Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C1C=CN=CC=1)C.O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: Cc1cc(O)c(-c2ncccc2C)nc1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ncccc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Dimethyl sulfoxide (1.4 ml) was added to 5,6,3′-trimethyl-[2,2′]bipyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline (94 mg), cesium carbonate (137 mg), and 4-(N,N-dimethylamino)-pyridine (51 mg), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (29 mg, yield 52%).
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([O:21][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1)=[O:20])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CCCCNc1cccc(C(=O)O)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCC=CCCCNc1cccc(C(=O)OC2CCCCO2)c1

Procedure:
A mixture of 7 g. 3-(4-tetradecenylamino)benzoic acid, 2 g. dihydropyran and 100 mg. anhydrous p-toluenesulfonic acid in 50 ml. toluene is stirred at room temperature for 20 hours. The solution is washed with saturated sodium bicarbonate, dried, and evaporated. The residue is collected and crystallized from methylcyclohexane to yield the product as white crystals.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9]CC)=[O:8])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>[OH-].[Na+]>[Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1c[nH]c(Br)c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c(Br)c1-c1ccc(Cl)cc1

Procedure:
Ethyl 5-bromo-4-(p-chlorophenyl)pyrrole-3-carboxylate (15 g., 0.045 mmol) is added to 200 mL of 10% sodium hydroxide and the slurry heated to reflux. After everything appears to dissolve the mixture is refluxed an additional 40 minutes. The mixture is cooled, filtered and the filtrate acidified. The white precipitate (8.0 g, 58%) is collected and dried. The solid has m.p. >205° C. and an NMR (d6 -DMSO) which showed a pyrrole proton at 7.52 (d). The mass spectrum is also consistent for a monobrominated compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH2:8])=[O:7].[CH3:9][NH:10][CH3:11]>C(O)C>[CH3:9][N:10]([CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH2:8])=[O:7]
Reactant: CNC
Reactant: NC(=O)CCCCBr
Solvent: CCO
Product: CN(C)CCCCC(N)=O
Reaction time: 3 h
Yield: 70 %

Procedure:
5-Bromopentanamide (10.11 g) was dissolved in ethanol (50 ml) and a 33% solution of dimethylamine in ethanol (20 ml) added. The solution was allowed to stand at room temperature for 3 hours, more dimethyl amine added (20 ml) and the solution allowed to stand at room temperature for 18 hours. The solution was evaporated to an oil which was dissolved in dilute HCl and the solution of pH 2 was washed twice with dichloromethane, basified with NaOH, saturated with NaCl and extracted 10 times with dichloromethane. The combined latter extracts were dried over K2CO3 and evaporated to give 5-dimethylaminopentanamide as acolourless solid (5.72 g, 70%) (mp 86°-7°).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]3[C:28]=2[CH3:29])[S:10]([CH2:13][CH2:14]Br)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH2:34]([NH:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH:35]([CH3:37])[CH3:36]>C(#N)C>[F:1][C:2]([F:33])([F:32])[O:3][C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]3[C:28]=2[CH3:29])[S:10]([CH2:13][CH2:14][N:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)CNCC(C)C
Reactant: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)CCBr)nc2cc(C(F)(F)F)ccn12
Solvent: CC#N
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)CCN(CC(C)C)CC(C)C)nc2cc(C(F)(F)F)ccn12
Temperature: 80 °C
Yield: 93.9 %

Procedure:
To a solution of compound 17-H (0.004 g, 0.007 mmol) in acetonitrile (0.4 mL) was added diisobutylamine (0.009 g, 0.071 mmol) and the reaction mixture was heated at 80° C. for 18 h. The solvent was removed in vacuo and the resulting residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 106 as a white solid (0.004 g, 97%); MS m/z (M+H+) 609.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:17])=[CH:13][CH:14]=2)[C:9]1=[O:18]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2ccc(C)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 1.33 h
Yield: 82 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 80 minutes while stirring through a solution, cooled to -70°, of 16.3 g of (RS)-2-(2-buten-1-yl)-6-methyl-1-indanone in 300 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 8.95 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 300 ml of dichoromethane and, after the addition of 40 ml of water and 40 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. The crude product obtained was recrystallized from diethyl ether/hexane. 12.7 g (82%) of (RS)-2-(2-oxoethyl)-6-methyl-1-indanone were obtained as a light yellow solid with m.p. 53°-54°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([CH:13]=[CH2:14])[N:10]=[C:9]([CH:15]=[C:16]([CH3:18])[CH3:17])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:19])[C:7]1[CH:8]=[C:9]([CH2:15][CH:16]([CH3:17])[CH3:18])[N:10]=[C:11]([CH2:13][CH3:14])[CH:12]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cc(C=C(C)C)n1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)OC(C)(C)C)cc(CC(C)C)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.8 %

