Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][CH2:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:25]=2)[NH:20][CH:19]=1)=[O:17])=O)C1C=CC=CC=1>CC(C)=O.CS(O)(=O)=O.C=O.[Pd]>[CH3:9][N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][CH2:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:30])=[O:31])[CH:25]=2)[NH:20][CH:19]=1)=[O:17]
Reactant: O=C(c1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: C=O
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CN1CCC[C@@H]1C(=O)c1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Yield: 65 %

Procedure:
A suspension of (R)-benzyl-2-(5-(2-(phenylsulfonyl)ethyl)-1H-indole-3-carbonyl)-pyrrolidine-1-carboxylate (5.0 g) in 50 ml acetone, methanesulfonic acid, formaldehyde and 10% Pd/C was subject to hydrogenation at 45 psi. Upon completion of the reaction the catalyst was filtered off and the solvent removed under vacuum to provide the title compound in about 65-75% yield. Mass (M+Na) 419.5
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][Li]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a solution of 1-(6-chloropyridin-3-yl)ethanone (2.0 g, 12.85 mmol) in THF (Volume: 25 mL) was added methyllithium (16.07 mL, 25.7 mmol) at 0° C. The reaction was stirred for 1 hr and allowed to warm to room temperature. The resulting deep red solution was quenched with water (Volume: 50 mL), extracted with EtOAc (1×50 mL), and the organic layer was dried over MgSO4. The organic phase was filtered and the filtrate was evaporated to dryness via rotary evaporation. The resulting material was purified via MPLC (DCM:MeOH, 95:5) to provide 2-(6-chloropyridin-3-yl)propan-2-ol (0.985 g, 5.74 mmol, 44.6% yield) as a dark red solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 5 H) 5.32 (s, 1 H) 7.44 (d, J=8.34 Hz, 1 H) 7.90 (dd, J=8.34, 2.53 Hz, 1 H) 8.49 (d, J=2.53 Hz, 1 H). ESI-MS:m/z 172.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:49])([F:48])[C:37]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:38]=1[NH2:39]>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([C:30]([F:32])([F:33])[F:31])[CH:24]=2)[CH:12]=[C:13]([NH:39][C:38]2[CH:40]=[C:41]([C:44]([F:45])([F:46])[F:47])[CH:42]=[CH:43][C:37]=2[C:36]([F:35])([F:48])[F:49])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield from 2-(5′-fluoro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 2,5-bis-(trifluoromethyl)aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1N1CCC(S(N2CCC(OC3C=CC(C(F)(F)F)=CC=3)CC2)(=O)=O)(C(OC)=O)CC1.[N:37]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C([O-])=O.[NH4+].C(=O)([O-])[O-].[K+].[K+].ClC1N=CC=CN=1>CO.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:46][S:43]([N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)(=[O:45])=[O:44]
Reactant: COC(=O)C1(S(=O)(=O)N2CCC(Oc3ccc(C(F)(F)F)cc3)CC2)CCN(c2ncccn2)CC1
Reactant: NS(=O)(=O)N1CCCCC1
Agent: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(Nc1ncccn1)N1CCCCC1
Temperature: 85 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Part G: Preparation of methyl 1-(2-pyrimidinyl)4-[[4-[4-(trifiuoromethyl)phenoxy]-1-piperidinyl]sulfonyl]-4-piperidinecarboxylate. To a slurry of the piperidine sulfonamide from part F (6.3 g, 12.0 mmol) in methanol (25 mL) was added ammonium formate (2.2 g, 34.5 mmol). The system was purged with nitrogen for 10 min. The nitrogen stream was removed and palladium on carbon (1.2 g of 10 weight % on activated carbon, 50% water) was added. The reaction was refluxed for forty five min, cooled, filtered through Celite under N2, and concentrated in vacuo. The residue (6.21 g, 13.8 mmol) was dissolved in dry dimethylformamide (28 mL) and potassium carbonate (5.7 g, 41.4 mmol) and 2-chloropyrimidine (3.16 g, 27.6 mmol) were added. The reaction was stirred at 85° C. for one hr and then concentrated in vacuo. The residue was taken up in ethyl acetate and filtered through Celite. The filtrate washed with water two times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. The product was recrystallized (methanol) to give the N-pyrimidinyl piperidine sulfonamide as a white solid (4.94 g, 68%).
Reaction SMILES: CO[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]>C(Cl)Cl>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH:12][CH:3]=[CH:4][C:5](=[O:7])[CH3:6]
Reactant: NCc1ccccc1Cl
Reactant: COC=CC(C)=O
Solvent: ClCCl
Product: CC(=O)C=CNCc1ccccc1Cl
Yield: 99.7 %

