Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35]C=[C:33]([C:37](F)([F:39])F)[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(Cl)(Cl)[Cl:98]>>[Cl:98][C:2]1[S:6][C:5]([C:7]([NH:16][C@@H:17]([CH2:30][C:31]2[CH:36]=[CH:35][C:37]([F:39])=[CH:33][CH:32]=2)[CH2:18][N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (201 mg, 0.91 mmol) [prepared according to the procedure of Example 95], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (301 mg, 0.87 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (519 mg, 1.11 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (186 mg, 32%): LC-MS (ES) m/z=553 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:23]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.C(N)(C)C.[CH3:52][C:53]([OH:57])([C:55]#[CH:56])[CH3:54]>>[OH:57][C:53]([CH3:54])([CH3:52])[C:55]#[C:56][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:23]=1
Reactant: C#CC(C)(C)O
Reactant: CC(C)NCc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Solvent: CC(C)N
Product: CC(C)NCc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 39 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((isopropylamino)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with isopropylamine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a brown solid (16 mg, 39%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][C:11]2[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:16]=2)=[C:4]([OH:25])[CH:3]=1.[OH2:26].[CH3:27]C1C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:27][O:26][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([CH2:10][C:11]3[NH:12][C:13](=[O:23])[CH:14]=[C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[N:16]=3)[O:25][C:4]=2[CH:3]=1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1O
Solvent: Cc1ccccc1C
Product: COc1ccc2nc(Cc3nc(N4CCOCC4)cc(=O)[nH]3)oc2c1
Temperature: 20 °C
Yield: 78.9 %

Procedure:
500 mg of the N-(4-fluoro-2-hydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are mixed into 40 ml of xylene, and 155 mg of 4-methylbenzenesulphonic acid hydrate are added. The reaction mixture is brought to reflux for 3 hours. After cooling to 20° C., the reaction mixture is concentrated to dryness under reduced pressure and then the residue is chromatographed on a silica gel column, eluent: CH2Cl2/MeOH: 95/05. 220 mg of 2-[(6-methoxy-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[N:28]=[C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[S:30][CH:31]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[S:30][CH:31]=[C:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[F:20])[N:28]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4F)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 45.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (273 mg, 0.835 mmol), 1-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (153 mg, 45.8%) as a solid.
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[C:10](=O)([O-])[O-].[K+].[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.CI>C(#N)C>[CH3:10][O:6][C:5]1[C:4](=[O:9])[CH:3]=[CH:2][CH:1]=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cccccc1O
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cccccc1=O
Yield: 91.8 %

Procedure:
To the mixture of 20 g (0.16 mol) of tropolone (2-hydroxy-2,4,6-cycloheptatrienone), 68 g (0.48 mol) of anhydrous potassium carbonate, 6.1 g (0.016 mol) of dicyclohexyl-18-crown-6 and 750 ml of acetonitrile were added 117 g (0.8 mol) of methyl iodide with stirring. After stirred under reflux for 10 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. After washing with 13.8% aqueous solution of potassium carbonate and water. After drying with magnesium sulfate anhydrous, dichloromethane was evaporated under reduced pressure, and the residue was subjected to purification by means of silica gel column chromatography. Elution was carried out by using ethyl acetate and the solvent was evaporated under reduced pressure to give 20 g of 2-methoxytropone (2-methoxy-2,4,6-cycloheptatrienone) (yield: 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:53][CH2:54][CH:55]([OH:67])[CH2:56][N:57]1[CH2:66][CH2:65][C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58]1>C(Cl)Cl>[CH2:58]1[C:59]2[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:65][CH2:66][N:57]1[CH2:56][CH:55]([OH:67])[CH2:54][NH:53][C:19]([C:18]1[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=1)[CH2:15][N:8]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)O)c1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To a solution of 3-(((tert-butoxycarbonyl)(tetrahydro-2H-pyran-4-yl)amino)methyl)benzoic acid (300 mg, 0.89 mmol) in DCM (8 mL) was added EDCI (257 mg, 1.34 mmol), HOBt (181 mg, 1.34 mmol), Et3N (270 mg, 2.67 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (183 mg, 0.89 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated to give the title product (350 mg, Yield 65%). LCMS (m/z): 524.3 (M+1).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][C:20]=4[F:33])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][N:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[F:33][C:20]1[CH:21]=[C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([OH:4])[CH2:6][CH2:7]2)[C:12]2[N:13]([N:37]=[CH:38][N:39]=2)[C:14]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@@H](O)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1 g), 6N hydrochloric acid (10 mL) and tetrahydrofuran (15 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 mL), sodium borohydride (0.11 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.085 g, 9%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH3:38][I:39]>C1(C)C=CC=CC=1.CCOCC>[I-:39].[CH3:1][CH:2]1[N:6]([CH3:38])[CH:5]=[CH:4][NH+:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:37])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:20][CH:21]=2)=[CH:11][CH:12]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccc(-n3ccnc3C)cc2)cc1
Reactant: CI
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccc([NH+]3C=CN(C)C3C)cc2)cc1
Product: [I-]
Yield: 93.3 %

