Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:15][CH2:16][CH:17]([OH:19])[CH3:18])=[CH:6][N:7]2[C:12]=1[C:11](SC)=[N:10][CH:9]=[N:8]2)([CH3:3])[CH3:2].C([Si](C(C)C)(C(C)C)[N:24]1[C:28]2=[N:29][CH:30]=[C:31]([NH2:33])[CH:32]=[C:27]2[CH:26]=[CH:25]1)(C)C.ClC1C=CC=C(C(OO)=O)C=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)(Cl)Cl.C1COCC1>[CH:1]([C:4]1[C:5]([O:15][CH2:16][CH:17]([OH:19])[CH3:18])=[CH:6][N:7]2[C:12]=1[C:11]([NH:33][C:31]1[CH:32]=[C:27]3[CH:26]=[CH:25][NH:24][C:28]3=[N:29][CH:30]=1)=[N:10][CH:9]=[N:8]2)([CH3:3])[CH3:2]
Reactant: CSc1ncnn2cc(OCC(C)O)c(C(C)C)c12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(O)COc1cn2ncnc(Nc3cnc4[nH]ccc4c3)c2c1C(C)C
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 0.9 %

Procedure:
1-(5-Isopropyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol (262 mg, 0.93 mmol, obtained from Example 25 using procedure in Step B of Example 7) and 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (290 mg, 0.93 mmol) were dissolved in chloroform and m-chloroperbenzoic acid (60%, 535 mg, 1.86 mmol) was added. The mixture was heated at 120° C. for 10 min in a Personal Chemistry Smith Enrys Optimizer™ microwave oven. The solution was evaporated in vacuo and the residue was purified by preparative HPLC. The isolated product was dissolved in of THF (10 mL) and TBAF (1.0 M, 0.2 mL, 0.2 mmol) was added. The mixture was stirred for 5 min. and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC to afford the title compound (3 mg, 1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:25][CH3:26])[CH2:9][C@H:10]([CH2:21][CH2:22][CH2:23][CH3:24])[C:11]([NH:13][O:14]C2CCCCO2)=[O:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:25][CH3:26])[CH2:9][C@H:10]([CH2:21][CH2:22][CH2:23][CH3:24])[C:11]([NH:13][OH:14])=[O:12])=[CH:4][CH:3]=1
Reactant: CCCC[C@@H](C[C@@H](OC)c1ccc(F)cc1)C(=O)NOC1CCCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@@H](C[C@@H](OC)c1ccc(F)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of (2S)-2-((R)-2-(4-fluorophenyl)-2-methoxyethyl)-N-(tetrahydro-2H-pyran-2-yloxy)hexanamide (43 mg, 0.12 mmol) in 3 mL DCM was slowly added 3 mL TFA followed by stirring for 30 min at room temperature. The solvent was evaporated and the product isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to give 26 mg of the title compound as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: OCc1nc2cc(Br)cnc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that the reaction was conducted using 3.00 g of 6-bromo-2-hydroxymethyl-3H-imidazo-[5,4-b]pyridine (prepared as described in Preparation 58), 0.58 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 0.92 ml of methyl iodide and 60 ml of dimethylformamide. After completion of the reaction with methyl iodide, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 50:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 1.40 g of the title compound, melting at 142-144° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:4][C:3]=2[O:2]1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:48]2[CH:55]=[CH:54][C:51]([CH2:52][Cl:53])=[CH:50][CH:49]=2)[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:68].Cl>>[ClH:53].[ClH:68].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=5)[CH:19]=4)[CH2:13][CH2:12]3)[CH2:52][C:51]3[CH:54]=[CH:55][C:48]([C:40]4[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:38]([O:37][CH3:36])[CH:39]=4)=[CH:49][CH:50]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(-c2ccc(CCl)cc2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc(CN(c3ccc4c(c3)OCO4)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cc2)cc(OC)c1OC

