Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:14]([CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH3:54][N:55]([CH3:60])[C:56](=[O:59])[CH:57]=[CH2:58]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:23][CH3:24])[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:6]=2[C:5]2[CH:4]=[CH:3][C:2](/[CH:58]=[CH:57]/[C:56]([N:55]([CH3:60])[CH3:54])=[O:59])=[CH:11][C:10]=2[N:9]=1
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Reactant: C=CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3cc(/C=C/C(=O)N(C)C)ccc3c2n1CC1CCOCC1
Temperature: 120 °C
Yield: 63.8 %

Procedure:
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.58 g, 1.5 mmol) in N,N-dimethylformamide (10 mL). To the solution was added in succession, a solution of palladium acetate (37 mg, 0.15 mmol) and tri-ortho-tolylphosphine (91 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL), triethylamine (3.0 eq. 0.6 mL), and a solution of N,N-dimethylacrylamide (178 mg, 1.8 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel was sealed and heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (100 mL) and washed with saturated aqueous potassium carbonate (50 mL). The fractions were separated and the organic fraction was concentrated to dryness. The resulting off-white solid was purified by chromatography using a HORIZON HPFC system, (silica cartridge, 0-15% CMA/chloroform). A final recrystallization from acetonitrile provided 390 mg of (2E)-3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylprop-2-enamide as an off-white crystalline solid, mp>260° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([CH2:16]O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.Cl.[CH2:31]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[CH3:32].C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([CH2:16][NH:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1cn(Cc2ccccc2)nc1CO
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CNCc1nn(Cc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.4 g (5.6 mmol) of (1-benzyl-4-nitro-1H-pyrazol-3-yl)methanol was dissolved in 20 ml of dichloromethane. 0.53 ml (6.7 mmol) of methanesulfonyl chloride and 1.0 ml (7.3 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 50 ml of ethanol. 1.6 g (11.2 mmol) of glycine ethyl ester hydrochloride and 1.4 g (16.8 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70° C. overnight. The insoluble matter was filtered. The solvent was evaporated and the residue was treated with ethyl acetate as the extracting solvent by an ordinary method, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:16][C@@H:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:4]2[CH2:3]1.C(O)(C(F)(F)F)=O.[OH-]>CO>[CH3:1][C:2]1[CH2:3][C@H:4]2[CH2:8][NH:7][CH2:6][C@H:5]2[CH:16]=1
Reactant: C=C1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C1
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC1=C[C@@H]2CNC[C@@H]2C1
Reaction time: 0.5 h
Yield: 148 %

