Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([N:4]2[C:13]3[C:8](=[CH:9][C:10](F)=[C:11](Cl)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)CC1.N1CCCCC1.CC(C)=O.N12CCCC1=NCCC2>C(N(CC)CC)C.N1C=CC=CC=1.CS(C)=O.C(#N)C.CN(C)C=O>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][CH:5]=[C:6]1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(O)c1c[nH]c2ccccc2c1=O
Reaction time: 38 h

Procedure:
1-Cyclopropyl-6-fluoro-7-{(4-amino/substituted amino /disubstituted amino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl)1-1-piperidinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and isomers were prepared by heating a mixture of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with appropriate {4-(amino/substituted amino/disubstituted amino/hydroxy-3-alkyl/3,3-dialkyl/3,5-dialkyl/3,3,5-trialkyl)}piperidine in an organic solvent optionally in the presence of a base at 50°-120° C., preferably 90° C. for 4-72 hr. The solvent may be selected from acetone, alcohol, acetonitrile, dimethyl sulphoxide, N,N-dimethylformamide preferably acetonitrile or dimethyl sulphoxide. The base may be selected from triethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,7-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably triethylamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][C:37]=1[N:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1.Cl>C(O)(C)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[C:37]([N:43]5[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]5)[CH:38]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1N1CCN(C)CC1

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (which may be prepared according to a procedure similar to Example 11, Step C) and [4-(methyloxy)-3-(4-methyl-1-piperazinyl)phenyl]amine are heated in isopropanol with catalytic conc. HCl at approximately 85° C. to afford the product. ES-LCMS m/z 647 (M+H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][N:6]([CH3:30])[CH:7]([CH2:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]=O.C([BH3-])#N.[Na+].O>CO>[NH2:3][CH2:2][CH2:1][NH:4][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([OH:17])[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH:7]([N:6]([CH3:30])[CH3:5])[CH3:8]
Reactant: NCCN
Reactant: CCCCC(=O)C(CC(C=O)N(C)C)(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(CC(c1ccccc1)(c1ccccc1)C(O)CCCCNCCN)N(C)C
Temperature: 25 °C

Procedure:
Ethylenediamine was added to a solution of 2-dimethylamino-4,4-diphenyl-5-oxononanal (12 mg), as prepared in Example 1, in methanol (0.5 ml). After the mixture was stirred at room temperature, sodium cyanoborohydride (10 mg) was added. The mixture was stirred at room temperature for 18 hours, water was added, and the aqueous mixture was extracted with chloroform. The combined extracts were washed with brine and dried (MgSO4). Rotary evaporation gave a crude product which was further dried in vacuo to yield 4 mg of N-(2-aminoethyl)-8-dimethylamino-6,6-diphenyl-5-hydroxynonylamine.
Reaction SMILES: [N:1]([O-])=O.[Na+].O.[NH2:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[S:12]([CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:17])(=[O:14])=[O:13]>C(O)(=O)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][NH:18][C:16]([C:15]2[S:12](=[O:14])(=[O:13])[C:11]3[CH:10]=[CH:9][S:8][C:7]=3[NH:6][N:1]=2)=[O:17])=[CH:25][CH:24]=1
Reactant: O=N[O-]
Reactant: Nc1sccc1S(=O)(=O)CC(=O)NCc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)C1=NNc2sccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A solution containing sodium nitrite (0.06 g) and water (1 mL) is cooled to 0° C. before adding a solution of 2-((2-amino-3-thienyl)sulfonyl)-N-(4-chlorobenzyl)-acetamide (Preparation 54, 0.255 g) in hot acetic acid (10 mL) dropwise. The solution is warmed to room temperature and stirred for 30 minutes. The reactionmixture is poured into a beaker containing ice. The crude product is collected by filtration and dried under high vacuum to provide 0.18 g (66%) of the title compound as a brown solid. Physical characteristics: MS (ESI+) m/z 356 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10](=O)[CH3:11])=[CH:4][C:3]=2[O:2]1.Cl.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([CH2:21][O:22][NH2:23])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:10](/[C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)\[CH3:11])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: C/C(=N\OCc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)OCO2
Yield: 87 %

Procedure:
3′,4′-Methylenedioxyacetophenone (22) (150 mg, 0.914 mmol) was condensed with compound 19 (206 mg, 1.01 mmol) according to the general procedure II-A defined above. After being heated for 3 h the reaction mixture was cooled and the resulting solid filtered off and washed with cold isopropanol (3.0 mL) to afford the title compound CP30255 (250 mg, 87%) as a yellow solid, m.p. 158.7-160.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5](=[CH:9]N(C)C)[C:6](=O)[CH3:7])[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][NH2:21]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:9]=[N:21][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[C:6]=1[CH3:7])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: NNc1ccccn1
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccn2)c1C
Yield: 84.8 %