Procedure:
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 4-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a dihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Br>>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1CBr
Reactant: COC(=O)c1cccc2nc(-c3c(F)cccc3F)[nH]c12
Product: COC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 76 %

Procedure:
Methyl 2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (Example 100) (16.15 g, 56.0 mmol) and 2,6-difluorobenzyl bromide (14.67 g, 70.86 mmol, 125 M%) were reacted. The crude product was purified using flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether, yielding white crystals of methyl 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (17.63 g, 42.55 mmol, 76% yield). M.p. 184-186° C. 1H NMR (200 MHz, CD2Cl2): δ7.94 (dd, J=1.1, 7.6 Hz, 1H, H5), 7.72 (dd, J=1.1, 8.2 Hz, 1H, H7), 7.56 (m, 1H, H4′), 7.37 (dd, J=7.6, 8.2 Hz, 1H, H6), 7.26 (m, 1H, H4″), 7.09 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.39 (s, 2H, CH2PhF2), 3.95 (s, 3H, CO2CH3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)(=[O:18])=[O:17])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:30]1[CH2:31][CH2:32][CH:27]([CH2:26][NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:16]([NH:15][C:6]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:18])[CH2:28][CH2:29]1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CCCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCNCC2)ccc2c1CCCC2
Reaction time: 3 h

Procedure:
A solution of Example 557A (0.587 g, 1.1 mmol) in CH2Cl2 (10 mL) was treated with TFA (2 mL). The reaction was stirred for 3 hours, concentrated, and diluted with CH2Cl2. The organic layer was washed with pH 7 buffer solution, dried (MgSO4), filtered, and concentrated to provide the desired product. (MS (ESI(+)) m/e 458 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH2:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:27]=[C:28]=[O:29])[CH2:25][CH3:26].O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH:23][C:28]([NH:27][CH2:24][CH2:25][CH3:26])=[O:29])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCN=C=O
Reactant: CC(C)(C)c1ccc(-c2[nH]c3nccnc3c2CCCN)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCNC(=O)NCCCc1c(-c2ccc(C(C)(C)C)cc2)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propylamine (0.0324 mmol). The [Example 24] in tetrahydrofuran (2 mL) was treated with n-propyl-isocyanate (0.0324 mmol). The solution was stirred at room temperature for 12 hours and then treated with water (3 mL). The resulting precipitate was filtered, then washed with water and then dried under vacuum at 50° C. to give the title compound as a beige solid. MS: 394 (MH+). HPLC (Method C): RT=3.25 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH2:14]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8]/[C:9](=[CH:27]\[C:26]3[CH:29]=[CH:30][C:23]([O:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:24][CH:25]=3)/[C:10](=[O:11])/[C:12](=[CH:27]/[C:26]3[CH:29]=[CH:30][C:23]([O:22][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:24][CH:25]=3)/[O:13][C:4]=2[CH:3]=1
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: CCCCCCCCOc1ccc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3ccc(OCCCCCCCC)cc3)C2=O)cc1

Procedure:
Calone is reacted with 4-octyloxybenzaldehyde analogously to the reaction conditions of Example 1, giving 7-methyl-2,4-bis[1-(4-octyloxyphenyl)meth-(Z)-ylidene]benzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](Cl)=[CH:6][C:5]=1[NH:12][C:13](=[O:24])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH3:15].[H-].[Na+].Cl.C1C[O:32][CH2:31]C1>>[Cl:10][C:9]1[CH:8]=[C:7]([O:32][CH3:31])[CH:6]=[C:5]2[C:4]=1[C:3](=[O:25])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:15])[C:13](=[O:24])[NH:12]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(OC)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C2(C)C(=O)Nc3cc(OC)cc(Cl)c3C2=O)cc1
Reaction time: 10 h
Yield: 41 %

