Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][C:14]3[N:13](S(C4C=CC(C)=CC=4)(=O)=O)[N:12]=[C:11]([NH2:26])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[C:1]1([C:7]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([NH:26][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(N)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)c1ccccc1

Procedure:
But starting with 0.3 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazole-3ylamine, 0.095 cm3 of triethylamine and 0.088 cm3 of benzoyl chloride in cm3 of dichloromethane. After flash chromatography on a column of silica [eluent: dichloromethane], 0.14 g of N-(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)benzamide is thus obtained in the form of a foam, the characteristics of which are as follows:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=O.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:3]([C:5]2[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[N:14][O:15][C:16]=3[CH2:17][OH:18])[CH:9]=2)=[O:2])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nn1C
Product: Cn1nc(OCc2c(-c3ccc(Cl)cc3)noc2CO)cc1C(=O)NC1CC1
Yield: 30 %

Procedure:
As described for example 100f, 5-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.27 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (32 mg, 30%) which was obtained as a white solid. MS: m/e=403.2 [M+H]+.
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[C:9]#[N:10]>CCO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([C:9](=[N:1][OH:2])[NH2:10])[CH:11]=1
Reactant: COc1ccc(F)cc1C#N
Reactant: NO
Solvent: CCO
Product: COc1ccc(F)cc1C(N)=NO
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Hydroxylamine (4.97 ml; 82.7 mmol; 5 eq.) was added to a suspension of 5-fluoro-2-methoxybenzonitrile (Aldrich 527734; 2.5 g; 16.5 mmol; 1 eq.) in EtOH (30 mL) and the resulting mixture was stirred at room temperature for 3 days then to dryness to afford the title compound (3.04 g, 100%) as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC([CH2:14][N:15](C)[C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([C:28]4[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:29]=4[Cl:35])[C:22](=[O:27])[N:23]3[CH3:26])=[CH:18][N:17]=2)=CC=1>C(Cl)Cl>[NH2:34][C:32]1[CH:31]=[CH:30][C:29]([Cl:35])=[C:28]([C:21]2[C:22](=[O:27])[N:23]([CH3:26])[C:24]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:15][CH3:14])[CH:25]=3)[CH:33]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)ccc2Cl)c(=O)n3C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc2c(cn1)cc(-c1cc(N)ccc1Cl)c(=O)n2C
Yield: 58.7 %

Procedure:
TFA (10 mL, 134 mmol) was added to a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chlorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (4 g, 9.2 mmol) in DCM (50 mL) and heated to reflux for 3 h. The reaction mixture was concentrated under reduced pressure, dissolved in HCl, washed with EtOAc (3×), neutralized with satd. Na2CO3 and extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by chromatography to give 3-(5-amino-2-chlorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1.7 g, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.63 (s, 1H), 7.06-7.00 (m, 2H), 6.54-6.50 (m, 2H), 6.14 (s, 1H), 5.21 (s, 2H), 3.48 (s, 3H), 2.84 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 314.9 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:24]([CH:28]([C:32](O)=[O:33])[C:29]([OH:31])=[O:30])[CH2:25][CH2:26][CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:32]([CH:28]([CH2:24][CH2:25][CH2:26][CH3:27])[C:29]([OH:31])=[O:30])=[O:33])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CCCCC(C(=O)O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(C(=O)O)C(=O)NCc1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), 2-butylmalonic acid (200 mg, 1.24 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature for 30 min. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified with purified with a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 70% CH3CN in water at a flowrate of 20 mL/min. The fractions were dried with EZ GeneVac to give 2-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]hexanoic acid. LC-MS m/z 446 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:17])[CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O[CH:21](O)[C:22]([F:25])([F:24])[F:23])C.O>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10](/[N:17]=[CH:21]/[C:22]([F:25])([F:24])[F:23])[CH2:11][CH2:12][C:13]([F:14])([F:16])[F:15])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N)CCC(F)(F)F
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H](CCC(F)(F)F)/N=C/C(F)(F)F

