Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH2:18])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[N+:20]([C:23]1[C:24]([CH:34]=O)=[N:25][N:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:27]=1)([O-:22])=[O:21]>CO>[F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]2[NH:18][C:34]([C:24]3[C:23]([N+:20]([O-:22])=[O:21])=[CH:27][N:26]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:25]=3)=[N:19][C:4]=2[CH:3]=1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: Nc1cc(F)c(OCCCN2CCCCC2)cc1N
Solvent: CO
Product: O=[N+]([O-])c1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCCN3CCCCC3)cc2[nH]1

Procedure:
A solution of 200 mg of 4-fluoro-5-(3-piperidin-1-ylpropoxy)benzene-1,2-diamine and 181 mg of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde in 15 mL of methanol is stirred at ambient temperature over night. The reaction medium is concentrated to dryness under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on a 20 g silica cartridge, eluent: 100/0 to 80/20 dichloromethane/methanol. 280 mg of 5-fluoro-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-6-(3-piperidin-1-ylpropoxy)-1H-benzimidazoleare isolated in the form of a red lake. Analytical LC/MS: Tr=2.51 min, [M+H]+=472.97 DAD=36%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[CH:4]=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+].O>CO>[CH3:13][NH:14][CH2:11][C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: Cn1ccc2ccc(C=O)cc21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc2ccn(C)c2c1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
1-Methyl-1H-indole-6-carbaldehyde (146 mg, 0.91 mmol) was dissolved in anhydrous methanol (4 ml). Methylamine (0.35 ml of 33% solution in ethanol, 2.81 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (4 ml). Sodium borohydride (34.9 mg, 0.92 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (10 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford methyl-(1-methyl-1H-indol-6-ylmethyl)-amine (139 mg, 87%) as a yellow oil: 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=8.0 Hz, 1H), 7.34 (s, 1H), 7.240 (d, J=3.6, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.345 (d, J=4.0 Hz, 1H)), 3.75 (s, 3H), 3.73 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:37])[CH2:10][CH2:11][CH:12]=[C:13]1[CH:18]2[CH:16]3[CH:17]2[CH2:19][CH:14]1[CH:15]3[C:20]1[NH:28][C:27]2[C:26](=[O:29])[N:25]([CH2:30][CH2:31][CH3:32])[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22]=2[N:21]=1>CCO.Cl.[Pt]>[CH3:37][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][CH:13]1[CH:18]2[CH:16]3[CH:17]2[CH2:19][CH:14]1[CH:15]3[C:20]1[NH:28][C:27]2[C:26](=[O:29])[N:25]([CH2:30][CH2:31][CH3:32])[C:24](=[O:33])[N:23]([CH2:34][CH2:35][CH3:36])[C:22]=2[N:21]=1
Reactant: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4=CCCN(C)C)C53)nc2n(CCC)c1=O
Agent: [Pt]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4CCCN(C)C)C53)nc2n(CCC)c1=O

Procedure:
8-[5-(3-Dimethylamino-propylidene)-tricyclo[2.2.1.02,6]hept-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione; compound with trifluoro-acetic acid was hydrogenated under 60 psi using Pt/C 5% in EtOH (10 ml) and 1 ml conc. HCl overnight. Catalyst was filtered and solvent was removed under reduced pressure. Crude product was purified by HPLC Yield 30 mg. Mass (ES+ 414).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][NH:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=2)[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:33]([BH3-])#N.[Na+].[OH-].[Na+]>C(#N)C.C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][N:18]([CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=2)[CH2:20]1)[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C(N[C@@H]1CCCC[C@H]1CNC1CCc2cc(F)ccc2C1)OCc1ccccc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1)C1CCc2cc(F)ccc2C1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A solution of benzyl((1R,2S)-2-{[((2RS)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino]methyl}cyclohexyl)carbamate (300 mg, 0.73 mmol) in acetonitrile (4 mL) was treated with formaldehyde (37% aqueous, 300 μL), sodium cyanoborohydride (138 mg, 2.19 mmol) and a few drops of acetic acid. After stirring at room temperature, the mixture was treated with aqueous sodium hydroxide (1.0 N) and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonia, to provide a gum (280 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]=[CH:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]([S:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1Cl
Reactant: Sc1ccccc1
Solvent: CCO
Product: CC(C)(C)C(=O)CC(Sc1ccccc1)c1ccc(Cl)cc1Cl
Yield: 81.7 %

Procedure:
A mixture of 25.7 g of 2,4-dichlorobenzalpinacolone, Triton-B (4 drops) and 300 ml of ethanol was heated to 50°-60° C. Thiophenol (12.1 g) was added dropwise to the mixture and refluxed for 6 hours. The reaction mixture was concentrated, ice water was added thereto, and extracted with ether. After the removal of the ether by distillation, the oil residue was treated with n-hexane, and the resulted crystals were dried to give 30 g of the captioned compound. m.p. 79°-80° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20]([O:22]C)=O)[O:17][C:16]2=[O:24])[CH:3]=1.[NH3:25]>CO>[F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20]([NH2:25])=[O:22])[O:17][C:16]2=[O:24])[CH:3]=1
Reactant: N
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C(C)C)C(=O)O1
Solvent: CO
Product: CC(C)n1c(=O)oc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21