Procedure:
To a solution of 4,6-dichloro-2-[2-(4-methoxy-phenyl)-propionylamino]-benzoic acid methyl ester (1.00 g, 2.62 mmol) in dry THF (30 mL) was added NaH (0.32 g, 7.86 mmol, 60% dispersed in mineral oil) at room temperature. The reaction mixture was stirred for 10 hours at reflux temperature, and then poured into 1N HCl aqueous solution. The resulting mixture was extracted with ethyl acetate (100 mL×2). The organic layer was washed with brine (100 mL) and water (100 mL×2), dried over anhydrous MgSO4, and concentrated in vacuo. The objective compound (0.36 g, 41%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=2:1): 1H NMR (200 MHz, CDCl3) δ 1.71 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.46 (d, J=1.6 Hz, 1H, ArH) 6.56 (d, J=1.6 Hz, 1H, ArH), 6.77 (dd, J=6.9 Hz, 2.0 Hz, 2H, ArH), 7.14 (dd, J=6.9 Hz, 2.0 Hz, 2H, ArH), 8.77 (br s, 1H, NH); m.p. 222-224° C.; MS(EI) m/e 345 [M+], 162, 134, 119, 91; HRMS m/e cacld. for C18H16NO4Cl 345.0768, found 345.0759.
Reaction SMILES: [C:1](=[O:22])([O:3][C@H:4]([CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([NH2:7])=[S:6])[NH2:2].C(=O)([O-])O.[K+].Cl[CH2:29][C:30](=[O:32])[CH3:31]>C(COC)OC>[C:1](=[O:22])([O:3][C@@H:4]([C:5]1[S:6][CH2:29][C:30]([OH:32])([CH3:31])[N:7]=1)[CH:8]([C:18]([CH3:19])([CH3:21])[CH3:20])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[NH2:2]
Reactant: CC(C)(C)C(c1c[nH]c2ccccc12)[C@@H](OC(N)=O)C(N)=S
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: COCCOC
Product: CC1(O)CSC([C@H](OC(N)=O)C(c2c[nH]c3ccccc23)C(C)(C)C)=N1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of (R)-tert-butyl-1-amino-3-(1H-Indol-3-yl)-1-thioxopropan-2-yl carbamate (6.49 g, 20.3 mmol) in anhydrous dimethoxyethane (100 mL) was mixed with powdered potassium hydrogencarbonate (10.1 g, 101 mmol) and chloroacetone (9.69 g, 8.4 mL, 101 mmol) and stirred for 8 h at 70° C. and over the weekend at 45° C. The reaction mixture was then filtered and the filtrate concentrated to low volume in a vacuum.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](N)=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1)(=[O:5])=[O:4].C(O)(=[O:22])C.S(=O)(=O)(O)O.N(OCCC(C)C)=O>O>[CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:22])=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1)(=[O:5])=[O:4]
Reactant: CC(=O)O
Reactant: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1
Agent: CC(C)CCON=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(C(=O)O)c(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
A mixture of 4-(N,N-dimethylsulphamoyl)-2-trifluoromethylbenzamide (1.38 g), acetic acid (10 ml) and concentrated sulphuric acid (0.5 ml) were heated to 70° C. and isoamyl nitrite (15 ml) was added over 4 hours. After cooling the mixture was poured into water and extracted with ethyl acetate and washed with water. The organic phase was extracted with 2M sodium carbonate and the aqueous layer acidified to pH 1 with 2M HCl. This was extracted with ethyl acetate, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue passed through a short silica column eluting with dichloromethane-ethyl acetate to give 4-(N,N-dimethylsulphamoyl)-2-trifluoromethylbenzoic acid (0.98 g) as a white solid, m.p. 188.8°-189.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=3)=[CH:15][CH:14]=1)[C:5]2=O.O.[NH2:30][NH2:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH3:27])[CH:20]=4)=[CH:15][CH:14]=3)=[CH:7][NH:31][N:30]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: CCOc1cccc(-c2ccc(-c3coc4cc(O)c(Cl)cc4c3=O)cc2)c1
Solvent: CCO
Solvent: O
Product: CCOc1cccc(-c2ccc(-c3c[nH]nc3-c3cc(Cl)c(O)cc3O)cc2)c1

