Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[N:3]1[O:19][S:20]([O-:23])(=[O:22])=[O:21].C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>ClCCl>[O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[N:3]1[O:19][S:20]([OH:23])(=[O:22])=[O:21]
Reactant: O=C(NC1CCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium [({(2S,5R)-7-oxo-2-[(piperidin-4-ylamino)carbonyl]-1,6-diazabicyclo[3.2.1]oct-6-yl}oxy)sulfonyl]oxidanide (22.4 mg, 0.050 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under nitrogen was added trifluoroacetic acid (0.1 mL, 1.298 mmol) dropwise. The reaction mixture was stirred for 1 hour then concentrated under vacuum. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was washed with ether (2× to afford the title compound contaminated with tetrabutylammonium hydrogen sulfate and pyridine. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation to afford the title compound as a white solid. LC-MS (negative ionization) m/e 347 (M−H); LC-MS (positive ionization) m/e 349 (M+H), 381 (M+Na); 1H NMR (600 MHz, D2O; unreferenced) (δ, ppm) 4.19 (1H, br d, J=2.5 Hz), 3.98-4.06 (2H, m), 3.47 (2H, br d, J=13 Hz), 3.31 (1H, br d, J=12 Hz), 3.12 (2H, br dd, J=13, 3 Hz), 3.06 (1H, d, J==12 Hz), 2.04-2.21 (m, 4H), 1.87-1.95 (1H, m), 1.72-1.83 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([OH:26])=O)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][O:29][C:30](=[O:33])[CH2:31][NH2:32].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(OC(N1CCCN(C2C=CC([N+]([O-])=O)=C(C(NCC(O)=O)=O)C=2)CC1)=O)(C)(C)C>C(Cl)Cl.Cl.COC(=O)CN>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([C:24]([NH:32][CH2:31][C:30]([O:29][CH3:28])=[O:33])=[O:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])c(C(=O)O)c2)CC1
Reactant: COC(=O)CN
Agent: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])c(C(=O)NCC(=O)O)c2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
4-(3-Carboxy-4-nitro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (37.27 g, 102 mmol) and 107.1 mmol of glycine methyl ester hydrochloride salt were suspended in methylene chloride. To this suspension was added 102 mmol of N-hydroxybenzotriazole and the mixture was cooled with an ice-water bath. Triethylamine (214 mmol) was added, effecting a solution. At this time 1.1 equivalents of 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride was added. This mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 days. At this time, thin layer chromatography indicated the presence of 4-[3-(carboxymethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester. An additional 5.1 mmol each of glycine methyl ester hydrochloride salt and N-hydroxybenzotriazole as well as 10.3 mmol of triethylamine were added. The reaction mixture was stirred at room temperature for another 24 hour. At this time, the reaction mixture was diluted with methylene chloride, washed with water, with 10% (wt/vol) KHSO4 solution, with water again, with saturated sodium bicarbonate aqueous solution, with water again, and finally with brine. The methylene chloride solution was concentrated to dryness in vacuo, resulting in a dark brown oil. The oil was purified by flash column chromatography: the column was loaded with a methylene chloride solution, followed by elution with ethyl acetate:hexane (7:3), and then finally with ethyl acetate. In this manner, fractions were collected and concentrated in vacuo to provide 42.05 g (94.4%) of 4-[3-(methoxycarbonylmethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O.CCOC(C)=O>CCO>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccccc1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: NCCCCOc1ccccc1
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
A mixture of 2-(4-phenoxybutyl)1H-isoindole-1,3(2H)-dione (10.10 g, 3.27 mmol) and 25% hydrazine solution in water (2.88 ml, 13.10 mmol) in EtOH (30 ml) was warmed at reflux. After 1.5 h, EtOAc was added and the mixture was extracted with brine. The combined aqueous phases were then re-extracted with EtOAc and all the organic phases combined. These were then extracted with 1N HCl, the acidic aqueous phases combined, basified with 2N NaOH and re-extracted into EtOAc before evaporating to dryness to give the title compound (0.411 mg, 67%) as an oil. 1H NMR (500 MHz CDCl3): δ 7.32-2.26 (m, 2H), 6.95 (t, 1H), 4.00 (t, 2H), 2.80 (t, 2H), 1.90-1.82 (m, 2H), 1.68-1.62 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl>C(OCC)(=O)C.ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A 500 ml round bottom flask was loaded with 4-nitrobenzoyl chloride (10.2 g, 53.9 mmol) and dichloromethane (100 ml) and cooled to 0° C. Pyridine (10 ml, 124 mmol) was added, followed by tert-butyl piperazine-1-carboxylate (10.2 g, 54.8 mmol) (solid, in portions) while stirring at 0° C. After the addition was completed, the ice bath was removed and the reaction mixture stirred while allowing the reaction to warm to room temperature overnight. The mixture was poured into a separating funnel loaded with 250 ml ethyl acetate and 250 ml 1N aq. HCl. The layers were separated, the organic layer washed one more time with 1 M aq. HCl, then with sat. aq. NaHCO3 solution (2×), then brine (1×), then dried over MgSO4, filtered and concentrated in vacuum. 12.9 g tert-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate were isolated as a white solid. MS (ESI) m/z 280 (M+H—C4H8), 236 (M+H-BOC). 1H NMR (CDCl3) δ ppm 8.28 (d, 2H, J=8.6), 7.57 (d, 2H, J=8.6), 3.76 (bs, 2H), 3.53 (bs, 2H), 3.39 (bs, 2H), 3.33 (bs, 2H), 1.46 (s, 9H).