Procedure:
(3aR,6aS)-tert-Butyl 5-methylenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Tetrahedron 1993, 49(23), 5047-54) (114 mg, 0.51 mmol) was taken into a minimum of neat TFA and the solution was allowed to stand for 30 minutes at room temperature. The mixture was then concentrated and the residue taken into methanol and concentrated again then dried. The residue thus obtained was taken into methanol (5 mL) and basified using Bio-Rad AG-1X hydroxide form resin. The mixture was then filtered and concentrated and dried to give impure (±)-(3aR,6aS)-5-methyl-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (93 mg) as an amorphous residue that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[Cl:19]NC(=O)CCC(N)=O.O.C(OCC)(=O)C>CN(C=O)C>[Cl:19][C:3]1[C:2]([OH:1])=[N:7][C:6]2[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=[CH:10][C:5]=2[C:4]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc(O)nc2c1cnn2C(C)C
Reactant: NC(=O)CCC(=O)NCl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)c(O)nc2c1cnn2C(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a stirred solution of ethyl 6-hydroxy-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1.3 g, 5.2 mmol) in DMF (7 mL), N-chlorosuccinamide (1.11 g, 8.35 mmol) was added. The resulting reaction mixture was stirred at 60° C. for 1 h. On completion of reaction, water was added to it and extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (1 g, 69.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].Br[C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:13]1[O:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: Oc1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cc(F)ccc2F)o1
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a solution of 2,5-difluorophenol (3360 mg, 25.83 mmol) in N,N-dimethylformamide (60 mL) was sodium hydride (1032 mg, 25.83 mmol, 60% in oil), which was then stirred for 1 hour. 5-Bromo-2-furaldehyde (3826 mg, 21.52 mmol) was added to the reaction solution, and the solution was stirred at 60° C. for 12 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then, concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (1104 mg, 4.92 mmol, 22.9%) was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[I:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[C:10]([NH:12][CH2:13][C:14](=[O:16])[CH3:15])=O.[OH-].[Na+]>O>[I:6][C:7]1[CH:8]=[C:9]([C:10]2[O:16][C:14]([CH3:15])=[CH:13][N:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)CNC(=O)c1cccc(I)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(-c2cccc(I)c2)o1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
Concentrated sulfuric acid (13 mL) was added to 3-iodo-N-(2-oxopropyl)benzamide (1.33 g, 4.39 mmol) obtained in Step 2, and the mixture was stirred at 100° C. for 1.5 hours. The mixture was poured into iced water, neutralized with a 4 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 2-(3-iodophenyl)-5-methyl-1,3-oxazole (1.20 g, 96%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[N:7][OH:8])[C:4](=[N:9][OH:10])[C:3]1=[O:11]>O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3]>[CH3:1][N:2]1[C:3](=[O:11])[C:4]2[C:5](=[N+:7]([O-:8])[O:10][N:9]=2)[CH2:6]1
Reactant: CN1CC(=NO)C(=NO)C1=O
Agent: [Fe+3]
Agent: O=C([O-])[O-]
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: O
Product: CN1Cc2c(no[n+]2[O-])C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
A solution of 13.0 g (38 mmol) of potassium hexacyanoferrate(III) in 40 ml of water and 3 ml of saturated sodium carbonate solution is added dropwise to a suspension of 1.0 g (6.4 mmol) of 1-methyl-2,3,4-pyrrolidinetrione-3,4-dioxime in 50 ml of ethyl acetate, and the mixture is stirred at room temperature for 2 hours. The organic phase is separated off and concentrated, and the residue is purified by flash chromatography (ethyl acetate/cyclohexane 60:40). 0.34 g (34%) of 5,6-dihydro-5-methyl-4H-pyrrolo[3,4-c][1,2,5]oxadiazole-4-one-1-oxide and -3-oxide is obtained in the ratio 1:2 (NMR), m.p. 49°-52° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH3:19])=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:20].[CH2:21]([O:23]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:22]>>[C:21]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH3:19])=[C:14]([CH3:18])[CH:15]=2)[C:10]1=[O:20])(=[O:23])[CH3:22]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2c(cc1C)C(=O)C(Cc1ccncc1Br)C2
Product: CC(=O)c1cnccc1CC1Cc2cc(C)c(C)cc2C1=O

Procedure:
The title compound 111 is prepared according to the procedure reported in Example 36.5 with compound 107 (235 mg, 0.71 mmol) and (1-ethoxyvinyl)tri(n-butyl)stannane (0.24 mL, 0.71 mmol) as reactants. White solid. (Yield 125.0 mg, 60%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11](=[O:25])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5]1.[C:26]([OH:37])(=O)[C:27]1[CH:35]=[CH:34][CH:33]=[C:29]([C:30]([OH:32])=O)[CH:28]=1>>[NH2:1][CH2:2][CH2:3][NH:4][C:30]([C:29]1[CH:28]=[C:27]([CH:35]=[CH:34][CH:33]=1)[C:26]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11](=[O:25])[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5]1)=[O:37])=[O:32]
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: NCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Product: NCCNC(=O)c1cccc(C(=O)NCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1

Procedure:
The title compound was prepared following a similar procedure as described in Example 13, by substituting the appropriate biphenyl-2-ylcarbamic acid 1-(aminoethyl)piperidin-4-yl ester in place of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester and substituting isophthalic acid in place of terephthalic acid.
Reaction SMILES: [OH-].[K+:2].ClC1C=CC(CS)=CC=1.C(=S)=S.[K].[Cl:16][C:17]1[CH:27]=[CH:26][C:20]([CH2:21][S:22][C:23](=[S:25])[SH:24])=[CH:19][CH:18]=1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[C:23](=[S:24])([S-:25])[S:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:27][CH:26]=1.[K+:2]
Reactant: S=C(S)SCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: SCc1ccc(Cl)cc1
Solvent: S=C=S
Solvent: O
Solvent: Cc1ccccc1
Product: S=C([S-])SCc1ccc(Cl)cc1
Temperature: 18 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 100 ml of water and 13.0 g (200 mmol) of 86.4% KOH is added 26.4 ml (31.7 g, 200 mmol) of 4-chlorobenzyl mercaptan at 20° C. Then 100 ml of toluene and 100 mg of tetrabutylammonium bisulfate, a phase transfer catalyst, is added and the reaction mixture stirred for 0.5 hours. The reaction mixture is cooled to 18° C. and 26.6 ml (220 mmol) of carbon disulfide is added. After stirring for 0.5 hours, the yellow color of the water layer indicates the formation of the potassium salt of p-chlorobenzyl trithiocarbonic acid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>>[C:21]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:22]=[CH:23][C:24]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and biphenyl-4-carboxylic acid chloride, there is obtained ethyl N-(4-biphenylylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 52°-58° C.;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27]OC[CH2:24]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29](OC(N1CCN(C2C=CC=CC=2O)CC1)=O)(C)(C)C.CN1CCCC(O)C1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]2[CH2:29][CH2:27][CH2:28][N:23]([CH3:24])[CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2OCCN2CCOCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: CN1CCCC(O)C1
Product: CN1CCCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)C1