Procedure:
A solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoro-pentan-2-amine (3.00 g, 11.06 mmol) and trifluoroacetaldehyde ethyl hemiacetal (1.6 g, 11.1 mmol) in benzene (20 mL) was refluxed for 2 hours during which time water was collected in a Dean-Stark trap. The solvent was removed in vacuo yielding crude (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-trifluoro-N-[(1E)-2,2,2-trifluoroethylidene]pentan-2-amine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:26])[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14][CH2:13][C:12]([CH3:18])([CH:15]=[N:16]O)[CH2:11][CH2:10]1>C1COCC1>[NH2:16][CH2:15][C:12]1([CH3:18])[CH2:11][CH2:10][C:9]([N:8]([CH3:26])[CH3:7])([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:14][CH2:13]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(C)(C=NO)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C1(c2cccc(F)c2)CCC(C)(CN)CC1

Procedure:
Lithium aluminium hydride (440 mg, 11.6 mmol) was suspended in abs. THF (50 mL) in argon, mixed in drops with a solution of the title compound of step 3 (1.54 g, 5.53 mmol) in abs. THF (20 mL) and boiled for 4 h with reflux. The batch was then hydrolysed with water (10 mL) at 10° C. and filtered off over diatomaceous earth. The THF was removed in a vacuum, the residue adjusted to pH 11 with 1N NaOH and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue was purified by flash chromatography with MeOH+2% NH3.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)(=[O:17])=[O:16])[N:12]([C:25]2[C:26]([F:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:11]=1)C)(C)(C)C.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.CC(O)C>[ClH:39].[F:31][C:26]1[C:25]([N:12]2[C:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)(=[O:17])=[O:16])=[CH:14][C:10]([CH2:9][NH:7][CH3:6])=[N:11]2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Cc1cccc(S(=O)(=O)c2cc(CN(C)C(=O)OC(C)(C)C)nn2-c2cccnc2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cc(S(=O)(=O)c2cccc(C)c2)n(-c2cccnc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
tert-Butyl({1-(2-fluoropyridin-3-yl)-5-[(3-methylphenyl)sulfonyl]-1H-pyrazol-3-yl}methyl)methylcarbamate (302 mg) was dissolved in ethyl acetate (2 mL) and 2-propanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 216 mg, yield 83%). melting point 202-205° C.
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[CH:13]=[O:14].C1(C)C=CC=CC=1>O>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[C:13]([OH:2])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC1CCCC(C)(C)C1C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCCC(C)(C)C1C(=O)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 40 g of nitric acid (60% aqueous solution) and heated to 55° C. To the solution was added dropwise 95 g (0.62 mole) of 2,2,6-trimethylcyclohexanecarbaldehyde (4) composed of 90% of the trans-form and 10% of the cis-form synthesized in Synthesis Example 2-A) described above over a period of 2 hours. Thereafter, the reaction was carried out for 3 hours at the same temperature. Then, 100 g of toluene and 100 g of water were added to the reaction mixture at room temperature to wash with water and form an organic layer and an aqueous layer separately. The organic layer was washed thrice with 100 g of a saturated aqueous sodium chloride solution, and 80 ml of the toluene was distilled off under reduced pressure by means of an evaporator, to provide 104 g of crude 2,2,6-trimethylcyclohexanecarboxylic acid (5) composed of 89% of the trans-form and 11% of the cis-form (boiling point: 44° to 54° C.). The mass spectra of the cis- and trans-forms of the acid (5) were the same as those in Synthesis Example 1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.Cl[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH2:38])([CH3:37])[CH3:36])=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1.FC(F)(F)C([O-])=O>>[CH3:37][C:35]([NH:38][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:36])[CH2:34][C:31]1[CH:32]=[CH:33][CH:28]=[CH:29][C:30]=1[C:39]([F:40])([F:41])[F:42]
Reactant: CC(C)(N)Cc1ccc(Cl)cc1C(F)(F)F
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(Cc1ccccc1C(F)(F)F)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 252 mg (1 mmol) 2-(4-chloro-2-trifluoromethyl-phenyl)-1,1-dimethyl-ethylamine are reacted and worked up analogously to the method described for Example 2c). White solid. Yield: 165 mg (31%, trifluoroacetate); mass spectroscopy [M+H]+=425.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([CH:18]=O)=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([CH2:18][N:29]4[CH2:30][CH2:31][CH:26]([NH:25][C:23](=[O:24])[C:22]([F:21])([F:32])[F:33])[CH2:27][CH2:28]4)=[CH:13][C:12]=3[CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C=O)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(CN2CCC(NC(=O)C(F)(F)F)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carbaldehyde (2.0 g) and 4-trifluoroacetamidopiperidine (1.56 g) dissolved in 1,2-dichloroethane (50 ml) was added under ice cooling sodium triacetoxyborohydride (1.8 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. Thereto were added triethylamine (1.1 ml) and sodium triacetoxyborohydride (0.8 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was neutralized with a 1 N aqueous solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and then was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals (3.0 g). A portion of the crystals was recrystallized from ethyl acetate/hexane to obtain 1-(7-(4-methylphenyl)-2,3-dihydro-1-benzooxepin-4-ylmethy)-4-trifluoroacetamidopiperidine as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1
Yield: 67.3 %