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])[CH3:3].[CH2:13]=O>[Cl-].[Zn+2].[Cl-]>[CH:2]([C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[CH2:13][Cl:1])([CH3:4])[CH3:3]
Reactant: Cl
Reactant: C=O
Reactant: COc1ccccc1C(C)C
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1ccc(CCl)cc1C(C)C
Temperature: 0 °C

Procedure:
Hydrochloric acid gas is bubbed into a mixture of 55 g of o-isopropylanisole, 35 g of formaline and 9 g of zinc chloride with ice cooling and stirring for hours. The reaction mixture is added to ice water and the mixture is extracted with ether to give 70 g of crude 3-isopropyl-4-methoxybenzyl chloride. Potassium cyanide (26 g) is added to 400 ml of acetonitrile, 100 mg of 18-crown 6 is added thereto, and the benzyl chloride compound obtained above is dropped thereinto with refluxing and stirring. After the dropping is completed, the mixture is heated to reflux for ten hours with stirring. The reaction solution is then concentrated in vacuo, water is added to the concentrate, and the mixture is extracted with ether. The resulting extract is purified by subjecting to a distillation in vacuo to give 40 g of 3-isopropyl-4-methoxybenzyl cyanide, boiling point under 1 mm Hg 120°-125° C.
Reaction SMILES: [Br-:1].[Br:2][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:25][NH:26][CH3:27]>C(O)C.O>[BrH:2].[Br-:1].[CH3:25][N:26]([CH3:27])[CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNC
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CCO
Product: Br
Product: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 82 %

Procedure:
To a suspension of 3-bromopropyltriphenylphosphonium bromide (1.0 g, 2.1 mmol) in ethanol (5 mL) was added a solution of 40% dimethylamine in water (3 mL) at room temperature. The mixture was stirred and heated at 100° C. for 30 min in a sealed microwave tube. After the reaction mixture was concentrated under reduced pressure, the solid residue was recrystallized in acetonitrile to afford (3-(dimethylamino)propyl)triphenylphosphonium bromide hydrobromide salt (0.90 g, 82%) as a white solid, and was used in the following step. ESI MS m/z 348.3 (Ph3PCH2CH2CH2NMe2)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.COC(=O)CN.[CH2:27]([N:29](CC)[CH2:30]C)C>CN(C=O)C>[CH3:27][N:29]([CH3:30])[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reactant: CCN(CC)CC
Agent: COC(=O)CN
Solvent: CN(C)C=O
Product: CN(C)c1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A mixture of compound 6 (40 mg, 0.1 mmol), glycine methyl ester (310 mg, 2.47 mmol), and triethylamine (0.7 mL, 5.0 mmol) in DMF (2 mL) was heated for 22 h at room temperature. After cooling, the mixture was evaporated to dryness and purified on a silica gel column (chloroform-methanol, 20:1) to give compound 12 (25 mg, 53.5%) as a colorless solid. 1H NMR (DMSO-d6) δ 3.06 (s, 6 H, N(CH3)2), 3.58 (s, 3 H, 9-CH3), 4.55 (br s, 2 H, CH2), 7.10 (pseudo t, J=8.0 and 7.6 Hz, 1 H, H-16), 7.38 (d, J=7.7 Hz, 1 H, H-17), 7.56 (d, J=8.0 Hz, 1 H, H-15), 7.70 (s, 1 H, H-13), 7.77 (s, 1 H, H-8), 7.92 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH:15]([OH:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:12])[F:13])=[N:9][CH:10]=1
Reactant: COCOc1cnc(C(F)(F)F)cc1C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1cnc(C(F)(F)F)cc1C(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 1-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)ethanol (3.2 g, 13 mmol) and NaHCO3 (3.2 g, 38 mmol) in DCM (100 ml) was added Dess Martin Periodinane (5.9 g, 14 mmol). The reaction mixture was stirred at rt in 16 h, the solid was filtered, the filtrate was concentrated, then taken up and stirred in ether/EtOAc. The precipitated white solids were filtered and discarded. The filtrate was concentrated to give the title compound as a light yellow oil. MS (m+1): 250.2.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:24])=[O:23])=[C:17]([NH:25][CH2:26][C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)[CH:16]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:35][C:36]([CH3:38])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C>[F:33][C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([F:34])[CH:30]=1)[CH2:26][NH:25][C:17]1[CH:16]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH:36]([CH3:38])[CH3:35])[CH2:3][CH2:2]3)=[CH:9][CH:10]=2)[N:20]=[CH:19][C:18]=1[CH2:21][C:22]([NH2:24])=[O:23]
