Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.[CH:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:30])[CH3:29]>>[CH:28]([N:31]1[CH2:36][CH2:35][N:34]([C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]4[CH:25]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:27])([F:1])[F:26])[N:5]=[CH:6][N:7]=5)[N:10]=[C:11]4[C:17]=3[CH:18]=2)=[O:23])[CH2:33][CH2:32]1)([CH3:30])[CH3:29]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)-c2nc(-c4ncnn4CC(F)(F)F)cn2CCO3)CC1

Procedure:
Following the procedure for 109, 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 1-isopropylpiperazine gave 120. MS: (ESI+)=490.2. 1H NMR (400 MHz, DMSO) δ 8.38 (d, J=2.0 Hz, 1H), 8.10 (d, J=5.4 Hz, 2H), 7.37 (dd, J=8.4, 2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 5.87 (q, J=8.8 Hz, 2H), 4.57 (s, 4H), 3.49 (s, 4H), 2.68 (dt, J=13.0, 6.6 Hz, 1H), 2.45 (s, 4H), 0.97 (d, J=6.5 Hz, 6H)
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:1]
Reactant: CCCOc1cc(C(N)=O)cc(C(=O)OC)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOc1cc(C#N)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
A suspension of methyl 3-(aminocarbonyl)-5-propoxybenzoate (2.0 g, 8.2 mmol) in a dichloromethane (25 mL) at 0° C. was treated with pyridine (1.3 mL, 17 mmol) and then trifluoroacetic anhydride dropwise (1.4 mL, 9.9 mmol). The reaction was stirred at 0° C. for 20 minutes and then stirred overnight at ambient temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography using a 40% dichloromethane/hexanes afforded 1.5 g (84%) of methyl 3-cyano-5-propoxybenzoate as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=O)[CH2:2][CH3:3].[CH3:18][O:19][C:20]1[CH:21]=C(O)[CH:23]=[CH:24][CH:25]=1.OS(O)(=O)=O.C(OCC)(=O)C>ClCCCl.O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:8]2[C:23]3[C:14](=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)[O:13][C:11](=[O:12])[CH:10]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cccc(C(=O)CC(=O)OC)c1
Reactant: COc1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOc1cccc(-c2cc(=O)oc3cc(OC)ccc23)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
A solution of methyl 3-(prop-1-yloxy)benzoylacetate (745 g) (a compound of Formula (a)) in 1,2-dichloroethane was combined under nitrogen with a solution of 3-methoxyphenol (488 g) in 1,2-dichloroethane (2.5 L) and cooled to 0° C. Concentrated H2SO4 (626 mL) was added dropwise and the mixture was stirred vigorously at RT for 90 minutes. Ethyl acetate (3 L) and H2O (3 L) were added and the layers were equilibrated and separated. The aqueous layer was extracted again with ethyl acetate and the combined organic layers were washed with H2O, 5% aqueous NA2CO2CO3, 5% aqueous NaOH, H2O, and brine (2 L each). The organic phase was dried with MgSO4 and concentrated to dryness to yield 841 g (86%) of 4-[3-(prop-1-yloxy)phenyl]-7-methoxycoumarin. The product was recrystallized from ethanol/isopropanol followed by ethyl acetate/isopropanol to give 533 g (63% recovery) of 4-[3'-(prop-1-yloxy)phenyl]-7-methoxycoumarin. 300 MHz 1H NMR (CDCl3) δ 1.05 (t, J=7 Hz, 3 H), 1.83 (m, J=7 Hz, 2 H), 3.88 (s, 3 H), 3.96 (t, J=7 Hz, 2 H), 6.21 (s, 1 H), 6.79 (dd, J1 =2 Hz, J2 =9 Hz, 1 H), 6.88 (d, J=2 Hz, 1 H), 6.94 (m, 3 H), 7.40 (t, J 8 Hz, 1 H), 7.42 (d, J=9 H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:36])[N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH2:25][CH2:26][C:27]#[N:28])[CH:20]=[C:19]([Cl:37])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[OH2:39].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:27]([CH2:26][CH2:25][N:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[C:23](=[O:36])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=[C:19]([Cl:37])[CH:20]=1)(=[O:39])[NH2:28]
Reactant: O
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)c2ccccc2Cl)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2-{3-chloro-5-[(2-chloro-phenyl)-(2-cyano-ethyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.055 g) and water (0.020 ml) in a mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stirred at room temperature for 2 h and then the solvent removed under reduced pressure. The residue was purified by preparative hplc to give title compound (0.035 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]([CH3:18])[S:4]([C:7]1[CH:8]=[N:9][C:10]([Sn](C)(C)C)=[CH:11][C:12]=1[CH3:13])(=[O:6])=[O:5])[CH3:2].[NH2:19][C:20]1[C:25]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32](=[O:36])[NH:31][CH2:30][CH2:29]3)=[CH:24][C:23](Br)=[CH:22][N:21]=1>>[NH2:19][C:20]1[N:21]=[CH:22][C:23]([C:10]2[CH:11]=[C:12]([CH3:13])[C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:18])(=[O:6])=[O:5])=[CH:8][N:9]=2)=[CH:24][C:25]=1[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32](=[O:36])[NH:31][CH2:30][CH2:29]2
Reactant: CCN(C)S(=O)(=O)c1cnc([Sn](C)(C)C)cc1C
Reactant: Nc1ncc(Br)cc1-c1ccc2c(c1)CCNC2=O
Product: CCN(C)S(=O)(=O)c1cnc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)cc1C
Yield: 15.1 %

