Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: CCCn1c(N)cc(=O)n(C)c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(N)c(N=O)c(=O)n(C)c1=O
Yield: 81.7 %

Procedure:
6-Amino-3-methyl-1-n-propyluracil (10.46 g, 57.8 mmol) was dissolved in 10 ml of acetic acid at 90° C. Then, with stirring, a solution of sodium nitrite (4.19 g, 60.8 mmol) in 100 ml of water was added in 10 ml portions over 5 minutes. A purple color formed immediately followed by a purple precipitate. The mixture was cooled in the freezer for 20 minutes and then the precipitate was collected by vacuum filtration, washed with water (2×30 ml) and acetone (2×10 ml), and air-dried to give 6-amino-3-methyl-5-nitroso-1-n-propyluracil as purple needles (10.02 g, 83%). 1H NMR (DMSO-d6 +D2O) δ0.89 (t, J=8 Hz, 3 H), 1.55 (sextet, J=8 Hz, 2 H), 3.27 (s, 3 H), 3.80 (t, J=8 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Oc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOc1ccc2ncnc(Nc3ccc(F)c(Cl)c3)c2c1
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-(3'-chloro-4'-fluoroanilino)-6-hydroxyquinazoline was reacted with 3-dimethylaminopropyl chloride hydrochloride to give 4-(3'-chloro-4'-fluoroanilino)-6-(3-dimethylaminopropoxy)quinazoline in 72% yield; NMR Spectrum: 1.98 (m, 2H), 2.34 (s, 6H), 2.51 (t, 2H), 4.22 (t, 2H), 7.48 (t, 1H), 7.52 (m, 1H), 7.75 (d, 1H), 7.85 (m, 1H), 7.91 (m, 1H), 8.18 (m, 1H), 8.54 (s, 1H), 9.72 (broad s, 1H); Elemental Analysis: Found C, 60.5; H, 5.3; N, 14.9; C19H20ClFN4O requires C, 60.5l; H, 5.3; N, 14.9%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)[CH:7]=2)[N:13]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)c1
Product: Nc1ccc(-c2cc(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example E.59) (0.202 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.19 g, 81%). MS (ISP) 462.0 [(M+H)+]; mp 196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)[CH:6]=[CH:7][CH:8]=1.[OH:26]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=[O:26])[CH:6]=[CH:7][CH:8]=1
Reactant: OO
Reactant: COc1cccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)c1
Product: COc1cccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)c1

Procedure:
Prepared analogous to Example 2 from 6-[4-(3-methoxyphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([CH2:30][C:31]2[CH:48]=[CH:47][CH:46]=[CH:45][C:32]=2[C:33]([NH:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=2)=[O:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:40]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33](=[O:34])[C:32]4[CH:45]=[CH:46][CH:47]=[CH:48][C:31]=4[CH2:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:44][CH:43]=3)=[O:41])[CH2:6][C:5]=12
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a solution of 0.75 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.57 g of N,N-diisopropylethylamine in 50 ml of methylene chloride is added 1.53 g of 4-[[2-(phenylmethyl)benzoyl]amino]benzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried (Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through hydrous magnesium silicate two additional times to give upon concentration in vacuo to give 1.97 g of the desired product as an amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.[CH2:45]([O:47][CH2:48][CH2:49]Cl)[CH3:46]>>[CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[N:30]([CH2:46][CH2:45][O:47][CH2:48][CH3:49])[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: CCOCCCl
Reactant: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2ccc(Cl)cc2)cc(OC)c1OC
Product: CCOCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3cc(OC)c(OC)c(OC)c3)c3ccc(Cl)cc3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 21.1 using N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-chlorophenyl)butyl)-3,4,5-trimethoxybenzamide and 2-chloroethyl ethyl ether to give the title compound.
Reaction SMILES: [I:1]I.C([Sn](CCCC)(CCCC)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)=[CH:12][C:11]2=[O:27])CCC.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[I:1][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)=[CH:12][C:11]2=[O:27]
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2oc(-c3ccc(N(C)C)cc3)cc(=O)c2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(-c2cc(=O)c3cc(I)ccc3o2)cc1