Procedure:
Dissolve 2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (0.662 g, 3.57 mmol) and pyridin-2-yl-hydrazine (0.410 g, 3.75 mmol) in ethanol (15 mL) and reflux for 2 hr. Evaporate the mixture then dilute with saturated sodium bicarbonate and extract three times with ethyl acetate. Dry the solution (sodium sulfate), filter and concentrate. Purify using silica gel chromatography, eluting with 50:50 ethyl acetate:hexane to give 5-methyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester as a white solid (0.700 g, 85%). MS (m/z): 232 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[NH:22][CH2:21][CH2:20][O:19][CH3:18])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Product: COCCNC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Starting from trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid and 2-methoxy-ethylamine the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]2)=[CH:6][C:5]=1[Cl:16].[OH-].[Li+]>O1CCCC1>[Cl:16][C:5]1[CH:6]=[C:7]([N:10]2[CH:14]=[CH:13][C:12]([CH3:15])=[N:11]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(-n2ccc(C)n2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Yield: 79.2 %

Procedure:
A solution of 2-chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic acid methyl ester of Step A (1.42 g, 5.6 mmol) in 20 mL of tetrahydrofuran containing 6 mL of 1 M aqueous lithium hydroxide was stirred overnight at ambient temperature. The reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water and brine, and dried over sodium sulfate. Evaporation of the solvent afforded the title compound (1.05 g ), m.p. 192-193° C.
Reaction SMILES: [CH2:1]1[CH2:10][C:8](=O)[C:4]2[CH:5]=[CH:6][S:7][C:3]=2[CH2:2]1.C[Si]([C:15]#[N:16])(C)C>C(#N)C.[I-].[Zn+2].[I-]>[C:15]([C:8]1[C:4]2[CH:5]=[CH:6][S:7][C:3]=2[CH2:2][CH2:1][CH:10]=1)#[N:16]
Reactant: O=C1CCCc2sccc21
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CC#N
Product: N#CC1=CCCc2sccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of zinc iodide (6.2 g) in acetonitrile (200 ml) were added 4-keto-4,5,6,7-tetrahydrothianaphthene (20 g) and trimethylsilylcyanide (18 ml) successively. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated. The residue was dissolved in pyridine (65 ml), followed by adding phosphryl chloride (15 ml) dropwise at room temperature. The mixture was refluxed for 30 minutes. The reaction mixture was cooled with ice and thereto was added dropwise isopropanol. The reaction mixture was poured onto ice water and extracted with ethyl acetate. The extract was washed by hydrochloric acid, water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and concentrated to give the title compound (17 g) having the following physical data.
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][CH:5]=1)[CH:2]=[CH2:3].CSC.B.[OH-:19].[Na+].OO.[Cl-].[NH4+]>O1CCCC1.C(O)C>[OH:19][CH2:3][CH2:2][CH2:1][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:7]=2[O:6][CH:5]=1
Reactant: C=CCc1coc2c(OC)cccc12
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Cl-]
Solvent: CSC
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc2c(CCCO)coc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
3-(2-propenyl)-7-methoxybenzofuran (2.19 g) was dissolved in anhydrous tetrahydrofuran (25 ml) under argon atmosphere and the solution was cooled to 0° C. Borane dimethylsulfide complex (2M solution in THF, 6.1 ml) was added and the solution was stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C. and ethanol (20 ml), 3N aqueous sodium hydroxide solution (1.3 ml) and 30% hydrogen peroxide solution (1.5 ml) were added. After stirring the reaction solution at room temperature for another 15 minutes, the reaction mixture was poured into saturated aqueous ammonium chloride solution, and the resultant was extracted with ethyl acetate. The organic layer was washed with water and with saturated brine, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: cyclohexane/ethyl acetate=3/1-2/1) to obtain the desired compound (1.42 g, yield: 59%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2.[OH-].[Li+].Cl>CO.O>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:21])/[CH2:14][CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[C:9]([O:22][CH3:23])[C:8]([CH3:24])=[C:7]2[C:3]=1[C:4](=[O:25])[O:5][CH2:6]2
Reactant: COC(=O)C(C)C/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CC(C)C(=O)O)C(=O)OC2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoate (0.85 g) in methanol (10 ml) was added a solution of lithium hydroxide (0.4 g) in water (5 ml). After 4 hours at room temperature, the solution was poured into ice water, acidified with 10% aqueous hydrochloric acid, and extracted with ethyl acetate. The extract was dried and evaporated to give (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl -4-hexenoic acid, mp 120°-3° C. (tert-butylmethyl ether/hexane).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[C:17][Si](C)(C)C)=[C:9]([F:22])[CH:8]=2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[CH:17])=[C:9]([F:22])[CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C#C[Si](C)(C)C)c(F)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cc2c(=O)nc(CCCC)[nH]c2cc1F
Temperature: 60 °C
Yield: 90.7 %