Procedure:
Prepared from methyl (5R)-3-(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 4, 0.250 g, 7.39 mmol) and ammonia in methanol (5 ml) according to the method of EXAMPLE 86, Step 10 (0.14 g, 59%); MS for C14H14FN3O5 m/z 324 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 7.88 (br s, 1H), 7.63 (br s, 1H), 7.53 (d, 1H), 7.44 (dd, 1H), 5.04 (dd, 1H), 4.55 (m, 1H), 4.26 (t, 1H), 4.02 (dd, 1H), 1.41 (dd, 6H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:36]3[CH:37]=[N:38][CH:39]=[C:40]([C:41]#[N:42])[CH:43]=3)[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(ethyl(2-hydroxyethyl)amino)nicotinamide (Stage 182.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.10 min, m/z=486.3 [M+H]+, m/z=488.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=6.97 Hz, 3H) 3.15 (q, J=7.09 Hz, 2H) 3.37 (t, J=5.99 Hz, 2H) 3.44-3.55 (m, 2H) 4.62 (br. s, 1H) 7.36 (d, J=9.29 Hz, 2H) 7.82-7.90 (m, 2H) 8.11 (d, J=2.45 Hz, 1H) 8.54 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 9.04 (dd, J=5.62, 1.96 Hz, 2H) 10.26 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19]([O:26][C:27]([C:29]1[O:30][C:31]([CH:34]=O)=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]([C:29]1[O:30][C:31]([CH:34]=[CH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)o1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)o1
Temperature: 0 °C
Yield: 87.8 %

Procedure:
A solution of diethylphosphonoacetic acid tert-butyl ester (1.54 g, 6.09 mmol) in tetrahydrofuran (3 mL) was added dropwise to a suspension of 60% sodium hydride (0.19 g, 4.87 mmol) in tetrahydrofuran (50 mL) with stirring at 0° C. After stirring at room temperature for 20 minutes, a solution of 5-formyl-2-furancarboxylic acid benzyl ester (1.0 g, 4.06 mmol) in tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was worked up according to a conventional method, and the object product was extracted by column chromatography (10-30% ethyl acetate/hexane mixed solvent) to give the title compound (1.17 g)
Reaction SMILES: OC1C=C(C[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[OH:19])C=C(O)C=1.C[O:21][C:22]1[C:29]([CH3:30])=[C:28]([O:31]C)[CH:27]=[CH:26][C:23]=1[CH:24]=O>>[OH:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([OH:31])=[C:29]([CH3:30])[C:22]=1[OH:21]
Reactant: Oc1cc(O)cc(CCCc2ccc(O)cc2O)c1
Reactant: COc1ccc(C=O)c(OC)c1C
Product: Cc1c(O)ccc(CCCc2ccc(O)cc2O)c1O

