Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl[S:15]([OH:18])(=[O:17])=[O:16]>N1C=CC=CC=1>[CH2:1]([NH:13][S:15](=[O:17])(=[O:16])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCCCCN
Solvent: c1ccncc1
Product: CCCCCCCCCCCCNS(=O)(=O)O

Procedure:
Dodecyl amine (0.1 mol) is added to a round bottom flask equipped with magnetic stirrer and dissolved in anhydrous pyridine. Next, chlorosulfonic acid (0.1 mol) is added dropwise with stirring to the chilled solution. The resulting product, dodecyl sulfamic acid, is then collected by filtration, washed with water and dried in an oven.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:22])[N:4]=[C:3]1[N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C1COCC1.[H][H]>[Pd].CCOC(C)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][CH2:11][CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:38])([CH3:1])[C:3]([N:23]([C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[N:4][C@:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To an argon flushed flask was added tert-butyl N-[(4aR,11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.94 g, 3.50 mmol) and THF (35 ml), followed by a slurry of palladium on carbon (0.75 g, 0.70 mmol) in EtOAc (5 ml). The gas in flask was replaced with hydrogen balloon for three times. The mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The mixture was filtered through celite plug and concentrated to give tert-butyl N-[(4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.80 g, 98% yield) as an off-white solid. m/z (ESI) 524.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][S:6][CH2:5][S:4][CH2:3]1.CCCCCC.C([Li])CCC.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>O1CCCC1>[CH3:19][Si:20]([CH3:22])([CH3:21])[CH:5]1[S:6][CH2:7][N:2]([CH3:1])[CH2:3][S:4]1
Reactant: CN1CSCSC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CSC([Si](C)(C)C)SC1

Procedure:
5-Methyl-1,3,5-dithiazine, 2.7 g, was dissolved in 20 ml of tetrahydrofuran and 14 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow at -73° C. The mixture was stirred at the same temperature for an hour. Then, 2.4 g of trimethylsilyl chloride was dropwise added to the mixture at the same temperature. After completion of the dropwise addition, the temperature of the reaction mixture was gradually elevated to 0° C. and then stirred for 90 minutes to give crude 2-trimethylsilyl-5-methyl-1,3,5-dithiazine. Without purifying the crude product, 14 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added thereto at -10° C. followed by stirring for 30 minutes. After cooling to -73° C., a solution of 4.5 g of 4-phenoxypropiophenone in 10 ml of tetrahydrofuran was dropwise added. After completion of the dropwise addition, the temperature was gradually elevated to room temperature followed by stirring for 14 hours. After saturated sodium chloride aqueous solution was added to the mixture, it was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =2 : 1) to give 5.5 g of the product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([CH3:21])=[C:6]([CH3:20])[C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].Cl.[Cl:30][CH2:31][C:32](=N)OCC>C(Cl)(Cl)Cl>[Cl:30][CH2:31][C:32]1[N:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]2[C:6]([CH3:20])=[C:5]([CH3:21])[N:4]=[C:3]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:2]=2[N:1]=1
Reactant: CCOC(=N)CCl
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCNC(=O)OC(C)(C)C)c1C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc(Oc2ccccc2)c2nc(CCl)n(CCCNC(=O)OC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 72 h
Yield: 115.7 %

