Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:12][C:13]1[CH:14]=[C:15]([CH:51]=[CH:52][CH:53]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][C:20]=1[C:31]1[CH:32]=[C:33]([CH:48]=[CH:49][N:50]=1)[C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40](C(F)(F)F)[CH:39]=1)=[O:35])=[O:17])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8](C)[CH2:7][CH2:6]1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>O1CCCC1>[CH2:37]([NH:36][C:34](=[O:35])[C:33]1[CH:48]=[CH:49][N:50]=[C:31]([C:20]2[CH:21]=[C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:23]=[CH:24][C:19]=2[NH:18][C:16](=[O:17])[C:15]2[CH:51]=[CH:52][CH:53]=[C:13]([CH2:12][N:2]([CH3:1])[CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]3)[CH:14]=2)[CH:32]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CN1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CN(CCN1CCNCC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccccc3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The free base of N-benzyl-2-(2-(3-((methyl(2-(piperazin-1-yl)ethyl)amino)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide was prepared as described in the preparation of 2-(2-(3-((methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)methyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)-benzyl)isonicotinamide 40. Into a 50-mL round-bottom flask, was placed a solution of this free base (150 mg, 0.21 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), acetyl acetate (26 mg, 0.25 mmol, 1.20 equiv), and pyridine (33 mg, 0.42 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 44 mg (17%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.25 (s, 1H), 9.56-9.52 (m, 1H), 8.93-8.91 (d, J=5.1 Hz, 1H), 8.33-8.26 (m, 2H), 8.04 (s, 1H), 7.96-7.93 (d, J=7.8 Hz, 1H), 7.85-7.83 (d, J=6.3 Hz, 1H), 7.70-7.55 (m, 6H), 7.29-7.26 (d, J=8.7 Hz, 1H), 4.64-4.62 (d, J=5.7 Hz, 2H), 4.29 (s, 2H), 3.54 (s, 4H), 3.30-3.21 (m, 6H), 3.03 (s, 2H), 2.80-2.73 (m, 3H), 2.66 (s, 3H), 1.99 (s, 3H), 1.73 (s, 4H), 1.60-1.59 (d, J=4.8 Hz, 1H). MS (ES, m/z): 756 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:19]([C:22]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:13](=[O:18])[CH2:14]2)=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])([O-:21])=[O:20]
Reactant: COC(=O)c1cc(CC=O)ccc1[N+](=O)[O-]
Reactant: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Product: COC(=O)c1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)C(=O)C2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 1-[2-(4-Nitrophenyl)ethyl]piperazin-2-one and Methyl 2-nitro-5-(2-oxoethyl)benzoate following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 457 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.CCCCCC.[N:24]1([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[CH:32]=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25]1>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:32]([C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([N:24]3[CH:28]=[CH:27][CH:26]=[CH:25]3)[CH:30]=2)[OH:33])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: O=Cc1cccc(-n2cccc2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(O)c2cccc(-n3cccc3)c2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
To a solution of 4-bromo-2-ethoxy-1-methoxy-benzene (1.5 g, 6.5 mmol) in THF (30 mL) was added a solution of n-butyllitium in hexane (2.4 mL, 2.5 N, 6.0 mmol) at −78° C. and kept for 20 min. To the mixture was added 3-pyrrol-1-yl-benzaldehyde (1.0 g, 5.8 mmol) at −78° C. After 18 h, water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with HCl (0.5 N, 50 mL), sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent gave (3-ethoxy-4-methoxy-phenyl)-(3-pyrrol-1-yl-phenyl)-methanol (1.9 g, 100% crude yield). The sample was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([N:15]3[CH:19]=[CH:18]N=C3)=[N:10][CH:11]=2)[N:6]([CH:20]([CH3:22])[CH3:21])[C:5]1=[O:23])[CH:2]=[CH2:3].[CH2:24]([N:26]([CH2:37][CH3:38])[CH2:27][CH2:28][O:29][C:30]1[CH:36]=CC(N)=[CH:32][CH:31]=1)[CH3:25]>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([NH:15][C:19]3[CH:18]=[CH:36][C:30]([O:29][CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:24][CH3:25])=[CH:31][CH:32]=3)=[N:10][CH:11]=2)[N:6]([CH:20]([CH3:22])[CH3:21])[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)c2cnc(-n3ccnc3)nc2n(C(C)C)c1=O
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: C=CCn1c(=O)c2cnc(Nc3ccc(OCCN(CC)CC)cc3)nc2n(C(C)C)c1=O
Temperature: 180 °C
Yield: 36.6 %

Procedure:
A mixture of 200 mg (0.64 mmol) of 3-allyl-7-(imidazol-1-yl)-1-isopropyl-1H-pyrimido[4,5-d]pyrimidine-2,4-dione and 400 mg (1.92 mmol) of 4-(2-diethylaminoethoxy)aniline is heated at 180° C. for 3 hours. The reaction mixture is cooled, dissolved into chloroform, and chromatographed on silica eluting with 4:96 methanol/chloroform. The resulting oily material partially crystallizes on standing, and the mixture is triturated with diethyl ether/hexane and filtered to give 106 mg (36%) of the title compound: mp 90-96° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC=CC=1>[CH2:12]1[CH2:13][O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=Cc1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1OCCO2
