Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26].[C:27](OCC)(=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[CH3:19][N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:21]1=[O:26]
Reactant: CN1CCCCC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)C1CCCN(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
20.4 g of diisopropylamine (0.1 mol) were dissolved in 200 ml of dry THF under nitrogen and cooled in a freezing mixture. 80 ml n-butyllithium in hexane (2.5 M, 0.2 mol) were added dropwise slowly. After the addition it was allowed to stir for 60 minutes and then 22.6 g N-methyl-2-piperidone (0.2 mol) were added dropwise. The reaction mixture was stirred for another 20 min in the freezing mixture. In a second flask, 87.7 g diethyl oxalate (0.6 mol) in 100 ml of dry THF were cooled in a freezing mixture and the cooled reaction mixture was cannulated with stirring in small portions to it. It was left overnight under stirring to warm to room temperature. The THF was removed on a rotary evaporator and the residue was taken up in 80 ml half concentrated hydrochloric acid. The aqueous phase was extracted five times with 300 ml ethyl acetate, the combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator to dryness. The excess diethyl oxalate was removed by distillation (2-3 mbar, 80° C.) and 45 g of crude product were obtained. 10.4 g product was obtained as white crystals with a melting point of 23° C. after crystallization from diethyl ether/n-hexane.
Reaction SMILES: [N:1]1[CH:6]=CC=[CH:3][C:2]=1[C:7]([NH:9][C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[O:8].N1C=CC=C(C(NC2NC3C=CC=CC=3N=2)=O)C=1.N1C=CC(C(NC2NC3C=CC=CC=3N=2)=O)=CC=1.[S:55]1C=CC=C1C(NC1NC2C=CC=CC=2N=1)=O.C(NNC1NC2C=CC=CC=2N=1)(=O)C1C=CC=NC=1>>[S:55]1[CH:3]=[C:2]([C:7]([NH:9][C:10]2[NH:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[O:8])[N:1]=[CH:6]1
Reactant: O=C(Nc1nc2ccccc2[nH]1)c1cccs1
Reactant: O=C(Nc1nc2ccccc2[nH]1)c1ccccn1
Agent: O=C(NNc1nc2ccccc2[nH]1)c1cccnc1
Agent: O=C(Nc1nc2ccccc2[nH]1)c1cccnc1
Agent: O=C(Nc1nc2ccccc2[nH]1)c1ccncc1
Product: O=C(Nc1nc2ccccc2[nH]1)c1cscn1

Procedure:
Substitution of an equivalent amount of other heterocyclic acid chlorides, e.g., pyridine 2-, 3-, and 4-carboxylic acid chlorides; thenoyl 2- and 3-chlorides, coumariloyl chloride for thiazole-4-carboxylic acid chloride provides a convenient synthesis for: 2-(pyridine-2-carboxamido)benzimidazole, 2-(pyridine-3-carboxamido)benzimidazole, 2-(pyridine-4-carboxamido)benzimidazole, 2-(thiophene-2-carboxamido)benzimidazole, 2-(coumariloyl)aminobenzimidazole, m.p. 293°- 295° C. λmax. 327 mμ, E11%cm. 1024 and 2-nicotinamidoaminobenzimidazole, λmax. 319 mμ, E1cm.1% 429.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.Cl[S:29]([C:32]1[C:33]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[C:34]([O:41][CH2:42][C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(=[O:31])=[O:30]>>[C:48]1([C:33]2[C:32]([S:29](=[O:31])(=[O:30])[NH2:8])=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=2[O:41][CH2:42][C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: O=C(O)c1cc(OCc2ccsc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Product: NS(=O)(=O)c1cc(C(=O)O)cc(OCc2ccsc2)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-4-phenyl-3-(3-thenyloxy)benzoic acid, and following the procedure described, 4-phenyl-5-sulfamyl-3-(3-thenyloxy)-benzoic acid is obtained with a melting point of 222°-223° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.Cl[CH2:8][CH2:9][C:10]1[N:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH:14]=2>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][CH2:9][C:10]1[N:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)[CH:14]=2
Reactant: CC1CCCN1
Reactant: N#Cc1ccc(-c2ccc3cc(CCCl)nnc3c2)cc1
Product: CC1CCCN1CCc1cc2ccc(-c3ccc(C#N)cc3)cc2nn1
Temperature: 65 °C
Yield: 43 %