Procedure:
To a solution of the above 2-(2-methyl-propenyl)-6-vinyl-isonicotinic acid tert-butyl ester (444 mg, 1.71 mmol) in MeOH (15 mL), Pd/C (50 mg, 10% Pd) is added and the mixture is stirred under 1 atm of H2 at rt for 15 h. The catalyst is filtered off and the filtrate is evaporated. The remaining residue is purified by CC on silica gel eluting with heptane:EA 5:1 to give 2-ethyl-6-isobutyl-isonicotinic acid tert-butyl ester (391 mg) as a colourless oil; LC-MS: tR=1.15 min, [M+1]+=264.11.
Reaction SMILES: C(NC(=O)/C=C(\O[C:11](=[O:30])[C:12]1[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=1[NH:23][CH2:24][C:25]1[O:29][CH:28]=[CH:27][CH:26]=1)/C)(C)(C)C.[NH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(#N)C>[O:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C:11](=[O:30])[C:12]2[CH:17]=[C:16]([S:18]([CH3:21])(=[O:19])=[O:20])[C:15]([Cl:22])=[CH:14][C:13]=2[NH:23][CH2:24][C:25]2[O:29][CH:28]=[CH:27][CH:26]=2)[CH2:36][CH2:37]1
Reactant: NCCN1CCOCC1
Reactant: C/C(=C/C(=O)NC(C)(C)C)OC(=O)c1cc(S(C)(=O)=O)c(Cl)cc1NCc1ccco1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(C(=O)NCCN2CCOCC2)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-tert-butyl-3-(2-furfurylamino-4-chloro-5-methylsulfonylbenzoyloxy)crotonamide (4.00 g.; 0.0085 mole) and N-(2-aminoethyl)morpholine (2.21 g.; 0.017 mole) are added to acetonitrile (100 ml.). The resulting solution is stirred at room temperature for 24 hours. The acetonitrile is removed under reduced pressure, and the residue is triturated with butyl chloride to give N-(2-morpholinoethyl)-2-furfurylamino-4-chloro-5-methylsulfonylbenzamide which after drying yields 2.7 g. (72%), m.p. 127°-130° C. Several recrystallizations from butyl chloride yields product with m.p. 132°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].CCN(CC)CC.Cl[Si:37]([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](O[Si](C)(C)C)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 64.8 %