Temperature: 135 °C
Yield: 49 %

Procedure:
12.04 g of 2,3-dihydroxybenzaldehyde was dissolved in 120 ml of dry DMF. To this solution, 9.0 ml of 1.2-dibromoethane, 12.1 g of anhydrous potassium carbonate and 1.1 g of cupric oxide were added. The reaction solution was refluxed under heating for three hours on a hot water bath at 135° C. The reaction solution was diluted with 700 ml of benzene and then washed with 500 ml of water. The aqueous layer was separated and extracted with benzene (500 ml×2 times). The extracted organic layers were combined to the previously separated organic layer, the combined organic layer was dried over anhydrous magnesium sulfate. The inorganic salt was removed by filtration, and the reaction solution was concentrated under reduced pressure to obtain a brown syrup. This syrup was purified by silica gel column chromatography (n-hexane/acetone=5/1). The eluted solution was concentrated under reduced pressure, and the residue was recrystallized from n-hexane/acetone to obtain 7.0 g of the above identified compound as white crystals (melting point: 63°-64° C.) (yield: 49%). The mother solution was concentrated and dried to obtain 3.2 g of the above identified compound as crude syrup (yield: 22%).
Reaction SMILES: [Br:1][C:2]1([Br:9])[CH2:4][C:3]1([Br:8])[CH2:5][CH2:6][OH:7].N1C=CC=CC=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[Br:1][C:2]1([Br:9])[CH2:4][C:3]1([Br:8])[CH2:5][CH2:6][O:7][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: OCCC1(Br)CC1(Br)Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OCCC1(Br)CC1(Br)Br)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
While cooling a solution of 3.00 g (0.00929 mol) of 1,1,2-tribromo-2-(2-hydroxyethyl)cyclopropane in methylene chloride with 0.901 ml (0.0111 mol) pyridine to 0° C., 1.18 ml (0.00929 mol) of benzene sulfonyl chloride was added dropwise via pipet. Allowed to warm to room temperature. After 3 days, water was added. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 3.10 g of 80% pure 1,1,2-tribromo-2-(2-benzenesulfonyloxyethyl)cyclopropane as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[C:11]1([C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([N:22]1[CH2:23][CH2:24][CH:19]([C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:18])[CH2:20][CH2:21]1)(=[O:28])=[O:27]
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
Neat DIPEA (1.54 ml, 8.86 mmol) was added dropwise to a solution of phenyl(4-piperidinyl)methanone hydrochloride (1 g, 4.43 mmol) in CH2Cl2 (20 ml) at 0° C. Then, neat MsCl (377 μL, 4.87 mmol) was slowly added and the cooling bath was removed. After 30 minutes, the reaction was quenched with water and diluted with CH2Cl2. After separation, the organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The final ketone 1 was obtained as a white solid (1.16 g, 98%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[CH:19]=1.[CH2:20]([O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH3:21]>CC(N(C)C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15](=[O:17])[N:14]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:32])[C:13](=[O:18])[C:12]=2[CH:19]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCCCCCCn1c(=O)oc2ccc(Cl)cc2c1=O
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
Sodium carbonate (194.0 g, 1.8 mot) was added to a 5 liter, 4-neck, round bottomed, flask containing 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione (323.1 g, 1.6 mol) and dimethylacetamide (970 ml). Ethyl-8-bromooctanoate (459.0 g, 1.8 mol) was added in one portion to the stirring reaction mixture. The atmospheric pressure in the reaction vessel was reduced to 550 mm Hg and heating of the reaction mixture was started. The reaction temperature was maintained at 70° C. for approximately 5 hours before heating and vacuum were discontinued. The reaction mixture was allowed to cool to room temperature overnight. The reaction mixture was vacuum filtered and the filter cake was washed with ethyl alcohol (525 ml). Deionized water (525 ml) was slowly added to the stirred filtrate and a white solid precipitated. An ice/water bath was placed around the reaction vessel and the slurry was cooled to 5° C. After stirring at this temperature for approximately 15 minutes the solids were recovered by vacuum filtration and the filter cake was washed first with ethanol (300 ml) and then with heptane (400 ml). After drying overnight at room temperature in vacuo, 598.4 g (99.5%) of ethyl 8-(6-chloro-2H-1,3-benzoxazine-2,4(3H)-dionyl)octanoate was obtained. An additional 66.6 g of ethyl 8-(6-chloro-2H-1,3-benzoxazine-2,4(3H)-dionyl)octanoate was made by this same method.
