Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20](O)[CH2:21][OH:22].CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=3)[O:22][CH2:21][CH2:20][O:9]2)=[CH:15][CH:14]=1
Reactant: OCCO
Reactant: Nc1ccc(C(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: Nc1ccc(C2(c3ccc(F)cc3)OCCO2)cc1[N+](=O)[O-]
Reaction time: 72 h
Yield: 33.2 %

Procedure:
A mixture of 26 parts of (4-amino-3-nitrophenyl)(4-fluorophenyl)methanone, 12 parts of 1,2-ethanediol, 10 parts of 4-methylbenzenesulfonic acid, 32 parts of butanol and 360 parts of benzene is stirred and refluxed for 96 hours with water-separator. Another 5 parts of 4-methylbenzenesulfonic acid are added and stirring at reflux is continued for 72 hours. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and 2% of methanol and then trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 10.1 parts (33.2%) of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-2-nitrobenzenamine; mp. 105° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:37]=[CH:36][C:26]2[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:28][O:29][C:25]=2[CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:33]4[CH2:32][CH2:31][CH:30]([C:27]5[C:26]6[CH:36]=[CH:37][C:23]([F:22])=[CH:24][C:25]=6[O:29][N:28]=5)[CH2:35][CH2:34]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 6-fluoro-3-piperidine-4-yl-benzo[d]isoxazole (Table No.1, SM 8) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=506.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[CH2:20]([N:22]=[C:23]=[S:24])[CH3:21]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:23](=[S:24])[NH:22][CH2:20][CH3:21])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CCN=C=S
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Br)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=S)SC1C2=C(CCCC2)C(=O)N1c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
In 20 ml of dichloromethane was dissolved 3.4 g of 2-(4-bromo-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 1.0 g of ethyl isothiocyanate, together with one drop of triethylamine, was added to the solution, followed by stirring at room temperature for 5 hours. The dichloromethane was distilled off under reduced pressure, and the resulting crystals were washed with cold ethanol and dried, thereby producing 3.8 g (yield of 88%) of the subject compound. Recrystallization from ethanol yielded white crystals, m.p. 130°-131° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:11]2[C:19]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[N:13]([Si](C(C)C)(C(C)C)C(C)C)[CH:12]=2)O)=[CH:5][N:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]([CH2:9][C:11]2[C:19]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[CH:7][N:8]=1
Reactant: CSc1ncc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncncc23)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CSc1ncc(Cc2c[nH]c3ncncc23)cn1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
To a solution of (2-methylsulfanyl-pyrimidin-5-yl)-(7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol (55, 2.75 g, 6.40 mmol) in 50.0 mL of 1,2-dichloroethane, triethylsilane (8.00 mL, 50.1 mmol) and trifluoroacetic acid (4.00 mL, 51.9 mmol) were added. The reaction was heated at 80° C. overnight, then concentrated under vacuum, combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 2-15% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (56, 1.20 g). MS (ESI) [M+H+]+=258.2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6](Cl)(Cl)[C:7]([F:10])([F:9])[F:8].[CH2:13]([C:15]1[CH:30]=[C:29]([O:31][CH2:32][CH:33]=[C:34]([Cl:36])[Cl:35])[CH:28]=[C:27]([CH2:37][CH3:38])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH:25]=O)[CH3:14].C(OC(=O)C)(=O)C>[Zn].CN(C)C=O>[CH2:13]([C:15]1[CH:30]=[C:29]([O:31][CH2:32][CH:33]=[C:34]([Cl:35])[Cl:36])[CH:28]=[C:27]([CH2:37][CH3:38])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24]/[CH:25]=[C:6](\[Cl:5])/[C:7]([F:10])([F:9])[F:8])[CH3:14]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCCOCC=O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCCOC/C=C(\Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 192.5 %

Procedure:
To a mixture of 0.12 g of aluminum chloride and 50 ml of N,N-dimethylformamide was added 3.04 g of 1,1,1-trichlorotrifluoroethane. After stirring at room temperature for 1 hour, 1.21 g of 5-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetaldehyde was added, and the reaction mixture was further stirred at room temperature for 4 hours, to which 1.38 g of acetic anhydride was added. After stirring at room temperature for 1 hour, 0.88 g of zinc dust was added, and the reaction mixture was stirred at room temperature for 12 hours and filtered. The filtrate was poured into 50 ml of diluted hydrochloric acid and extracted twice with 100 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.91 g of (Z)-3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(5-(3-chloro-4,4,4-trifluoro-2-butenyloxy)pentyloxy)benzene (yield, 72%), nD26.0 1.4958.
Reaction SMILES: [Br:1][C:2]1[C:21](Br)=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].C(O)(=O)C.C([O-])(=O)C.[Na+].[H][H]>[Pd]>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: NC(=O)C1(N2C(=O)c3ccc(Br)c(Br)c3C2=O)CCCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)C1(N2C(=O)c3cccc(Br)c3C2=O)CCCCC1

