Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:12].C(N(CC)CC)C.[Cl:26][CH2:27][C:28]1[N:32]=[C:31](Cl)[S:30][N:29]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:12][C:31]1[S:30][N:29]=[C:28]([CH2:27][Cl:26])[N:32]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(CCl)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.3 %

Procedure:
A solution of N-L-leucyl-L-proline methyl ester hydrochloride (2.22 g, 8 mmol) and triethylamine (2.8 mL, 20 mmol) in DMF (50 mL) was stirred at room temperature for 15 min. Then, a solution of 3-chloromethyl-5-chloro-[1,2,4]thiadiazole (0.34 g, 2 mmol) in DMF (10 mL) and tetra-butylammonium bromide (100 mg) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water and extracted into ethyl acetate. The organic layer was washed with a saturated ammonium chloride solution, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (7/3, 6/4 and 1/1) afforded N-(3-chloromethyl-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester as a white foam, 0.49 g, 65.3% yield. 1H-NMR (CDCl3) δ7.56 (d, J=8.2 Hz, 1H, NHCH), 4.78 (m, 1H, NHCH), 4.60 (dd, J=8.5, 4.6 Hz, 1H, CHCO2), 4.46 (s, 2H, CH2Cl), 4.09 (m, 1H), 3.69-3.73 (m, 1H), 3.74 (s, 3H, OMe), 2.25-2.30 (m, 1H), 1.68-2.11 (m, 6H), 0.99-1.03 (2d, 6H, 2Me); MS (m/z) 375 (M+ +1), 357, 305, 246, 218, 162, 150, 130.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][N:22]=1>>[F:20][C:21]1[N:22]=[CH:23][C:24]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: OB(O)c1ccc(F)nc1
Product: O=C(O)c1csc(COc2ccc(-c3ccc(F)nc3)cc2)n1

Procedure:
2-[4-(6-Fluoro-pyridin-3-yl)-phenoxymethyl]-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 23 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 2-fluoropyridine-5-boronic acid (available from Frontier Scientific, Inc., Logan, Utah). Mass spectrum MH+=331.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:7])[CH2:4][CH2:5][CH3:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([O:30][CH3:31])[CH:17]=1.Cl>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:8]([C:3](=[O:7])[CH2:4][CH2:5][CH3:6])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:17][C:18]=1[O:30][CH3:31])#[N:29]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: COc1cc(CBr)ccc1-c1ccccc1C#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(OC)c1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (1.80 g) in tetrahydrofuran (50 mL) was added dropwise a solution of ethyl butyrylacetate (9.50 g) in tetrahydrofuran (30 mL). After stirring for 30 min, 4′-(bromomethyl)-2′-methoxybiphenyl-2-carbonitrile (8.79 g) was added. The mixture was stirred at room temperature for 15 hr, and 1 M hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give ethyl 2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate. Then, a solution of the obtained ethyl 2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate, ethanimidamide hydrochloride (3.25 g) and 28% sodium methoxide (9.91 g) in methanol (70 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (5.63 g, 52%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(#N)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2([CH2:3][CH2:2][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: c1c[nH]cn1
Reactant: ClCCC1(c2ccc(Cl)cc2)OCCO1
Solvent: CC#N
Product: Clc1ccc(C2(CCn3ccnc3)OCCO2)cc1

Procedure:
A mixture of 2-(2-chloroethyl)-2-(4-chlorophenyl)-1,3-dioxolane (from 2.03 g of β,p-dichloropropiophenone as in Preparation 3) and imidazole (3.5 g) in acetonitrile (5 ml) were heated at 100° for 24 hours and the solvent removed. After addition of water (30 ml) and ether (30 ml) and shaking, a white solid separated and was collected by filtration. Washing with water, ether and drying in air gave 1-[2-(2-(4-chlorophenyl)-1,3-dioxolan-2-yl]ethyl]imidazole. Further product was obtained by separation of the ether layer, washing, drying (MgSO4) and concentrating.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:28][N:29]([CH3:34])[CH2:30][CH:31](O)[CH3:32]>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH:31]([CH3:32])[CH2:30][N:29]([CH3:34])[CH3:28])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)CN(C)C
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Solvent: O=S(Cl)Cl
Product: CC(CN(C)C)OC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1