Procedure:
Compound 32 was synthesized following a similar procedure as described for compound 30 using as starting materials 2,4-dibenzyloxyacetophenone and 2,4-dimethoxy-3-methylbenzaldehyde. 1H-NMR (MeOD, 500 MHz): δ 6.879 (d, 1H, J=8.5 Hz), 6.747(d, 1H, J=8.0 Hz), 6.352(d, 1H, J=1.5 Hz), 6.341(d, 1H, J=4.0 Hz), 6.285(dd, 1H, J=8.0 Hz & 2.5 Hz), 2.567(dd, 4H, J=8.0 & 7.5 Hz), 2.133(s, 3H), 1.786-1.817 (m, 2H). 13C-NMR (MeOD, 125 MHz): δ 155.486(C), 155.316(C), 153.428(C), 152.906(C), 130.295(CH), 126.523(CH), 120.933(C), 120.518(C), 111.556(C), 106.788(CH), 106.377(CH), 102.283 (CH), 30.767(CH2), 29.649(CH2), 29.127(CH2), 7.833(CH3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.025 g, 0.053 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was added with triethylamine and thereby made basic. Then, the mixture was azeotroped with toluene, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.012 g, 60%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C.C(OCC)(=O)C>[Br:46][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)Cc1cc(-c2ccc(CO)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cc1cc(-c2ccc(CBr)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
3-(4-Hydroxymethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (280 mg, 0.734 mmol, see step (a) above) was dissolved in DMF (10 mL). PPh3 (459.2 mg, 1.75 mmol) and CBr4 (580.3, 1.75 mmol) were added to the resultant solution. The mixture was stirred for 24 h at room temperature and then diluted with ethyl acetate. The organic phase was washed with water (50 mL) and brine (50 mL) and then dried over MgSO4. After removing the solvents, the residue was purified by column chromatography using hexane:acetone (5:1) as eluent to give the sub-title compound (314.9 mg, 0.709 mmol, 76% yield).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:39])[C:21]([CH3:38])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:37])[CH:34]([CH3:35])[CH3:36])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)C)cn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-dimethylpropyl]-3-pyridinecarboxamide (Intermediate 17, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2-dimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([C:33](=[N:35]O)[NH2:34])[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([C:33]2[N:35]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH2:12]3)[O:24][N:34]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1cccc(Cl)c1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(Cl)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 40 mg (42% of theory)
Reaction SMILES: C([N:8]([CH3:31])[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:9]([CH2:31][NH:8][C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(C)Cc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccc(C3(NCCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.5 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[1-(benzyl-methylamino)-cyclopropyl]-phenylethynyl}-benzoate (Compound 115, 65.0 mg, 0.16 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 45.0 mg (75%) of the title compound as a solid.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH2:12][SiH:13]([Cl:15])[Cl:14])[Cl:11]>C1C=CC=CC=1>[Cl:9][Si:10]([Cl:11])([CH2:12][SiH:13]([Cl:15])[Cl:14])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Solvent: c1ccccc1
Product: Cl[SiH](Cl)C[Si](Cl)(Cl)C=Cc1ccccc1
Reaction time: 2 h
Yield: 5.5 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)methane in the presence of RhCl(PPh3)3. Into the same apparatus as described in Example 1 were added 0.99 g of bis(dichlorosilyl)methane, 0.102 g of RhCl(PPh3)3, and 20 ml of dried benzene. The flask content was heated to reflux and 0.52 ml of phenylacetylene was added over a 10 minute period. The flask content was refluxed, with stirring, for another 2 hours and then the solvent removed at atmospheric pressure. The products were vacuum distilled at 67 Pa to give a mixture comprising 0.9 g of 3,3,5,5-tetrachloro-1-phenyl-3,5-disilapent-1-ene (TCD-GC area 5.5%) and 3,3,5,5-tetrachloro-1,7-diphenyl-3,5-disilahepta-1,6-diene (TCD-GC area 66.5%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2].[S:28](Cl)([Cl:31])(=[O:30])=[O:29]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:28]([Cl:31])(=[O:30])=[O:29])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Product: CCCCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.3 g (0.81 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-heptyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one (Example 22A). This gives 0.3 g (78.9%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].O.[NH2:32][NH2:33]>CN(C=O)C>[N+:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:33][N:32]=1)([O-:29])=[O:28]
Reactant: NN
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 85.1 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (643 mg, 1.60 mmol, prepared in Synthetic Example 20) in DMF (16 ml) was added hydrazine monohydrate (80%, 230 μl, 5.74 mmol, 3.6 eq.), and the mixture was treated in the same manner as in Example 24 to give 3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (541 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1.CC([O-])=O.[Na+].Cl.[NH2:26][OH:27]>CO>[CH3:1][C:2]1[C:3]([C:17](=[N:26][OH:27])[CH3:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1
Reactant: NO
Reactant: CC(=O)c1cc2ncn(C3CCCCO3)c2cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1cc2ncn(C3CCCCO3)c2cc1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a mixture of 1-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanone (1.1 g, 4.3 mmol) and NaOAc (3.5 g, 43 mmol) in MeOH (20 mL) at RT was added hydroxylamine hydrochloride (896 mg, 12.9 mmol). The reaction mixture was stirred at 80° C. for 0.5 h then concentrated in vacuo. Water (200 mL) was added, and the mixture was extracted with EtOAc (50 mL×3), dried (MgSO4), and concentrated in vacuo to afford 1-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanone oxime as a yellow solid (1.1 g, 90.2%). MS (ESI): m/z=194.3 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=1)[C:20]([OH:22])=[O:21])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc([N+](=O)[O-])c(C(=O)O)c1

Procedure:
For the preparation of the ester starting material, MS: 468 (18, M+NH4), 451 (100, M+H), N-(t-butoxycarbonyl)-β-alanine and 5-amino-2-nitrobenzoic acid are reacted to give 5-[3-(1-t-butoxyformamido)propionamido]-2-nitrobenzoic acid, MS: 354 (17, M+H), the latter is reacted with β-alanine t-butyl ester to give N-[5-[3-(1-t-butoxyformamido)propionamido]-2-nitrobenzoyl]-β-alanine t-butyl ester and this is hydrogenated on Pd/C in ethanol.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[N+:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Oc1ccccc1
Product: O=[N+]([O-])c1cccc(Oc2ccccc2)c1

Procedure:
This compound is prepared according to a method analogous to that described in Example 1.1 using 1-fluoro-3-nitro benzene (15.4 g, 0.106 mol) and phenol (10 g, 0.106 mol) as starting compounds. After treatment, an orange-coloured oil is obtained.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].O>CN(C=O)C>[C:1]([S:3][CH:7]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)C(Cl)c1ccc(C)c(C)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(SC(C)=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Potassium thioacetate (CH3COSK, 8.31 g) was added in small portions to a solution of ethyl 2-chloro-2-(3,4-dimethylphenyl)acetate (15 g) in DMF (80 ml). The mixture was stirred at room temperature for 2 hours, at the end of which time it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give ethyl 2-acetylthio-2-(3,4-dimethylphenyl)acetate (16.5 g, 94%) as an oil.