Procedure:
A mixture of 1.5 g of N-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-4-(tetradecyloxy)benzeneacetamide and 2.11 g of methyl iodide in 25 ml of toluene is refluxed under argon for 2 hours, cooled, diluted with ether and the solid collected. The cake is dried to give 1.8 g of the desired product as a white solid, m.p. 140°-143° C.
Reaction SMILES: N1C=CC=CC=1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[Cl:24][C:25]1[CH:26]=[C:27]([NH:32]C2C=CC=CC=2)[CH:28]=[C:29]([Cl:31])[CH:30]=1.CC(C)N=C=NC(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[C:27]([NH:32][C:21]([C:14]2([C:11]3[CH:10]=[CH:9][C:8]([I:7])=[CH:13][CH:12]=3)[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[O:23])[CH:28]=[C:29]([Cl:31])[CH:30]=1
Reactant: CN1CCC(C(=O)O)(c2ccc(I)cc2)CC1
Reactant: Clc1cc(Cl)cc(Nc2ccccc2)c1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)Nc2cc(Cl)cc(Cl)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
To a solution of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid pyridine salt (440 mg, 1.04 mmol, see Example 6) and 3,5-dichlorophenylaniline (0.20 g, 1.24 mmol, 1.2 eq.) in anhydrous DMF (5 mL) was added DIC (0.326 mL, 2.08 mmol, 2 eq.) followed by DMAP (0.006 g, 0.052 mmol, 5 mol %). The mixture was stirred at room temperature for 16 h and then it was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was separated, washed with H2O (3×40 mL) and saturated brine (50 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude material was purified by silica gel chromatography by eluting with 10% MeOH/EtOAc to give 175 mg (34%) of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid (3,5-dichloro-phenyl)-amide as a white solid. MS(ESI): 489.1/491.1.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][C@@H:7]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)C.[OH-].[K+]>C(O)C.C(O)CO.O>[CH2:29]([O:28][C:14]1[CH:15]=[C:16]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:18][C:13]=1[C@H:7]1[CH2:8][C@@H:9]([OH:12])[CH2:10][CH2:11][NH:6]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2C(=O)OCC)c(OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Solvent: CCO
Product: CCCCCCC(C)(C)c1ccc([C@H]2C[C@@H](O)CCN2)c(OCc2ccccc2)c1
Temperature: 185 °C
Yield: 79.7 %

Procedure:
To a solution of 4.62 g (9.59 mmole) of N-ethoxycarbonyl-cis-2-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidinol in 5 ml ethanol is added a solution of 4.2 g (75 mmole) of potassium hydroxide in 25 ml ethylene glycol and 4.2 ml water. The resultant mixture is evaporated at reduced pressure to remove ethanol and is then heated to reflux (bath 185° C.). After 24 hours material boiling at 80°-100° C. is removed by distillation, 6 ml ethylene glycol is added and the reaction continued at reflux for 17 hours. After cooling, the mixture is added to 500 ml dichloromethane and 80 ml water. The organic extract is washed with 80 ml saturated sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting crude oil is purified via column chromatography on 300 g of silica gel eluting in 20 ml fractions with 2.5% triethylamine, 2.5% methanol, 95% ethyl ether (fractions 1-109) and 5% triethylamine, 5% methanol, 90% ethyl ether (fractions 110-200). Fractions 138-190 gave 3.13 g (83%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](OC)[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[C:4]([NH2:18])[C:3]=1[NH2:19].[CH3:20][C:21](=O)[C:22](=O)[CH3:23].C[CH2:27][OH:28]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]2[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[C:14]([O:28][CH3:27])[CH:15]=2)=[C:4]2[C:3]=1[N:19]=[C:22]([CH3:23])[C:21]([CH3:20])=[N:18]2
Reactant: CCO
Reactant: CC(=O)C(C)=O
Reactant: COc1cccc(-c2c(OC)cc(Br)c(N)c2N)c1
Product: COc1cc(OC)cc(-c2ccc(Br)c3nc(C)c(C)nc23)c1