Procedure:
Racemic 2-methylpyrrolidine (0.5 mL, neat) was added to the product from Example 169D (0.01 g, 0.034 mmol) and heated to 65° C. in a sealed tube for 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to afford the product in 43% yield as a brown-yellow semi-solid. 1H NMR (CD3OD, 300 MHz) δ8.72 (m, 1H), 8.20 (dd, J=3, 9 Hz, 1H), 8.16 (s, 1H), 8.11 (d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 3.58-3.46 (m, 4H), 2.85-2.65 (m, 2H), 2.57-2.51 (m, 1H), 2.03-1.90 (m, 1H), 1.89-1.83 (m, 2H), 1.56-1.50 (m, 1H), 1.21 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 343.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:14])[NH:12][CH3:13])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH3:20][C:21]1[NH:35][C:24]2=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:26]=[CH:27][CH:28]=[C:23]2[CH:22]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.CO>[Cl:15][C:7]1[CH:8]=[C:9]([CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([C:22]1[C:23]2[C:24](=[C:25]([NH:29][C:30]([CH:32]3[CH2:33][CH2:34]3)=[O:31])[N:26]=[CH:27][CH:28]=2)[NH:35][C:21]=1[CH3:20])=[O:6])[C:11]([NH:12][CH3:13])=[O:14]
Reactant: Cc1cc2ccnc(NC(=O)C3CC3)c2[nH]1
Reactant: CNC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)c(C(=O)c2c(C)[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of 2,6-dichloro-4-(methylcarbamoyl)benzoic acid (276 mg, 1.1 mmol) in dry dichloromethane, was added thionyl chloride (5 mL) and heated at 100° C. for about 3 hours. The mixture was concentrated under vacuum. The residue was dissolved in dry dichloromethane (3 mL) and added to the stirred solution of N-(2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (120 mg, 0.55 mmol) in aluminium chloride (743 mg, 5.57 mmol) drop wise. The resulting reaction mixture was stirred overnight at room temperature. After completion, methanol (10 mL) was added cautiously to quench the reaction mass followed by concentration under vacuum. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with aq. sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, and concentrated. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded 3,5-dichloro-4-({7-[(cyclopropylcarbonyl)amino]-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)-N-methylbenzamide (70 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[OH-].[Na+]>O>[CH3:12][O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:18](=[O:17])[NH:19][C:4]2=[O:6]
Reactant: N#C[O-]
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Reaction time: 4 h
Yield: 64.4 %

Procedure:
2-Amino-5-methoxybenzoic acid (13.0 g, 77.8 mmol, 1.0 eq.) was suspended in water (200 mL) and glacial acetic acid (5.2 mL) at 35° C. A freshly prepared solution of potassium cyanate (8.21 g, 101.4 mmol, 1.3 eq.) in water (86 mL) was added dropwise to the stirred mixture. After 4 h, NaOH (104.0 g, 2600 mL, 33.4 eq.) was added in portions, keeping the reaction temperature below 40° C. A clear solution was obtained momentarily before a precipitate formed. After cooling, the precipitate was filtered off and dissolved in hot water which was acidified to pH 5. The precipitate was collected and washed with water, dried by lyophilization to afford 9.63 g of 6-methoxyquinazoline-2,4(1H, 3H)-dione as a white solid (65%). LCMS m/z=193.1 (M+1) (Method B) (retention time=1.22 min). 1H NMR (400 MHz, DMSO-d6): δ 11.26 (s, 1H), 11.01 (s, 1H), 7.31-7.25 (m, 2H), 7.10 (d, 1H, J=8.8 Hz), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[N+:15]([O-])=O)([CH3:6])[C:3]([OH:5])=[O:4]>O1CCCC1.[Ni]>[CH3:6][C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(Nc1ccc(Cl)cc1[N+](=O)[O-])C(=O)O
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(Nc1ccc(Cl)cc1N)C(=O)O

Procedure:
48 g (mol/5.36) of 2-methyl-(4'-chloro-2'-nitroanilino)-propionic acid, in 480 ml of tetrahydrofuran, are hydrogenated in the presence of 10 g of Raney nickel in a one-liter autoclave. H2 pressure when cold: 135 kg. Pressure drop (calculated 24.5 kg - actual 30 kg). Temperature: 70°-90° C. Duration: 21/2 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH3:17])[CH:5]([F:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>ClCCCl>[CH3:1][O:2][C:3]([C:4]1([CH:5]([F:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17][O:24]1)=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(C)C(F)CCCCc1ccccc1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Product: COC(=O)C1(C(F)CCCCc2ccccc2)CO1
Reaction time: 8 h

