Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([O:18]C)=[O:17])[C:3](=[O:9])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[Li+].[OH-].Cl>CO>[O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17])[C:3](=[O:9])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCCCN1C(=O)C(=O)c1cccs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(C(=O)N1CCCCC1C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Intermediate 2 (2.45 g, 8.72 mmol) was dissolved in MeOH (50 mL). LiOH solution (1 N, 13 mL) was added at 0° C., and the mixture was stirred at the same temperature for 2 h and at room temperature for 16 h. The reaction mixture was acidified with 1 N HCl, and extracted with ethyl acetate. The organic phase was washed with brine and dried with MgSO4. After evaporation of the solvent and drying under vacuum, a yellow solid was obtained, and was used for the next step without purification.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClCCl>CN(C)C=O>[CH2:20]([O:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2]([CH:1]=[O:13])=[CH:3][C:4]=1[O:5][CH3:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1OCc1ccccc1
Reaction time: 25 h
Yield: 87.6 %

Procedure:
To a stirring suspension of syringaldehyde (25.19 g, 138 mmol) and potassium carbonate (38.14 g, 276 mmol, 2 equ) in N,N-dimethyl formamide (500 ml) was added benzyl bromide (20 ml, 168 mmol, 1.2 equ). The reaction was stirred for 25 hours, then poured into dichloromethane. The organic solvent was washed with water (5×) then dried (MgSO4) and concentrated in vacuo to give a pink oil. This was recrystallised from hexane to give 31 (32.9 g, 87 %).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]3)[CH2:12][CH:11]2[OH:27])=[C:6]([F:28])[C:5]=1[F:29])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CC(O)C>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]3)[CH2:12][C:11]2=[O:27])=[C:6]([F:28])[C:5]=1[F:29])[CH3:2]
Reactant: CCCCCC1CCC(C2CCC(c3ccc(OCC)c(F)c3F)C(O)C2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCCCC1CCC(C2CCC(c3ccc(OCC)c(F)c3F)C(=O)C2)CC1

Procedure:
46.7 g of 4-(4-ethoxy-2,3-difluorophenyl)-4′-pentylbicyclohexyl-3-ol were dissolved in 600 ml of dichloromethane, and 20 g of Celite were added. 28.0 g of pyridinium chlorochromate were added with stirring, and the mixture was stirred overnight at RT. After 10 ml of 2-propanol had been added, the mixture was stirred for 1 hour and then subjected to conventional work-up, giving 4-(4-ethoxy-2,3-difluorophenyl)-4′-pentylbicyclohexyl-3-one.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:23](=[O:27])[C:24]([NH2:26])=[O:25])=[C:9]([CH3:22])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].CCOC(C)=O>CO>[NH2:26][C:24](=[O:25])[C:23]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:28])=[O:2])[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[CH3:22])=[O:27]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A mixture of 660 mg (1.7 mmol) of ((3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid methyl ester and 10 mL of 1N NaOH in 30 mL of methanol was heated to maintain reflux for 1 hour, cooled to room temperature and stirred for 0.5 hour. The mixture was concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic to pH 2-3 with 1N HCl and extracted with EtOAc. On concentrating the EtOAc solution, 431 mg (69% yield) of ((3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid crystallized, melting at 218-220° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][N:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O.C(Cl)(Cl)Cl.Cl>O>[CH3:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:7][CH:8]=[C:9]([CH3:13])[CH:10]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: Cc1cnc(NCCCN)c(C)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cnc(NCCCNc2ncc(Cc3ccc(C)nc3)c(=O)[nH]2)c(C)c1