Reaction SMILES: CC([O-])(C)C.[K+].[OH:7][C:8]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[F:17][C:18]([F:33])([S:29](F)(=[O:31])=[O:30])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22]>C1COCC1>[F:33][C:18]([F:17])([S:29]([O:7][C:8]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])(=[O:31])=[O:30])[C:19]([F:27])([F:28])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22]
Reactant: Cc1cccc(C=O)c1O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(C=O)c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
A 1.04 M THF solution of t-BuOK (3.7 mL, 3.9 mmol) was added to a THF solution (0.5 mL) of 2-hydroxy-3-methylbenzaldehyde (500 mg, 3.7 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (1.16 g, 3.9 mmol) and the reaction was stirred at room temperature. After 30 min the temperature was increased to 40° C. After 5 min the resulting mixture was partitioned with DCM and water, and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated to yield a 4:1 w/w mixture of the title compound and starting material, which mixture was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][N:25]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-2-(6-methoxypyridin-3-yl)-6-(3-(piperazin-1-yl)propoxy)-1H-inden-1-one (90 mg, 1.2 eq, 0.2 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (20%).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[C@@H:12]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:13])=CC=1)([O-])=O.C(=O)([O-])[O-].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:18]([O:17][C:15](=[O:16])[NH:14][C@H:12]([C:11](=[O:10])[NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:13])([CH3:19])([CH3:20])[CH3:21]
Reactant: NCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-propionic acid 4-nitro-phenyl ester (200 mg, 0.645 mmol) and MP-carbonate (664 mg, 1.93 mmol, Biotage, Part #:800268) in CH2Cl2 (1.5 mL) was added benzylamine (70 mg, 0.645 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was then filtered and concentrated in vacuo to afford ((S)-1-benzylcarbamoyl-ethyl)-carbamic acid tert-butyl ester, m/z 279.4 [M+1]+.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:29](=[O:30])[CH2:28][N:27]([CH3:31])[C:26]1=[S:32])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:29](=[O:30])[CH2:28][N:27]([CH3:31])[C:26]1=[S:32])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C)C1=S)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C)C1=S)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 27.4 %

Procedure:
A solution of 0.209 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-N-(3-methyl-5-oxo-2-thioxo-1-imidazolidinyl)valeramide in 5 ml of methanol was treated with 0.020 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2.5 hours at room temperature and then evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether/hexane (2:1) to give 0.048 g of (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methyl-N-(3-methyl-5-oxo-2-thioxo-1-imidazolidinyl)valeramide in the form of a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 87.7 %

Procedure:
To a biphasic solution of 4-amino-1-benzylpiperidine (6.0 g, 31.6 mmol), K2CO3 (8.71 g, 63.1 mmol) in CH2Cl2 (200 mL) and water (100 mL) was added benzoyl chloride (4.86 g, 34.7 mmol) in 20 mL of CH2Cl2 at 0° C. with stirring. After stirring for 4 h at room temperature, the layers were separated. The organic layer was washed with water, dried over MgSO4 and filtered. The solvent was removed in vacuo to obtain 1-benzyl-4-benzamidopiperidine (8.16 g, 87% yield) as a white solid. It was used in the next step without purification.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][OH:43])[CH2:39][CH2:40]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCCN1CCN(CCO)CC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCN(CCO)CC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[4-(4-amino-butyl)-piperazin-1-yl]-ethanol by the procedure analogous to Example 1. MS (APCI, m/z): 527 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18].CCCCCC>C1C=CC=CC=1>[Cl:1][C:2]1[C:8]([C:9]([F:11])([F:10])[F:12])=[CH:7][C:6]([Cl:13])=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:17](=[O:18])[C:16]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:15]=1[F:14])=[O:21]
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 2,5-dichloro-3-trifluoromethyl aniline (0.6 g) in 10 ml of dry benzene was added dropwise a solution of 2,6-difluorobenzoylisocyanate (0.5 g) in 5 ml of dry benzene under water-cooling and the solution was stirred for one hour at room temperature. 50 ml of n-hexane was added to the above solution and the precipitated crystal was filtered. The crystal was washed with n-hexane to obtain the desired product 0.9 g. (m.p. 205°-207.5° C.)