Procedure:
A solution of 8a (0.08 g, 0.20 mmol), NEt3 (0.1 mL, 0.72 mmol) and chlorotrimethylsilane (0.1 mL, 0.79 mmol) in CH2Cl2 (30 mL) was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3 (2×10 mL) and H20 (50 mL), dried (Na2SO4), and the solvent was removed under reduced pressure. The resulting crude solid was purified by column chromatography (eluent: ethyl acetate/nhexanes) to afford 16 (0.06 g, 68%) as a white solid, mp 197-200° C.; 1H NMR (CDCl3): δ 0.14 (9H, s, (CH3)3SiO; 1.11 (3H, s, H-19); 1.48 (3H, s, H-29); 1.50-1.73 (3H, m, H-7α,β and H-11β); 1.79 (1H, ddd, J=3.0, 3.0, 10.5 Hz, H-6α); 2.03 (1H, dd, obscured, H-8); 2.06 (1H, s, H-10); 2.10-2.38 (3H, m, H-3α,β and H-6β); 2.57 (1H, dd, J=5.1, 10.5 Hz, H-11α); 2.69 (1H, dd, J=3.9, 12.9 Hz, H-4); 3.72 (3H, s, CO2CH3); 4.12 (1H, dd, J=7.5, 11.7 Hz, H-2); 5.56 (1H, dd, J=5.1, 11.4 Hz, H-12); 6.38 (1H, dd, J=0.8, 1.7 Hz, H-14); 7.40 (1H, m, H-15); 7.42 (1H, m, H-16).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl>[C:26]([O:29][CH2:30][C:31]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:21][CH2:22]1)=[O:32])(=[O:28])[CH3:27]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C)[Si](OCC1CCNCC1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5 g of the crude product from Example 20A are suspended in 24 ml of dichloromethane and cooled to 0° C. 1.88 g (13.79 mmol) of acetoxyacetyl chloride and 5.9 ml (42.42 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 8 h. After addition of 25 ml of dichloromethane the mixture is washed once with 10 ml of water and once with 10 ml of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the residue is purified chromatographically on silica gel 60 (mobile phase: gradient cyclohexane/ethyl acetate 20:1→1:1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1>C(=O)(O)[O-].[Na+]>[CH:1]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=1)=[O:3]
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)Cc1ccc(NC=O)cc1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of acetic anhydride (14.3 mL, 151 mmol) and formic acid (22.8 mL, 605 mmol) was stirred at room temperature for 1 h. Methyl (4-aminophenyl)acetate (5.00 g, 30.3 mmol) was added and the resulting mixture was stirred overnight. Saturated aqueous sodium bicarbonate (10 mL) was added and the resulting mixture was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.31 g) as a yellow oil, which was used in the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][C:10]([O:12]N1C(=O)CCC1=O)=O.[NH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:85]=[CH:84][C:38]([C:39]([C:41]2[CH:83]=[CH:82][C:44]([O:45][CH2:46][CH2:47][CH2:48][NH:49][C:50](=[O:81])[CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH:65][C:66](=[O:80])[CH2:67][CH2:68][CH2:69][CH2:70][CH:71]3[CH:78]4[CH:74]([NH:75][C:76](=[O:79])[NH:77]4)[CH2:73][S:72]3)=[CH:43][CH:42]=2)=[O:40])=[CH:37][CH:36]=1>C(Cl)Cl>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH2:9][C:10](=[O:12])[NH:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([C:41]2[CH:83]=[CH:82][C:44]([O:45][CH2:46][CH2:47][CH2:48][NH:49][C:50](=[O:81])[CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH:65][C:66](=[O:80])[CH2:67][CH2:68][CH2:69][CH2:70][CH:71]3[CH:78]4[CH:74]([NH:75][C:76](=[O:79])[NH:77]4)[CH2:73][S:72]3)=[CH:43][CH:42]=2)=[O:40])=[CH:84][CH:85]=1
Reactant: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Reactant: NCCCOCCOCCOCCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCCCC3SCC4NC(=O)NC43)cc2)cc1
Solvent: ClCCl
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCOCCOCCOCCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCCOCCOCCOCCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoate (0.65 g, 2.43 mmol) was added to a solution of crude N-(3-(4-(4-((3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)amino)-benzoyl)phenoxy)propyl)-1-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide (2 g, 2.11 mmol) in DCM (20 mL) and the reaction mixture was stirred for 2 hs at room temperature. Upon completion, reaction was then concentrated under reduced pressure, and purified by silica gel chromatography (DCM to DCM:MeOH, gradient) to yield 1.70 g (1.55 mmol, 73%) N-(3-(4-(4-((17-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-15-oxo-4,7,10-trioxa-14-azaheptadecyl)-amino)benzoyl)phenoxy)propyl)-1-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12-tetraoxapentadecan-15-amide as yellow oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[CH2:20]([C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[N:32][CH:33]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+].O>C(O)CCC>[CH2:20]([C:28]1[CH:33]=[N:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:36][CH:35]=2)=[N:30][CH:29]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCc1cnc(-c2ccc(OCC(F)CCCCC)cc2)nc1
Reaction time: 5.5 h

Procedure:
0.43 g (1.5 mmol) of the thus obtained (+)-2-fluoroheptyl p-toluenesulfonate and 0.28 g (1.0 mmol) of 5-octyl-2-(4-hydroxyphenyl)pyrimidine were mixed with 0.2 ml of 1-butanol, followed by sufficient stirring. To the solution was quickly added a previously obtained alkaline solution of 0.048 g (1.2 mmol) of sodium hydroxide in 1.0 ml of 1-butanol, followed by 5.5 hours of heat-refluxing. After the reaction, 10 ml of distilled water was added, and the mixture was extracted respectively once with 10 ml of benzene and 5 ml of benzene, followed by drying with an appropriate amount of anhydrous sodium sulfate, distilling-off of the solvent and purification by silica gel column chromatography (chloroform) to obtain 0.17 g (0.43 mmol) of objective (+)-5-octyl-2-[4-(2-fluoroheptyloxy)phenyl]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]1.Br[CH2:19][N:20]1[C:24](=[O:25])[C:23]2[C:26]([CH:32]([CH3:34])[CH3:33])=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[S:21]1(=[O:36])=[O:35].[F-].[K+]>CN(C=O)C.O>[CH:32]([C:26]1[C:23]2[C:24](=[O:25])[N:20]([CH2:19][O:13][C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:9]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:11]=3)[S:21](=[O:36])(=[O:35])[C:22]=2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=1)([CH3:34])[CH3:33]
Reactant: O=C1CC(C(F)(F)F)=NN1c1ccccc1Cl
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1Cl)C2=O
Yield: 43 %

