Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]=O)=[CH:5][CH:4]=1.N1CCC[C@@H]1C(O)=O.ClN1C(=O)CCC1=O.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[N:40][C:39]([NH2:42])=[N:38][CH:37]=2)=[CH:32][C:31]=1[F:43]>C(Cl)(Cl)Cl>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[N:38][C:39]3[N:40]([C:10]([S:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:11][N:42]=3)[N:41]=2)=[CH:32][C:31]=1[F:43]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: COc1ccc(SCC=O)cc1
Agent: O=C(O)[C@H]1CCCN1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(Sc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) reaction mixture of [(4-methoxyphenyl)thio]acetaldehyde (36.4 mg, 0.2 mmol) and D-proline (4.6 mg, 0.04 mmol) in chloroform (1.2 mL) was added N-chlorosuccinimide. (26.7 mg, 0.2 mmol). The reaction mixture was stirred at 0° C. for 30 min, then gradually warmed to RT for 2 h. To the reaction mixture was added [6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (26.9 mg, 0.1 mmol). The reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in isopropanol (2 mL) and heated at 100° C. overnight. After cooling, the reaction mixture was filtered and the filtrate was purified by RP-HPLC (pH=10) to afford the desired product. LCMS: (M+H)+=431.0.
Reaction SMILES: Cl.C[O:3][CH:4](OC)[CH2:5][NH:6][C:7]([C:9]1[NH:10][N:11]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:8]>O.CC(C)=O>[OH:3][CH:4]1[N:10]2[N:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[C:9]2[C:7](=[O:8])[NH:6][CH2:5]1
Reactant: COC(CNC(=O)c1cc(COc2ccccc2)n[nH]1)OC
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C1NCC(O)n2nc(COc3ccccc3)cc21
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 27 %

Procedure:
A 2M solution of HCl in H2O was added to a solution of 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid (2,2-dimethoxy-ethyl)-amide (1.25 g, 4.09 mmol) in acetone (7 mL). The mixture was stirred at 100° C. for 5 minutes under microwave irradiation. The solvent was evaporated in vacuo and the residue was supported on silica gel and purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0, then MeOH in AcOEt 0/100 to 10/90). Desired fractions were collected and the solvents evaporated in vacuo. The residue was triturated with diethyl ether to yield (rac)-7-hydroxy-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (286 mg, 30% yield) as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.[B:25]1(B2OC(C)(C)C(C)(C)O2)[O:29]C(C)(C)C(C)(C)[O:26]1.C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:15]2[CH2:16][C@@H:14]2[CH2:13][O:12][C:3]2[C:2]([B:25]([OH:29])[OH:26])=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][N:9]=3)[N:4]=2)=[N:18][CH:19]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2B(O)O)nc1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine (LL2) (800 mg, 2.1 mmol), bis(pinacolato)diboron (789 mg, 3.1 mmol), potassium acetate (813 mg, 8.3 mmol) and PdCl2(dppf) (303 mg, 0.41 mmol) in dioxane (10.4 mL) under N2 was heated at 100° C. for 14 hours. The reaction mixture was cooled to ambient temperature, partitioned between EtOAc (125 mL) and sat. sodium bicarbonate (25 mL), washed with water (25 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (20% to 100% EtOAc in hexanes; hydrolysis on silica gel to boronic acid led to elution with 9:1 chloroform/methanol) to afford the title compound as a brown foam. LRMS m/z (M+H) 352.1 found, 352.1 required.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]1([C:15]([F:18])([F:17])[F:16])[CH2:14][O:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[CH2:39]([OH:41])[CH3:40]>>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24](=[O:31])[NH:25]2)[C:12]([CH2:14][O:41][CH2:39][CH3:40])([OH:13])[C:15]([F:17])([F:16])[F:18]
Reactant: COc1ccc(C(Nc2cc(F)cc3[nH]c(=O)ccc23)C2(C(F)(F)F)CO2)c(Cl)c1F
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCOCC(O)(C(Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F

Procedure:
70 mg (0.15 mmol) 5-{[(2-chloro-3-fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-7-fluoro-1H-quinolin-2-on obtained in example 3 are stirred with 84 mg (0.26 mmol) Caesium carbonate in 0.67 ml ethanol. After 40 hours water is added and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (ethyl acetate) yields 22 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[C:13]1([CH3:24])[CH:18]=[CH:17][C:16]([S:19]([NH:22][NH2:23])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CCO>[S:19]([NH:22][N:23]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)([C:16]1[CH:15]=[CH:14][C:13]([CH3:24])=[CH:18][CH:17]=1)(=[O:20])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: COc1ccc2c(c1)CCC2=O
Solvent: CCO
Product: COc1ccc2c(c1)CCC2=NNS(=O)(=O)c1ccc(C)cc1
Yield: 98.1 %

Procedure:
A mixture of 5.00 g (31 mmol, Aldrich) of 5-methoxy-1-indanone and 6.33 g (34.0 mmol, Aldrich) of p-toluenesulfonhydrazide in 50 ml EtOH was heated on a steam bath until homogeneous. The solution was cooled and the solid which formed was filtered to yield 10.05 g (99%) of title compound as cream colored crystals: m.p. 195°-196° C.
