Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][N:7]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[C:8](=[O:34])[CH2:9][N:10]([C:12](=[O:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:22])=[C:16]([O:31][CH3:32])[CH:15]=1)[CH3:11])C.[OH-].[Na+]>C(O)C>[CH3:45][O:44][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=1[O:42][CH3:43])[CH2:35][N:7]([C:8](=[O:34])[CH2:9][N:10]([C:12](=[O:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:22])=[C:16]([O:31][CH3:32])[CH:15]=1)[CH3:11])[CH2:6][CH2:5][C:4]([OH:46])=[O:3]
Reactant: CCOC(=O)CCN(Cc1ccc(OC)c(OC)c1)C(=O)CN(C)C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CC(=O)N(C)CC(=O)N(CCC(=O)O)Cc2ccc(OC)c(OC)c2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-{(3,4-dimethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid ethyl ester [2.0 g, Reference Example 4(a)] in ethanol (50 ml) was treated with sodium hydroxide (3.5 ml, 1M). After stirring at room temperature for 3 hours the mixture was concentrated to dryness. The residue was dissolved in water (12 ml) and the pH of the solution was adjusted to 1.0 by addition of concentrated hydrochloric acid (0.25 ml) and then extracted three times with dicliloromethiane. The resultant solid was collected and recrystallised twice from 20% aqueous isopropanol to give 3-{(3,4-dimethoxy-benzyl)-[({[3-methoxy-4-(3-o-tolylureido)phenyl]-acetyl}-N-methylamino)-acetyl]-amino}-propionic acid (Compound C) as a white solid (0.25 g,), m.p. 183-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[CH3:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2([OH:63])[CH2:62][CH2:61][NH:60][CH2:59]2)=[N:56][CH:57]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:60]3[CH2:61][CH2:62][C:58]([C:55]4[CH:54]=[CH:53][C:52]([CH3:51])=[CH:57][N:56]=4)([OH:63])[CH2:59]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1ccc(C2(O)CCNC2)nc1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(C)cn3)C2)cc1Cl
Yield: 54.4 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(5-methylpyridin-2-yl)pyrrolidin-3-ol dihydrochloride (10 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z: calcd for C21H20ClN3O4: 413.1142, found 413.1143.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][S-:25].[Na+]>O1CCOCC1>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[C:5]([N+:16]([O-:18])=[O:17])=[C:6]([S:25][CH3:24])[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]
Yield: 45.9 %

Procedure:
A stirred solution of 335 mg (0.95 mmol) trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 663 mg (9.46 mmol) sodium methanethiolate in 20 ml dry dioxane under argon was heated at reflux for one hour. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate) followed by recrystallisation from ether/hexane afforded 110 mg (46%) 4-furan-2-yl-6-methylsulfanyl-5-nitro-pyrimidin-2-ylamine as a yellow crystalline solid. EI-MS ni/e (%): 252 (M+, 22), 235 (26), 223 (66), 207 (100), 178 (86), 161 (44), 134 (62), 94 (90).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1.C([Mg]Br)CC=C>CN1C(=O)CCC1>[CH2:20]([C:4]1[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH2:19][CH:18]=[CH2:22]
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: C1CCOC1
Agent: C=CCC[Mg]Br
Solvent: CN1CCCC1=O
Product: C=CCCc1nc(Cl)nc2c1CCC2c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
A 250 mL three-neck round bottom flask equipped with a refluxed condenser and nitrogen inlet was charged with 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2 g, 7.54 mmol), Fe(acac)2 (0.400 g, 1.131 mmol), THF (84 mL) and NMP (6.4 mL). The resulting solution was cooled to −78° C. and but-3-enyl magnesium bromide was added (20 mL) dropwise over twenty min. During the addition, the color of the reaction mixture changed from deep red to brown. After stirring for 1 h at −78° C., another 20 mL of but-3-enyl magnesium bromide was added and stirred for further 1 h. The reaction mixture was allowed to warm to 0° C. and quenched with saturated ammonium chloride solution (250 mL). It was then extracted with MTBE (2×200 mL), washed with brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to get a crude brown oil. It was purified by a Teledyne Isco instrument using a 40 g silica column and 4-7% ethyl acetate in pet ether to get 4-(but-3-enyl)-2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.1 g, 51.2%). LC-MS (M+H)+=285.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.24 (3H, m), 7.14-7.12 (2H, m), 5.89-5.83 (1H, m), 5.09-5.00 (2H, m), 4.37 (1H, t, J=7.2 Hz), 3.04-3.01 (1H, m), 2.94-2.92 (1H, m), 2.85-2.81 (2H, m), 2.71-2.66 (1H, m), 2.55-2.51 (2H, m), 2.23-2.19 (1H, m).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:34]4[CH2:35][CH2:36][CH2:37][N:31]([CH3:30])[CH2:32][CH2:33]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: CN1CCCNCC1
Product: CN1CCCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-(4-methyl-[1,4]-diazepan-1-yl)-nicotinamide was prepared starting from intermediate E and N-methylhomopiperazine. MS calcd. for C28H28ClN5O2 [(M+H)+] 502.2, obsd. 502.0.