Procedure:
A solution of 4-methoxy-3-buten-2-one (100.1 mg, 1 mmol) and 2-chlorobenzylamine (141.6 mg, 1 mmol) in dry CH2Cl2 (5 mL) is stirred under reflux for 2 h. The solvent is evaporated under reduced pressure to afford the title compound 45 as a yellow oil (Yield 209 mg, 100%).
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].Cl[C:11]1[NH:16][C:15](=[O:17])[C:14]([F:18])=[CH:13][N:12]=1>C1(C)C=CC=CC=1>[CH2:1]([O:7][C:11]1[NH:16][C:15](=[O:17])[C:14]([F:18])=[CH:13][N:12]=1)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=c1[nH]c(Cl)ncc1F
Reactant: OCC1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(OCC2CCCO2)ncc1F
Reaction time: 15 h
Yield: 72 %

Procedure:
A 40 g quantity of tetrahydrofurfuryl alcohol and 7.2 g of sodium hydride are added to 200 ml of absolute toluene, and the mixture is stirred at 75°-80° C for 15 hours. Subsequently 14.9 g of 2-chloro-5-fluoropyrimidin-4-one is added to the reaction mixture, and the resulting mixture is heated in a sealed tube at 148° to 150° C for 5 hours for reaction. The resulting reaction mixture is treated in the same manner as in Example 6 to give 15.4 g of white crystalline 2-tetrahydrofurfuryloxy-5-fluoropyrimidin-4-one in a yield of 72.0%, m.p. 89°-91° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][N:8]=1)(=O)=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[O:24]1[CH2:25][CH2:26][N:21]([CH2:6][C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)nc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture containing (5-(tert-butoxycarbonylamino)pyridin-2-yl)methyl methanesulfonate (114; 1.70 g), morpholine (48; 1.0 g, 11.3 mmol) and K2CO3 (2.30 g, 16.9 mmol) in acetonitrile (30 mL) was stirred at room temperature for 12 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=1:1 to 1:3) to afford tert-butyl 6-(morpholinomethyl)pyridin-3-ylcarbamate 115 (1.20 g, 71% for two steps).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH2:11]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:12]1[O:14][CH2:13]1.Cl>>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:13][CH:12]([OH:14])[CH2:11][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22]
Reactant: COCCOCCO
Reactant: COCCOCCOCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COCCOCCOCC(O)COCCOCCOC
Temperature: 70 °C
Yield: 74.9 %

Procedure:
44.0 g (1.1 mol) of NaOH pellets were added to 360 g (3.0 mol) of diethyleneglycol monomethyl ether, and 176 g (1.0 mol) of 2-(2-methoxyethoxy)ethyl glycidyl ether was gradually dropwise added while stirring at 70° C. After the completion of dropwise addition, the mixture was stirred for about one hour and then stood for cooling at room temperature. Then, the mixture was neutralized with hydrochloric acid, a precipitated salt was filtered off and the liquid was condensed. The liquid was purified by vacuum distillation to give 222 g of 1,3-bis[2-(2-methoxyethoxy)ethoxy]-2-propanol (yield: 75%). The distillation temperature was from 171 to 175° C./0.8 mmHg.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=O)[C:8]2[N:12]([CH3:15])[CH:13]=[CH:14][C:7]=2[S:6]1(=[O:17])=[O:16].Cl.[NH2:19][OH:20].C([O-])(=O)C.[K+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9](=[N:19][OH:20])[C:8]2[N:12]([CH3:15])[CH:13]=[CH:14][C:7]=2[S:6]1(=[O:17])=[O:16]
Reactant: NO
Reactant: Cn1ccc2c1C(=O)CN(CCCCl)S2(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cn1ccc2c1C(=NO)CN(CCCCl)S2(=O)=O
Yield: 87.9 %

Procedure:
A suspension of 300 mg (1.08 mmol) of Compound 16, 113 mg (1.62 mmol) of hydroxylamine hydrochloride and 159 mg (1.62 mmol) of potassium acetate in 10 ml of methanol was refluxed for 7 hours. To the reaction mixture, 75 mg (1.08 mmol) of hydroxylamine hydrochloride and 106 mg (1.08 mmol) of potassium acetate were added, followed by further refluxing for 13 hours. Post treatment and purification were conducted as in Example 9, whereby 277 mg of the title compound were obtained (yield: 88%).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:16]([C:17]4[C:22]([C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][C:14](B(O)O)=[C:13]1[C:8]=3[CH:9]=[CH:10][CH:11]=[CH:12]1.[Br:26][C:27]1[CH:28]=[C:29](I)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:26][C:27]1[CH:28]=[C:29]([C:14]2[CH:15]=[C:16]3[C:7](=[C:8]4[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]4)[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:22]2[C:17]3=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cc2c3ccccc3c3ccccc3c2c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc3c4ccccc4c4ccccc4c3c3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Under an argon atmosphere, 3.86 g of the benzo[g]chrysene-10-boronic acid which had been prepared in Synthesis Example 3, 2.83 g of 3-bromoiodobenzene, 0.231 g of tetraxis(triphenylphosphine)palladium(0), 40 mL of toluene and 20 mL of a 2M aqueous solution of sodium carbonate were placed in a flask. The resultant was refluxed with stirring for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and an organic phase which had been separated was washed with water and then with saturated brine, and dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting residue was purified by a silica gel column chromatography, whereby 4.12 g (yield: 95%) of 10-(3-bromophenyl)benzo[g]chrysene was obtained.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:9]([N:26](C)[CH2:27][CH2:28][NH2:29])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>N1CCCCC1.CN(C=O)C>[CH3:9][NH:26][CH2:27][CH2:28][NH:29][C:1](=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CN(CCN)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CCC(=O)O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CNCCNC(=O)CCC(=O)O
Reaction time: 0.17 h