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(3′-ethoxy-biphenyl-4-yl)-7-hydroxy-chromen-4-on (0.2 g, 0.69 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:26]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1)=[N+:27]=[N-:28]
Reactant: OCc1ccc2nc[nH]c2c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccc2nc[nH]c2c1
Temperature: 25 °C

Procedure:
To a cooled (0° C.) suspension of 5-(hydroxymethyl)-benzimidazole (920 mg, 6.2 mmol) in THF (12 mL) was added sequentially DPPA (1.46 mL, 6.8 mmol) and DBU (1.11 mL, 7.4 mmol). The resulting solution was heated to reflux for 5 h, cooled to RT, and concentrated in vacuo. The residue was partitioned between sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Silica gel chromatography (15% MeOH—CHCl3), afforded the title compound as a brown solid: Rf (8:1:1 EtOAc-MeOH—NH4H)=0.31; m.p. 110-114° C.; 1H NMR (400 MHz, DMSO-d6): δ8.25 (s, 1H), 7.27 (d, J=8.4, 1H), 7.62-7.60 (m, 2H), 7.20 (d, J=8.2 Hz, 1H), 8.24 (s, 1H); HRMS (FAB) C8H8N5 calcd. 174.1847 (M+1). Found 174.1222.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CC1=Cc2cc(OCc3ccccc3)ccc2OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde (25.0 g, 0.14 mol) and potassium carbonate (39.2 g, 0.28 mol) in 500 ml of DMF is treated with benzyl bromide (26.7 g, 0.16 mol). The mixture is stirred overnight at room temperature. Water is added and three extractions with dichloromethane are carried out. The extract is dried (MgSO4) and evaporated to dryness. The residue is crystallized from hot ethyl acetate to give 6-benzyloxy-2H-1-benzopyran-3-carboxaldehyde, m.p. 112°-114° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:22][C:23](=[O:28])[CH2:24][C:25](=O)[CH3:26])[CH:6]=[CH:7][C:8]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:2].[NH3:29]>CO>[NH2:29]/[C:25](/[CH3:26])=[CH:24]\[C:23]([NH:22][C:5]1[CH:6]=[CH:7][C:8]([N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:28]
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1C#N
Reactant: N
Solvent: CO
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of N-(3-cyano-4-(dihexylamino)phenyl)-3-oxobutanamide (1.47 g, 3.81 mmol), MeOH (15 mL) and ammonia (15 mL) was stirred at rt overnight. The mixture was concentrated in vacuo to give the title compound as black oil (1.30 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH2:14].[C:16](OC(=O)C)(=[O:18])[CH3:17]>CCCCCCC>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH:14][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Solvent: CCCCCCC
Product: COC(=O)c1cc(OC)c(OC)cc1NC(C)=O