Procedure:
A chloroform solution of iodine (1 ml, 1 M) was added to a chloroform solution (5 ml) that contained compound 9 (30 mg, 0.054 mmol) at room temperature. The obtained mixture was reacted at room temperature for 30 minutes, and a saturated sodium bisulfite aqueous solution (5 ml) was then added thereto, so as to terminate the reaction. The chloroform layer was separated, and it was then dried over sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, and the residue was then subjected to silica gel column chromatography using ethyl acetate/hexane (1/9) as an elution solvent, so as to obtain a product of interest, 6-iodo-4′-dimethylaminoflavone (compound 11). Yield: 10 mg (yield constant: 47.3%) 1H NMR (300 MHz, CDCl3) δ8.54 (s, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.29 (d, J=9.0 Hz, 1H), 6.71-6.80 (m, 3H), 3.09 (s, 6H). MS m/z 392 (MH+).
Reaction SMILES: [CH2:1]([S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)(=[O:5])=[O:4])[CH3:2].[ClH:24].O.[H][H]>C(O)C.[Pd]>[ClH:24].[CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)/C=C/c1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution of the product of stage (i) (280 mg) in a mixture of ethanol (40 ml), 2N hydrochloric acid (0.7 ml) and water (5 ml; added to dissolve some precipitated hydrochloride of the starting material) was hydrogenated at room temperature and atmospheric pressure, using 10% palladium on carbon (50% w/w with H2O, 330 mg) as the catalyst. After 1 h; when 22 ml (0.92 mmol) of hydrogen had been absorbed, the reaction was stopped. The mixture was filtered and the filtrate was evaporated to give a foam (302 mg). The foam was crystallised from ethanol (ca. 3 ml) to give the title compound (196 mg) as a powder, with m.p. 229°-232°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:5]=[C:4]2[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:15](=[O:18])[NH:16][CH2:17][C:3]=12.[CH3:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:7]=[C:2]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][C:28]=3[CH3:27])[C:32]([OH:34])=[O:33])[C:3]=2[CH2:17][NH:16][C:15]1=[O:18]
Reactant: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 150 °C
Yield: 99.5 %

Procedure:
To the solution of 5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (191 mg, 0.50 mmol) in dioxane (15 mL) and water (5 mL) were added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (197 mg, 0.75 mmol), K2CO3 (415 mg, 3.0 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.025 mmol). The reaction mixture was heated to 150° C. for about 15 minutes with microwave. The reaction mixture was concentrated to dry then was added DMSO (2 mL), water (0.5 mL) and HOAc (1 drop). The solution was filtered and applied to the reverse phase HPLC to afford the titled compound 0.24 g (quantitative). LC-MS m/z 483 (M+H)+; 1H-NMR (CD3OD) 2.36 (s, 3 H), 2.76 (s, 6H), 3.16 (s, 2 H), 3.56 (s, 2 H), 4.13 (s, 2 H), 7.21 (m, 1 H), 7.53 (m, 2 H), 7.95 (s, 1 H), 8.09 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:39]O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([O:33][CH3:39])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=S(=O)(O)O
Product: CCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (465 mg) and conc. sulfuric acid (7.2 g) in methanol (60 ml) was heated for 24 hours under reflux. After removal of solvent, the residue was suspended with water, to which was added 1N-NaOH to adjust to pH 3-4, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, followed by evaporation of the solvent. The residue was purified by column chromatography on silica gel. Recrystallization from ethanol afforded colorless prisms (310 mg), m.p. 195°-196° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH3:16])[CH:6]=1)(=O)C.[H-].[Na+].F[C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28].O>CN1CCCC1=O>[CH3:16][C:12]1[N:11]([C:7]2[CH:6]=[C:5]([NH:4][C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[CH:10]=[CH:9][CH:8]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CC(=O)Nc1cccc(-n2ccnc2C)c1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nccn1-c1cccc(Nc2ccc(I)cc2[N+](=O)[O-])c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 2j from Example 5 (2 g, 9.3 mmol) in dry N-methyl-2-pyrrolidone (20 ml) is added sodium hydride (0.37 g of a 60% dispersion in mineral oil) in portions at 0° C. under nitrogen. The mixture is stirred for 1 hour, the last 30 min. at room-temperature. 1c from Example 1 (2.67 g, 10 mmol) is added and the temperature is raised to 40-50° C. over night. After cooling the mixture is poured into water (100 ml) and extracted with dichloromethane. The organic phase is extracted with 4M hydrochloric acid. The acidic extract is cooled in ice, rendered alkaline by addition of sodium hydroxide (12M) and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue is extracted with a mixture of dichloromethane and diethyl ether (1:1). This extract is concentrated under reduced pressure and the residue is dissolved in dimethoxyethane (60 ml). Aqueous sodium hydroxide (28 ml, 1 M) is added and the mixture is stirred at ambient temperature over night. The mixture is poured into water (200 ml) and a small volume of ethanol is added with stirring. The product is filtered off, washed with water and dried to leave 6j (2 g, 51%). Mp 135-136° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:11]([C:10](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCC=O
Reactant: O=Cc1ccccc1
Product: CCCCCCC(C=O)=Cc1ccccc1

