Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1C=CC(S([N:11]([N:13]=O)[CH3:12])(=O)=O)=CC=1.[OH-].[K+].[N+:17](=[CH2:19])=[N-:18].[CH3:20][C:21]1[CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]=1C>C(OCCOCCO)C.CCOCC.C(O)(=O)C>[N+:11](=[CH2:12])=[N-:13].[CH3:1][C:19]12[CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:21]1([CH3:23])[CH2:20][N:18]=[N:17]2
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CCOC(=O)C1C(C)=C1C
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCOCCOCCO
Product: CCOC(=O)C1C2(C)CN=NC12C
Temperature: 0 °C
Reaction time: 336 h

Procedure:
Diazomethane was prepared from Diazald (21.5 g), KOH (6.6 g) in 2-(2-ethoxyethoxy)ethanol (35 mL). To the diazomethane solution in Et2O was added ethyl 2,3-dimethylcycloprop-2-enecarboxylate as obtained above. The mixture was stirred at 0° C. for 14 days in the dark. A solution of acetic acid in Et2O was added to quench off remaining diazomethane and the volatiles were removed in vacuo. Remaining starting material was removed by Kugelrohr distillation to afford ethyl 1,5-dimethyl-2,3-diaza-bicyclo[3.1.0]hex-2-ene-6-carboxylate (1.25 g, 6.9 mmol) as a yellowish oil in 10% yield over 2 steps.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.C(N(CC)CC)C.[NH:33]1[CH2:39][CH2:38][CH2:37][C@H:34]1[CH2:35][OH:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]([N:33]2[CH2:39][CH2:38][CH2:37][C@H:34]2[CH2:35][OH:36])[N:8]=1
Reactant: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OC[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In the solution of ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-methanesulfinyl-5-pyrimidine carboxylate in DCM was added triethylamine (4.24 g, 42 mmol). The mixture was cooled in an ice bath, then was added L-prolinol (2.2 g, 19.8 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 3 h. The reaction was monitored by LC-MS. After the completion of the reaction, the reaction mixture was washed with water, dilute hydrochloric acid, sodium bicarbonate aqueous solution and brine, each once. The organic phase was dried over sodium sulfate and concentrated until the solvent was removed. The product was used in subsequent procedures without further purification.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:6]=1)C=C.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:7]1[CH:6]=[C:5]([NH2:4])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[O:27][CH3:26])[CH:13]=2)[N:8]=1
Reactant: C=CCNc1cc(NCc2ccccc2OC)nc2ccc(Cl)cc12
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2nc(NCc3ccccc3OC)cc(N)c2c1

Procedure:
The title compound, MS: m/e=415.5 (M+H+), was prepared in accordance with the general method of example 44 from N4-allyl-6-chloro-N2-(2-methoxy-benzyl)-quinoline-2,4-diamine and 2-methoxybenzylamine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[N+:38]([O-:40])=[O:39])[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([N+:38]([O-:40])=[O:39])=[C:29]([O:28][CH3:27])[CH:30]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
1.2 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 1.08 g of 3-methoxy-4-nitrobenzoic acid and 0.96 g of dicyclohexylcarbodiimide are dissolved in a mixture of 30 ml of methylene chloride and 8 ml of dimethylformamide under ice-cooling. A catalytic amount of 4-(dimethylamino)pyridine is added to the solution, and said mixture is stirred at room temperature overnight. After the reaction, the precipitates are removed by filtration. The filtrate is washed with an aqueous potassium carbonate solution and then with water, dried and evaporated to remove solvent. The residue is purified by silica gel chromatography (solvent, chloroform:methanol=20:0.3). 1.2 g of (+)-cis-2-(4-methoxyphenyl)-3-(3-methoxy-4-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as an oil. Yield: 67.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](Cl)=[O:26])(=[O:21])[CH3:20]>O1CCCC1>[C:19]([S:22][CH2:23][CH:24]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6])=[O:26])(=[O:21])[CH3:20]
Reactant: Cc1cc(N)cc(C(=O)O)c1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Nc1cc(C)cc(C(=O)O)c1
Yield: 51.8 %