Procedure:
Commercially available 2-amino-4,5-dimethoxy-benzoic acid methyl ester (3 g, 0.014 mol) and acetic anhydride (4.03 mL, 0.0426 mol) were heated in heptane at 100° C. for 3 hours. After removal of heptane in vaccuo, the crude product of 2-acetylamino-4,5-dimethoxy-benzoic acid methyl ester was obtained and used without further purification. LC/MS: m/z 254 (M+H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1>CC(N(C)C)=O.[Na+].[Cl-].CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH:12]=[CH:11][N:10]=1
Reactant: c1nc[nH]n1
Reactant: Clc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Clc1cc(-n2cncn2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60 wt. %. in mineral oil, 400 mg, 10.0 mmol, 5.0 eq) was carefully suspended in 5 mL of DMA (caution: intensive gas development). To the mixture was added carefully 1,2,4-triazole (691 mg, 10.0 mmol, 5.0 eq) and the mixture was stirred at room temperature for 30 min. 2,4-Dichloropyridine (300 mg, 2.0 mmol, 1.0 eq) was added in portions and the reaction mixture was heated at 100° C. for 3.5 hours. The mixture was allowed to cool to room temperature and diluted with saturated NaCl solution (25 mL) and EtOAc (15 mL). The separated aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic layers were washed with saturated NaCl solution (25 mL), dried over sodium sulfate and concentrated under reduced pressure. Purification by silica column chromatography with EtOAc/hexanes (3/1) provided 2-chloro-4-(1H-1,2,4-triazol-1-yl)pyridine as a white solid. Yield: 290 mg. ES/MS m/z 181.1 (MH+).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:24]=2)[CH2:15][CH:16](O)[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:42])CC)C>ClCCl>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][CH:16]([F:42])[C:17]([F:18])([F:19])[F:20])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:32])[F:33])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol (474 mg, 0.00094 mol) in 4.5 mL of dichloromethane at 0° C. was added.(diethylamino)sulfur trifluoride (378 mg, 0.0023 mol). The reaction mixture was warmed to room temperature and stirred for 2 h, then quenched with water and extracted with dichloromethane. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with :19-ethyl acetate in hexane to afford 240 mg (50%) of the desired N-(3-phenoxyphenyl)-N-(3,3,3,2-tetra-fluoropropyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine product as a yellow oil. HRMS calcd. for C24H19F8NO2: 506.1366 [M+H]+, found: 506.1368. 1H NMR (CDCl3) δ7.26 (m, 3H), 7.20 (m, 5H), 6.87 (d, 2H), 6.62 (d, 1H), 6.50 (s, 1H), 6.49 (d, 1H), 5.87 (t, 1H), 4.89 (d, 1H), 4.77-4.52 (m, 1H), 4.73 (d, 1H), 4.60 (s, 2H). 19F NMR (CDCl3) δ−69.83 (t, 3F), −88.63 (s, 2F), −137.19 (dt, 2F), −228.82 (1F).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][CH:8]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[O:21]1[CH2:25]CC[CH2:22]1>CCCCCC>[CH3:22][O:21][CH:25]=[CH:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH:8]([CH3:7])[CH2:9][CH2:10][CH3:11])=[CH:14][CH:15]=1
Reactant: CCCC(C)Oc1ccc(C=O)cc1
Reactant: C1CCOC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCC(C)Oc1ccc(C=COC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing butyllithium dissolved in hexane was added to a solution containing 120 g of methoxymethyltriphenylphosphoni bromide dissolved in tetrahydrofuran (THF), in an atmosphere of argon, and the mixture was stirred for one hour at room temperature. A solution of the compound (30) dissolved in THF was added thereto and stirring was continued for two hours. The reaction solution was washed with water, was dried over magnesium sulfate, and was then concentrated. The residue was purified by column chromatography to obtain 1-(2-methoxyethenyl)-4-(1-methylbutyloxy)benzene (31).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>O>[CH2:7]([NH:11][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:8][CH2:9][CH3:10]
Reactant: C=CC(=O)OC
Reactant: CCCCN
Solvent: O
Product: CCCCNCCC(=O)OC
Reaction time: 2 h

Procedure:
Methyl acrylate (344 g; 4 moles) was placed in a flask and 642.4 g (8.8 moles) of n-butylamine were added thereto while stirring by cooling with water to keep it at not higher than 50° C. After two hours, the addition reaction was complete but an impurity, namely butoxyamine-N,N-bis-3-propionic acid methyl ester, was produced in an amount of about 12% in terms of the ratio of the area of its peak that of to methyl beta-butylaminopropionate on a gas chromatogram.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[Cl:20][C:21]1[NH:25][N:24]=[C:23]([CH3:26])[CH:22]=1>>[Cl:20][C:21]1[N:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH3:11])=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:3]=2)[N:24]=[C:23]([CH3:26])[CH:22]=1
Reactant: Cc1cc(Cl)[nH]n1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Product: Cc1cc(Cl)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 6 from (2-chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine and 5-chloro-3-methyl-1H-pyrazole.