Procedure:
A solution of 1-(3,4-dibromophthalimido)cyclohexanecarboxamide in acetic acid containing one equivalent of sodium acetate is reduced with hydrogen in the presence of palladium on carbon to give the product 1-(3-bromophthalimido) cyclohexanecarboxamide, m.p. 199°-200° C.
Reaction SMILES: [F-].[K+].Br[C:4]1[N:21]([CH2:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)[C:7]2[C:8]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[N:9][C:10]([C:12]#[N:13])=[CH:11][C:6]=2[N:5]=1.[NH:30]1[C:35](=[O:36])[CH2:34][NH:33][C@H:32]2[CH2:37][CH2:38][CH2:39][C@H:31]12.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:20][C:18]1[CH:19]=[C:14]([C:8]2[C:7]3[N:21]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:4]([N:33]4[CH2:34][C:35](=[O:36])[NH:30][C@H:31]5[CH2:39][CH2:38][CH2:37][C@H:32]45)=[N:5][C:6]=3[CH:11]=[C:10]([C:12]#[N:13])[N:9]=2)[CH:15]=[N:16][CH:17]=1
Reactant: O=C1CN[C@H]2CCC[C@@H]2N1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1CC[C@H](Cn2c(N3CC(=O)N[C@H]4CCC[C@@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
A vial was charged with potassium fluoride (163 mg, 2.81 mmol), 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 250 mg, 0.562 mmol), (4aS,7aS)-octahydro-2H-cyclopenta[b]pyrazin-2-one (189 mg, 1.349 mmol), DMSO (1730 μl) and DIEA (491 μl, 2.81 mmol). The vial was capped and heated to 100° C. overnight. The mixture was then cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (0-20% MeOH in DCM) afforded 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aS,7aS)-3-oxooctahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C27H30ClN7O [M+H]+ 504. found 504.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2S(C)(=O)=O)=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>C(#N)C.CCOCC.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[N:23]=[N:24][N:25]=[C:9]23)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)c1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: O=c1cc(C(F)(F)F)n2nnnc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(4-Chlorophenyl)-3,4-dihydro-2-methanesulfonyl-6-trifluoromethylpyrimidin-4-one (1.1 g) was dissolved in a mixture of acetonitrile (20 ml) with ether (20 ml) and was added with sodium azide (0.24 g) under ice-cooled condition. The thus obtained mixture was stirred for 30 minutes at room temperature and was added with saturated brine (50 ml). The mixture was extracted with ether and then dried on anhydrous magnesium sulfate followed by distilling off the solvent under reduced pressure. The residue was purified by a preparative thin-layer plate of silica gel (developing solvent: ethyl acetate/hexane=1.5/8.5) to give the compound of interest (0.7 g) as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:15]>C(C1C=CC=CC=1)(C)(C)C>[C:1](=[NH:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N
Solvent: CC(C)(C)c1ccccc1
Product: N=C(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 28 %

Procedure:
91.1 g of benzophenone, 150 ml of tert-butylbenzene and 2 g of 200-mesh silica-alumina (Nikki Kagaku K.K., N-635) were fed to the same reactor as in Example 11. The reactor was heated, and ammonia gas was continuously fed to the reactor at a feed rate of 1.5 Nl/min, while keeping the contents at 170° C, and reaction was carried out under 8 atm. for one hour. The withdrawn gas was cooled and condensed tert-butylbenzene was refluxed into the reactor. After the completion of the reaction, benzophenoneimine was obtained in yield of 28%.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Li+].Cl.[C:19]1([C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N+]=[N-])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[OH:1][C@H:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4]
Reactant: CCOC(=O)[C@H](O)CCc1ccccc1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@H](O)CCc1ccccc1
Reaction time: 3.5 h
Yield: 38.4 %