Procedure:
The support bound N-(Fmoc)-N-methyl ethylenediamine succinate (105) was treated with 20% piperidine/DMF (10 mL—applied and then allowed to drain). An additional amount of 20% piperidine/DMF (10 mL) was then added and the slurry was agitated for 10 minutes. The support was then washed with DMF (10 mL×2), CH2Cl2 (10 mL×2) and finally with DMF (10 mL×2). The deprotected support (106) was then immediately used in Step 5.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[C:20]([CH3:37])=[N:21][C:22]([CH:25]4[CH2:29][CH2:28][N:27]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:26]4)=[CH:23][CH:24]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:38])[O:4][N:3]=1.[CH3:39][C:40](N=C(N(C)C)N(C)C)([CH3:42])[CH3:41].BrCC(C)C>C(#N)C>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:25]([C:22]2[N:21]=[C:20]([CH3:37])[C:19]([N:18]([CH2:39][CH:40]([CH3:42])[CH3:41])[S:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:38])=[CH:14][CH:13]=3)(=[O:16])=[O:17])=[CH:24][CH:23]=2)[CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC(C)CBr
Solvent: CC#N
Product: Cc1nc(C2CCN(Cc3ccccc3)C2)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 80 °C
Yield: 48.9 %

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-{2-methyl-6-[1-(phenylmethyl)-3-pyrrolidinyl]-3-pyridinyl}benzenesulfonamide (211 mg, 0.396 mmol) and N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (67.9 mg, 0.396 mmol) in acetonitrile (3 mL) was added 1-bromo-2-methylpropane (0.086 mL, 0.792 mmol). The reaction vessel was sealed and heated at 80° C. for 8 hours. The reaction mixture was separated between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with brine and dried over magnesium sulphate. The solvent was removed in vacuo. The sample was purified by flash silica (Si) chromatography (0-25% methanol-dichloromethane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product (114 mg) as a brown gum. LCMS (2 min, formic) Rt 1.01 min, m/z (ES+) 589 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6].N1C=CC=CC=1.[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:33]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:34])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6]
Reactant: COc1ccccc1C(=O)NS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C1CCCC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccccc1C(=O)NS(=O)(=O)c1ccc(NC(=O)C2CCCC2)cc1
Reaction time: 2 h
Yield: 74 %

Procedure:
2.8 g (9 mmol) of 2-methoxy-N-(4-aminophenylsulfonyl)benzamide are suspended in 100 ml of dioxane, 0.72 g (9 mmol) of pyridine and 1.21 g (9 mmol) of cyclopentan-ecarbonyl chloride are added at 0° C., and the mixture is stirred for 2 hours at this temperature. The reaction mixture is subsequently transferred into water, and the resulting precipitate is filtered off with suction. After drying, 2.68 g (73%) of N—[4-(2-methoxy-benzoylsulfamoyl)phenyl]cyclopentanecarboxamide of melting point 202-206° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=1I>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:21]1[CH:22]=[C:23]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:24]=[CH:25][C:20]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(Cl)c(I)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(S(C)(=O)=O)ccc1Cl