Procedure:
A mixture of 1.0 g of 2-butyl-7-fluoro-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone, 20 ml of 1N sodium hydroxide and 25 ml of methyl alcohol is heated at 60° C. for 5 hours then evaporated in vacuo. The residue is dissolved in 100 ml of water and acidified. The resulting solid is collected and dried to afford 700 mg of the desired product as a yellow solid, m.p. 218° C.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:25](=[O:50])[NH:26][CH:27]([C:36](=[O:49])[N:37]([CH2:41][CH:42](OCC)OCC)[CH2:38][CH2:39][F:40])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])(=[O:16])=[O:15])C1C=CC=CC=1.[CH:52]([OH:54])=[O:53]>>[CH2:28]([O:53][C:52](=[O:54])[NH:10][CH:11]1[C:25](=[O:50])[N:26]2[CH:27]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[C:36](=[O:49])[N:37]([CH2:38][CH2:39][F:40])[CH2:41][CH:42]2[N:13]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])(=[O:15])=[O:16])[CH2:12]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(CN(CCF)C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1)OCC
Reactant: O=CO
Product: O=C(NC1CN(S(=O)(=O)c2ccc(Cl)cc2Cl)C2CN(CCF)C(=O)C(Cc3ccc(Cl)cc3)N2C1=O)OCc1ccccc1
Reaction time: 6 h

Procedure:
A solution of 3.13 g (3.96 mmol) of benzyl[1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)(2-fluoroethyl)carbamoyl]ethylcarbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]carbamate in 20 ml of formic acid was heated to 60° C. and stirred for 6 hours. The reaction mixture was concentrated in vacuo, diluted with EtOAc and washed with 1N NaHCO3 solution and brine. The organic phase was isolated, dried (MgSO4) and concentrated in vacuo. This crude substance was subjected to a flash chromatography on 120 g of SiO2 (elution with EtOAc/heptane, gradient 50-100%). 350 mg of the substance benzyl[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-(2-fluoroethyl)-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate were obtained. Further elution of the column provided 980 mg of the compound corresponding to the benzyl[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-(2-hydroxyethyl)-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate byproduct. The monoisotopic MW expected in the LC/MS=694 and the measured value of (M+H)=695 agree with the structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([O:26][CH3:27])[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>>[C:33]([N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[C:13]([O:26][CH3:27])[CH:12]=2)[N:9]=1)(=[O:36])[CH:34]=[CH2:35]
Reactant: COc1cc(-c2nc([C@@H]3CCCN3)n3ccnc(N)c23)ccc1C(=O)Nc1ccccn1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)c(OC)c2)c2c(N)nccn12
Yield: 35.5 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxy-N-(pyridin-2-yl)benzamide (intermediate 19) and acryloylchloride, to afford the title compound (14 mg, 35.5%). Data: UPLC (C) Rt: 1.74 min; m/z 484.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5](I)=[CH:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C.[Cu](I)I.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>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:6][CH:7]=1
Reactant: N#Cc1nc(I)ccc1N
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(N)c(C#N)n1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 9, using 3.8 grams (0,015 mole) of 3-amino-2-cyano-6-iodopyridine (prepared in Step A of Example 10), 2.1 grams (0.021 mole) of trimethylsilylacetylene, 10.6 mL of triethylamine, 0.13 gram of copper iodide, and 0.29 gram of bis(triphenylphosphine)palladium(II) chloride in 50 mL of acetonitrile, yielding 3-amino-2-cyano-6-(trimethylsilylethynyl)pyridine.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([OH:23])=O)[C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.Cl>[CH:1]1([C:7]2[C:15]3[CH:10]=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:14]=3[N:9]3[CH2:20][C:21](=[O:23])[N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-6-(methoxycarbonyl)-1H-indol-1-yl]acetic acid in DCM (0.08 M), DIPEA (3.5 eq) and HATU (2.5 eq) were added and the mixture stirred at RT overnight. The solution was diluted with DCM and HCl (1N) and the 2 phases separated. The aqueous phase was extracted with DCM (2×). The combined organic phases were then washed with a saturated aqueous solution of NaHCO3 and brine before being dried over Na2SO4, filtered and concentrated in vacuo. The crude was then used in the next step without further purification; MS (ES+) m/z 474 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])/[C:4](/[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[C:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5]\[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.C([O-])=O.[NH4+].O=O.CO.C(#N)C.O>C(O)(=O)C.[Pd].C(O)=O>[CH3:1][O:2][C:3](=[O:37])/[C:4](/[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5]\[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)/C(=C\c1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: O=O
Solvent: O
Solvent: CC#N
Solvent: O=CO
Product: COC(=O)/C(=C\c1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 120 °C