Reactant: CC(C)=O
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCCNCC3)cc2)cc1NCc1cc(F)cc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)N1CCCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
60 mg of 6-{[4-(1,4-diazepan-1-yl)phenyl]amino}-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 227) was suspended in 1.5 mL of chloroform, to which 0.2 mL of acetone, 4.1 mg of acetic acid and 58 mg of sodium triacetoxyborohydride were added, and stirred at room temperature for 4 hours. To the reaction mixture, saturated sodium bicarbonate in water was added, extracted with chloroform, and the extract was dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=20:1), recrystallized from methanol-ether to obtain 37 mg (53%) of the title compound as a white crystalline powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N:37]([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:49]>C(Cl)Cl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:22]([CH2:23][OH:24])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:41]=[C:35]5[CH2:36][N+:37]([O-:49])([CH3:40])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:42])[N:27]([CH3:43])[N:26]=3)[CH:20]=[CH:19][N:18]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)cc2C1
Solvent: ClCCl
Solvent: CO
Product: Cn1nc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CC[N+](C)([O-])C3)c1=O
Reaction time: 18 h
Yield: 30.8 %

Procedure:
To a solution of 6-tert-butyl-8-fluoro-2-(3-(hydroxymethyl)-4-(1-methyl-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)phthalazin-1(2H)-one (500 mg, 854 μmol, 1 equiv.) in DCM (10 ml) was added 3-chlorobenzoperoxoic acid (191 mg, 854 μmol, 1 equiv.). The reaction mixture was stirred for 18 h. The reaction mixture was diluted with methylene chloride and washed with 1.0 N NaOH (aq). The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford a liquid that gradually hardened to a low melting, yellow solid under vacuum, overnight. The solid was dissolved in a minimum of methanol, diluted with methylene chloride and loaded onto a column. The crude material was purified by flash chromatography (silica gel, 40 g, 50% 60:10:1 DCM:MeOH:NH4 OH in DCM) to give 2-(6-(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H) -yl)-3-(hydroxymethyl)pyridin-4-yl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 5-oxide (158.5 mg, 263 μmol, 30.9% yield) as a yellow solid. (M+H)+=602 m/e. 1H NMR (300 MHz, METHANOL-d4) d ppm 1.47 (s, 9 H) 3.45 (s, 3 H) 3.74 (dt, J=12.46, 2.46 Hz, 1 H) 3.89 (s, 3 H) 4.07 (td, J=11.80, 4.72 Hz, 1 H) 4.25-4.43 (m, 1 H) 4.45-4.62 (m, 2 H) 4.61-4.85 (m, 3 H) 6.13 (s, 1 H) 7.54-7.79 (m, 2 H) 7.87 (d, J=1.51 Hz, 1 H) 8.07 (s, 1 H) 8.50 (d, J=2.64 Hz, 1 H) 8.66 (d, J=5.29 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:25]([CH:28]([CH3:30])C)=[C:26]=[O:27]>C(N(CC)CC)C>[C:26]([N:25]1[CH2:28][CH2:30][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[Cl:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:27])[CH2:8][CH2:7][CH3:16]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1Cl
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3Cl)c3ccccc23)CC1

Procedure:
The Title Compound was Prepared Following the General Procedure in Scheme 5, beginning with 4-(2-chloro-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.86 (s, 1H), 8.68 (d, 1H), 8.35 (d, 1H), 8.25 (d, 1H), 8.13 (d, 1H), 8.0 (m, 1H), 7.74 (m, 3H), 7.64 (m, 3H), 4.00 (d, 1H), 3.60 (d, 1H), 3.26 (m, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.17 (t, 2H), 1.46 (m, 2H), 1.43 (q, 2H), 1.17 (m, 1H), 0.82 (t, 3H); LC/MS m/z 512 (M−H)−, 514 (M+H)+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][C:14]([CH3:20])([CH2:17][C:18]#[CH:19])[CH2:15][OH:16]>N1CCCCC1.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>[CH3:13][C:14]([CH3:20])([CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1)[CH2:15][OH:16]
Reactant: C#CCC(C)(C)CO
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(C)(CO)CC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 1-iodo-4-trifluoromethoxy-benzene (3.56 g, 12 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol) and cuprous iodide (95 mg, 0.5 mmol) in piperidine (40 ml) was degassed (Ar) and stirred for 30 min at 50° C. under an argon atmosphere. 2,2-Dimethyl-pent-4-yn-1-ol (1.25 g, 10 mmol, 90% purity) [Magnus, Philip; Slater, Martin J.; Principe, Lawrence M. Journal of Organic Chemistry (1989), 54(21), 5148-5153] in piperidine (20 ml) was added within 60 min at 50° C. During the addition the oil bath temperature was slowly raised to 80° C. starting after 30 min. The mixture was stirred for 2 h at this temperature. The reaction mixture was cooled to ambient temperature, poured into a solution of aqueous 10% KHSO4/ice water 1/1 and extracted two times with ether. The combined extracts were washed with aqueous 10% KHSO4 and aqueous 10% NaCl and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt 2:1 to 1:1) to give 1.91 g (7 mmol, 70%) of the title compound as yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C([Li])CCC.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>O1CCCC1.CCCCCC>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CCCN1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCCC2=O)cc1
Temperature: -20 °C
Reaction time: 0.42 h
Yield: 50.5 %

Procedure:
1.65 g of 2-pyrrolidinone in solution in 75 cm3 of tetrahydrofuran is cooled to -5° C., and 12.1 cm3 of a 1.6M solution of n-butyllithium in hexane is added, maintaining the temperature between -5° C. and 0° C. Agitation is carried out for 25 minutes at -5° C.; the mixture is cooled to -20° C. and 4.5 g of 4-tert-butyl-phenylsulphonyl chloride is added [Recueil Trav. Chim. Pays-Bas, 53, 1101 (1934)]. After allowing to return to ambient temperature, the tetrahydrofuran is evaporated off under reduced pressure, the residue is taken up with water, filtered and crystallized from ethanol. 2.75 g of expected product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:26])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:12]([O:14][C:15]([C:17]1([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[Br:1])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(C)cc2Br)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of 2-bromo-4-methyl-benzoic acid (314 mg, 1.46 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (300 mg, 1.46 mmol), HATU (666 mg, 1.75 mmol) in anhydrous DMF (1.8 mL) is added DIPEA (381 μL, 2.19 mmol). The resulting solution is stirred at RT overnight. Poured reaction into water (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers and concentrated in vacuo. The residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0-30% EtOAc in heptane) to give product (276) as off-white solid (445 mg, 76%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a solution of 3,3,3-trifluoropropan-1-ol (5.0 g, 43.8 mmol) in CH2Cl2 (25 mL) and pyridine (25 mL) was added 4-(dimethylamino)pyridine (0.27 g, 2.2 mmol) followed by p-toluenesulfonyl chloride (8.4 g, 43.8 mmol). The mixture was allowed to stir at ambient temperature for 72 h then was quenched with 5% aqueous HCl (20 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×7 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (8.0 g, 29.8 mmol, 68% yield). MS (DCI/NH3) m/z 286 (M+NH4)+.