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-chloro-2-iodo-4-(methylsulfonyl)benzene (Intermediate 74), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:19])([F:18])[CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=1>CO>[F:19][C:4]([F:3])([F:18])[CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1
Reactant: COC(=O)c1ccc(OCCC(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCC(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
2M sodium hydroxide (5 mL) is added to a solution of methyl 6-(3,3,3-trifluoropropoxy)nicotinate (1.37 g, 5.50 mmol, Step-1) in methanol (30 mL) is stirred for 2 hours at 60° C. After removal of the solvent, the residue is dissolved in water (30 mL) and acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.15 g (86% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]2=[O:28])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.O1CCOCC1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:28])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCOc1ccc(N2CCNCC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To tert-butyl 4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate (540 mg, 1.38 mmol) was added 4M HCl in dioxane (2.07 mL, 8.30 mmol). The reaction mixture was stirred at room temperature for 2 h. The precipitate was filtered, washed with hexane (5 mL) and dried. The crude product was purified by column chromatography (79/20/1 DCM/MeOH/NH4) to afford 325 mg (80%) of 1-(4-(heptyloxy)phenyl)piperazin-2-one as a colorless solid. LCMS-ESI (m/z) calculated for C17H26N2O2: 290.4. found 291.0 [M+H]+, tR=1.49 min. (Method 4).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:36][C:37]1[CH:38]=[C:39]2[C:43](=[C:44]([N:46]([CH3:55])[S:47]([C:50]3[S:51][CH:52]=[CH:53][CH:54]=3)(=[O:49])=[O:48])[CH:45]=1)[NH:42][C:41]([C:56]([NH:58][CH2:59][CH2:60][S:61]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)=[CH:40]2.C(=O)([O-])O.[Na+]>ClCCl>[S:61]1[CH2:60][CH2:59][N:58]=[C:56]1[C:41]1[NH:42][C:43]2[C:39]([CH:40]=1)=[CH:38][C:37]([F:36])=[CH:45][C:44]=2[N:46]([CH3:55])[S:47]([C:50]1[S:51][CH:52]=[CH:53][CH:54]=1)(=[O:49])=[O:48]
Reactant: CN(c1cc(F)cc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cc(F)cc2cc(C3=NCCS3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
A mixture of triphenylphosphine oxide (522 mg), trifluoromethanesulfonic anhydride (0.158 mL), and dichloromethane (10 mL) was stirred for 15 min under ice-cooling. Then, 5-fluoro-7-[methyl(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (205 mg) was added, and the mixture was stirred for 3 hr under ice-cooling. The reaction solution was poured into aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-5:5), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (92 mg, yield 75%) as colorless prism crystals. melting point 188-189° C.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]4=[N:40][N:41]=[C:42]([C:43]5[CH:47]=[C:46]([CH3:48])[O:45][N:44]=5)[N:32]4[N:31]=3)=[CH:24][N:23]=2)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>C(Cl)Cl>[CH3:48][C:46]1[O:45][N:44]=[C:43]([C:42]2[N:32]3[N:31]=[C:30]([O:29][CH2:28][C:25]4[CH:26]=[CH:27][C:22]([C:9]5([OH:8])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]5)=[N:23][CH:24]=4)[C:39]4[C:34]([C:33]3=[N:40][N:41]=2)=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:47]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C5(O)CCN(C(=O)OC(C)(C)C)CC5)nc4)nn23)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C5(O)CCNCC5)nc4)nn23)no1
Reaction time: 6 h
Yield: 62.1 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred solution of 1,1-dimethylethyl 4-hydroxy-4-[5-({[3-(5-methylisoxazol-3-yl){1,2,4]triazolo[3,4-α]phthalazin-6-yl]oxy}methyl)pyridin-2-yl]-1-piperidine carboxylate(707 mg, 1.27 mmol) in CH2Cl2 (30 ml) at room temperature and the reaction stirred for 6 h. The reaction mixture was concentrated under reduced pressure, 2N NaOH solution (30 ml) was added and the resulting precipitate was filtered off. After dissolving in MeOH/CH2Cl2 (60 ml) and dry loading onto alumina, the crude residue was purified by column chromatography on alumina using 5-7% MeOH/CH2Cl2 containing 1% NH3 to yield the desired phthalazine (361 mg, 62%). 1H NMR (360 MHz, d6-DMSO) δ 8.80 (1H, s), 8.55 (1H, d, J=7.1 Hz), 8.23 (1H, d, J=7.1 Hz), 8.15-8.03 (2H, m), 7.93 (1H, t, J=7.1 Hz), 7.71 (1H, d, J=7.4 Hz), 7.07 (1H, s), 5.67 (2H, s), 5.06 (2H, s), 2.91 (2H, t, J=11.2 Hz), 2.74 (2H, d, J=11.2 Hz), 2.60 (3H, s), 2.04 (2H, td, J=12.4, 4.0 Hz), 1.44 (2H, d, J=12.4 Hz). m/z (ES+) 458 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].CCOC(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(OS(C)(=O)=O)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-3-methylphenol (35.0 g, 277 mmol) in 100 mL of methylene chloride at 0° C. was added triethylamine (77 mL mL, 554 mmol), followed by methanesulfonyl chloride (32.2 mL, 416 mmol). The reaction was allowed it to warm to room temperature and stirred at room temperature for 1 hr. The solution was poured into EtOAc, washed with H2O and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting yellow solid product was used without further purification.