Reaction SMILES: [C:1]([NH:4][CH:5](Br)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].CCN(CC)CC.[CH3:24][N:25]([CH3:34])[S:26]([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)(=[O:28])=[O:27].[Li]CCCC.[NH4+].[Cl-]>O.C1COCC1>[C:1]([NH:4][CH:5]([C:32]1[N:31]=[CH:30][N:29]([S:26](=[O:28])(=[O:27])[N:25]([CH3:34])[CH3:24])[CH:33]=1)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Br)C(=O)NCc1ccccc1
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NC(C(=O)NCc1ccccc1)c1cn(S(=O)(=O)N(C)C)cn1
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a cooled (-78° C.) THF solution (150 mL) of 2-acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) and BBr3 (1M solution in CH2Cl2, 9.0 mL, 9.0 mmol)) was added Et3N (1.62 g, 16.0 mmol), and then a THF solution of the 2-lithio salt of N,N-dimethylimidazole-1-sulfonamide (generated by the addition of n-BuLi (2.5M in hexane, 3.9 mL, 9.68 mmol) into a cooled (-78° C.) THF solution (25 mL) of N,N-dimethylimidazole-1-sulfonamide (1.54 g, 8.8 mmol)) was added during a 15 min interval. The reaction mixture was stirred at this temperature (30 min) and then at room temperature (45 min). A saturated aqueous NH4Cl solution (50 mL) and H2O (50 mL) were then sucessively added to the reaction, and the aqueous mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2SO4), and the volatile materials were removed by distillation in vacuo. The residue was purified by flash column chromatography on SiO2 gel (4% MeOH/CHCl3) to give 0.50 g (17%) of the desired product: mp 145°-147° C. (recrystallized from EtOAc/hexane); Rf 0.35 (4% MeOH/CHCl3); IR (KBr) 3400, 1640, 1530, 1380, 720 cm-1 ; 1H NMR (DMSO-d6) δ 1.96 (s, C(O)CH3), 2.77 (s, N(CH3)2), 4.25 (dd, J=6.0, 15.5 Hz, CHH), 4.34 (dd, J=6.0, 15.5 Hz, CHH), 5.43 (d, J=8.0, Hz, CH), 7.19-7.30 (m, 5 PhH), 7.40 (s, C5H), 8.17 (s, C2H), 8.42 (d, J=8.0 Hz, NH), 8.67 (t, J=6.0 Hz, NH); 13C NMR (DMSO-d6) 22.42 (C(O)CH3), 37.80 (N(CH3)2), 42.11 (CH2), 51.40 (CH), 115.50 (C5), 126.64 (C4'), 126.94 (2C2' or 2C3'), 128.12 (2C2' or 2C3'), 136.70 (C2), 139.17 (C1'), 140.26 (C4), 168.93 (C(O)NH), 169.09 (C(O)CH3) ppm; mass spectrum (FD) 380 (M+ +1, 34), 248 (13), 247 (100), 108 (64).