Procedure:
2-(3-Aminopropylamino)-3,5-dimethylpyridine (0.81 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.04 g) were fused together on an oil bath at 140° C. for 6 hr. On cooling the resulting mixture was equilibrated between chloroform and water (pH adjusted to 5.5 with dil. hydrochloric acid). The pH of the aqueous solution was raised to 6.5 and the product extracted out with chloroform. After drying (MgSO4) and stripping, recrystallisation from ethyl acetate and finally twice from ethanol/water gave 2-[3-(3,5-dimethylpyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone 2.4H2O, (0.83 g; 49%) m.p. 104°-5° C. (softens ca 90° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[H-].[Na+].Br[C:23]([CH3:29])([CH3:28])[C:24](C#N)=[O:25]>C1COCC1>[CH3:28][C:23]1([CH3:29])[C:24](=[O:25])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([CH3:1])[CH:3]=2)[O:19]1
Reactant: CC(C)(Br)C(=O)C#N
Reactant: CSc1ccc(C(=O)Cc2cccc(F)c2)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
437 mg of 1-{3-methyl-4-(methylthio)phenyl}-2-(3-fluorophenyl)-ethanone in 50 ml dry THF was stirred with 67 mg of 60% oil dispersion of sodium hydride for an hour at 0° C., which was followed by dropwise addition of 0.8 ml α-bromoisobutyryl cyanide diluted with 25 ml THF. The reaction solution was slowly warmed to room temperature and was stirred overnight. Then the solvent was removed in vacuo and the resulting residue was extracted with 50 ml water and dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and was purified by column chromatography (hexane/ethylacetate=6:1) to yield 312 mg of 2,2-dimethyl-4-(3-fluorophenyl)-5-{3-methyl-4-(methylthio)phenyl}-3(2H)-furanone. NMR: δ1.55 (s, 6H), 2.27 (s, 3H), 2.48 (s, 3H), 7.36 (m, 4H), 7.32 (m, 1H), 7.45 (m, 2H). IR 1694, 1601, 1385, 1260, 1192.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]#[N:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)([CH3:21])([CH3:20])[CH3:19].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:16]#[N:17])[C:13]([O:15][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: N#CC(NC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)C(C#N)NC(=O)OCc1ccccc1
Yield: 67.4 %

Procedure:
To a mixture of 2-benzyloxycarbonylamino-2-cyanoacetic acid (2.00 g, 8.54 mmol), toluene (20 ml) and t-butyl alcohol (6.33 g, 85.4 mmol), was added trifluoroacetic acid anhydride (7.17 g, 34.2 mmol) dropwise and the solution was stirred for half an hour. The reaction solution was neutralized by adding 10% NaOH aqueous solution (18 g), the organic layer was separated and washed with water three times, dried over sodium sulfate, insoluble materials were filtered and the filtrate was condensed to give t-butyl 2-benzyloxycarbonylamino-2-cyanoacetate (1.67 g, yield 67.4%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C1(C)C=CC=CC=1>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]\[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(/C=C\N(C)C)c([N+](=O)[O-])cn1
Temperature: 90 °C
Yield: 63 %

Procedure:
To a solution of N-(4-methyl-5-nitropyridin-2-yl)acetamide (1 g, 5 mmol, Step a) in dry dimethylformamide (10 mL), dimethylformamide dimethyl acetal (1.5 mL, 11 mmol) was added and the resulting reaction mixture was heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, toluene was added and evaporated under vacuum followed by triturating with diethyl ether and filtration to afford N-{4-[(Z)-2-(dimethylamino)ethenyl]-5-nitropyridin-2-yl}acetamide (0.8 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:21]([CH3:23])[CH3:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][CH2:8][C:7]=2[N:20]=1.C([O-])([O-])=O.[K+].[K+].CO.O>>[CH3:1][O:2][C:3]1[C:4]([N:21]([CH3:23])[CH3:22])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][NH:10][CH2:9][CH2:8][C:7]=2[N:20]=1
Reactant: COc1nc2c(cc1N(C)C)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1nc2c(cc1N(C)C)C(C)CNCC2
Yield: 68.2 %