Reaction SMILES: C(OC([N:8]([CH:46]1[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[C:25]([CH3:38])=[N:26][N:27]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=5)[C:28]=4[CH3:29])=[CH:22][N:21](C(OC(C)(C)C)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>CO.CCOCC.Cl>[F:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:23]2[C:17]3[C:18](=[N:19][CH:20]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([NH:8][CH:46]5[CH2:47][CH2:48][NH:49][CH2:50][CH2:51]5)=[CH:14][CH:13]=4)[CH:16]=3)[NH:21][CH:22]=2)[C:25]([CH3:38])=[N:26]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2ncc(-c3ccc(N(C(=O)OC(C)(C)C)C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(NC4CCNCC4)cc3)cc12
Yield: 20.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(4-((tert-butoxycarbonyl)(1-(tert-butoxycarbonyl)piperidin-4-yl)amino)phenyl)-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (25 mg, 0.050 mmol) was deprotected in methanol/ether HCl (3/2 ml). This afforded 5 mg (31.2% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.70 (s, 1H), 8.59 (s, 1H), 7.80 (s, 1H), 7.72-7.70 (d, 2H), 7.46-7.40 (m, 1H), 7.02-7.18 (d, 2H), 7.12-7.09 (m, 2H), 7.02-7.00 (d, 1H), 5.51 (s, 2H), 3.85-3.80 (m, 1H), 3.52-3.47 (d, 2H), 3.20-3.10 (t, 2H), 2.33-2.13 (m, 8H), 2.13-1.83 (m, 2H). MS: m/z=494.9 (M+1), HPLC: 95.22% in method B.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]/[CH:10]=[CH:11]/[CH2:12][N+:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C>[Cl-:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][N+:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:7][CH:8]=1
Reactant: CCCCCCC[N+](CC)(CC)C/C=C/Cc1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCCCCCC[N+](CC)(CC)CCCCc1ccc(Cl)cc1

Procedure:
Add 2.1 g (5.6 mmole) of (E)-4-(4-chlorophenyl)-N,N-diethyl-N-heptyl-2-buten-1-aminium chloride to a suspension of 0.11 g catalyst (rhodium (5%) on carbon) in 100 ml glacial acetic acid and stir under 1 atmosphere hydrogen for 19 hours at room temperature. Filter through celite and then wash celite with 100 ml H2O. Combine filtrates and extract into 4×100 ml methylene chloride. Wash methylene chloride extracts with 1×100 ml 1N HCl, 2×250 ml saturated aqueous sodium bicarbonate and 200 ml saturated aqueous sodium chloride. Dry methylene chloride over sodium sulfate, filter and evaporate solvent to provide 4-chloro-N,N-diethyl-N-heptylbenzenebutanaminium chloride. Dissolve product in 75 ml H2O/MeOH (50:50) and pour onto column containing 6 g anion exchange resin (hydroxide form BIO-RAD AG-1-X8). Elute sample through column with distilled water and collect eluate having pH≥9. Wash this aqueous solution with 2×150 ml methylene chloride. Titrate sample to pH= 5.0 with 10% phosphoric acid and to pH=4.5 with 0.1N phosphoric acid. Evaporate to provide 1.25 (51%) of title compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:28]I>C(OCC)C>[CH3:28][O:3][CH:4]([C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(O)c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCC(OC)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of sodium hydride (0.5 g) in ethyl ether at 0° C. is added 2-[3-(1-hydroxyhexyl)phenoxymethyl]quinoline (1.8 g) in ether. The mixture is allowed to warm to room temperature. Methyl iodide (0.6 ml) is added and the reaction is stirred at room temperature for three days. The reaction mixture is quenched with saturated aqueous ammonium chloride and extracted with ethyl ether. The organic extract is washed with water, dried (MgSO4) and concentrated to an oil, which is purified by HPLC on silica gel using a 1:9 ratio of ethyl acetate/hexane as an eluent.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:25]([N:27]1[CH2:38][CH2:37][CH2:36][C@H:28]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)C1C=CC=CC=1.N1CCC[C@H]1C(OC(C)(C)C)=O>[OH-].[OH-].[Pd+2].C(OCC)(=O)C.C(O)C>[CH3:23][C:21]([CH3:24])([O:20][C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:25]([N:27]1[CH2:38][CH2:37][CH2:36][C@H:28]1[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[O:26])[NH2:11])=[O:19])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
A mixture of the 1,1-dimethylethyl ester product from part (a) (4.13 g., 7.73 mmole) and palladium hydroxide/carbon catalyst (400 mg.) in ethyl acetate (90 ml.) and ethanol (10 ml.) is stirred under a hydrogen atmosphere (balloon). The system is evacuated and refilled with fresh hydrogen every 30 minutes. After stirring for 3 hours, the catalyst is removed by filtration (Teflon millipore) and the filtrate is concentrated at reduced pressure to give 3.15 g. of 1-[N6 -](1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@@H:16]2[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>O1CCOCC1>[ClH:29].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@@H:16]2[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@@H](F)C1