Reaction SMILES: [I-:1].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH2:3]([I:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [I-]
Reactant: CCCCCCCCBr
Agent: [Na+]
Product: CCCCCCCCI
Yield: 100 %

Procedure:
N-substituted perhydro-s-triazine compounds can be used to increase the solubility of alkali or alkaline earth metal salts in an organic medium. Increasing the solubility of such salts catalyzes the reaction between the salts and other components of the organic medium. For example, 5 percent of a tris(n-octylpolyoxyethylene)-N,N',N"-perhydro-s-triazine compound catalyzes the reaction between sodium iodide and n-octyl bromide at 80° C. for 1 hour to form 100 percent yield of n-octyl iodide.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:10]([C:22]#[N:23])=[C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]2=[C:13]([CH:21]=1)[CH2:14][O:15][CH2:16]3.C(Cl)[Cl:25]>C(#N)C.[Cu](Cl)Cl>[Cl:25][C:9]1[C:10]([C:22]#[N:23])=[C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]2=[C:13]([CH:21]=1)[CH2:14][O:15][CH2:16]3
Reactant: N#Cc1c(N)cc2c3c(cccc13)COC2
Reactant: ClCCl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1c(Cl)cc2c3c(cccc13)COC2
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl nitrite (27.5 ml, 208 mmol) was added to a suspension of copper (II) chloride (22.5 g, 167 mmol) in anhydrous acetonitrile (500 mL) at room temperature under nitrogen atmosphere. The resulting dark green suspension was heated to the internal temperature of 65° C., and a solution of 5-amino-6-cyano-1H,3H benzo[de]isochromene (29.2 g, 139 mmol) in anhydrous acetonitrile (1000 mL) was added thereto. The reaction solution was stirred at 65° C. for 30 minutes, and then allowed to return to room temperature. The reaction solution was diluted with methylene chloride. The mixture was washed in succession with 1N aqueous hydrochloric acid solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using methylene chloride, and dried under reduced pressure. The title compound was obtained as yellow solid material (27.7 g, 87%).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:28]([OH:30])=[O:29])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:42]=[CH:41][CH:40]=[CH:39][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[C:28]([O:30][CH2:2][C:1]#[N:4])=[O:29])=[O:22])=[N+:15]=[N-:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1N=[N+]=[N-])C(=O)OCC#N
Reaction time: 3.5 h
Yield: 100 %

Procedure:
N,N-Diisopropylethylamine (205 μL, 1.176 mmol) and subsequently bromoacetonitrile (373 μL, 5.34 mmol) were added to a solution of (S)-5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoic acid (Compound tk61) (435.5 mg, 1.069 mmol) in acetonitrile (1 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 3.5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 5-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk62) (477.2 mg, quant.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].OS(O)(=O)=O.[CH3:17]O>C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:17])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: CO
Reactant: O=C(O)c1ccc(F)c(Br)n1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 6-bromo-5-fluoropicolinic acid (1.0 equiv.) in methanol (0.2 M) was added H2SO4 (4.2 equiv.) and the reaction was stirred at room temperature for two hours. Upon completion of the reaction as monitored by LC/MS, the reaction was diluted with ethyl acetate and quenched slowly with saturated aqueous NaHCO3. The reaction was poured into a separatory funnel and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-bromo-5-fluoropicolinate as a white solid (>99%). LC/MS=233.9/235.9 (M+H), Rt=0.69 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39]([NH:41][NH2:42])=[O:40])(=[O:13])=[O:12].C(N(C(C)C)C(C)C)C.[Br:52][CH2:53][CH2:54][CH2:55][C:56](Cl)=[O:57]>C1COCC1>[Br:52][CH2:53][CH2:54][CH2:55][C:56]([NH:42][NH:41][C:39]([C@@H:15]1[CH2:16][C@@H:17]([S:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:18][N:14]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:40])=[O:57]
Reactant: NNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C(Cl)CCCBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCBr)NNC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