Procedure:
The title compound was prepared in a manner similar to 4-[2(2-Morpholin-4-yl-ethoxy)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester except that 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester was coupled to 1-methyl-piperidin-3-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([C:25](=[O:27])[CH3:26])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25](=[O:27])[CH3:26])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC(=O)c1cccc2c1CCNC2C
Product: CC(=O)c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-ethanone to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:28]=[CH:27][C:26]([OH:29])=[CH:25][N:24]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:18][CH2:19][CH2:20][N:21]([C:23]5[N:24]=[CH:25][C:26]([O:29][CH2:32][CH2:33][N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)=[CH:27][N:28]=5)[CH2:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(O)cn5)CCO4)c3n2)cn1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(OCCN6CCOCC6)cn5)CCO4)c3n2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
(S)-2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-ol 26 mg (0.066 mmol) was dissolved in DMF 2 ml, and 4-(2-chloroethyl)morpholinehydrochloride 14.8 mg (0.079 mmol) and potassium carbonate 28 mg (0.19 mmol) were added, followed by stirring at 80° C. overnight. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give (S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(2-morpholinoethoxy)pyrimidin-2-yl)morpholine 5 mg (15%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10].O>C1C=CC=CC=1>[CH3:9][O:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CO
Solvent: c1ccccc1
Solvent: O
Product: COCc1ccccc1
Yield: 93 %

Procedure:
To a solution of 1.57 g (10 mmol) of benzyl chloride in 40 ml of benzene, 5.57 g (15 mmol) of the tris(dimethylamino)[tris(dimethylamino)phosphoranilideneamino]phosphonium salt of methanol, said salt having had been synthesized in a similar manner as in Example 1, were added at 0° C., followed by a reaction at room temperature for 3 hours. Water (50 ml) was then added to the reaction mixture to terminate the reaction. An organic layer was separated, washed successively with 20 ml of water and 20 ml of a saturated aqueous solution of sodium chloride, and then concentrated to dryness. The resulting liquid compound was distilled, whereby benzyl methyl ether, the target compound, was obtained as a colorless liquid compound in an amount of 1.13 g. Its yield was 93%.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:15]([C:12]1[CH:11]=[C:10]([CH3:14])[C:3]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[C:2]([CH3:1])[CH:13]=1)(=[O:17])[CH3:16]
Reactant: COC(=O)COc1c(C)cccc1C
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: COC(=O)COc1c(C)cc(C(C)=O)cc1C

Procedure:
7 Grams of methyl 2,6-dimethylphenoxyacetate, 3.4 ml of acetic anhydride and 100 ml of carbon disulfide were mixed at 0° C., and to the mixture was added 17.9 g of aluminum chloride, and the resulting mixture was heated until gas was evolved. After the gas-evolution was ceased, the reaction mixture was refluxed for 30 minutes under heating. Then water was added to the solution. The resulting mixture was extracted with di-isopropyl ether, washed with water, dried over anhydrous magnesium sulfate. The oily solution was concentrated to obtain an oily substance. The oily substance was chromatographed on silica gel to obtain 6.1 g of methyl 4-acetyl-2,6-dimethylphenoxyacetate, nD21.6 1.5165.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH2:9][C:8](=[O:19])[NH:7][C:6]=2[CH:20]=1.CCN(CC)CC.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>C1COCC1>[CH2:32]([O:31][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH2:9][C:8](=[O:19])[NH:7][C:6]=2[CH:20]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccc2c(c1)NC(=O)CC(c1cccc(Br)c1)=N2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CC(c2cccc(Br)c2)=Nc2ccc(NC(=O)OCc3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.5 %