Procedure:
Following General Procedure B, the title compound (150 mg, 68%) was prepared from 5-Chloro-2-methylsulfanyl-phenylamine (110 mg, 0.64 mmol) and 4-Chloro-benzenesulfonyl chloride (134 mg, 0.64 mmol).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH:6]1([C:12]2[NH:13][S:14](=[O:23])(=[O:22])[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>OS(O)(=O)=O>[CH:6]1([C:12]2[NH:13][S:14](=[O:22])(=[O:23])[C:15]3[CH:21]=[C:20]([N+:1]([O-:4])=[O:2])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=S1(=O)NC(C2CCCCC2)=Nc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)=N2
Temperature: 25 °C

Procedure:
To a stirred solution of KNO3 (1.2 g; 11.5 mmol) and conc. H2SO4 (8 ml) at 5° C. was added a solution of 3-cyclohexyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide in conc. H2SO4 (8 ml). The reaction mixture was allowed to warm up to r.t. and left with stirring over night. The product was precipitated by slow addition of ice and isolated by filtration. The crude product (4.3 g) was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[C:30]([O:32][CH3:33])=[O:31]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[C:23]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=1)[C:12]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C=O)ccc1OC
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Product: COC(=O)c1cc(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)ccc1OC

Procedure:
By the method of Example 44, 6-benzyloxy-4-chromanone (20.95 g) and 4-methoxy-3-methoxycarbonylbenzaldehyde were converted to present title product, 25.75 g (73%); tlc (19:1 CH2Cl2 :ether) Rf 0.70.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]([CH2:14][CH2:15]O)[CH2:11][CH:12]=[CH2:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:30]([NH2:33])[CH:31]=[CH2:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([CH2:11][CH:12]=[CH2:13])[CH2:14][CH2:15][N:33]2[CH2:30][CH:31]=[CH2:32])=[CH:4][CH:3]=1
Reactant: C=CCN
Reactant: C=CCN(CCO)C[C@H](O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN1CCN(CC=C)[C@H](c2ccc(Cl)cc2)C1
Temperature: 5 °C
Reaction time: 12 h
Yield: 102.5 %