Procedure:
The method of claim 1 or 2, wherein α-hexylcinnamaldehyde is prepared via aldol condensation of benzaldehyde and n-octanal.
Reaction SMILES: [F:1][CH:2]([F:24])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[N:6][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:4]1.[CH3:25][NH:26][CH3:27]>>[F:24][CH:2]([F:1])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][N:26]([CH3:27])[CH3:25])=[N:6][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:4]1
Reactant: COc1ccc(-c2nc(-c3cccc(C=O)c3)n(C(F)F)n2)cc1
Reactant: CNC
Product: COc1ccc(-c2nc(-c3cccc(CN(C)C)c3)n(C(F)F)n2)cc1

Procedure:
Using 3-[2-difluoromethyl-5-(4-methoxy-phenyl)-2H-[1,2,4]triazol-3-yl]-benzaldehyde and dimethylamine the title compound was prepared as a white amorphous solid (83.4% yield), MS: m/e=359.168 (M+H+).
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][CH2:6][OH:7].[CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[CH2:9]>C(O)C>[OH:7][CH2:6][CH2:5][S:4][CH2:9][CH2:8][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccncc1
Reactant: OCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCSCCc1ccncc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (1.62 g., 0.03 mole) was dissolved in 36 ml. of stirring absolute ethanol and the solution cooled in an ice bath. 2-Mercaptoethanol (2.34 g., 0.03 mole) in 6 ml. of absolute ethanol was added over approximately 5 minutes. Finally, 4-vinylpyridine (3.22 g., 0.03 mole) in approximately 20 ml. of absolute ethanol was added over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 23 hours. The reaction mixture was concentrated to a thick oil (7.28 g.). The oil was diluted with a small amount of chloroform (a strong exotherm occurred, leading to refluxing of the chloroform) and chromatographed on silica gel, with large volumes of chloroform and finally chloroform/1% methanol as eluant. Product containing fractions (from the latter eluant) were combined and evaporated to yield the free base of 4-[2-(2-hydroxyethylthio)ethyl]pyridine [2.49 g.; oil; m/e calcd.: 183, found: 183; ir (film): 3.10, 3.45, 3.52, 6.23, 7.07, 9.40, 9.57, 9.98 and 12.44μ; pnmr/CDCl3 /TMS/δ: 8.53 (m, 2H), 7.17 (m, 2H), 3.77 (t, 2H), 3.57 (s, 1H, exchanges with D2O), 2.85 (m, 4H) and 2.73 ppm (t, 2H)].
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[C:4](=[O:13])[NH:3]1.Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2](=[O:1])[N:3]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:4]2=[O:13])#[N:12]
Reactant: N#Cc1ccc2c(c1)C(=O)NC2=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(C#N)cc2C1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
1,3-Dioxoisoindoline-5-carbonitrile (0.522 g, 3.03 mmol) was dissolved in dry DMF (10 ml), then tert-butyl 2-bromoacetate (0.672 ml, 4.55 mmol) and K2CO3 (0.629 g, 4.55 mmol) were added. The resulting suspension was stirred at 90° C. for 3 hours. The solvent was evaporated under vacuum, and the crude was dissolved in ethyl acetate. The precipitate was filtered and washed with ethyl acetate; the filtrate was evaporated under vacuum and the residue was purified by silica gel flash chromatography (petroleum ether:ethyl acetate=9:1 to 70:30) affording tert-butyl 2-(5-cyano-1,3-dioxoisoindolin-2-yl)acetate (0.507 g, 1.771 mmol, 58.4% yield, MS/ESI+ not detectable [MH]+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:11]=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[C:30]([Cl:37])[CH:29]=1>C1(C)C=CC=CC=1>[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[N:10]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)=[O:36])=[C:30]([Cl:37])[CH:29]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)N(Cc2ccccc2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, benzyl-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine (example 7.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester in toluene for 72 h under reflux conditions to give the title compound as yellow oil. MS: m/e=547.0 [M+H+].
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH3:15]I.O>CN(C)C=O>[CH3:15][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:3](=[O:5])[CH3:4])[CH:14]=2)[CH:10]=[CH:11]1
Reactant: CC(=O)c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ccn(C)c2c1
Reaction time: 1 h