Procedure:
Treatment of 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1.5 g, Example 33b) with thionyl chloride (15 ml) followed by 1-dimethylamino-2-propanol (1.71 ml) as described in Example 33c gave 2-dimethylamino-1-methylethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (1.47 g). δ (360 MHz, DMSO-d6) 1.34 (3H, d, CHCH3), 2.22 (6H, s, N(CH3)2), 2.45 and 2.62 (2H, 2dd, CH2N), 5.29 (1H, m, CO2CH), 5.58 (2H, s, OCH2), 7.41 (3H, m, m,p-ArH), 7.59 (2H, d, 0-ArH), 7.69 (1H, s, 3-H), 7.85 (1H, d, 6-H) and 8.12 (1H, d, 8-H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:29]([O:31]C)=[O:30])=[C:21]([C:23]3[N:27]([CH3:28])[N:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:14][C@@H:13]1[O:33][CH2:34][CH:35]=[CH2:36])=[O:10].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:29]([OH:31])=[O:30])=[C:21]([C:23]3[N:27]([CH3:28])[N:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:14][C@@H:13]1[O:33][CH2:34][CH:35]=[CH2:36])=[O:10]
Reactant: C=CCO[C@H]1CN(c2nc(-c3ncnn3C)c(C(=O)OC)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCO[C@H]1CN(c2nc(-c3ncnn3C)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Yield: 45.7 %

Procedure:
A solution of methyl 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate (Example 30, 90 mg, 0.162 mmol) and 2N sodium hydroxide (4 mL) in methanol (30 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water, which was acidified to pH 3 with 2 N hydrochloric acid (2 mL). The resulting solid was collected by filtration and dried to afford 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylic acid (40 mg, 72%) as solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.N1C=CC=CC=1.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17].O>C(#N)C>[C:15]([N:2]1[C:3](=[O:8])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: O=C1NC2C=CC1C2
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: CC(C)C(=O)N1C(=O)C2C=CC1C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
45.1 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in acetonitrile (310 ml) and pyridine (39 ml) under nitrogen. At 10° C., 54.1 g of isobutyryl chloride were added dropwise over the course of 1 h. The reaction was then stirred at room temperature for 5 h. 140 ml of water were added to the mixture, and the acetonitrile was evaporated off in vacuo. The aqueous phase was extracted with 4×120 ml of ethyl acetate. The combined organic phases were washed with 1N HCl (50 ml), saturated NaHCO3 (50 ml) and NaCl (50 ml) solutions, dried with sodium sulphate and completely evaporated. The residue was boiled under reflux in n-hexane (240 ml) with active charcoal. After filtration of the active charcoal, the filtrate was cooled to 0° C. and the title compound was filtered. 54.5 g of product were obtained. The yield was 76%.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:22]([O:24][CH3:25])=[O:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (3 ml) was suspended 60% sodium hydride (20 mg). The compound 1 (124 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, methyl chloroformate (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-methoxycarbonyl-quinoline (compound 6, 100 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[N:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[C:4]=1[NH:19][C:20](=O)[CH3:21])#[N:2].C([OH:25])C.[OH-].[K+].OO>O.CO.C(O)(=O)C>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([N:5]2[C:4]3[N:19]=[C:20]([CH3:21])[NH:2][C:1](=[O:25])[C:3]=3[C:7]([CH3:8])=[N:6]2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CCO
Reactant: CC(=O)Nc1c(C#N)c(C)nn1-c1ccc(S(C)(=O)=O)cc1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1nc2c(c(C)nn2-c2ccc(S(C)(=O)=O)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In to a 50 mL round-bottomed equipped with a stir bar and a reflux condenser was added, N-[4-cyano-2-(4-methanesulfonyl-phenyl)-5-methyl-2H-pyrazol-3-yl]-acetamide (30 mg, 0.079 mmol), H2O (0.6 mL), and ethanol (1 mL) followed by 20% aquous KOH (0.33 mL). The reaction mixture turned purple and the solid dissolved after addition of KOH. Hydrogen peroxide (0.25 mL) was then added to the above solution. After stirring 15 min at room temperature, the reaction mixture was heated at 75° C. overnight. After cooled to room temperature acetic acid was added slowly until the pH attained a range between 6-6.5. The mixture was then diluted with H2O and methanol. The resulting precipitate was collected by filtration and washed with H2O, methanol, diethyl ether and dried under vacuum. The crude product was used directly in the next step without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 1.71 (s, 2H), 2.39 (s, 3H), 2.51 (s, 1H), 3.25 (s, 3H), 8.05 (d, 2H), 8.46 (d, 2H). LCMS: calculated C14H14N4O3S 318.08, observed 319.1 (MH+)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]12[CH2:32][C:29]([CH2:33]O)([CH2:30][CH2:31]1)[CH2:28][CH2:27][CH2:26]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:25]12[CH2:32][C:29]([CH2:33][O:11][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])([CH2:30][CH2:31]1)[CH2:28][CH2:27][CH2:26]2
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: OCC12CCCN(CC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(OCC12CCCN(CC1)C2)c1c[nH]c2ccccc12
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of indole-3-carboxylic acid (1.45 g, 9 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.53 g, 9.4 mmol), stirred for one hour, and degassed with a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.2.1]octane-5-methanol (1.42 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (9.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The acid 1,1'-carbonyldiimidazole adduct (suspension) was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 5% methanol/methylene chloride). The concentrated filtrate was recrystallized from acetonitrile (2 crops) to afford 1.34 g (52%) of colorless solid; mp 183.5°-185.0° C.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:13]([C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[C:5]=32)=[CH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1cc(C(C)C)ccc1C2
Reaction time: 0.75 h
Yield: 54.9 %