Procedure:
3-Amino-5-methylbenzoic acid (1.9 g) is dissolved in a 60% aqueous solution of tetrahydrofuran (30 ml) containing triethylamine (2.3 g), and to the mixture is added dropwise a solution of 2-acetylthiomethyl-3-phenylpropionyl chloride (3.2 g) in tetrahydrofuran (20 ml) with stirring under ice cooling, and the mixture is stirred at room temperature for 2 hours. Tetrahydrofuran is distilled off under reduced pressure, and the residue is extracted with ethyl acetate (100 ml). The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then ethyl acetate is distilled off under reduced pressure. The residue is dissolved in acetonitrile and purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desited compound are collected and concentrated into dryness under reduced pressure to give the title compound (2.4 g).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[C:36]4[C:31](=[CH:32][N:33]=[C:34](Br)[CH:35]=4)[N:30]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)[N:29]=3)[N:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH4+].[Cl-]>CCCCCC.O1CCCC1>[C:6]([CH2:7][C:34]1[CH:35]=[C:36]2[C:28]([C:24]3[N:23]=[C:22]([N:19]4[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15])[CH2:17][CH2:18]4)[CH:27]=[CH:26][CH:25]=3)=[N:29][N:30]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:31]2=[CH:32][N:33]=1)#[N:8]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(CC#N)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
A solution of 0.940 mL of 1.6 M of n-Butyllithium in hexane was added dropwise to a solution of 0.102 mL, (1.95 mmol) of acetonitrile in tetrahydrofuran at −78° C. The mixture was stirred for 30 min and a solution of 272 mg (0.500 mmol) of 4-{6-[5-bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was added. The brown mixture was stirred for 30 min at −50° C. and 2 ml of saturated aqueous NH4Cl was added. The mixture was allowed to warm to room temperature and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 44 mg (17%) of tert-Butyl 4-(6-(5-(cyanomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate. ESI MS m/z 504.2 (M+1).
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:33])=[C:12]([C:18]([I:32])=[C:19]([NH:22][C:23]([CH:25]3[CH2:29][O:28]C(C)(C)[O:26]3)=O)[C:20]=2[I:21])[CH2:13]CC([O-])=O)=[O:8])[CH2:4][O:3]1.C([O-])([O-])=[O:36].[Cs+].[Cs+].CC1(C)[O:46][CH:45]([C:47](Cl)=[O:48])[CH2:44][O:43]1>CC(N(C)C)=O.CS(C)=O>[OH:46][CH:45]([CH2:44][OH:43])[C:47]([N:22]([CH2:23][CH:25]([OH:26])[CH2:29][OH:28])[C:19]1[C:18]([I:32])=[C:12]([C:11]([I:33])=[C:10]([NH:9][C:7](=[O:8])[CH:5]([OH:6])[CH2:4][OH:3])[C:20]=1[I:21])[CH2:13][OH:36])=[O:48]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OCC(C(=O)Cl)O1
Reactant: CC1(C)OCC(C(=O)Nc2c(I)c(CCC(=O)[O-])c(I)c(NC(=O)C3COC(C)(C)O3)c2I)O1
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: O=C(Nc1c(I)c(CO)c(I)c(N(CC(O)CO)C(=O)C(O)CO)c1I)C(O)CO
Reaction time: 192 h