Agent: Cl
Solvent: C1COCCO1
Product: F[C@H]1CNCC[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (0.12 g, 0.31 mmol, E-2 from step E) in 1,4-dioxane (3 mL) was added a 4 M HCl in dioxane solution (2 mL, 8 mmol) and the reaction mixture was stirred at rt overnight. The solvent was then evaporated and the solid was triturated with ethyl acetate and dried to afford E-2a (3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine hydrochloride (0.09 g, 83% yield) as an off-white solid. LCMS (method O) RT: 0.95 min m/z 286 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 1.92-1.92 (m, 1H), 2.29-2.33 (m, 1H), 3.04-3.14 (m, 3H), 3.45-3.60 (m, 2H), 4.83-4.95 (m, 1H), 5.10 (s, 2H), 7.01-7.04 (m, 2H), 7.25-7.31 (m, 2H), 7.32-7.46 (m, 5H), 9.09 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].C([O-])(O)=O.[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1>C1COCC1.CCO>[Cl:17][C:18]1[N:23]=[C:22]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9](=[O:11])[CH3:10])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: CC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reaction time: 96 h

Procedure:
1-(2-Amino-phenyl)-ethanone hydrochloride (1.72 g, 1.0 mmol) and NaHCO3 (3.4 g, 4 mmol) were slurried in a mixture of THF (4 mL) and EtOH (16 mL) prior to adding 2,4,5-trichloropyrimidine (1.84 g, 1.0 mmol). The reaction was stirred for 4 days, filtered and washed with water (10×10 mL) to afford -[2-(2,5-dichloro-pyrimidin-4-ylamino)-phenyl]-ethanone as a white solid that was used without further purification in the subsequent step.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:35]([NH2:37])=[O:36])[CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[C:23]([C:35]([NH2:37])=[O:36])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:16]2[CH2:17][CH2:18][N:13]([S:10]([CH2:9][CH2:8][CH2:7][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)(=[O:12])=[O:11])[CH2:14][CH2:15]2)=[CH:29][CH:30]=1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Product: NC(=O)c1cc(-c2ccc(F)cc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Yield: 22.8 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(4-fluorophenyl)-1H-indole-7-carboxamide (0.059 mmol) and pyrrolidine (0.025 mL, 0.295 mmol) were allowed to react in the presence of K2CO3 (37 mg, 0.118 mmol) and NaI (Cat. 2 mg). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (6.9 mg, 23%).
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].O=S(=O)=O.[F:10][C:11]([F:18])([F:17])[C:12]([F:16])=[C:13]([F:15])[F:14]>>[C:12]1([F:16])([C:11]([F:18])([F:17])[F:10])[S:2](=[O:5])(=[O:3])[O:1][C:13]1([F:15])[F:14]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=S1(=O)OC(F)(F)C1(F)C(F)(F)F
Temperature: -45 °C
Reaction time: 0.15 h
Yield: 66 %

Procedure:
A 100 mL Parr™ reactor was charged with 63.8 g of 65% oleum (0.52 mole SO3), cooled to -45° C., evacuated, and then charged with 62 grams (0.44 mole) liquid hexafluoropropene from a cold trap (-78° C.). The reaction mixture was allowed to warm to room temperature. At 20° C. a slight exotherm was observed which increased to a maximum temperature of 56° C. and a pressure of 965 kPa over a 9 minute period. Following the exotherm the reactor was held at 42° C. for 6 hours while the mixture was agitated. The reactor was then vented of excess HFP (with the recovery of 0.7 g HFP) and the contents of the reactor were decanted to yield 103.8 grams (g) of a two phase reaction product. The upper layer (90.6 g) was separated from the lower layer, washed with concentrated sulfuric acid to remove residual SO3 and then distilled to give 63.3 grams of HFP suitone (66% yield with respect to the consumed olefln) with boiling point (b.p.) 45°-50° C. NMR analysis of a higher boiling fraction (b.p. 50°-167° C., yield 25 g) revealed a mixture oftetrafluoropropionic acid derivatives and fluorosulfonic acid. A small portion of this fraction was refluxed in methanol for one hour to give tetrafluoropropionic acid methyl ester (yield 12% based on hexafluoropropene consumed). HFP sultone, after heating with concentrated sulfuric acid for 17 hours at 40° C., was recovered by distillation with 95% yield.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][N:6]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[C:9]([C:15]([NH:17][NH2:18])=[O:16])[CH:8]=[N:7]1>O.Cl>[CH3:5][N:6]1[C:10]([S:11]([NH2:12])(=[O:13])=[O:14])=[C:9]([C:15]([N:17]=[N+:18]=[N-:1])=[O:16])[CH:8]=[N:7]1