Procedure:
A solution of 500 mg (2.0 mmol) of β-fluoro-α-methylbenzene-heptanoic acid methyl ester in 50 ml of 1,2-dichloroethane is treated with 1.38 g (8 mmol) of m-chloroperoxybenzoic acid and 20 mg of 4,4'-thiobis(6-t-butyl-m-cresol). The mixture is heated to reflux and maintained under nitrogen for 10.5 hours. An additional 1.38 g (8 mmol) of m-chloroperoxybenzoic acid and 20 mg of 4,4'-thiobis(6-t-butyl-m-cresol) is added and reflux is continued for 8 hours.
Reaction SMILES: [P:1]([Cl:14])(Cl)(=[O:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[CH2:15]([OH:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CCCCCCCCCC.CN1C=CN=C1>ClCCl.CCCCCC>[P:1]([Cl:14])(=[O:12])([O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[O:31][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Cl)Cl)cc1
Agent: Cn1ccnc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCOP(=O)(Cl)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
p-Nitrophenyl phosphorodichloridate (75 g, 0.29 mol) in anhydrous dichloromethane (300 mL) was added to a 1 L, three necked, round-bottomed flask with stir bar that had been purged with N2. A solution of hexadecanol (71.03 g, 0.29 mol) and N-methylimidazole (23.35 mL, 0.29 mol) in anhydrous dichloromethane (250 mL) was added dropwise over a period of 2 hours. The reaction mixture was stirred for an additional 1 hour before pouring into a 1 L separatory funnel. N-methylimidazole hydrochloride salts separated at the bottom as an oil and were removed from the funnel. Dichloromethane was removed from the mixture at less than 30° C. under vacuum to give an amber oil which was taken up in hexane (400 mL) and placed in a freezer overnight. The reaction mixture was then thawed and the soluble portion was filtered to remove the crystals of p-nitrophenyl phosphorodichloridate. The solvent was removed from the filtrate via rotary evaporation at less than 35° C. to give n-hexyl p-nitrophenyl phosphorochloridate.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[O:11][CH:12]([NH:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:13]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:9])(C)(C)C>N1CCCCC1.Cl.O1CCOCC1>[NH2:7][CH:8]([C:10]1[N:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:12](=[O:11])[C:13]2[C:14](=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[N:15]=1)[CH3:9]
Reactant: CC(NC(=O)OC(C)(C)C)C1=Nc2cccc(Cl)c2C(Nc2cc(F)cc(F)c2)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: CC(N)c1nc2cccc(Cl)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
A solution of compound 169 (1.68 mmol) in piperidine (2 mL) was stirred for 3 h at ambient temperature. Evaporation of the reaction mixture to dryness under high vacuum gave a yellow foam. This foam was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred for 17 h at ambient temperature. The reaction mixture was then concentrated to dryness, basified with 10% aqueous potassium carbonate (40 mL) and extracted with MTBE (3×20 mL). Combining the organic extracts, drying over sodium sulfate and concentrating to dryness afforded a solid residue. This residue was dissolved in d-chloroform (5 mL), and warmed for 15 h at 50° C. After cooling to ambient temperature, the reaction mixture was washed with water (3×10 mL), dried over sodium sulfate and evaporated to dryness, affording a 98% yield of compound 170 as a white solid. m.p. 200-202° C.; 1H NMR (CDCl3) δ (ppm) 7.65 (m, 2H), 7.49 (m, 1H), 7.01 (t, 1H, J=6.6 Hz), 6.89 (m, 2H), 3.68 (m, 1H), 1.33 (d, 3H, J=6.6 Hz), 1.25 (s, 2H); m/z=336 (M+H). The reaction described above and compound 170 are shown below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:33][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH:24]=2)[C:11]1=[O:19]
Reactant: COC(=O)c1ccccc1-n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 60 °C
Yield: 85.5 %

Procedure:
To a solution of 2-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-benzoic acid methyl ester (30 mg, 0.11 mmol) in DMF (1.0 mL) are added (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (46 mg, 0.13 mmol) and K2CO3 (31 mg, 0.22 mmol) at room temperature. The solution is heated to 60° C. for 16 hr and it is cooled down to room temperature for another 48 hr. Then 30 mL of water is added. The mixture is extracted with EtOAc (3×30 mL) and the combined organic layers are washed with water (3×100 mL), dried with Na2SO4 and concentrated to give crude product. Purification by preparative TLC affords 40 mg (86%) of 2-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-benzoic acid methyl ester.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Yield: 99.5 %

Procedure:
To a solution of tert-butyl 4-({[(2S,5R)-6-benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 206 (0.25 g, 0.54 mml) in methanol (15 mL) was added 10% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 207 (0.20 g, 99%) as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:6]([O:8][CH2:9][C:10]([N:18]([CH3:20])[CH3:19])([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:11][CH3:12])=[O:7].[C:28]([OH:37])(=[O:36])[C@@H:29]([C@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[C:6]([O:8][CH2:9][C:10]([N:18]([CH3:19])[CH3:20])([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:11][CH3:12])=[O:7].[C:28]([O-:37])(=[O:36])[C@@H:29]([C@H:31]([C:33]([O-:35])=[O:34])[OH:32])[OH:30]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CCC(COC(=O)c1cc(OC)c(OC)c(OC)c1)(c1cccs1)N(C)C
Solvent: CCO
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reaction time: 8 h