Procedure:
tert-Butyl 3-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]propylcarbamate (68.8 g, 178 mmol), prepared as described in U.S. Pat. No. 6,545,016, Example 17, Parts A through C, was dissolved in chloroform (600 mL). Ethyl 2-chloroacetimidate hydrochloride (56.0 g, 354 mmol) was added to the solution and the reaction mixture was stirred at 60° C. for 72 hours. The reaction mixture was diluted with chloroform (200 mL), washed with brine (2×600 mL), and the layers were separated. The combined organics were dried over magnesium sulfate, filtered through CELITE filter aid, and concentrated under reduced pressure to afford 91.62 g of tert-butyl 3-[2-(chloromethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]propylcarbamate.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16](F)=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[C:9]2[CH2:24][N:25]([C:29](=[O:39])[NH:30][C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:38])[C:26]([CH3:28])([CH3:27])[C:8]2=[N:7]1)=O)C.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C1COCC1>[Cl:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[NH:30][C:29]([N:25]1[CH2:24][C:9]2[C:8](=[N:7][NH:6][C:10]=2[NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([N:44]3[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]3)=[C:15]([NH2:20])[CH:14]=2)[C:26]1([CH3:27])[CH3:28])=[O:39]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1)CN(C(=O)Nc1c(Cl)cccc1Cl)C2(C)C
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(C(=O)Nc3[nH]nc4c3CN(C(=O)Nc3c(Cl)cccc3Cl)C4(C)C)cc2N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a solution of 3-(3-Nitro-4-fluoro-benzoylamino)-5-(2,6-dichloro-phenylcarbamoyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.28 g, 0.48 mmol) in dry THF (10 mL), N-methylpiperazine (0.16 L, 1.40 mmol) was added. The reaction was stirred at room temperature for four hours, the solvent removed under reduced pressure and the crude product purified by flash chromatography (CH2Cl2/MeOH 90/10) to afford 0.20 g (yield 70%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])=[O:2].[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC=CC=1.C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:16][CH2:17][O:18][CH:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: OCCO
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C2OCCO2)c([N+](=O)[O-])c1
Yield: 78.3 %

Procedure:
To a solution of methyl 4-formyl-3-nitrobenzoate (9.0 g, 43.0 mmol) in toluene (150 mL) was added ethylene glycol (7.20 mL, 129 mmol) followed by p-TsOH (0.409 g, 2.152 mmol) and the reaction mixture was heated at reflux temperature with azeotropic removal of H2O using a Dean-Stark trap for 4 h. The reaction mixture was then cooled and diluted with DCM. The DCM layer was then washed with saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated to yield a residue. The residue was dissolved in minimal quantity of DCM and purified by silica gel chromatography to yield the desired product (8.53 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.27 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 6.38 (s, 1H), 4.00 (dt, J=3.8, 1.9 Hz, 2H), 3.94 (dt, J=3.8, 1.9 Hz, 2H), 3.91 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].BrBr.C(=O)([O-])[O-:13].[Ca+2]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH:9]=[O:13]
Reactant: Cc1ccc(F)c(F)c1
Reactant: O=C([O-])[O-]
Agent: BrBr
Agent: [Ca+2]
Solvent: O
Product: O=Cc1ccc(F)c(F)c1
Reaction time: 2 h

Procedure:
In a 250 ml three-necked flask equipped with a magnetic stirrer, thermometer, condenser, and dropping funnel is placed 25.6 g (0.2 mol) of 3,4-difluorotoluene. The liquid is heated to 105° and illuminated as 67 g (0.42 mol) of bromine is added slowly. The temperature is kept between 105°-110° C. while the first half of the bromine is added over a period of one hour. The rest of the bromine is added over approx. a 2 hour period, and the temperature is raised to 150° and kept there for 5 minutes. The reaction mixture is cooled and transferred to a 1 liter 3-necked flask with a motor driven stirrer and condenser. 120 ml H2O and 90 g of calcium carbonate are added, and the mixture is refluxed for 20 h with good stirring. The reaction mixture is steam distilled until no further oil is collected. The oil is taken up in methylene chloride and dried over MgSO4. Evaporation of the solvent yields 3,4-difluorobenzaldehyde which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[F:12].[NH3:13]>>[F:12][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[C:4]=1[NH2:13]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Product: Nc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 70 °C
Yield: 84 %