Procedure:
Dissolve (R)-2-hydroxy-4-phenylbutyric acid, ethyl ester (4.16 g, 20 mmol) in methanol (40 mL). Add 1N lithium hydroxide (25 mL, 25 mmol) and stir under an atmosphere of argon for 3.5 hours. Acidify with 1N hydrochloric acid (25 mL), saturate with sodium chloride and extract with ethyl acetate (3×25 mL). Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Take up the residue in methylene chloride (20 mL) and add diphenyldiazomethane (3.36 g, 17.3 mmol). Stir overnight and wash with saturated sodium hydrogen carbonate (2×). Dry (MgSO4), evaporate the solvent in vacuo and recrystallize (methylene chloride/hexane then again with cyclohexane) to give (R)-2-hydroxy-4-phenylbutyric acid, diphenylmethyl ester as white needles (2.3 g, 38%); mp 82°-84° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:16])[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[F:17])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 1 (1.0 g, 4.4 mmol), 2-fluoroaniline (463 μl, 4.8 mmol) in CH2Cl2 (25 ml) at 0° C. was added DCC (0.99 g, 4.8 mmol) in several portions. The mixture was stirred at room temperature overnight. The white precipitate was removed by filtration. After removal of solvent, the residue was purified by column chromatography (silica gel, hexane/ethyl acetate, 4:1) to give 3-(2-fluorophenylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (2) as a colorless oil (1.13 g, 80%).
Reaction SMILES: [CH2:1]=O.[C:3]([C:7]1[CH:8]=[C:9]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[C:10]([O:37][CH3:38])=[C:11]([NH:13][C:14](=[O:36])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][C:23]3[CH:28]=[C:27]([CH2:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:26]=[CH:25][N:24]=3)[CH:16]=2)[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[H][H]>[Pd].CO>[C:3]([C:7]1[CH:8]=[C:9]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])[C:10]([O:37][CH3:38])=[C:11]([NH:13][C:14](=[O:36])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([O:22][C:23]3[CH:28]=[C:27]([CH2:29][CH:30]4[CH2:31][CH2:32][N:33]([CH3:1])[CH2:34][CH2:35]4)[N:26]=[CH:25][N:24]=3)[CH:16]=2)[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: C=O
Reactant: [H][H]
Reactant: COc1c(NC(=O)c2ccc(C)c(Oc3cc(CC4CCNCC4)ncn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: COc1c(NC(=O)c2ccc(C)c(Oc3cc(CC4CCN(C)CC4)ncn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
40 μl Paraformaldehyde (37% in water) and 30 mg palladium on activated charcoal (10%) are added to 260 mg N-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-4-methyl-3-(6-piperidin-4-ylmethyl-pyrimidin-4-yloxy)-benzamide in 10 ml of methanol and the reaction mixture is hydrogenated at ambient temperature and a partial hydrogen pressure of 4 bar. After the uptake of hydrogen has ended the catalyst is suction filtered and the filtrate is evaporated down. The flask residue is chromatographed on aluminium oxide with dichloromethane/methanol (99:1→95:5) as eluant.
Reaction SMILES: N1([N:7]=[CH:8][C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)CCCCC1.C1COCC1.C(O)C.[ClH:41]>C(OCC)(=O)C.[Pd]>[ClH:41].[ClH:41].[NH:12]1[CH:13]=[C:9]([CH2:8][NH2:7])[N:10]=[CH:11]1
Reactant: C(=NN1CCCCC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCc1c[nH]cn1
Temperature: 80 °C
Yield: 29 %

Procedure:
To a solution containing 450 mg of piperidin-1-yl-(1-trityl-1H-imidazol-4-yl-methylene)amine in 3.5 mL of 3N hydrogen chloride in ethyl acetate are added 90 mg of 10% Pd/C, 0.5 mL of THF and 0.9 mL of ethanol. The reaction medium is placed under a hydrogen pressure of 6 bar and heated at 80° C. for 3 hours. After filtering off the catalyst and evaporating off the solvents, the crude product obtained is chromatographed on silica gel (eluent: 6/4 DCM/MeOH). 50 mg of C-(1H-imidazol-4-yl)methylamine dihydrochloride in the form of a white powder are obtained in a yield of 29%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1)(=[O:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(N)nn4c3-c3ccccc3)cc2)CCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of tert-butyl {1-[4-(6-amino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6.3 (0.10 g, 0.22 mmol) in DCM (4 mL) was added pyridine (0.036 mL, 0.44 mmol, 2 equiv) and acetic anhydride (0.027 mL, 0.29 mmol, 1.3 equiv). The reaction mixture was stirred for 24 h at room temperature, additional acetic anhydride (0.042 mL, 0.44 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for an additional 24 h. The resulting mixture was concentrated under reduced pressure to give tert-butyl {1-[4-(6-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.11 g, 100%) which was used without further purification:
Reaction SMILES: [CH2:1]([C@H:4]1[C@:21]2(O)[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3].C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC[C@]5(O)[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[K+].[Br-]>CC(C)=O.C(OCC)(=O)C>[CH2:1]([C@H:4]1[C:21]2[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Agent: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
6β-Propargyl-5α-hydroxyandrostane-3,17-dione (10). The 6β-propargyl bisketal 8 (0.6 mmol) was dissolved in acetone (30 ml) and p-TSOH (5 mg) was added. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, washed (5% NaHCO3, brine, water) and dried. The ethyl acetate was removed in vacuo and the product was purified by column chromatography to yield the dione 90% yield; m.p. 145°-146° C.; IR (KBr) 3475 (C C--H), 3300 (OH), 2100, 1735 and 1715 (C=O) cm-1 ; 1H-NMR (CDCl3) δ 0.91 (s, 3H, 18-CH3), 1.21 (s, 3H 19-CH3), 3.0 (d, 1H, 4β-H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)CN)#[N:2].C(#N)C.[C:14](=[O:17])([O-])[OH:15].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>[Ru]=O.O>[C:1]([C:3]1[CH:10]=[C:9]([CH:8]=[CH:5][CH:4]=1)[C:14]([OH:15])=[O:17])#[N:2]
Reactant: O=C([O-])O
Reactant: N#Cc1cccc(CN)c1
Agent: O=[Ru]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cccc(C(=O)O)c1
Temperature: 80 °C
Yield: 55.8 %

