Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:34][CH:31]5[CH2:33][CH2:32]5)=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: NC1CC1
Agent: Cl
Product: O=C(NC1CC1)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 12.9 mg (0.23 mmol) of cyclopropylamine are reacted together by general method E. 17.6 mg (31.1% of theory) of the title compound are obtained.
Reaction SMILES: CON(C)[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOC(C)=O>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[O:22])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1ccccc1CS(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Cc2ccccc2C=O)cc1
Temperature: 25 °C

Procedure:
To a solution of N-methoxy-N-methyl-2-{[(4-methylphenyl)sulfonyl]methyl}benzamide (0.645 mmol) in 5 mL THF at −78° C. is added 1.0 M solution of LiAlH4 in THF (0.709 mmol) slowly with stirring. The reaction is stirred at −78° C. for 1 hr and gradually warmed up to RT. The reaction mixture is diluted with EtOAc and washed with H2O. The solution is dried over Na2SO4 and the solvent is evaporated to give a quantitative yield of 2-{[(4-methylphenyl)sulfonyl]methyl}benzaldehyde.
Reaction SMILES: [CH2:1]([CH2:16]/[C:17](/[CH3:36])=[CH:18]/[CH2:19][CH2:20]/[C:21](/[CH3:35])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:34])=[CH:26]/[CH2:27][CH2:28]/[C:29](/[CH3:33])=[CH:30]/[CH2:31]Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[CH2:37]([NH2:47])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1.O>C1COCC1>[CH2:1]([CH2:16]/[C:17](/[CH3:36])=[CH:18]/[CH2:19][CH2:20]/[C:21](/[CH3:35])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:34])=[CH:26]/[CH2:27][CH2:28]/[C:29](/[CH3:33])=[CH:30]/[CH2:31][NH:47][CH2:37][C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Reactant: NCc1ccc2c(c1)OCO2
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CNCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
In 10 ml of THF was dissolved 4.56 g of farnesylgeranylgeranyl bromide, 3.01 g of piperonylamine was added and stirred at room temperature for one hour. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and then brine, dried over magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (using as a developing solvent hexane-ethyl acetate (4:1)→ethyl acetate) to give 1.14 g of N-farnesylgeranylgeranylpiperonylamine as a yellow liquid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[N:7]=[C:6]([CH3:20])[C:5]=2[C:21](O)=[O:22])[CH2:3][CH2:2]1.[N:24]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=3)[N:7]=[C:6]([CH3:20])[C:5]=2[C:21]([N:32]2[CH2:33][CH2:34][CH:29]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:30][CH2:31]2)=[O:22])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C2CC2)c1C(=O)O
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C2CC2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
The title compound was prepared from 5-Cyclopropyl-3-methyl-1-(4-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidin-1-yl-piperidine in direct analogy to the general procedure used in example 150. MS: 463.2 (MH+).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:13])O[C:10](=[O:12])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C>[CH2:14]([N:21]1[C:10](=[O:12])[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([OH:13])=[N:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: NNCc1ccccc1
Solvent: CC(=O)O
Product: O=c1cc(-c2ccccc2)c(O)nn1Cc1ccccc1
Yield: 344 %

Procedure:
3-Phenylfuran-2,5-dione (2.00 g, 11.5 mmol), benzylhydrazine (3.36 g, 17.2 mmol) and acetic acid (2 mL) were heated to 140° C. for 3 h in a 20 mL heavy-walled sealed tube under microwave irradiation. Upon cooling, a white precipitate formed which was filtered and washed three times with hexane and DCM. The white solid was dried under reduced pressure to give the title compound (11.01 g). LCMS m/z=279.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 5.13 (s, 2H), 7.00 (s, 1H), 7.42-7.26 (m, 5H), 7.49-7.43 (m, 3H), 7.66-7.60 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=2[Cl:41])[CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[OH-].[Na+].Cl>CO.O>[Cl:41][C:32]1[C:33]([C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:15]([CH2:16][CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:42])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(CCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cccc(CCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Yield: 65.5 %