(step 27) To 150 mg (0.25 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid hydrazide in 65 ml THF were added 52 μl (0.3 mmol, 1.2 eq) iPr2EtN and 29 μl (0.25 mmol) 4-bromobutyryl chloride at 0° C. The solution was stirred at RT for 2 h, the solution was concentrated and redissolved in ethyl acetate/H2O. The inorganic phase was extracted with ethyl acetate and, the organic phase was washed with brine and dried over Na2SO4. Column chromatography with ethyl acetate:hexane 1:1 yields 170 mg (92%) (2S,4R)-1(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid N′-(4-bromo-butyryl)-hydrazide which was dissolved in 120 ml DMF and treated with 17 mg (0.38 mmol, 55% in mineral oil). NaH and the solution stirred for 2 h, was concentrated and dissolved in ethyl acetate/H2O. The inorganic phase was extracted with ethyl acetate, the organic phase washed with brine and dried over Na2SO4. The crude product was purified by column chromatography yielding 75 mg (45%) (2S,4R)-4-tritylsulfanyl -1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid (2-oxo-pyrrolidin-1-yl)-amide as white foam and 40 mg (25%) (2S,4R)-1-[4-tritylsulfanyl-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-tetrahydro-pyridazin-3-one as white foam. The two compounds were treated separately in TFA (2 ml/mmol tritylsulfanyl) with 10 eq triethylsilane at 0° C. to RT, until no educt could be detected, to yield (2S,4R)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid (2-oxo-pyrrolidin-1-yl)-amide as white foam, MS: 420 (MH+) and (2S,4R)-1-[4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-tetrahydro-pyridazin-3-one as white foam, MS: 420 (MH+), respectively.
Reaction SMILES: [C:1]1([CH:7]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:8]([OH:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl.O>[Cl:23][CH2:24][C:25]([NH:10][CH2:9][CH:8]([OH:11])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:26]
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CN
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1OC(c1ccccc1)C(O)CNC(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A mixture of 2.73 g of 3-phenyl-2-hydroxy-3-(2-methoxy-phenoxy)-propylamine in 50 ml of methylene chloride and 0.56 g of NaOH in 15 ml of water was stirred at 0° C. Under vigorous stirring dropwise addition was made to the mixture over 30 minutes, again at 0° C., of 1.58 g of chloroacetyl chloride in 2 ml of methylene chloride. After the addition, the stirring was continued at 0° C. for 30 minutes. The layers were separated and the aqueous phase extracted with CH2Cl2. The organic extracts were combined and washed with water, dried over Na2SO4 and evaporated to dryness. There was obtained 3.49 g of N-chloroacetyl-2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)propylamine (oil). Yield 100%.
Reaction SMILES: O.[C:2]1(C)[CH:7]=CC(S(O)(=O)=O)=C[CH:3]=1.[Br:13][CH2:14][C:15]([CH2:20][Br:21])([CH2:18][OH:19])[CH2:16][OH:17]>CC(C)=O.COC(OC)(C)C>[Br:13][CH2:14][C:15]1([CH2:20][Br:21])[CH2:18][O:19][C:2]([CH3:7])([CH3:3])[O:17][CH2:16]1
Reactant: OCC(CO)(CBr)CBr
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(CBr)(CBr)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Para-toluenesulfonic acid monohydrate (0.1 eq) was added at 0° C. to a 0.2M solution of 2,2-bis(bromomethyl)propane-1,3-diol in acetone/2,2-dimethoxypropane (10:1) and the solution was stirred for 2 h at RT. Filtration over a pad of neutral alumina with EtOAc afforded the title compound as a white solid after evaporation of the solvent in vacuo (quant). 1H NMR (300 MHz, CDCl3, 300 K) δ 3.80 (s, 4H), 3.58 (s, 4H), 1.42 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH3:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4](=[O:15])(=[O:14])[N:3]=1.C(NC1C=CC=CC=1)C.[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:62]=[CH:63][CH:64]=2)[O:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)C2N(C)C3C=CC=CC=3S(=O)(=O)N=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:62]=[CH:63][CH:64]=2)[O:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)[C:2]2[N:7]([CH2:8][CH3:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[S:4](=[O:15])(=[O:14])[N:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc(CN(CCCOc2cccc(CN3CCCCC3)c2)C2=NS(=O)(=O)c3ccccc3N2C)cc1
Reactant: CCN1C(Cl)=NS(=O)(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCNc1ccccc1
Product: CCN1C(N(CCCOc2cccc(CN3CCCCC3)c2)Cc2ccc(OC)cc2)=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A 0.8 g quantity of 3-chloro-4-ethyl-1,2,4-benzothiadiazine-1,1-dioxide in the form of white crystals prepared in the same manner as in Reference Example 4 with the exception of using N-ethylaniline in place of N-methylaniline was added to a solution of 1.2 g of the N-[3-[3-(piperidinomethyl)phenoxy]propyl]-4'-methoxybenzylamine obtained in Example 1, (iii) in 12 ml of chloroform, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was purified in the same manner as in Example 1, giving 1.67 g of 3-[N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-4'-methoxybenzylamino]-4-ethyl-1,2,4-benzothiadiazine-1,1-dioxide (yield 88% ). This compound was converted to an oxalic acid salt in the same manner as in Example 1 to obtain 1.81 g of a compound 15 in the form of white crystals as listed in Table 1 (yield 92% ). M.p.: 85°~90° C.