Procedure:
N,N'-Bis(2,2-dimethyl-1,3-dioxolane-4-carbonyl)-3,5-diamino-2,4,6-triiodobenzylacetate (408 mg, 0.50 mmol) was dissolved in a mixture of dimethylacetamide (4 ml) and DMSO (4 ml) containing Cs2CO3 (1.80 g, 5.52 mmol) and 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid chloride (2.0 ml). After stirring for 8 days, aqueous NaH2PO4 (100 ml) was added and the mixture was extracted with diethyl ether (2×150 ml). The combined organic phases were washed with water (6×100 ml), dried (Na2SO4) and evaporated. The residue was dissolved in a mixture of methanol (10 ml) and water (10 ml) and pH was adjusted to 12 with aqueous NaOH. After stirring for 2 h, concentrated HCl (1.0 ml) was added and stirring was continued for 16 h. After neutralization, the solvents were evaporated and the residue was purified by preparative HPLC. Yield: 149 mg (39%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:46]1([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[S:57])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)CC1
Reaction time: 3 h
Yield: 26 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (130 mg) and (+)-10-camphorsulfonic acid (138 mg) in ethanol (3.0 ml) was added a solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.5 ml) at room temperature, followed by stirring for 3 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (48.5 mg, 26%) as white powder.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH:3]([CH3:4])[CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH2:11]>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH:11][CH:3]([CH3:4])[CH2:2][C:1]([OH:5])=[O:6]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC1CC(=O)O1
Solvent: CCOCC
Product: CC(CC(=O)O)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
86 g (1.00 mole) of β-butyrolactone was added to 146 g (1.00 mole) of 3-chloro-4-fluoroaniline, and this mixture was stirred at 80°-90° C. for 30 minutes and then allowed to cool to room temperature. To the resulting reaction solution was added 1000 ml of ether. This mixture was filtered to remove any insoluble matter, and the filtrate thus obtained was extracted with 750 ml of a 2N aqueous solution of sodium hydroxide. This extract was acidified with 130 ml of concentrated hydrochloric acid and then extracted with 1000 ml of ether. The ether layer was separated, dried over anhydrous sodium sulfate and then evaporated to dryness. Thus, there was obtained 111 g (47.9% yield) of 3-(3-chloro-4-fluoro-anilino) butyric acid in the form of pale-yellow oily matter.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([I:14])[CH3:13]>>[I-:14].[CH2:12]([N+:7]1([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:13]
Reactant: C1CCC(N2CCCC2)CC1
Reactant: CCI
Product: CC[N+]1(C2CCCCC2)CCCC1
Product: [I-]
Yield: 86 %

Procedure:
N-cyclohexylpyrrolidine prepared in example 1 was quaternized with ethyl iodide according to the procedure describe in example 4 (using ethyl iodide in place of methyl iodide). The reaction afforded N-Ethyl-N-cyclohexylpyrrolidinium iodide in 86% yield. The iodide salt was exchanged with Bio-Rad AG 1-X8 ion-exchange resin as described in example 4 for the N-methyl-N-cyclohexylpyrrolidinium iodide. The exchange procedure afforded N-ethyl-N-cyclohexylpyrrolidinium hydroxide in 89% yield (titration analysis).
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.CCOC(C)=O.CCCCCCC>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(Br)cc3c2CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2ccc3[nH]c4c(c3c2)CCN(C(=O)c2ccccc2)CC4)cc1
Yield: 36.6 %

Procedure:
A mixture of 3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.738 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium (0.23 g, 0.20 mmol) in dimethoxyethane (5.0 mL) and a solution of 4-methoxyphenylboronic acid (0.365 g, 2.4 mmol) in dimethoxyethane (5.0 mL) and sodium carbonate solution (2 M, 7.0 mL) were reacted in a manner similar to Preparation 1. Column chromatography (silica gel, 20-60% EtOAc/heptane) afforded 0.29 g (37%) of the title compound as a yellow foam: mp 140-145° C.; 1H NMR (300 MHz, CDCl3) δ 7.92, 7.59-7.49, 7.43, 7.37-7.30, 7.03-6.94, 4.09-3.98, 3.85, 3.75-3.65, 3.25-3.14, 2.95-2.85.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@@H:4]([NH2:10])[C@H:5]([OH:9])[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C@@H:4]([NH:10][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C@H:5]([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@@H](N)[C@H](O)C(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(C)cc1)[C@H](O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2S,3R)-2-amino-3-hydroxy-4-methyl-pentanoic acid methyl ester (0.50 g, 3.4 mmol) and triethylamine (0.69 g, 6.8 mmol) in dichloromethane (10 mL) was added 4-methyl-benzenesulfonyl chloride (0.71 g, 3.7 mmol) at 0° C. After stirring for 2 hours at room temperature, the mixture was washed with water and the organic layer was separated and then dried over sodium sulfate. After removal of solvent, the residue was used in next step without purification. MS: calc'd (MH+) 316, measured (MH+) 316.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.ClCCl>O1CCOCC1>[Cl:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:15][CH2:14]1
Reactant: ClCCCN1CCNCC1
Reactant: O=C1CCCC(=O)O1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CCCC(=O)N1CCN(CCCCl)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
1.5 g of glutaric anhydride and then 2.13 g of N-(chloropropyl)piperazine in solution in 5 cm3 of dioxane and 1 cm3 of dichloromethane are added to 15 cm3 of dioxane in a round-bottomed flask kept under an argon atmosphere. After stirring for 2 hours at 20° C., the solvent is evaporated under reduced pressure (2.7 kPa) at 20° C., to give 3.75 g of 5-[4-(3-chloropropyl)piperazin-1-yl]-5-oxopentanoic acid in the form of a yellow oil which is used as it is.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11].[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].N1C=CN=C1>O>[O:6]([C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11])[Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCCOc1ccccc1)c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCOc2ccccc2)c1
Reaction time: 10 h