Procedure:
To (R)-1-(4-chlorophenyl)-2-[(2-hydroxyethyl)(2-propenyl)amino]-1-ethanol (724 mg, 2.5 mmol) produced in Example 13, tetrahydrofuran (2.51 g) and triethylamine (868 mg, 3.5 equivalents) were added. The mixture was cooled to 5° C. Methanesulfonyl chloride (899 mg, 3.2 equivalents) was added dropwise thereto, and then allylamine (839 mg, 6.0 equivalents) was added dropwise thereto. The temperature of the mixture was raised to 25° C., and then the mixture was stirred for 12 hours. To the mixture, 10 wt % aqueous solution of sodium carbonate (4.15 g) was added. After the organic layer and aqueous layer were separated, the aqueous layer was extracted with toluene (5 mL). The organic layers were combined, and washed twice with distilled water (5 mL). The obtained organic layer was concentrated and dried under vacuum, to obtain 709 mg of the title compound as pale yellow oil (yield: 92%, chemical purity: 81.7 area %).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[N:7]=1
Reactant: NCC1CC1
Reactant: Clc1ccnc(Cl)n1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccnc(NCC2CC2)n1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
In a microwave reaction vessel, slurry 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), cyclopropylmethylamine (550 μL, 6.0 mmol), and diisopropylethylamine (2.35 mL, 13.4 mmol) in toluene (3 mL). Irradiate in microwave (300 watts) at 120° C. for 30 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1 to 3:7 over 30 min; 40 mL/min) to obtain the desired intermediate (157.5 mg, 15%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:18][CH2:17][CH2:16][CH2:15][Cl:14])[CH2:4][CH2:3]1
Reactant: ClCCCCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1CCN(CCCCCl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
In a 2 L three-necked round bottomed flask was added N-methyl-piperazine (100.16 g, 1.0 mol), acetone (1000 mL), and anhydrous potassium carbonate (276.42 g, 2.0 mol, 2.0 equiv.). The flask was equipped with a mechanical stirrer and a condenser. 4-chloro-1-bromo-butane (188.6 g, 1.1 mol, 1.1 equiv.) was added dropwise under continuous stirring at room temperature over a period of 30 min. The suspension mixture was then stirred at 40° C. The progress of the reaction was monitored by TLC, which confirmed the reaction was completed after 4 hours. The mixture was cooled to room temperature and the insoluble materials were removed by filtration and washed with dichloromethane (2×100 mL). The combined filtrates were concentrated under vacuum until they became dry. The residue was then mixed with dichloromethane (500 mL). Insoluble materials were removed by filtration and washed by dichloromethane (2×100 mL). The combined filtrate and washings were concentrated and purified through a flash silica gel column, which gave the expected product as light yellow oil. (92.5 g, 48.5% yield).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[K+].[NH:12]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:13][C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([CH2:27]Br)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15]>>[NH:12]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH2:13][C:14]([NH:16][C@H:17]([C:21]([N:23]1[CH2:31][CH2:30][CH2:29][C@H:24]1[C:25]([CH2:27][O:8][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])=[O:26])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)CBr
Reactant: O=C(O)c1ccccc1
Agent: [F-]
Agent: [K+]
Product: CC(C)[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)COC(=O)c1ccccc1

Procedure:
Benzoic acid (1.19 g, 9.78 mmol), KF (0.568 g, 9.78 mmol), 16 (2.35 g, 4.89 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[C:32]([NH2:33])=[C:31]2[O:34][CH2:35][O:36][C:30]2=[CH:29][CH:28]=1>C(O)(C)C>[Cl:26][C:27]1[C:32]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:9][C:10]=3[N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:5]=[CH:4][N:3]=2)=[C:31]2[O:34][CH2:35][O:36][C:30]2=[CH:29][CH:28]=1
Reactant: Clc1ncnc2cc(OCCN3CCCC3)cc(N3CCOCC3)c12
Reactant: Nc1c(Cl)ccc2c1OCO2
Solvent: CC(C)O
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCCN4CCCC4)cc(N4CCOCC4)c13)OCO2
Temperature: 80 °C
Yield: 9.4 %

Procedure:
A mixture of 4-chloro-5-morpholino-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.27 g), 6-chloro-2,3-methylenedioxyaniline (0.14 g) and isopropanol (4 ml) was stirred and heated to 80° C. for 1 hour. The mixture was evaporated and the residue was dissolved in a 49:1 mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was poured onto a column of silica and eluted with a 97:3 mixture of methylene chloride and a saturated methanolic ammonia solution. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.035 g); NMR Spectrum: (CDCl3) 1.85 (br s, 4H), 2.65 (br s, 4H), 3.0 (m, 2H), 3.08 (m, 2H), 3.18 (d, 2H), 3.82 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 6.05 (s, 2H), 6.75 (d, 1H), 6.95–7.1 (m, 3H), 8.52 (s, 1H); Mass Spectrum: M+H+ 498 and 500.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[OH-].[Na+]>O>[N:5]1[CH:6]=[CH:7][C:2]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:4]=1
Reactant: C1CNCCNC1
Reactant: Brc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(N2CCCNCC2)ccn1
Temperature: 100 °C
Yield: 40.1 %

Procedure:
A mixture of 2 g of 4-bromopyridine and 10 g of homopiperazine is heated at 100° C. for 4 hours. 100 ml of water are added to the reaction mixture and the resulting mixture is basified to pH 10 by addition of 10% NaOH solution and extracted three times with 100 ml of chloroform, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. 0.9 g of the expected product is obtained.