Procedure:
General method D was applied to N-ethyl-N,4-dimethyl-6-(trimethylstannyl)pyridine-3-sulfonamide (226 mg, 0.6 mmol) and 6-(2-amino-5-bromopyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (190 mg, 0.6 mmol) to give 6′-amino-N-ethyl-N,4-dimethyl-5′-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (41 mg, 33% yield) after purification by reverse phase preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84-8.88 (m, 2H), 8.56 (s, 1H), 8.23 (s, 1H), 8.06 (br. s., 1H), 8.00 (d, J=7.8 Hz, 1H), 7.49-7.56 (m, 2H), 3.38-3.48 (m, 2H), 3.23 (q, J=7.0 Hz, 2H), 3.00 (t, J=6.3 Hz, 2H), 2.81 (s, 3H), 2.61 (s, 3H), 1.09 (t, J=7.0 Hz, 3H); MS (EI) m/z=452.5 [M+1]+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[N:8]=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1Cl>>[Cl:6][C:7]1[N:8]=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Clc1cnnc(Cl)c1Cl
Product: CC(C)(C)Nc1c(Cl)cnnc1Cl

Procedure:
Following the general procedure of PREPARATION 41 and making non-critical variations but starting with t-butylamine (66.5 ml), and 3,4,5-trichloropyridazine, the title compound is obtained, NMR (300 MHz, CDCl3) 8.50, 5.09, and 1.55 δ.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:21]([O-:23])=[O:22])[CH2:5][C:6](=O)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].S(Cl)([Cl:26])=O>ClCCCl>[Cl:26][C:6]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[C:21](=[O:22])[O:23]1
Reactant: COCC(CC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: COCC1CC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)OC1=O

Procedure:
A 340 mg portion of the Compound (78) obtained in Example 78 was dissolved in 14 ml of 1,2-dichloroethane. To the solution was added 0.34 ml of thionyl chloride, and the mixture was heated for 5 hours under reflux. The solvent was evaporated off, and the residue was subjected to a column chromatography using Florisil, followed by elution with hexane-ethyl acetate (5:1) to give 152 mg of the subject Compound (79) as colourless oily product.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:18][C@H:17]1[C:31](=[O:34])[NH:32][CH3:33]>O1CCCC1>[CH3:8][S:9]([O:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:18][C@H:17]1[C:31](=[O:34])[NH:32][CH3:33])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
1.06 ml of triethylamine and subsequently 584 μl of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 2.13 g of (2S, 4S)-1-(2-hydroxyethyl)-4-(4-methoxybenzylthio)-2-methylcarbamoyl-pyrrolidine dissolved in 45 ml of dry tetrahydrofuran, and the mixture was stirred at 0° to 5° C. for 30 minutes. At the end of this time, the crystals which precipitated were collected by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, to afford 2.50 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.C1C=CC=CC=1.II.S(=O)(=O)(O)O.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>[Zn].O.C1(C)C=CC=CC=1>[OH:10][C:9]([C:8]1[CH:17]=[CH:18][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: COCOc1ccc(C(=O)c2ccccc2)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC(O)(c1ccccc1)c1ccc(OCOC)cc1
Yield: 39.9 %