Procedure:
A solution of 2.16 g of (RS)-2-(2-oxoethyl)-6-isopropyl-1-indanone and 80 mg of p-toluenesulfonic acid in 60 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.4 g (55%) of (RS)-1-(7-isopropyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([CH2:21][OH:22])[CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH2:21][CH:18]3[CH2:20][CH2:19]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: OCC1CC1
Product: CC(C)(C)OC(=O)N1Cc2ccc(OCC3CC3)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and cyclopropylmethanol. Off-white solid. MS (m/e): 234.1 ([M+H-Me2C═CH2]+, 100%)
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.O[C@@H:23]([CH3:35])[C:24]([N:26]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:28][O:29][CH3:30])=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][C@H:23]([C:24](=[O:25])[N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:31][CH2:32][O:33][CH3:34])[CH3:35])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COCCN(CCOC)C(=O)[C@H](C)O
Reactant: COC(=O)/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCN(CCOC)C(=O)[C@H](C)OC(=O)/C=C/C(=O)OC
Yield: 16.4 %

Procedure:
Following general procedure B2, (2E)-3-(methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF) (0.50 g, 3.84 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (0.88 g, 4.60 mmol) in 20 mL of dichloromethane (DCM) at ca. 0° C. (2S)-2-Hydroxy-N,N-bis(2-methoxyethyl)propanamide (0.63 g, 3.07 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes (2:1) afforded 0.16 g (14% yield) of the title compound (32) as a clear oil. 1H NMR (CDCl3, 400 MHz): δ 6.93-6.77 (m, 2H), 5.53 (q, J=6.4 Hz, 1H), 3.80 (s, 3H), 3.58-3.50 (m, 8H), 3.47-3.32 (2s, 6H), 1.49 (d, J=6.8 Hz, 3H). MS (ESI): m/z 318.05 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([C:5](=[NH:7])[NH2:6])[CH2:4][CH2:3]1.Br[C:9]1[C:10](=O)[CH2:11][CH2:12][C:13]=1[O:14]C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:2]1([C:5]2[NH:6][C:10]3[CH2:11][CH2:12][C:13](=[O:14])[C:9]=3[N:7]=2)[CH2:4][CH2:3]1
Reactant: COC1=C(Br)C(=O)CC1
Reactant: N=C(N)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2[nH]c(C3CC3)nc21
Temperature: 100 °C
Yield: 32 %