Procedure:
A mixture of 4-bromo-3′,6-dimethoxy-biphenyl-2,3-diamine (Step 85.7) (3 g, 9.3 mmol) and 2,3-butanedione (1 mL, 11.1 mmol, 1.2 equiv) in EtOH (60 mL) was stirred at reflux for 2 h, allowed to cool to it and stirred for 16 h. Additional 2,3-butanedione (0.4 ml) was added. The reaction mixture was stirred at reflux for 2 h, allowed to cool and concentrated to half of the initial volume. The resulting yellow precipitate was collected vacuum filtration providing 2.9 g of the title compound: ES-MS: 373.1/375.0 [M+H]+; tR=5.60 min (System 1).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CC(C)([O-])C.[K+].F[C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].Cl>C1COCC1.O>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH3:8]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C#N)c1cc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 107.2 %

Procedure:
To an ice-cold solution of ethyl cyanoacetate (10.9 mL, 102.4 mmol) in anhydrous THF (170 mL) under N2 is added of potassium tert-butoxide (12.07 g, 107.5 mmol). The formed white suspension is stirred for 15 min then treated with 3-fluoro-4-nitroanisole [Halfpenny, P. R.; Horwell, D. C.; Hughes, J.; Hunter, J. C.; Rees, D. C. J. Med. Chem. (1990), 33, 286-91] (8.86 g, 51.2 mmol). The suspension is heated at reflux for 1.5 h. The solution is poured into H2O, and the aqueous mixture is acidified to pH 2 with concentrated HCl. The mixture is extracted three times with ether then the combined organic phases are dried (MgSO4) and concentrated to an oil that is pumped at 0.3 mm for 2 days. The oil is dissolved in dichloromethane and purified by flash silica gel chromatography eluting with dichloromethane. The product fractions are combined and concentrated to leave cyano-(5-methoxy-2-nitrophenyl)acetic acid ethyl ester (14.5 g) as a light yellow oil that is about 93-95% pure. 1H NMR (CDCl3): δ8.29 (1H, d, J=9.2 Hz), 7.22 (1H, d, J=2.7 Hz), 7.04 (1H, dd, J=9.2, 2.7 Hz), 5.69 (1H, s), 4.31 (2H, q, J=7.0 Hz), 1.34 (3H, t, J=7.2 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.[NH:37]1[CH:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[N:38]1>ClCCl>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]3[CH2:19][CH2:20][N:21]([C:42]([C:40]4[CH:41]=[N:37][NH:38][CH:39]=4)=[O:43])[CH2:22][CH2:23]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cn[nH]c1
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)CC3CCNCC3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)CC3CCN(C(=O)c4cn[nH]c4)CC3)ccc21
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of N,N-dimethyl-2-(2-neopentyl-5-(piperidin-4-ylmethylsulfonyl)-1H-benzo[d]imidazol-1-yl) ethanamine (STEP C, 687 mg, 1.63 mmol) in dichloromethane (8 mL) were added triethylamine (230 microL, 1.63 mmol), 1H-pyrazole-4-carboxylic acid (201 mg, 1.80 mmol) and O-benzo-triazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (638 mg, 1,68 mmol) at room temperature. After 2 h, the mixture was diluted with dichloromethane (80 mL) and washed with sodium bicarbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by amine gel column chromatography (ethyl acetate-methanol, gradient) to give the title compound (757 mg, 90%) as a pale yellow grease.
Reaction SMILES: [F:1][C:2]([F:18])([S:15]([O-:17])=[O:16])[C:3]([F:14])([F:13])[C:4]([F:12])([F:11])[C:5]([F:10])([F:9])[S:6]([O-:8])=[O:7].[Na+].[Na+].OO.[OH-:23].[Na+].C(O)(=[O:27])C>>[F:9][C:5]([F:10])([S:6]([OH:27])(=[O:8])=[O:7])[C:4]([F:11])([F:12])[C:3]([F:13])([F:14])[C:2]([F:1])([F:18])[S:15]([OH:17])(=[O:16])=[O:23]
Reactant: [OH-]
Reactant: CC(=O)O
Reactant: O=S([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)[O-]
Agent: OO
Agent: [Na+]
Product: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)O