Procedure:
NaBH3CN (63.0 mg, 990 μmol) was added portionwise at room temperature to a solution of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (100 mg, 330 μmol) and HCHO (37% in H2O, 2.31 mmol) in MeCN (1 ml). The mixture was stirred at room temperature for 15 min before slow addition of HOAc (0.2 ml). The reaction was stirred at room temperature for an additional 3 h and was basified with aq. K2CO3 and extracted with DCM. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to provide 94.0 mg (86%) of 2-methoxy-N,N,5-trimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. MS (ESI) m/z 332. 2-Methoxy-N,N,5-trimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (35.0 mg, 106 μmol) was treated under basic condition (K2CO3/MeOH/H2O), as described above, to provide 17 mg (68%) of 2-methoxy-N,N,5-trimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. MS (ESI) m/z 236.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][N+:3]=1[O-].C(OC(=O)C)(=[O:15])C.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[OH:15][CH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: CCCOc1cc[n+]([O-])c(C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCOc1ccnc(CO)c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-methyl-4-propoxypyridine-1-oxide (8.6 g), acetic anhydride (8.6 ml) and concentrated sulfuric acid (two drops) was heated at 100° C. for five minutes, to which were added ice-water and an excess amount of sodium carbonate. The mixture was subjected to extraction with chloroform. The extract was dried with sodium sulfate, and the solvent was evaporated off. The residue was chromatographed on a column of silica-gel (200 g), which was eluted with carbon tetrachloride-acetone (5:3). The eluate was subjected to evaporation to remove the solvent. The residue (7.3 g) was dissolved in a solution of potassium hydroxide (2.8 g) in a mixture of water (3 ml) and methanol (60 ml). The resultant solution was stirred at room temperature for 15 minutes, to which were added ice-water and an excess amount of sodium carbonate. The mixture was subjected to extraction with ethyl acetate. The extract was dried with sodium sulfate, then the solvent was evaporated off. The residue was chromatographed on a column of silica-gel (150 g), which was eluted with 5% methanol-chloroform to yield 2-hydroxymethyl-4-propoxypyridine (4.4 g) as an oily substance.
Reaction SMILES: CO.Cl.[CH:4]1([C:7]([CH:39]2[CH2:41][CH2:40]2)([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=4)[CH:24]=[C:23]([CH3:38])[CH:22]=3)=[CH:17][N:16]=2)[NH:8][S@@](C(C)(C)C)=O)[CH2:6][CH2:5]1>O1CCOCC1.C([O-])(O)=O.[Na+]>[NH2:8][C:7]([CH:39]1[CH2:41][CH2:40]1)([CH:4]1[CH2:6][CH2:5]1)[C:15]1[N:16]=[CH:17][C:18]([C:21]2[CH:26]=[C:25]([NH:27][C:28]3[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:24]=[C:23]([CH3:38])[CH:22]=2)=[CH:19][CH:20]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(N[S@](=O)C(C)(C)C)(C3CC3)C3CC3)nc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(N)(C3CC3)C3CC3)nc2)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Methanol (5.00 mL) and HCl (4 M in dioxanes, 0.584 mL, 2.34 mmol) were added to (R)—N-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methyl}-2-methylpropane-2-sulfinamide (317.5 mg, 0.584 mmol) and the reaction mixture was stirred for 25 minutes at room temperature. An additional 150 uL of 4 M HCl in dioxane was added to the reaction mixture, stirred for 45 minutes, diluted with saturated aqueous NaHCO3 (20.0 mL) and extracted with ethyl acetate (30.0 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and was concentrated under reduced pressure to yield N-(3-{6-[amino(dicyclopropyl)methyl]pyridin-3-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine. MS APCI calc'd for C24H25F3N5 [M+H]+ 440. found 440.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[CH:15][C:14]1=[O:27])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:7]12[CH2:12][CH:10]([CH2:9][CH2:8]1)[CH2:11][CH:6]2[CH2:5][CH:4]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])=[CH:15][C:14]1=[O:27])[C:3]([OH:28])=[O:2]
Reactant: COC(=O)C(CC1CC2CCC1C2)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CC2CCC1C2)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
In a flask was placed 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (87 mg, 0.22 mmol) dissolved in tetrahydrofuran (3 mL). To this mixture at 25° C. was added a solution of lithium hydroxide monohydrate (19 mg, 0.44 mmol) in water (3 mL) and stirred for 1 h at 25° C. The mixture was then treated with a 1N aqueous hydrochloric acid solution to pH=2 and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (73 mg, 87%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][NH:12][C:4]=2[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: N#Cc1nc(Cl)cc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)cc2c1ncn2C1CCCCO1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
6-Chloro-1H-imidazo[4,5-c]pyridine-4-carbonitrile (620 mg) and p-toluenesulfonic acid monohydrate (10 mg) were suspended in ethyl acetate (10 ml) and heated to 60° C. 3,4-Dihydro-2H-pyran (0.48 ml) was added dropwise and the reaction stirred at 60° C. overnight. The reaction was quenched with 5 mL ammonium hydroxide before addition of water (100 mL) and ethyl acetate (200 mL). Organic layer was separated, dried over sodium sulphate and solvent was evaporated under reduced pressure. The crude product was dissolved in a minimum volume of EtOAc and heptane added. The resulting brown solid was collected by filtration to yield 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (630 mg). 1H NMR (DMSO) δ: 8.92 (s, 1H), 8.30 (s, 1H), 5.80 (d, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 2.19 (m, 1H), 2.11 (m, 1H), 1.62 (m, 4H).
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[N:24]=[C:25]=[S:26]>CN(C)C=O>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[N:24]1[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:25]1=[S:26]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: S=C=Nc1c(Cl)cc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=S)n1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 5 °C
Yield: 5.7 %