Procedure:
A solution of (3-{4-[(2-chloro-3-(trifluoromethyl)benzyl)-(2,2-diphenylethyl)-amino]butyl}phenyl)-acetic acid methyl ester (29 mg, 0.05 mmol) and NaOH (126 mg, 3.15 mmol) in MeOH (3 ml) and water (1 ml) was heated to 50° for 30 minutes. The reaction was cooled, neutralized with aqueous HCl (3.15 mmol), diluted with water and extracted with ethyl acetate. The extracts were dried and the solvent evaporated. Trituration of the residue with cyclohexane gave the title compound as a white powder (19 mg, 65%). MS (ESI) 580.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][N:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N+:35]([O-])=O)[C:19]2=[O:38])[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[C@H:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][N:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[NH2:35])[C:19]2=[O:38])[CH2:16][CH2:17]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(N2C(=O)N(c3ccccc3[N+](=O)[O-])C[C@H]2c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(CCNC(=O)OC(C)(C)C)N1CCC(N2C(=O)N(c3ccccc3N)C[C@H]2c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
To a solution of (3-{4-[(R)-3-(2-nitro-phenyl)-2-oxo-5-phenyl-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (180 mg, 0.334 mmol) in CH3OH (3 ml) was added Pd/C (20 mg, 50%). The mixture was hydrogenated under H2 (2 atm.) for 10 min. Filtration and concentration gave (3-{4-[(R)-3-(2-amino-phenyl)-2-oxo-5-phenyl-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (160 mg, 94%). Treatment with TFA (1 ml) and CH2Cl2 (1 ml) according to general procedure C gave (R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-1-(2-amino-phenyl)-4-phenyl-imidazolidin-2-one (114 mg, 94%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([I:15])=[N:9][N:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1)=O.Cl.[NH2:18][C:19]([NH2:21])=[NH:20].[OH-].[Li+]>C(O)(CC)C>[I:15][C:8]1[C:7]([C:5]2[CH:4]=[CH:3][N:18]=[C:19]([NH2:21])[N:20]=2)=[CH:11][N:10]([CH:12]([CH3:14])[CH3:13])[N:9]=1
Reactant: CC(C)n1cc(C(=O)C=CN(C)C)c(I)n1
Reactant: N=C(N)N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: CC(C)n1cc(-c2ccnc(N)n2)c(I)n1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of crude Intermediate 3-(dimethylamino)-1-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)prop-2-en-1-one (4.0 g, 12.0 mmol), guanidine hydrochloride (2.63 g, 27.6 mmol), lithium hydroxide (635 mg, 27.6 mmol), and sec-butanol (50 ml) was heated with stirring in a sealed reaction vessel at 110° C. for 20 h. The cooled reaction mixture was concentrated, then water was added and the mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated. Ethyl acetate was added to the solid residue, and the mixture was sonicated. The solid product was collected on a filter, rinsed with ethyl acetate, and dried to give the title compound as a tan solid. MS m/z 330.0 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:23]=1[CH2:24]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][C:22]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:23]=1[CH2:24][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)c(C)c1

Procedure:
To 60 ml DMF, was added 11-(piperidine-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.0 g, 0.0186 mole), 2,4,6-trimethylbenzyl chloride (4.2 g, 0.025 mole), milled K2CO3 (15 g, 0.1 mole) and KI (0.01 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]1[C:12]2[CH2:13][NH:14][CH2:15][C:11]=2[CH2:10][N:9]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[O:17].Cl[C:29]1[N:30]=[N:31][C:32]([O:35][CH2:36][CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:33][CH:34]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:40]1[CH2:41][CH2:42][CH:37]([CH2:36][O:35][C:32]2[N:31]=[N:30][C:29]([N:14]3[CH2:13][C:12]4[CH2:8][N:9]([C:16]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:24]([F:27])([F:25])[F:26])=[O:17])[CH2:10][C:11]=4[CH2:15]3)=[CH:34][CH:33]=2)[CH2:38][CH2:39]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Reactant: Clc1ccc(OCC2CCOCC2)nn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(OCC3CCOCC3)nn1)C2

Procedure:
(3,4,5,6-Tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (example 1b) (500 mg, 1.26 mmol) was reacted analogously to example 4b with 3-chloro-6-(tetrahydropyran-4-ylmethoxy)pyridazine (288.6 mg, 1.26 mmol). Yield: 129 mg (17%), M+H+: 475.18.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15][CH:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:18]([CH:16]([CH3:17])[CH3:15])(=[O:20])=[O:19])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-nitrophenylcarboxamide (2 g) in 150 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 530 mg of sodium hydride (60% oil dispersion). The reaction mixture was stirred for 20 minutes and then 2-propylsulfonylchloride (1.5 ml) was introduced dropwise via syringe. After 5 minutes the reaction mixture became homogeneous and was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with 300 ml of ethyl acetate and was washed with brine. The organic extracts were dried, concentrated in vacuo, and the residue was chromatographed on silica gel (chloroform-methanol, 95:5 v/v) to yield 0.6 g of the title compound in pure form.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][NH2:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]1[C:21]([C:22]#[N:23])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([O:24][CH3:25])=[CH:17][CH:18]=2)[N:13]=1>CN(C)C=O>[CH3:25][O:24][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:21]3[C:22]([NH2:23])=[N:10][N:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:12]3=[N:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2cc(C#N)c(Cl)nc2c1
Reactant: NNc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc3c(N)nn(-c4ccccc4)c3nc2c1
Temperature: 25 °C