Reaction SMILES: COC1C=CC(C([C@@:22]2([OH:61])[C@@H:26]([CH2:27][O:28][C:29]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(C3C=CC(OC)=CC=3)[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[O:25][C@@H:24]([N:52]3[CH:60]=[C:58]([CH3:59])[C:56](=[O:57])[NH:55][C:53]3=[O:54])[CH2:23]2)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1>C(#N)C.O>[CH2:47]([CH2:46][C:29]([O:61][C@@H:22]1[C@@H:26]([CH2:27][O:28][C:29]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[O:25][C@@H:24]([N:52]2[CH:60]=[C:58]([CH3:59])[C:56](=[O:57])[NH:55][C:53]2=[O:54])[CH2:23]1)=[O:28])[CH2:48][CH2:49][CH3:50]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@]2(O)C(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CC#N
Solvent: O
Product: CCCCCC(=O)O[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
To a stirred solution of 40.0 g of thymidine (0.165 mol) in 500 mL of pyridine was added 56.0 g of dimethoxytrityl chloride (0.165 mol), and the mixture was stirred at room temperature for 3 hours. To the mixture, 16.7 g of sodium hydrogen carbonate was added. The resulting mixture was stirred at room temperature for 30 min and evaporated under a reduced pressure. To the residue was added 500 mL of n-butyl acetate. To the stirred mixture was added 500 mL of water and the mixture was stirred for 10 min. Then, the organic layer was separated and washed with 500 mL of water. The organic layer was evaporated under a reduced pressure. The residue was recrystallized from 900 mL of n-butyl acetate to give a crystalline product, which was then collected by filtration. The crystalline product was dried in vacuo at 50° C. to a constant weight to give 74.6 g of the product. The product was analyzed by high performance chromatography (HPLC) with a reverse-phase octadecyl silica gel column using a mixture of acetonitrile/water (75/25) as an eluent and using a UV detector (254 nm), indicating a purity of 99.6%. A major impurity was 3′,5′-O-bis(4,4′-dimethoxytrityl)thymidine with an HPLC peak area of 0.3%. An yield was 75%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[O:21])=[CH:18][C:17]=1[O:35][CH3:36])=[O:4].[OH-].[Na+].Cl>O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[O:21])=[CH:18][C:17]=1[O:35][CH3:36])([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)O)cc12
Temperature: 60 °C
Yield: 10.2 %

Procedure:
A mixture of 4-(5-methoxycarbonyl-1-methyl-indol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)-benzamide (130.0 g), tetrahydrofuran (1.0 l) and 1N sodium hydroxide (1.0 l) was heated to about 60° C. overnight, then treated with additional 1N sodium hydroxide (200 ml) and heated an additional 5 hours at 60° C. (likely unnecessary). The cooled reaction mixture was acidified with 6N hydrochloric acid (25 ml) and extracted with ethyl acetate. The ethyl acetate solution was washed with brine (three times), dried (MgSO4) and evaporated to give a solid which was dried at 50° C. under vacuum to give 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenyl-sulfonyl)benzamide (12.9 g, 100% when calculated as 0.45 hydrate), mp 255°-257° C.; NMR (300 MHz, DMSO-d6): 2.60 (s, 3H, ArCH3), 3.76 (s, 3H, NCH3), 3.91 (s, 3H, OCH3), 4.05 (s, 2H, ArCH2Ar'), 7.15 (d, 1H), 7.19 (s, 1H), 7.39-7.51 (m, 5H), 7.58 (br t, 1H), 7.72 (dd, 1H), 8.03 (dd, 1H), 8.14 (d, 1H); anaylsis for C26H24N2O6S.0.45 H2O: calculated: C, 62.37; H, 5.01; N, 5.60%, found: C, 62.60; H, 5.03; N, 5.52%