Procedure:
0.485 g of 4-(methoxymethoxy)benzophenone was dissolved in 0.45 ml ethyl bromoacetate, 1.5 ml benzene and 1.5 ml toluene, mixed with 3.27 g of zinc and 50 mg of iodine, and then refluxed for 2 hours under a stream of argon. The reaction mixture was mixed with water, adjusted to pH 1 with concentrated sulfuric acid, and then extracted with benzene three times. The extract was filtrated to remove insoluble components, washed twice with water and once with brine, followed by drying over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was evaporated and purified via column chromatography on silica gel (ethyl acetate:hexane=1:5) to give ethyl 3-hydroxy-3-[4-(methoxymethoxy)phenyl]-3-phenylpropionate (263 mg, yield: 39.9%) as an oil.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][C@H:24]([OH:27])[CH2:25][OH:26])(OCC1C=CC=CC=1)=O>CO.[Pd]>[OH:27][C@H:24]([CH2:25][OH:26])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11]
Reactant: O=C(NCCCCc1ccccc1OC[C@H](O)CO)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCCc1ccccc1OC[C@H](O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a vigorously stirred solution of 69 (2 g, 5.4 mmol) in methanol (60 mL) under nitrogen was added Pd/C (10% wet, 0.5 g). The mixture was stirred 2 h at room temperature under an atmosphere of hydrogen then the pressure was released and the mixture was filtered through a pad of silica gel. The solvent was removed and the residue was purified by column chromatography (silica gel, 2:1:0.2 chloroform/ethanol/concentrated ammonium hydroxide) to provide 70 (1.18 g, 92%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.32 (m, 2H), 1.54 (m, 2H), 2.55 (m, 2H), 3.45 (m, 2H), 3.82 (m, 3H), 3.94 (m, 2H), 6.83 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:17]2[N:18]=[C:19]([CH3:22])[NH:20][CH:21]=2)[NH:10]S(C(C)(C)C)=O)=[CH:5][CH:4]=1.[ClH:23].CCOCC>CO>[Cl-:23].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:17]2[N:18]=[C:19]([CH3:22])[NH:20][CH:21]=2)[NH3+:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NS(=O)C(C)(C)C)c2c[nH]c(C)n2)cc1
Reactant: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(C([NH3+])c2c[nH]c(C)n2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of N-[(4-methoxyphenyl)(2-methyl-1H-imidazol-4-yl)methyl]-2-methylpropane-2-sulfinamide (0.735 mg, 2.287 mmol) in 10.0 ml of MeOH was added 2.0N HCl in Et2O (11.43 ml, 22.87 mmol), and the mixture was stirred at RT for 30 min. Solvent removed and the residue was dried under vacuum to give the crude title compound (0.568 g, 98%). ES-MS [M+1]+: m/z 218.1. This intermediate was carried over to the next step without further purification and characterization.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)#[CH:18]>CCOC(C)=O.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:21]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccc(OC)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 1-Ethynyl-4-methoxy-benzene (86 mg, 0.65 mmol) was then added, and the resulting solution was stirred for 3 h at 100° C. The reaction mixture was diluted with EtOAc/H2O. The resulting precipitate was filtered, washed with EtOAc/H2O, and dried under vacuum to provide 163 (101 mg, 71% yield) as a white solid. LC-MS (M+H=327, obsd.=327).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:22][CH3:23])=[N:8][N:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=2[CH3:21])[C:10]=1SC)=[O:5])[CH3:2].[C:24](=O)(O)[O-].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[S:40](=[O:43])(O)[O-:41].[Na+]>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:22][CH3:23])=[N:8][N:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:14]=2[CH3:21])[C:10]=1[S:40]([CH3:24])(=[O:43])=[O:41])=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: O=S([O-])O
Reactant: CCOC(=O)c1c(CC)nn(-c2c(C)cc(Br)cc2C)c1SC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CC)nn(-c2c(C)cc(Br)cc2C)c1S(C)(=O)=O
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A solution of 2.6 g (6.56 mmol) of 1-(4-bromo-2,6-dimethylphenyl)-3-ethyl-5-methylthio-1H-pyrazole4-carboxylic acid ethyl ester in 50 mL of THF in a 125 mL 3-neck RBF was stirred under N2 and cooled to 170° C. Then 0.826 9 (9.80 mmol) of anhydrous sodium bicarbonate was added followed by a solution of 6.79 g (19.6 mmol) of m-chloroperbenzoic acid dissolved in 40 mL of THF. During the addition, the temperature of the reaction mixture was not allowed to rise above 20° C. After 1 hour, an aliquot workup showed that the reaction mixture consisted of about 34% of the desired sulfone and about 66% of the intermediate sulfoxide and after stirring overnight at room temperature, the conversion to sulfone was complete. A solution of 50 mL of 20% sodium bisulfite was then added and the resulting reaction mixture was stirred for 15 minutes. The reaction mixture was diluted with 50 mL of water and the product was extracted into 100 mL of CH2Cl2. The organic extracts were washed twice with saturated bicarbonate solution and once with 20% sodium bisulfite solution. The organic layer was dried over sodium sulfate and evaporated to give the desired product (2.91 g) as a gum. 1H-NMR (CDCl3) δ 0.28 (3H,t,J=7), 1.42 (3H, t, J=7), 1.97 (6H, s), 2.93 (2H, q, J=7), 3.39 (3H, s), 4.42 (2H, q, J=7), 7.29 (2H, s).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C.C[N:35](C=O)C>CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([NH2:35])=[CH:30][CH:31]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1
Solvent: CO
Product: Nc1ccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)cc1
Reaction time: 22 h
Yield: 24 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (30 mg, 0.072 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:10) to furnish IV as a yellow oil (7 mg, 24%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:12])[CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1>ClCCl>[C:1]([O:5][C:6]([N:8]([CH3:12])[CH2:9][CH2:10][NH:11][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CN(CCNC(=O)CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a well stirred solution of N-(tert-Butoxycarbonyl)-N-methyl-ethylenediamine 101 (5.5 g, 0.032 mol) in dichloromethane (CH2Cl2, 30 mL) was added succinic anhydride 102 (3.2 g, 0.032 mol) in one portion. After stirring the reaction mixture for 1 hour at room temperature, a slurry resulted. This slurry was used in Step 2 without further work-up.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[S:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>C1(C)C=CC=CC=1>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][O:32][C:14](=[S:15])[NH:13][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)[CH2:27][CH2:28]2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(N=C=S)cc(OC)c1OC
Reactant: OCCCN1CCN(c2cccc(Cl)c2)CC1
Solvent: Cc1ccccc1
Product: COc1cc(NC(=S)OCCCN2CCN(c3cccc(Cl)c3)CC2)cc(OC)c1OC
Product: Cl
Yield: 38.7 %