Procedure:
A mixture containing m-cyanobenzylamine (13.2 g), acetonitrile (80 g), sodium hydrogencarbonate (76 g), water (500 g), sodium persulfate (95 g), and ruthenium oxide (0.25 g) was stirred for reaction at 80° C. over ten hours. After the precipitated solid was removed through filtration, the pH of the filtrate was adjusted to four through addition of sulfuric acid. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 8.2 g of m-cyanobenzoic acid (yield 56%, based on m-cyanobenzylamine). The m-cyanobenzoic acid obtained had a purity of 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.S(=O)(=O)(O)[OH:15].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:15])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=Cc1cc(Cl)cc2c1OCCO2
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cc(Cl)cc2c1OCCO2
Temperature: 5 °C
Yield: 77.2 %

Procedure:
7-Chloro-2,3-dihydro-1,4-benzodioxine-5-carbaldehyde (6.25 g, 31.4 mmol) was dissolved in acetone (150 mL) and the solution was then cooled to 5° C. A solution of CrO3 in sulfuric acid (4 M in 4 M H2SO4, 12.5 mL, 50 mmol) was added dropwise over 2 min and the mixture was refluxed for 30 min. Water (150 mL) was added and then most of the acetone was removed by evaporation. The mixture was extracted with ether (150 mL) and the organic solution was then extracted with a solution of NaOH (0.5 M, 150 mL). The aqueous solution was acidified with 2 M hydrochloric acid and then extracted with ether (150 mL). The organic solution was washed with brine and dried over Na2SO4. The solvent was removed by evaporation and the residue treated with CH2Cl2. After filtration and drying there was obtained 5.2 g (77%) of 7-chloro-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid. 1H NMR (400 MHz, acetone-d6): 4.3-4.4 (m, 4H), 7.1 (d, 1H), 7.3 (d, 1H), 11-12 (b, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1.N1C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl[C:41]([O:43][CH2:44][CH2:45][Cl:46])=[O:42]>O>[Cl:46][CH2:45][CH2:44][O:43][C:41](=[O:42])[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1
Reactant: O=C(Cl)OCCCl
Reactant: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC1CCC(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1)OCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of trans-N2-[4-(aminomethyl)cyclohexyl]-9-fluoro-5,6-dihydro-4H-benzo-[6,7]cyclohepta[d][1,3]thiazol-2-amine (5.00 g, 11.95 mmol), 20 ml anhydrous pyridine, and 8 ml diisopropylethylamine was stirred under N2. Then 2-chloroethyl chloroformate (1.40 ml, 13.6 mmol) was added dropwise to the stirring solution. The solution was stirred at room temperature for 2 hours and then poured into 250 ml water and extracted with 250 ml EtOAc. The extract was separated and evaporated to yield 100% (5.40 g) of the desired product as a highly viscous golden oil: 1H-NMR (CDCl3) δ 1.13 (3H, m), 1.43 (1H, m), 1.82 (2H, m), 2.06 (2H, m), 2.22 (2H, m), 2.81 (4H, m), 3.06 (2H, t, J=6.4 Hz), 3.25 (1H, m), 3.70 (3H, m), 4.31 (2H, t, J=5.7 Hz), 4.89 (2H, m), 6.82 (1H, t, J=2.8 Hz), 7.04 (1H, m), 7.70 (1H, dd, J=2.7, 10.8 Hz); 452 (ESMS, MH+).