Procedure:
To a suspension of 4.8 g sodium hydride (60%) in 200 ml dimethylformamide at 0° C. was added a solution of 9.9 ml phenylhydrazine in 250 ml dimethylformamide over a 15 min period. The mixture was stirred and allowed to warm to room temperature for 1 hour. 2-Chloro-7-methoxy-3-quinolinecarbonitrile (Example 3c) (19.68 g) was then added in portions. The reaction mixture was stirred overnight at room temperature, and then heated on a steam bath for two hours. Since starting material was still present, additional sodium hydride (3.2 g) was added and heating continued until thin layer chromatography indicated that no starting material remained. The mixture was quenched in saturated ammonium chloride solution and the mixture worked up in ethyl acetate solution. The crude product was purified by chromatography and recrystallized from ethyl acetate to give 2.3 g 7-methoxy-1-phenyl-1H-pyrazolo[3,4-b]quinolin-3-amine, brown solid, m.p. 159°-160° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[CH3:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CCCO
Reactant: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1
Product: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(-n3cc(CCO)nn3)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 445 (0.03 mmol) and but-3-yn-1-ol (0.06 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 30:70 to 100:0 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 194.7, 149.5, 146.2, 141.1, 138.2, 136.4, 135.7, 134.7, 134.1, 132.6, 131.2, 130.8, 127.4, 127.2, 125.6, 122.1, 120.7, 120.1, 115.8, 112.4, 61.5, 28.6, 19.9, 17.9
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:21]([O:23][C:24](=[O:41])[CH:25]=[C:26]1[CH:35]([CH3:36])[CH:34](Br)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[O:38][CH3:39])[C:27]1=[O:40])[CH3:22]>C1COCC1>[CH2:21]([O:23][C:24](=[O:41])[CH:25]([C:26]1[C:35]([CH3:36])=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[O:38][CH3:39])[C:27]=1[OH:40])[O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:22]
Reactant: COc1ccc(CO)cc1
Reactant: CCOC(=O)C=C1C(=O)c2cccc(OC)c2C(Br)C1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(OCc1ccc(OC)cc1)c1c(C)cc2c(OC)cccc2c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a solution of 4-methoxybenzyl alcohol (0.27 mL, 4 equiv) in THF (11 mL) at 0° C. was added KHMDS (0.5 M in toluene, 3.4 mL, 3 equiv) and the resulting mixture was allowed to stir for 10 min at 0° C. A solution of (4-bromo-5-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)-acetic acid ethyl ester (200 mg) in THF (1 mL) was added slowly. After stirring for 3 min at 0° C., the reaction was quenched with citric acid (1 M) and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (5-20% EtOAc/hexanes) to give 157 mg of pale orange oil (68% yield). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H27O6: 411.18. Found: 411.21.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:23][CH2:24][OH:25])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH:27]1([NH:30][C:31]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:31](=[O:32])[C:33]2[CH:40]=[CH:39][C:36]([C:37]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]([CH2:23][CH2:24][OH:25])[CH3:22])=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:35][CH:34]=2)[CH2:28][CH2:29]1
Reactant: CN(CCO)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Product: CN(CCO)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(C(=O)NC5CC5)cc4)nc3c2)cc1