Procedure:
1,2,3-Trifluoronitrobenzene (20.2 g, 114.1 mmol, Aldrich, Milwaukee) and methanolic ammonia (150 mL of a 2.0 molar solution, Aldrich, Milwaukee) were placed in a sealed tube and were heated to 70° C. for 2 h, after which time the solvents were removed in vacuo. The remaining residue was dissolved in ethyl acetate and was extracted with water, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the solvents were removed in vacuo to leave a yellow solid. The title compound was recrystallized from water-methanol to afford yellow needles (16.6 g, 84%); 1H NMR (DMSO-d6) δ: 7.94 (m, 1H, Ar—H), 7.56 (br s, 2H, NH2), 6.72 (m, 1H, Ar—H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>>[CH2:32]([O:31][C:29]([C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:6][CH2:5]3)=[O:3])=[CH:35][CH:34]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCOC(=O)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 34.2 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl 4-aminobenzoate (56.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-ethoxycarbonylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (24.9 mg).
Reaction SMILES: Cl[C:2]1[C:14]([Cl:15])=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1.O1CCOCC1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[Cl:29].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:15][C:14]1[C:2]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[C:28]([Cl:29])[CH:27]=2)=[CH:3][C:4]2[NH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[N:6][C:5]=2[CH:13]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)c(Cl)c3)cc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Compound number 258 (i.e., 6-chloro-5-(3,4-dichlorophenyl)-2-trifluoromethylbenzimidazole) was prepared as follows. A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. 5,6-dichloro-2-(trifluoromethyl)-1H-1,3-benzodiazole (200 mg, 0.78 mmol, 1.00 equiv), 1,4-dioxane (30 mL), (3,4-dichlorophenyl)boronic acid (229 mg, 1.20 mmol, 2.00 equiv), sodium carbonate (191 mg), water (8 mL) and Pd(PPh3)4 (34.7 mg) was placed into the flask. The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 82.4 mg (29%) of 6-chloro-5-(3,4-dichlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:41][CH2:40][C:32]2([O:36][C@H:35]3[CH2:37][CH2:38][CH2:39][C@H:34]3[O:33]2)[CH2:31][CH2:30]1.C([BH3-])#N.[Na+].O1CCCC1>C(OCC)(=O)C>[OH:36][C@H:35]1[CH2:37][CH2:38][CH2:39][C@H:34]1[O:33][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:41][CH2:40]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)O[C@H]2CCC[C@H]2O3)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[C@@H]3CCC[C@@H]3O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-({5-oxo-7-propyl-4-[(3a′R,6a′S)-tetrahydro-3a′H-spiro[cyclohexane-1,2′-cyclopenta[d][1,3]dioxol]-4-yl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (1.2 g), sodium cyanoborohydride (0.65 g), boron trifluoride-diethyl ether complex (1.3 mL) and tetrahydrofuran (30 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.82 g, 72%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:17]=[O:18])=[N:13][C:14]=1[CH2:15]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.P(Cl)(Cl)([Cl:27])=O>CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:17]=[O:18])=[N:13][C:14]=1[CH2:15][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(CO)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=Cc1ccc(OCc2ccccc2)c(CCl)n1

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxymethyl-2-pyridinecarboxaldehyde (5.86 g., 0.0241 mol) in 100 ml. of ethyl acetate is added 4.056 g. (0.0265 mol) of phosphorus oxychloride and the mixture is refluxed for 20 minutes. Additional phosphorus oxychloride (0.4 ml.) is introduced and the mixture is heated further for 30 minutes. The reaction mixture is cooled, diluted with ether and then washed with 5% sodium bicarbonate solution and brine. The ethereal solution is dried, treated with charcoal, filtered and evaporated to leave an oil which crystallizes to give 5-benzyloxy-6-chloromethyl-2-pyridinecarboxaldehyde, m.p. 72°-73°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1COCC1>[NH2:8][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([Cl:9])[C:2]=1[NH:1][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccnc(Cl)c1N
Solvent: C1CCOC1
Product: CC(=O)Nc1c(N)ccnc1Cl