Procedure:
A mixture 2,4-dihydro-2-(2-chlorophenyl)-5-trifluoromethyl-3H-pyrazol-3-one (543 mg; 2.06 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (600 mg, 1.72 mmol) and KF (250 mg, 3.44 mmol) in 7 ml of DMF was stirred at room temperature for 4 hours. The mixture was diluted with water, extracted with ether (3×), and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (2×, silica gel; 12-50% ethyl acetate in hexane; 10-50% methylene chloride/ethyl acetate) and recrystallized from ethyl acetate/hexane to afford 392 mg (43%) of 4-isopropyl-6-methoxy-2-[1-(2-chlorophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =2-Cl--Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as m.p. 134-1360° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:21][C:22](=[O:25])[CH2:23]Cl)[CH2:18][CH2:19][CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:17]([O:21][C:22]([CH2:23][S:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:25])[CH2:18][CH2:19][CH3:20]
Reactant: Sc1nc2cccnc2s1
Reactant: CCCCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)CSc1nc2cccnc2s1
Temperature: 25 °C
Yield: 99 %

Procedure:
Twenty-four (24) g of 2-mercaptothiazolo[5,4-b]pyridine was dissolved in 300 ml of N,N-dimethylformamide, and 43.3 g of potassium carbonate and 23.65 g of chloroacetic acid n-butyl ester were added to the solution, followed by one-hour stirring at room temperature. Seven hundred (700) ml of ethyl acetate was added to the solution, which was then washed with water three times, dehydrated over magnesium sulfate, dried and distilled to remove the solvent to obtain the title compound (39.9 g, 99%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31][CH2:32][CH3:33])=[CH2:30])CCC>CN(C=O)C.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>[CH2:32]([O:31][C:29]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:30])[CH3:33]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc2ncccc2c(F)c1Cn1nnc2ncc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 54.3 %

Procedure:
To a degassed solution of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (10 mg, 0.03 mmol) in DMF (1 mL) was added Pd(Ph3P)4 (3.1 mg, 2.65 μmol). After stirring for 20 min, tributyl(1-ethoxyvinyl)stannane (14.4 mg, 0.04 mmol) was added. The reaction was heated at 100° C. until the LC-MS showed its completion. The reaction mixture was filtered through celite and washed with ether. The filtration was washed with water, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography with hexane:EtOAc to give 6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (6.0 mg, 61%). 1H-NMR (400 MHz, CDCl3) δ ppm 9.16 (s, 1H), 8.98 (d, 1H), 8.43 (d, 1H), 7.65 (d, 1H), 7.48 (m, 1H), 6.17 (s, 2H), 5.60 (s, 1H), 4.57 (s, 1H), 4.04 (q, 2H), 1.49 (t, 3H). LCMS (method B): [MH]+=369.0, tR=2.45 min.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[N:10][N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:12]=2[CH3:13])[C:3]1=[O:21].[Cl:22][C:23]1[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][NH:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:23]1[C:24]([C:29]([F:31])([F:30])[F:32])=[N:25][N:26]([CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:9]=[N:10][N:11]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[C:12]=3[CH3:13])[C:3]2=[O:21])[C:27]=1[CH3:28]
Reactant: Cc1c(N2CCCC(Br)C2=O)cnn1-c1ccc(F)cc1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(N2CCCC(n3nc(C(F)(F)F)c(Cl)c3C)C2=O)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
To a solution of 3-bromo-1-[1-(4-fluorophenyl)-5-methylpyrazol-4-yl]piperidin-2-one (0.05 g, 0.14 mmol) in DMF (1.0 mL) was added 4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazole (0.031 g, 0.17 mmol), followed by potassium carbonate (0.029 g, 0.21 mmol). After stirring at room temperature for 1 h, the reaction was quenched with water. The aqueous layer was then extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.025 mmol, 23%). 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.44-7.35 (m, 2H), 7.22-7.13 (m, 2H), 4.94 (dd, J=9.9, 6.3 Hz, 1H), 3.90-3.70 (m, 2H), 2.73 (dddd, J=13.2, 11.5, 9.8, 3.3 Hz, I H), 2.47-2.38 (m, 1H), 2.36 (s, 3H), 2.31 (ddd, J=10.6, 5.4, 2.4 Hz, 1H), 2.17-2.12 (m, 1H), 2.13 (s, 3H); MS: (ES) m/z calculated for C20H18ClF4N5O [M+H]+ 456.1. found 456.1.