Reaction SMILES: Cl.C(O[C:5]1[C:6]2[C:7](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])C.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25]>>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][C:5]1[C:6]2[C:7](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2nn(C)cc2c1OCC
Reactant: CN(C)CCCN
Agent: Cl
Product: CCOC(=O)c1cnc2nn(C)cc2c1NCCCN(C)C

Procedure:
2.9 (0.01 mole) of 4-ethoxy-2-methyl-2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester, hydrochloride from Example 2 and 10 ml. of (3-dimethylaminopropyl)amine are refluxed for 3 hours. The excess of amine is removed in vacuo and the residue is treated with 10 ml. of cold water. 2.3 g. of 4-[(3-dimethylaminopropyl)amino]-2-methyl-2H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester; m.p. 61°-63° (methanol/water); is removed by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8](C(O)=O)[CH2:9][O:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:30])C=CC=CC=1.Cl>ClCCl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8](=[O:30])[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)OCC(C(=O)O)=C2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)OCC(=O)C2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
7-Methoxy-2H-chromene-3-carboxylic acid (6.07 g, 29.44 mmol) and triethylamine (4.8 ml, 34.48 mmol) were dissolved in dichloromethane (60 ml). Diphenylphosphoryl azide (6.54 ml, 29.44 mmol) was dissolved in toluene (24 ml) and added dropwise to the reaction mixture while slowly increasing the temperature to 60° C. 60 ml of toluene were added and the reaction mixture was stirred at 70° C. for 90 minutes. A 10 molar HCl solution (28 ml) was then added and the reaction mixture was stirred at reflux for 2 hours. After cooling to room temperature the phases were separated. The organic phase was extracted with an aq. NaHCO3 solution. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified by chromatography using silica gel with cyclohexane/ethyl acetate (100:0 to 95:5) as eluent, yielding the title product (1.47 g, 24% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O.C(Cl)Cl>CN(C)C=O>[CH2:22]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[C@H:12]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:13]([NH2:15])=[O:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: NC(=O)[C@@H](c1ccccc1)N(Cc1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To a solution of (R)-2-(4-chloro-benzenesulfonylamino)-2-phenyl-acetamide (350 mg, 1.1 mmol) in 4 mL of dimethylformamide are added benzylbromide (0.18 mL, 1.1 mmol) and potassium carbonate (179 mg, 1.3 mmol). The reaction is heated overnight at 50° C., poured into water/methylene chloride and extracted with methylene chloride. The combined organics are dried with sodium sulfate, concentrated in vacuo, and the resultant residue purified on silica gel chromatography to provide the title compound. C13 NMR (100 MHz, CDCl3) 50.3, 64.8, 127.6, 128.4, 128.6, 129.0, 129.1, 129.3, 129.4, 130.2, 133.9, 136.8, 138.6, 139.4, 171.7. MS 415.1 m/z (M+1).