Procedure:
Compound 235 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-(N-2-hydroxyethyl-N-methylamino)benzamide and 4-cyclopropylaminocarbonylbenzaldehyde. [M+H]+ calcd for C27H27N5O3: 470.22; found: 470.60.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH3:24])=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: CNCCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)cc1)CC1CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 0.1 g of (4-bromo-phenyl)-[4-(6-methylamino-hexyloxy)-phenyl]-methanone, 0.13 ml of diisopropylethylamine and 0.06 ml of bromomethyl-cyclopropane in 20 ml of dimethyl-acetamide is stirred at 50° C. for 24 hrs., concentrated and the residue is treated with sodium hydrogen carbonate solution and extracted with methylene chloride. The organic phases are washed with saturated sodium chloride solution, dried and evaporated. The residue is purified over silica gel with CH2Cl2 /MeOH/NH4OH (94/5.410.6 to 85/12.5/2.5). There is obtained 0.68 g of (4-bromo-phenyl)-[4-[6-(cyclopropylmethyl-methyl-amino)-hexyloxy]-phenyl]-methanone which is converted into the fumarate, MS: m/e 443 (M+H+, 1Br).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[Br:10]Br>C(O)(=O)C>[Br:10][CH2:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)s1
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(5-Bromothiophen-2-yl)ethanone (1 g, 4.87 mmol) was dissolved in glacial acetic acid (5 mL) and treated with bromine (0.25 mL) in acetic acid (2 mL) added dropwise. The reaction was stirred at ambient temperature overnight. The volatiles were removed in vacuo while care was taken so as to keep the bath temperature under 40° C. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 10 to 30% of ethyl acetate in hexanes to yield a off-white solid (0.85 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N)CN>>[CH2:14]([O:13][Si:9]([CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O:16][CH2:17][CH3:18])[O:10][CH2:11][CH3:12])[CH3:15]
Reactant: C1COCCN1
Reactant: CCO[Si](CCl)(OCC)OCC
Solvent: NCCN
Product: CCO[Si](CN1CCOCC1)(OCC)OCC
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
82 g of dry morpholine (pKb 5.67) were heated to 120° C. in a 500 ml four-necked flask having a reflux condenser, KPG stirrer and thermometer and 80 g of chloromethyltriethoxysilane were added in the course of 180 min with stirring. After the end of the addition, the temperature was reduced to 105° C. and 56.6 g of ethylenediamine (pKb 4.07) were added to the mixture in the course of 10 min with stirring, phase separation occurring. At constant temperature, stirring was effected for a further 30 min and the heavier ethylenediamine hydrochloride phase was then separated off. The upper phase was subjected to fractional distillation. 68 g (yield 68%) of 4-(triethoxysilylmethyl)tetrahydro-1,4-oxazine were obtained, the purity of which was determined as 98.4% by gas chromatography.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]4[O:24][CH2:25][O:26][C:18]=34)=[N:11][CH:12]=[N:13]2)=[C:8]([O:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:22]1[C:17]([NH:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:7][C:8]=3[O:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:13]=[CH:12][N:11]=2)=[C:18]2[O:26][CH2:25][O:24][C:19]2=[CH:20][CH:21]=1
Reactant: C1CCNCC1
Reactant: Clc1ccc2c(c1Nc1ncnc3cc(OCCCBr)cc(OC4CCOCC4)c13)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCCCN4CCCCC4)cc(OC4CCOCC4)c13)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(3-bromopropoxy)-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.536 g), piperidine (0.12 ml), potassium carbonate (0.4 g) and DMF (2 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under methylene chloride. The mixture was filtered and the filtrate was purified by column chromatography on silica using initially a 1:1 mixture of ethyl acetate and methylene chloride and then a 10:9:1 mixture of ethyl acetate, methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.53 g); NMR Spectrum: (CDCl3) 1.4–1.5 (m, 2H), 1.55–1.7 (m, 4H), 1.9–2.1 (m, 4H), 2.2–2.3 (m, 2H), 2.4 (m, 4H), 2.5 (m, 2H), 3.6–3.7 (m, 2H), 4.0–4.1 (m, 2H), 4.15 (m, 2H), 4.8 (m, 1H), 6.08 (s, 2H), 6.52 (d, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.35 (s, 1H); Mass Spectrum: M+H+ 541 and 543.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)([Cl:14])=O.CN(C=O)C>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([Cl:14])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cl)cc1I

Procedure:
3-Iodo-4-methylbenzoic acid (9.84 g) was dissolved in THF (50 ml) and thionyl chloride (4 ml) and DMF (0.05 ml) were added. The mixture was heated under ref lux for 3 hrs. The reaction mixture was concentrated under reduced pressure to give 3-iodo-4-methylbenzoyl chloride (10.18 g) as a brown powder. Then, by the reaction in the same manner as in Example 26-i), the title compound (3.47 g) was obtained from a solution of 3-iodo-4-methylbenzoyl chloride (4.00 g) and methylamine in THF (2M, 30 ml) as colorless powder crystals