Procedure:
To a slurry of 0.26 g (6.55 mmole) of NaH (60% oil dispersion) in 10 mL of dried N,N-dimethylformamide, a solution of 6-acetylindole (1.04 g, 6.55 mmole) in 5 mL of dried N,N-dimethylformamide was added at 0°-4° C. After 15 min. stirring at the same temperature, 1.45 g (10.1 mmole) of methyl iodide was added. The new mixture was stirred at the same temperature for 1 hour, poured into ice and water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 1-(1-methyl-1H-indol-6-yl)-ethanone after chromatographic purification on a silica gel column.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH:42]=[O:43]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=2)[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccccn3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and pyridine-2-carboxaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[O:4].COCN[C:21]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:8][C:9]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[O:4]
Reactant: COC(=O)c1sccc1NC(=O)C(F)(F)F
Reactant: COCNC(=O)C1CCOCC1
Product: COC(=O)c1sc(C(=O)C2CCOCC2)cc1NC(=O)C(F)(F)F

Procedure:
3-(2,2,2-Trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and tetrahydropyran-4-carboxylic acid methoxymethylamide were reacted by method M. The product with the molecular weight of 365.33 (C14H14F3NO5S) was obtained in this way; MS (ESI): 366 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:24])[OH:20])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A solution of 4-bromo-3-trifluoromethylanisole (13 g, 50 mmol) in dry THF (110 mL) was treated with butyllithium solution (2.5 M in hexane, 24 mL, 60 mmol) during ca. 5 min at −78° C. under nitrogen. After 15 min, the solution was treated with triisopropyl borate (23 mL, 100 mmol) during ca. 5 min at −78° C. After a further 30 min, the cooling bath was removed and the reaction solution was warmed to 23° C. and left for 3.5 h. At this time, the resulting opaque mixture was concentrated in vacuo and the residue was treated with 1 N aqueous hydrogen chloride (110 mL, 110 mmol) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with water (2×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated in vacuo to give the crude product as a tacky yellow solid (11 g) which was triturated overnight with hexane (100 mL). Vacuum filtration gave the title compound (7.9 g, 72%) as a white solid which was pure enough for further use.