Procedure:
To a solution of 22 (0.60 g, 1.6 mmol) in acetic acid (15 mL) was added Pd on carbon (10%, 300 mg) and ammonium formate (4.3 g, 55.8 mmol) (caution: in a large scale reaction exothermicity may be a problem; rigorous exclusion of oxygen is desirable) and heated at 120° C. for 20 h. Catalyst was filtered through a bed of Celite® and acetic acid was evaporated under reduced pressure. Water (50 mL) was added to the residue and solid separated was filtered. Pure Z-isomer was isolated by preparative HPLC using Intersil ODS-3 preparative column (250×4.6 mm, 5 μm) running at a rate of 15 mL per minute using methanol:acetonitrile:water (3:3:2) containing formic acid (0.05%): mp 65-66° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.05 (br s, 1H), 7.48 (d, J=9.2 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.13 (s, 1H), 7.03 (overlapped d, J=8.8 Hz, 2H), 7.01 (overlapped d, J=8.4 Hz, 2H), 6.56 (d, J=2.0 Hz, 2H), 6.49 (t, J=2.0 Hz, 1H), 4.90 (dd, J=9.2 and 4.4 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 6H), 3.38 (dd, J=14.8 and 4.8 Hz, 1H) and 3.13 (dd, J=14.4 and 9.2 Hz, 1H); MS (EI) m/z 300[M]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:45][CH3:46])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][C:16](=[O:36])[CH2:17][N:18]([CH2:26][CH2:27][O:28]CC3C=CC=CC=3)CC3C=CC=CC=3)=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[H][H].[ClH:49].O>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[ClH:49].[CH2:45]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][C:16](=[O:36])[CH2:17][NH:18][CH2:26][CH2:27][OH:28])=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]([C:9]=23)=[N:7]1)[CH3:46]
Reactant: [H][H]
Reactant: CCN(CC)CCn1nc2c3c(c(NC(=O)CN(CCOCc4ccccc4)Cc4ccccc4)ccc31)Oc1ccc(O)cc1-2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)CCn1nc2c3c(c(NC(=O)CNCCO)ccc31)Oc1ccc(O)cc1-2

Procedure:
A mixture of 1.3 g of the above acetamide and 0.10 g of 20% palladium hydroxide on carbon in 50 ml of glacial acetic acid stirred under hydrogen at atmospheric pressure until the hydrogen uptake measured 100 ml. The reaction mixture was filtered and coevaporated several times with methanol. The residue was dissolved in methanol and acidified with a solution of hydrogen chloride in 2-propanol. Further dilution with 2-propanol and cooling caused precipitation of a crystalline solid. The solid was isolated and dried to give 0.976 g of the product as a yellow crystalline solid with 2.5 equivalents of hydrogen chloride and 1.5 equivalents of water, mp 285° C. with decomposition.
Reaction SMILES: C[N+]1([O-])CCOCC1.[CH2:9]([C:12]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13]1)[CH2:10][CH3:11]>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:9]([C:12]1([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13]1)[CH2:10][CH3:11]
Reactant: CCCC1(CO)CCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCCC1(C=O)CCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 218.9 %

Procedure:
An ice-cold mixture of 4-methylmorpholine N-oxide (NMO) (1.683 g, 14.4 mmol), 1-3 (1.229 g, 9.59 mmol) and 4 Å molecular sieves (5.5 g) in dichloromethane (20 mL) was treated with tetrapropylammonium perruthenate (TPAP) (179 mg, 0.51 mmol). The mixture was stirred at 0° C. for 5 min. and then was allowed to warm to room temperature. After 1 h, the mixture was filtered through a pad of silica gel (dichloromethane) and the dichloromethane was evaporated. The crude product was combined with the crude product from another batch (starting with 4.986 g, 38.9 mmol of 1-3) and the combined product was purified by distillation under reduced pressure followed by flash chromatography on silica gel (15% ether/pentane) to give 1-4 (2.649 g, 43%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](OCC)=[O:9].[O-]CC.[Na+:16]>C(OCC)C>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[CH:8][O-:9].[Na+:16]
Reactant: CCOC=O
Reactant: O=C1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: O=C1CCCCC1=C[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Cyclohexanone (30 ml) and ethyl formate (24 ml) were dissolved in diethyl ether (150 ml), sodium ethoxide (21 g) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 10 hr. Insoluble material was collected by filtration, and washed with diethyl ether to give the object compound (49.2 g) as a solid.