Procedure:
To a stirred solution of 4 (50 mg, 0.15 mmol) in THF (5 mL) was added Et3N (0.031 mL, 0.22 mmol) followed by benzyl chloroformate (1.06 mL, 0.18 mmol) at 0° C. under inert atmosphere. The resulting reaction mixture was allowed to warm to RT and stirred for 12 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude material was purified by silica gel column chromatography [eluent: 35% EtOAc/hexane] to afford the title compound 82 (15 mg, 21.4%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.60 (bs, 1H), 10.00 (bs, 1H), 8.18 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.51-7.28 (m, 9H), 5.18 (s, 2H), 3.49 (s, 2H). MS (ESI): 466 [M+1]+
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>CN(C=O)C>[C:25]([O:28][CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)[O-]
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 100 °C
Yield: 51.9 %

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (159 mg, 0.5 mmol) in DMF (2 mL) was treated with sodium acetate (104 mg, 1.2 mmol). The mixture was heated at 100° C. for 2 h, than it was poured into ice-water. The precipitated solid was collected by filtration, washed with water, and dried. The crude product was crystallized from EtOAc-hexane to give the title compound as colorless needles (95 mg); mp 144-147° C.; 1H NMR (CDCl3) 7.37 (s, 1H), 7.33 (s, 1H), 7.19-7.24 (m, 2H), 6.97 (d, J=8.5, 1H), 6.15 (s, 2H), (s, 2H), 5.41 (s, 2H), 2.24 (s, 3H). Anal. calcd. for C19H14N2O6: C, 62.30; H, 3.85; N, 7.65. Found: C, 62.12; H, 3.92; N, 7.65.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([CH3:13])[NH:9]1>>[CH3:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([CH3:13])[N:9]1[CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: C[C@H]1CC[C@H](C)N1
Reactant: COC(=O)CBr
Product: COC(=O)CN1[C@@H](C)CC[C@@H]1C

Procedure:
By a procedure analogous to Example 6, methyl bromoacetate is reacted with trans-2,5-dimethylpyrrolidine (J. Amer. Chem. Soc. 1951, 73, 5230) to give methyl (trans-2,5-dimethylpyrrolidin-1-yl)acetate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:22]=3)[CH:17]=[CH:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C1COCC1>[Br:1][C:17]1[C:18]2[C:23](=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[N:15]([C:12]2[CH:11]=[CH:10][N:9]=[CH:14][CH:13]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3ccn(-c4ccncc4)c3c2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(Br)cn(-c4ccncc4)c3c2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
N-Bromosuccinimide (64.4 mg, 0.36 mmol) was added to a mixture solution of tert-butyl 4-(1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (137 mg, 0.36 mmol) in THF (12 mL) at −78° C. After stirring at −78° C. for 2 hours, the mixture was further stirred at 0° C. for 1 hour and then pyridine (88 μL, 1.09 mmol) was added. After filtering using a diatomite pad, the solution was adsorbed by adding silica gel. Purification by chromatography (silica gel, EA:Hx=4:1) yielded the target compound (49.1 mg, 30%) as white solid.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[C:22]1([C:7]2[S:6](=[O:28])(=[O:29])[N:5]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:9](=[O:10])[C:8]=2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccn1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccccn1

Procedure:
The title compound was prepared from 2-tert-butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) and 2-(bromomethyl)pyridine in a similar manner as described for e.g. Example 2 and 3. 1H NMR (500 MHz CDCl3): δ 8.65-8.60 (m, 1H), 7.74-7.67 (m, 1H), 7.56-7.51 (m, 2H), 7.50-7.41 (m, 4H), 7.31-7.17 (m, 4H), 7.10-7.05 (m, 2H), 5.35-5.28 (m, 1H), 5.01 (s, 2H), 2.94-2.84 (m, 2H), 2.50-2.42 (m, 2H), 1.45-1.35 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 159.4, 154.4, 149.7, 141.6, 137.1, 135.5, 131.7, 129.9, 128.8, 128.5, 128.4, 126.1, 124.9, 123.0, 121.9, 107.2, 44.9, 44.1, 35.3, 29.1, 28.2; Mass Spectrum: M−H+ 448.