Procedure:
To a mixture of 25 mL of acetonitrile and 15 mL of water were added 8.44 g (18.6 mmol) of diiodoperfluorobutane, 8.50 g (48.8 mmol) of sodium hydrosulfite, and 4.60 g (55 mmol) of sodium hydrogen carbonate. The resultant mixture was stirred at room temperature for 1 hour. This reaction mixture solution was filtered and the filtrate was cooled with ice. As a result, a white solid precipitated. This precipitate was taken out by filtration and dried to obtain sodium perfluorobutane-1,4-disulfinate in an amount of 6.8 g (98%). Subsequently, 7.2 g (19.2 mmol) of the sodium perfluorobutane-1,4-disulfinate was added to a mixture of 80 mL of aqueous hydrogen peroxide solution (30%) and 8 mL of acetic acid, and the resultant mixture was stirred at 60° C. for 4 hours. A reaction proceeded stoichiometrically. After completion of the reaction was ascertained by 19F-NMR spectroscopy, the reaction mixture was neutralized by adding 30 mL of 1-N NaOH solution thereto. Thus, an aqueous solution of perfluorobutane-1,4-disulfonic acid ((I)-44) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1)([O-:28])=[O:27]>C1(C)C=CC=CC=1>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:36]2)=[CH:33][CH:34]=1)([O-:28])=[O:27]
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (75 g), triethylamine (37.5 cc) and 4-(4-nitrophenyl)piperazine (55.3 cc) in toluene (600 cc). The mixture is heated for 10 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate as eluant (80-20 vol), and recrystallization from boiling methyl ethyl ketone (1100 cc), 2-{3-[4-(4-nitrophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide(41.8 g) is obtained, m.p. 186° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:17]C)(=O)[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].[C:19](=[S:21])=S.ClC(OCC)=O.[C:28]1([NH:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:10]1([CH:8]2[O:9][C:19](=[S:21])[N:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:7]2=[O:17])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: S=C=S
Reactant: NNc1ccccc1
Reactant: COC(=O)C(O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(c2ccccc2)OC(=S)N1Nc1ccccc1
Temperature: -30 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of potassium tert.-butoxide (11.22 g, 0.1 mole) in tetrahydrofuran (100 ml), held at 0° C. to -5° C., was treated portionwise with a solution of methyl mandelate (16.62 g, 0.1 mole) in tetrahydrofuran (70 ml), providing an orange-red solution. After 4 minutes carbon disulfide (6.04 ml, 0.1 mole) was added. After 5 minutes at 0° C. to -5° C., the orange solution was cooled to -30° C. and treated with ethyl chloroformate (9.5 ml, 0.1 mole). After 2 minutes the solution was warmed to -10° C. After 5 minutes at -10° C., the solution was cooled to -30° C. and treated with 97% phenylhydrazine (10.1 ml, 0.1 mole). The yellow solution was warmed to 25° C., and after 10 minutes the mixture was evaporated under reduced pressure to a turbid oil. The oil was mixed with water and 1-chlorobutane, the layers were separated, and the organic solution was washed with 1N HCl, water (twice), and saturated sodium bicarbonate solution. The dried (magnesium sulfate) solution was evaporated under reduced pressure to a yellow-orange oil, and the oil was dissolved in chloroform. A silica-gel filtration of the chloroform solution followed by evaporation of the filtrate under reduced pressure provided a green oil which began to solidify. Further purification was accomplished by crystallization from 1-chlorobutane. This procedure provided the product as 9.9 g (35% of theoretical) of a white solid, m.p. 140°-141° C. The infrared spectrum (Nujol mull) showed the characteristic absorption at 3295 cm-1 (N-H) and 1760 cm-1 (imide C=O).