Procedure:
2-Dimethylamino-2-(2-thienyl)butyl 3,4,5-trimethoxybenzoate (33.1 g) and L-(+)-tartaric acid (6.3 g) are dissolved in ethanol (200 ml) with heating and the solution is allowed to stand at room temperature overnight. The precipitates are collected by filtration, washed with ethanol and ether, dried and recrystallized from ethanol, whereby (+)-2-dimethylamino-2-(2-thienyl)butyl 3,4,5-trimethoxybenzoate·L-(+)-tartarate (14 g) is obtained.
Reaction SMILES: Br[CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[C:14](=[S:17])([S-:16])[NH2:15].[NH4+]>C(O)C.O>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([C:2]2[S:16][C:14]([SH:17])=[N:15][C:3]=2[CH3:4])=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(=O)C(Br)c1ccc(C#N)cc1
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1nc(S)sc1-c1ccc(C#N)cc1
Reaction time: 24 h
Yield: 25.8 %

Procedure:
A solution of 4-(1-bromo-2-oxopropyl)benzonitrile (4.65 g, 0.02 mol) in absolute ethanol (20 ml) was added over 10 minutes to a stirred suspension of ammonium dithiocarbamate (2.2 g, 0.02 mol) in absolute ethanol (20 ml) at ambient temperature and the reaction mixture stirred for an additional 24 hours. The reaction mixture was then diluted with H2O (50 ml), the bulk of the ethanol evaporated under reduced pressure and product extracted with ethyl acetate. The organic extract was dried (MgSO4), filtered and the filtrate concentrated in vacuo. Trituration of the residue with ethanol and filtration gave the title product (1.2 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:34](=[O:41])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCS(=O)(=O)N(C(=O)c1ccccc1)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a suspension of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide (0.2 g, 0.41 mmol) in dioxane (15 mL) were added benzoyl chloride (57 mg, 0.41 mmol) and triethylamine (0.14 g, 1.38 mmol). The reaction was stirred at rt for 1 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/EtOAc (v/v)=4/1) to afford the title compound as a white solid (0.14 g, 55%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: CO[C:3]1[C:8](OCOC)=[CH:7][C:6](OC)=[C:5](OCOC)[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C#CCCCC.C(#N)C.O.O[Si](O)=O>CO.S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O.N1C2C(=CC=CC=2)C=CC=1>[CH3:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:4]=[CH:3][CH2:8][CH2:7][CH2:6][CH3:5]
Reactant: CCCCC#CCCCCCCCc1c(OC)c(OCOC)cc(OC)c1OCOC
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: O=[Si](O)O
Solvent: CC#N
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: CCCCC=CCCCCCCC

Procedure:
1 Gram of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]tridec-8-yne prepared in the above-mentioned (2) was dissolved in 10 ml of methanol, to this solution was added 40 mg of 5%-palladium-barium sulfate-quinoline (1:1) and the mixture was catalytically reduced under a normal hydrogen pressure at room temperature for 4 hours. This reaction was traced by means of a high performance liquid chromatography. Thus, the reaction was determined by measuring the optical density (OD) at UV254 under conditions of ODS column, 80%-acetonitrile-water, 2 ml/minute. After the reaction was completed, the catalyst was removed by filtration, and methanol was removed by evaporation under reduced pressure, and the residue obtained was treated by means of a column chromatography ("Robar " column, LiChrosorb RP-8, Type C, manufactured by E. Merck A. G.) and eluted with 75%-acetonitrile-water at the flow rate of 5 ml/minute to obtain both Z-isomer and E-isomer, respectively. There was obtained 0.65 g of 1-[2,5-dimethoxy-3,6-bis-Imethoxymethoxy)phenyl]tridec-8 -ene (Z-isomer) as in the form of colorless oily substance.
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([C:25]#[N:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[NH:28][C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30].C(=O)([O-])[O-].[K+].[K+].O.[C:42]([O:45][CH2:46][CH3:47])(=O)C>>[C:25]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH2:47][C@H:46]1[CH2:42][O:45]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:28][C:29]([NH:31][CH:32]2[CH2:33][CH2:34]2)=[O:30])=[C:7]([CH3:6])[C:12]=1[CH3:13])#[N:26]
Reactant: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(O)c(C#N)cc23)c1C
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)NC2CC2)ccc(Oc2ccnc3cc(OC[C@H]4CO4)c(C#N)cc23)c1C
Temperature: 50 °C

Procedure:
Dimethylformamide (4 ml) was added to N-(2,3-dimethyl-4-(6-cyano-7-hydroxy-quinolin-4-yloxy)-phenyl)-N′-cyclopropylurea (476 mg), and then p-toluenesulfonic acid (2R)-glycidyl ester (365 mg) and potassium carbonate (340 mg) were further added and the mixture was heated at 50° C. for 4 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was washed with ethyl acetate to obtain the title compound (270 mg) as light yellow crystals.