Procedure:
Into a 250 mL round bottom flask was added 30 mL of dry dimethyl formamide. Five parts of hydroxy ester (53) and 3.5 parts of tert-butyldimethyl silyl chloride were added to the reaction flask with stirring. Three parts of Imidazole was added in portions and stirring was continued for 10 hours. The reaction mixture was diluted with 80 mL of water and the product was extracted with ethyl acetate. The organic layer was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an oil, yield 6.80 parts. This material was pure enough for next step of the reaction. The reaction proceeded as follows:
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34][C:33](SC)=[N+:32]([CH3:37])[C:31]=2[CH:38]=1.C(N(CC)CC)C>CO>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34](=[C:6]3[C:5](=[O:7])[N:4]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:3][CH:2]3[CH3:1])[CH2:33][N:32]([CH3:37])[C:31]=2[CH:38]=1
Reactant: Cc1cc(=O)n(-c2ccccc2)[nH]1
Reactant: COc1ccc2sc(SC)[n+](C)c2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)N(C)CS2=C1C(=O)N(c2ccccc2)NC1C
Reaction time: 3.5 h

Procedure:
3-Methyl-1-phenylpyrazolin-5-one (1.74 g, 0.01 mol) was mixed with 3.97 g (0.01 mol) 5-methoxy-2-methylthio-3-methylbenzothiazolium tosylate in 25 ml methanol. Triethylamine (1.01 g, 0.01 mol) was added. The mixture was stirred for 3.5 hours, then filtered and washed with methanol. After drying the yield was 276 g (79%), mp 155°-156° C., λmax=386 (ε=25,000).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[NH:12]1[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]1.CCN(CC)CC>CC#N>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:12]2[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Oc1ccc(OCCBr)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CCN(CCOc2ccc(O)cc2)CC1

Procedure:
To a stirred suspension of 4-(2-bromo-ethoxy)-phenol (600 mg, 2.77 mmol) and ethyl isonipecotate (470 μL, 3.06 mmol) in CH3CN (12 mL) was added Et3N (768 μL, 5.54 mmol). The resultant mixture was stirred at rt overnight and then concentrated to afford the title compound, which was used immediately in the next step. MS (ESI): mass calcd. for C16H23NO4, 293.16; m/z found, 294.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(C2CCCN2S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound, white solid, m.p. 122° C. and MS: m/e=332 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-methoxy-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([OH:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[N:31]1>O>[CH2:12]([O:11][CH:10]([O:14][CH2:15][CH3:16])[CH2:9][O:8][C:5]1[CH:4]=[N:3][C:2]([O:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][N:37]=[C:36]3[NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[N:7][CH:6]=1)[CH3:13]
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CCOC(COc1cnc(Cl)nc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OCC
Temperature: 200 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-Chloro-5-(2,2-diethoxyethoxy)pyrimidine (225 mg, 0.91 mmol) obtained in Example 7 and potassium tert-butoxide (116 mg, 1.04 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (100 mg, 0.42 mmol), and stirred at 200° C. for 18 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Moritex, acetone:hexane=2:3) to obtain 6-{[5-(2,2-diethoxyethoxy)pyrimidin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (177 mg, yield: 95%) as a pale orange amorphous solid.