Procedure:
A 5 ml dimethylformamide solution of 3.7 g ethyl 3-amino-4,4,4-trifluorocrotonate was added dropwise to a 30 ml dimethylformamide solution of 1.0 g of sodium hydride (purity: 55%) with stirring at 5° C. The mixed solution was stirred at room temperature for 15 minutes, then cooled to 5° C. and added dropwise with a 10 ml dimethylformamide solution of 5.0 g of 2,4,6-trichlorophenyl isothiocyanate. The resulting solution was heated to room temperature and further stirred at 130° C. for 2 hours. Then the solvent was distilled away under reduced pressure and the residue was dissolved by adding 200 ml of water and washed with diethyl ether. The obtained aqueous layer was added into a mixed solution of 30 ml of concentrated hydrochloric acid and 100 g of ice and extracted with 200 ml of ethyl acetate. The obtained organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure to obtain 2.8 g of a crude product. This product was purified by preparative thin-layer chromatography (developing solvent: a mixed solvent of chloroform and ethyl acetate) to obtain 0.43 g of the objective compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[CH2:2][C:3]#[CH:4].[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[C:13]1=[O:22])[CH2:19]2>C1COCC1>[I:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][C:3]#[C:4][C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH:13]2[OH:22])[CH2:19]3)=[CH:10][CH:9]=1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: C#CCCc1ccc(I)cc1
Solvent: C1CCOC1
Product: OC1C2CC3CC(C2)CC1(C#CCCc1ccc(I)cc1)C3
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a stirred solution of 1-(but-3-ynyl)-4-iodobenzene (0.36 g, 1.48 mmol) in anhydrous THF (0.5 ml) 2.8 M MeMgBr in THF (0.6 ml) was added at 0° C. under N2. After stirring for 0.5 h, the solution of 2-admantanone (0.24 g, 1.6 mmol) was added drop wise. This was stirred for 2 h at room temperature, than quenched with the solution of NH4Cl. The mixture was extracted with Et2O. The organic layer was dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2) to give the title product (0.34 g; 56%), as the creamy paste. 1H-NMR (CDCl3) 2.14-2.23 (m, 16H); 4.69 (s, 2H); 6.74 (d, 2H, J=6.87 Hz); 7.54 (d, 2H, J=6.81 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-c2cnccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using 5-methyl-2-(pyrazin-2-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 470 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].C(O)C>[N:11]1([CH:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(C(c2ccccc2)n2ccnc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1
Yield: 99.1 %

Procedure:
A solution of 39 parts of intermediate 42, namely 1-[(4-nitrophenyl)phenylmethyl]-1H-imidazole, in 240 parts of ethanol was hydrogenated at 3.105Pa and at room temperature with 20 parts of Raney nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 34.6 parts (99.1%) of 4-[(1H-imidazol-1-yl)phenylmethyl]-benzenamine (interm. 43).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)[NH2:2].C1N=CN([C:42](N2C=NC=C2)=[O:43])C=1>O1CCOCC1.CCOC(C)=O>[NH2:23][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:10]3[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:8][C:7]4[CH:6]=[CH:5][N:4]5[C:42](=[O:43])[NH:2][N:1]=[C:3]5[C:12]=4[N:11]=3)=[CH:18][CH:17]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC1(c2ccc(-c3nc4c(ccn5c(=O)[nH]nc45)cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl {1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) (30.0 mg, 0.0620 mmol) and CDI (40.4 mg, 0.249 mmol) in 1,4-dioxane (2 mL) was stirred at 100° C. for 15 h and then cooled to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel. The residue was treated with HCl in MeOH and the mixture was heated in a microwave reactor at 80° C. for 5 min. The solvent was evaporated and the residue was purified by reverse phase (H2O/0.1% TFAaq.-MeCN/0.1% TFAaq.) HPLC to give 9-[4-(1-aminocyclobutyl)phenyl]-8-phenyl[1,2,4]triazolo[4,3-h]-1,7-naphthyridin-3(2H)-one (7-6) as a colorless solid.