Reactant: O=N[O-]
Reactant: Cn1ncc(C(=O)NN)c1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1ncc(C(=O)N=[N+]=[N-])c1S(N)(=O)=O
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A solution of sodium nitrite (0.19 g) in 5 ml of water was added dropwise to a stirred solution of 1-methyl-5-sulfamoylpyrazole-4-carbohydrazide (0.55 g) in 8 ml of 1M hydrochloric acid at 0° C. The resulting mixture was stirred for 15 min and then filtered. The filter cake was washed with water and dried in vacuum to give 0.29 g (47%) of the title compound as a crystalline solid. The product was pure according to TLC (ethyl acetate) and was used immediately for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:18]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:27])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=3[S:8](=[O:27])[C:7]=2[CH:18]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)Sc1ccc(F)cc1C=C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)c1ccc(F)cc1C=C2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 1.7 gm. of 3-cyano-8-fluorodibenzo[b,f]thiepine in 90 ml. of methylene chloride and add 1.36 gm. of 85% m-chloroperbenzoic acid. Stir the mixture at room temperature for 90 minutes. Add 4 gm. of calcium hydroxide over 15 minutes. Filter and strip the filtrate to dryness. Triturate the residue in 30 ml. of ether for 2 hours. Separate the solids by filtration to obtain the title product. (mp. 240°-243° C.).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][SH:5].Br[CH2:10][CH2:11][CH2:12][CH3:13]>>[CH3:10][CH2:11][CH2:12][CH2:13][S:5][CH2:4][CH2:3][C@H:2]([NH2:1])[C:6]([OH:8])=[O:7]
Reactant: N[C@@H](CCS)C(=O)O
Reactant: CCCCBr
Product: CCCCSCC[C@H](N)C(=O)O

Procedure:
L-buthionine-SR-sulfoximine is prepared as described in Griffith, O. W., The Journal of Biological Chemistry, Vol. 257, No. 22, pp. 13704-13712, 1982. Such preparation is as follows: L-methionine, obtained commercially, is reductively demethylated using sodium in liquid ammonia to produce L-homocysteine. The L-homocysteine is alkylated with 1-bromobutane to form L-buthionine. The L-buthionine is converted to L-buthionine-SR-sulfoximine by reaction with sodium azide in chloroform/sulfuric acid. The L-buthionine-SR-sulfoximine product is isolated by chromatography on Dowex 50(H+) resin. L-buthionine-SR-sulfoximine. 6 gms, containing approximately equal amounts of the two diastereomers was dissolved in 34 ml of hot water (boiling water bath) to a final concentration of 0.8M. The solution was allowed to cool; crystallization occurred spontaneously. After standing overnight at 4° C., the crystals were collected by filtration. The filtrate was evaporated to dryness under reduced pressure. The solid (4.1 gms) was suspended in 50 ml of absolute ethanol, and 5 ml of trifluoroacetic acid was added dropwise. Hexane, 50 ml, was slowly added over a period of about 10 minutes to the stirred, clear solution. Stirring was then stopped, and crystallization was allowed to occur at room temperature. After 2 hours, the crystals were collected by filtration, washed with hexane and ether, and dried under vacuum. The yield was 2.8 gms. The crystals, 2.8 gms, are added to 35 ml of ethanol with stirring to form a solution. To this solution is added with stirring 3.5 ml of trifluoroacetic acid, followed by 35 ml of hexane (added slowly over a 10 minute period). Then stirring is stopped and crystallization is allowed to occur at room temperature. After 2 hours the crystals are collected by filtration, washed with hexane and ether, and dried under vacuum. The yield is 1.6 gms. The crystals consist of L-buthionine-S-sulfoximine trifluoroacetic acid addition salt (of greater than 99% purity). The yield is about 50% based on the initial L-buthionine-S-sulfoximine content of the starting material. The acid addition salt is converted to pure free zwitterion by dissolving in water, 20 ml, applying the resulting solution to a column of Dowex 50 (H+), 1.5×20 cm, then washing with water to elute trifluoroacetic acid leaving L-buthionine-S-sulfoximine bound to the resin. The resin is washed with 1 liter of 3M ammonium hydroxide, and the eluent collected in 10 ml fractions. The fractions containing amino acid are pooled, evaporated to dryness at reduced pressure and traces of ammonia are removed by treating with water and evaporating.