Procedure:
A mixture of cyclopropanecarboximidamide hydrochloride (0.757 g), 2-bromo-3-(methyloxy)-2-cyclopenten-1-one (1 g) and potassium carbonate (2.171 g) in N,N-dimethylformamide (15 mL) were heated at 100° C. for 3 h. Potassium carbonate (1 g) was added and the mixture heated at 110° C. for further 16 h. The reaction mixture was cooled down to room temperature and partitioned between dichloromethane (60 mL) and sat. aq. NH4Cl (60 mL). The 2 phases were separated, the aqueous was extracted with DCM (2×40 mL), the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient with a 0->20% Ethyl Acetate-MeOH wash at the end. The desired fractions (in the MeOH wash) were combined and concentrated under vacuum to give the title compound (272 mg), used crude in the next reaction. LC/MS MH+ 163, Rt 1.45 min (5 minute run).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)(=[O:5])=[O:4].ClC1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:26]=[C:25]([N:35]2[C:39]3[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:38]=3[N:37]=[C:36]2[CH:46]([F:48])[F:47])[N:24]=1.CCN(C(C)C)C(C)C>CO.C1COCC1.[Pd]>[F:48][CH:46]([F:47])[C:36]1[N:35]([C:25]2[N:26]=[C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:28]=[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[N:24]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:38]=2[N:37]=1
Reactant: CNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CNS(=O)(=O)C1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Yield: 39 %

Procedure:
The above carbamate was hydrogenated over 5% Pd on carbon in MeOH. After removal of the solvent, the residue was combined with 0.19 g (0.48 mmol) 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) and DIPEA in THF. The mixture was heated under reflux for 30 min and the solvent was concentrated. After dilution with water, the resulting solid was collected and dried. Chromatography on alumina, eluting with CH2Cl2/EtOAc (9:1), gave 0.127 g (39% yield) of 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-4-piperidinesulfonamide: mp (MeOH) 261-263° C.; 1H NMR (CDCl3) δ 7.87 (dd, J=8.4, 0.6 Hz, 1H), 7.46 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.93 (br d, J=13.5 Hz, 2H), 4.05 (s, 3H), 4.02 (q, J=5.3 Hz, 1H), 3.88 (m, 4H), 3.78 (m, 4H), 3.22 (tt, J=11.8, 3.7 Hz, 1H), 3.00 (m, 2H), 2.86 (d, J=5.3 Hz, 3H), 2.24 (br d, J=12.0 Hz, 2H), 1.85 (dq, J=12.5, 4.4 Hz, 2H); Anal. Calcd. for C22H28F2N8O4S: C, 49.1; H, 5.2; N, 20.8. Found: C, 49.2; H, 5.3; N, 21.0%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[NH:39]([CH2:43][CH2:44][OH:45])[CH2:40][CH2:41][OH:42].O>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:39]([CH2:43][CH2:44][OH:45])[CH2:40][CH2:41][OH:42])=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCN(CCO)CCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 52 mg), potassium carbonate (138 mg), and diethanolamine (53 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 41 mg (yield 82%) of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][CH2:9][C@:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@]1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
The compound (375 mg, 0.70 mmol) obtained in Example 61-1) was dissolved in tetrahydrofuran (7 mL). Tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 0.84 mL, 0.84 mmol) was added to the solution at room temperature, and the mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. Saturated aqueous sodium hydrogencarbonate (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=10% to 40%) to obtain the title compound (208 mg, 71%) in a white solid form.