Procedure:
A mixture of 3,4,5-trimethoxyphenylisothiocyanate (2.0 mmol) (produced as in Example 22) and 3-[4-(3-chlorophenyl) -1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (40 ml) was refluxed for 16 h. The solvent was evaporated and the residue resuspended in ethyl acetate, filtered and evaporated to dryness. The residue was submitted to flash chromatography on silica gel 60 eluting with toluene/ethyl acetate (1:1). The product was taken up in ethanol, which was treated with hydrogen chloride in ether to give 200 mg of the title compound. M.p. 175°-176° C. MS (70 eV): m/z 479 (M+, 0.5%), 254 (49), 225 (88), 209 (100), 182 (34).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[CH:5][N:6]2[C:11]=1[C:10]([Cl:12])=[N:9][CH:8]=[N:7]2.[CH3:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17]>C1COCC1>[Br-:1].[Cl:12][C:10]1[C:11]2=[C:3]([CH2:2][N+:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:13])[CH:4]=[CH:5][N:6]2[N:7]=[CH:8][N:9]=1
Reactant: CCN(CC)CC
Reactant: Clc1ncnn2ccc(CBr)c12
Solvent: C1CCOC1
Product: CC[N+](CC)(CC)Cc1ccn2ncnc(Cl)c12
Product: [Br-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
A mixture of 1C (2.7 g, 11 mmol), Et3N (5 ml, 36 mmol) in THF (20 ml) was stirred at rt for 12 h. The solid was filtered and rinsed with THF and Et2O, dried to give 1D (3.38 g, 89%). It had an analytical HPLC retention time=0.776 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M+=267.
Reaction SMILES: [OH-:1].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH3:7]O.[C:9]1(C)[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH3:7][O:1][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[O-:15].[CH:14]([OH:15])([CH3:9])[CH3:13]
Reactant: Cc1ccccc1O
Reactant: CO
Reactant: [OH-]
Agent: C[N+](C)(C)C
Product: CC(C)O
Product: COc1ccccc1[O-]
Yield: 200 %

Procedure:
To 5.28 ml of a commercially available 10% tetramethylammonium hydroxide-methanol solution (manufactured by TOKYO KASEI; 5.13 mmole equivalents) was added 0.555 g of o-cresol (5.13 mmoles). About 7 ml of a tetramethylammonium-2-methoxyphenolate-isopropanol solution (containing 5.13 mmoles of o-cresol) was obtained in the same manner as in Operation 1 in Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[CH:23][C:22]=2[CH2:26][CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:22]2[CH:23]=[N:24][O:25][C:21]=2[C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of ethyl 4-aminophenylacetate (0.32 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.37 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.28 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-ethoxycarbonylmethylphenyl)-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.56 g, yield 93%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 117–118° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[CH3:27][N:28]([CH3:35])[CH2:29][CH2:30][CH2:31]C(Cl)=O.[N:36]1[C:45]2[C:40](=[CH:41][C:42]([NH2:46])=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:31][CH2:30][CH2:29][N:28]([CH3:35])[CH3:27])[C@H:9]([C:24]([NH:46][C:42]2[CH:41]=[C:40]3[C:45](=[CH:44][CH:43]=2)[N:36]=[CH:37][CH:38]=[CH:39]3)=[O:26])[CH2:10]1
Reactant: Nc1ccc2ncccc2c1
Reactant: CN(C)CCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: CN(C)CCCC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)Nc1ccc2ncccc2c1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 4(dimethylamino)butanoyl chloride, and 6-quinolinamine the title compound was obtained in 95% purity by LC/MS. MS(ESI+): m/z=542.6.