-7.20 (m, 3 H), 6.42 (s, 1 H), 2.67-2.77 (m, 2 H), 2.62 (t, J=7.0 Hz, 2 H), 2.46 (t, J=7.0 Hz, 2 H), 2.37 (t, J=7.0 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:44])([CH3:43])[N:6]1[C:14]2[C:9](=[C:10]([C:15]3[CH:23]=[C:22]4[C:18]([CH:19]=[N:20][N:21]4[S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[C:17]([C:33]4[O:34][C:35]([C:38](OCC)=[O:39])=[CH:36][N:37]=4)[CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:4])[CH3:3].ClC1C=C2C(C=NN2S(C2C=CC=CC=2)(=O)=O)=C(C2OC(C(OCC)=O)=CN=2)C=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>ClCCl>[CH3:4][C:2]([Si:5]([CH3:44])([CH3:43])[N:6]1[C:14]2[C:9](=[C:10]([C:15]3[CH:23]=[C:22]4[C:18]([CH:19]=[N:20][N:21]4[S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])=[C:17]([C:33]4[O:34][C:35]([CH2:38][OH:39])=[CH:36][N:37]=4)[CH:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)c1cnc(-c2cc(-c3cccc4c3ccn4[Si](C)(C)C(C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)o1
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)c1cnc(-c2cc(Cl)cc3c2cnn3S(=O)(=O)c2ccccc2)o1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)n1ccc2c(-c3cc(-c4ncc(CO)o4)c4cnn(S(=O)(=O)c5ccccc5)c4c3)cccc21
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-[6-{1-[(1,1-dimethylethyl)(dimethyl)silyl]-1H-indol-4-yl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate (containing an impurity consistent with ethyl 2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazole-5-carboxylate)(0.84 g) in dichloromethane (10 ml) at −20° C. was added diisobutylaluminium hydride (2.68 ml, 2.68 mmol, 1M in hexanes). The reaction mixture was stirred at −20° C. for 2 h then 10% ammonium chloride solution (10 ml) added. The mixture was stirred for 5 min then extracted with dichloromethane (10 ml), the layers separated (hydrophobic frit) and the organic purified by silica gel chromatography, eluting with a gradient of cyclohexane and ethyl acetate. The desired fractions were concentrated to give the title compound as a pale yellow solid (0.36 g), which by LCMS contained an impurity consistent with 2-[6-chloro-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-oxazol-5-yl}methanol.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[CH:9](=O)CCCC>O>[C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:9]
Reactant: CCCCC=O
Reactant: CCCC=CC(=O)O
Solvent: O
Product: CCCCC=CC(=O)O
Yield: 84.8 %

Procedure:
The procedure followed was analogous to part (b) of Example 1, with the exception that (before the cracking reaction) the mixture was heated with 50 g of water at 90° C. for 60 minutes. 268 g of heptenoic acid (boiling point 139°-141° C./25) were obtained, corresponding to a yield of 84.8%, relative to valeraldehyde which had reacted.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[CH:8]=1)=[O:5]>CO.[Pd]>[NH2:17][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=1
Reactant: COCC(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: COCC(=O)Nc1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
Add Pd/C (10%, 30 mg) to the solution of 2-methoxy-N-(3-nitro-5-(trifluoromethyl)phenyl)acetamide (100 mg, 0.36 mmol) in methanol (6 mL), stir the mixture under hydrogen atmosphere at room temperature for 16 hrs. Filter off the solid, concentrate the filtrate under reduced pressure to yield the crude product (89 mg, 100%) which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26]([NH:28][NH2:29])=[O:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6](/[C:8](=[N:29]/[NH:28][C:26](=[O:27])[C:25]2[CH:30]=[CH:31][CH:32]=[C:23]([S:20]([N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)(=[O:21])=[O:22])[CH:24]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 20 %

Procedure:
1-(5-chloro-2-nitrophenyl)ethanone (30 mg, 0.150 mmol) and 3-(morpholinosulfonyl)benzohydrazide (42.9 mg, 0.150 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2), afforded the product (E)-N′-(1-(5-chloro-2-nitrophenyl)ethylidene)-3-(morpholinosulfonyl)benzohydrazide (15 mg, 0.030 mmol, 20.09% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.20 (m, 1H), 8.07 (m, 1H), 7.88 (m, 1H), 7.66 (m, 1H), 7.51 (m, 2H), 7.39 (m, 1H), 3.69 (m, 4H), 2.99 (m, 4H), 2.29 (s, 3H). Mass [M+H]+: 468.0