Procedure:
1.1 A solution of 10.0 g of 3,4-diamino-2-chloropyridine and 6.62 ml of acetic anhydride in 100 ml of THF is stirred at room temperature for 16 hours. The product is separated off and dried, giving 7.3 g of N-(4-amino-2-chloropyridin-3-yl)acetamide (“1”).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[OH:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][C:21]=1[O:24][CH3:25])[N:4]=[C:3]([CH2:2][O:32][C:33]1[N:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:10]1[CH:5]=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=1
Reactant: Cc1cccc(O)n1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(COc2cccc(C)n2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl)quinoline-3-carboxylate (1.5 g), 2-hydroxy-6-methylpyridine (0.4 g), potassium carbonate (0.511 g) and N,N-dimethylformamide (20 ml) was stirred at 120° C. for 2 hours. Then the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off. The residual oil was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate, ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)- 2-[(2-methyl-6-pyridyl)oxymethyl]quinoline-3-carboxylate (0.79 g, 46%) was obtained and recrystallized from chloroform/hexane.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[C:60]1[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=1>CN(C=O)C>[CH:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[C:60]1[CH:61]=[C:62]([NH:66][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:63]=[CH:64][CH:65]=1
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5ccccc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 87.2 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.015 g, 0.068 mmol) and HATU (0.029 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-naphthalen-2-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.025 g of product in 86% yield: LCMS (ESI) m/z 422 (MH+).
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:33]=[CH:32][C:30]([OH:31])=[C:28]([OH:29])[CH:27]=1)=[O:22])[CH2:13][C:14](=[O:20])[O:15]C(C)(C)C)=[O:10])C1C=CC=CC=1.C(O)(=O)/[CH:35]=[CH:36]/[C:37]1[CH:44]=[CH:43][C:41]([OH:42])=[C:39]([OH:40])[CH:38]=1>>[C:9]([NH:11][C@H:12]([C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:33]=[CH:32][C:30]([OH:31])=[C:28]([OH:29])[CH:27]=1)=[O:22])[CH2:13][C:14](=[O:20])[OH:15])(=[O:10])/[CH:35]=[CH:36]/[C:37]1[CH:44]=[CH:43][C:41]([OH:42])=[C:39]([OH:40])[CH:38]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)NCCc1ccc(O)c(O)c1
Product: O=C(O)C[C@H](NC(=O)/C=C/c1ccc(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1
Yield: 52.4 %

Procedure:
N-(N′-benzyloxycarbonyl-Oγ-tert-butyl-L-aspartyl)dopamine (1.0 g, 2.3 mmol) was deprotected by hydrogenolysis as described in example 5. The product thus obtained was then coupled with caffeic acid (621 mg, 3.5 mmol) according to the indications of example 4. Purification by flash chromatography using 30-50% AcOEt/CH2Cl2 containing 1% AcOH yielded 519 mg (47%) of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].[Li]CCCC.[CH:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C1COCC1>[C:17]1([CH:16]([OH:23])[C:3]#[C:2][CH2:1][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: C#CCOC1CCCCO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(C#CCOC1CCCCO1)c1ccccc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(prop-2-ynyloxy)-tetrahydro-2H-pyran (10.0 g, 71.4 mmol) in THF (40 mL) was added n-BuLi (2.5M, 31.4 mL, 78.6 mmol) at −78° C. The reaction mixture was kept for 1 h at −78° C. and then benzaldehyde (8.3 g, 78.6 mmol) was added at −78° C. The reaction mixture was stirred for 2 h and then slowly warmed to −30° C. before being poured into NaHCO3 (aq., 500 mL), extracted with ethyl acetate (3×200 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-yn-1-ol as a colorless oil (17.0 g, crude).
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[F:40][C:41]1[CH:42]=[C:43]([CH:48]2[CH2:53][CH2:52][CH:51]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][C:55]3=O)[CH2:50][CH2:49]2)[CH:44]=[CH:45][C:46]=1[F:47]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:57]1[CH2:56][CH2:55][CH:54]([CH:51]2[CH2:50][CH2:49][CH:48]([C:43]3[CH:44]=[CH:45][C:46]([F:47])=[C:41]([F:40])[CH:42]=3)[CH2:53][CH2:52]2)[CH2:59][CH2:58]1
Reactant: O=C1CCCCC1C1CCC(c2ccc(F)c(F)c2)CC1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(C2CCC(C3CCC(=CCC4OCCCO4)CC3)CC2)cc1F
Reaction time: 1 h

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.3 g, 27 mmols), followed by adding tetrahydrofuran (100 ml), suspending, and stirring under ice cooling till the liquid temperature reached 10° C. The reaction mixture was added potassium t-butoxide (3.0 g, 27 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, and dropwise adding a tetrahydrofuran (50 ml) solution of (4-(3,4-difluorophenyl)cyclohexylcyclohexanone (7.3 g, 25 mmols) over 30 minutes from the dropping funnel. Further, the resulting reaction mixture was stirred for 5 hours after completion of the dropwise addition, followed by adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(4-(3,4-difluorophenyl)cyclohexyl)cyclohexane.