Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.C[C:5]1([CH3:13])[O:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])O1.CN(C1C=CC=CN=1)C.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])C(Cl)=O>C(O)C>[CH3:23][C:24]1[CH:25]=[C:26]([C:7](=[O:12])[CH2:8][C:9]([O:10][CH2:5][CH3:13])=[O:11])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: Cc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
To a dichloromethane solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (10 g) and dimethylaminopyridine (17 g), a dichloromethane solution of 3-methyl-4-nitro-benzoyl chloride (14 g) was added dropwise under ice cooling. After stirring at room temperature for 3 hours and then adding 100 ml of ethanol, the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off under the reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N aqueous solution of hydrochloric acid. After drying the organic layer with sodium sulfate, the solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain ethyl 3-(3-methyl-4-nitro-phenyl)-3-oxo-propionate (12.4 g). mp; 207-211° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].[S:10](Cl)(=[O:13])(=[O:12])[NH2:11].C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][O:9][S:10](=[O:13])(=[O:12])[NH2:11]
Reactant: NS(=O)(=O)Cl
Reactant: Cc1ncsc1CCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ncsc1CCOS(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
4-Methyl-5-thiazoleethanol (10.0 g, 0.0698 mole) was dissolved in acetonitrile, chilled, and sulfamoyl chloride (10.44 g, 0.091 mole) was added to the stirred solution. Triethylamine (9.19 g, 0.091 mole) was added dropwise while maintaining the temperature between 20°-25° C. A yellow solid precipitated after the addition was completed. The reaction was stirred at room temperature overnight, evaporated to a residue, and the residue partitioned between ethyl acetate/acetonitrile (1:1) and sodium bicarbonate/sodium chloride (1:1). The organic phase was treated with charcoal, dried (magnesium sulfate), filtered, and evaporated to a residue (9.29 g). The residue was dissolved in a small amount of methanol and isopropanol was added. The first crop (2.0 g) crystallized out of isopropanol as the methanol was evaporated. The crystals were collected and dried to yield 2.0 g (13%) of solid, mp 80°-83° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]#[C:20][C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][OH:28])=[C:23]([CH3:31])[CH:22]=3)=[N:17][CH:18]=2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][S:2]([O:28][CH2:27][CH2:26][O:25][C:24]1[CH:29]=[CH:30][C:21]([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)=[CH:18][N:17]=2)=[CH:22][C:23]=1[CH3:31])(=[O:4])=[O:3]
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.74 mL (35.29 mmol) of methanesulfonic acid chloride was added dropwise at 0° C. to a solution of 10.70 g (29.41 mmol) of 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethanol and 4.08 mL (29.41 mmol) of triethylamine in 500 mL of THF and the mixture was then stirred for 2 hours at RT. The reaction mixture was filtered and the filtrate was evaporated down in vacuo. The residue was stirred with diethyl ether and water, and the precipitate was filtered off and dried in vacuo. Yield: 11.00 g (85% of theoretical); C23H20ClNO4S (M=441.928); calc.: molpeak (M+H)+: 442/444 (Cl); found: molpeak (M+H)+: 442/444 (Cl); HPLC-MS: 6.36 minutes (method C).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl.[NH2:26][OH:27]>CCO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:26][OH:27])=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)nc1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: ON=C(c1ccccc1)c1ccc(Cl)nc1
Yield: 88.8 %

Procedure:
The ketone issued from the precedent step (XIX*), e.g., (6-chloropyridin-3-yl)(phenyl)methanone (435 mg, 2 mmol), was dissolved in EtOH (40 mL). DIEA (1.027 mL, 6 mmol) and hydroxylamine hydrochloride (417 mg; 6 mmol) were added. The mixture was heated under reflux overnight. The solvents were removed. The resulting crude mixture was dissolved in ethyl acetate (40 mL) and was washed with three portions of water. The organic layer was dried over magnesium sulfate, filtrated and evaporated to give the desired product (XXXXIII*), e.g., (6-chloropyridin-3-yl)(phenyl)methanone oxime (413 mg, 89% yield). It was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>N1C=CC=CC=1.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[NH:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=3)=[CH:17][N:16]=2)=[N:3][CH:4]=1)#[N:9]
Reactant: Cc1ccc(Cc2cnc(NCCCN)[nH]c2=O)cn1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(Cc2cnc(NCCCNc3ccc(C#N)cn3)[nH]c2=O)cn1

Procedure:
2-Chloro-5-cyanopyridine (0.61 g), 2-(3-aminopropylamino)-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.09) and potassium carbonate (0.61 g) were heated together under reflux in pyridine (10 ml) for 2.5 hr. The mixture was stripped, the residue taken up in water and the pH adjusted to 3 with hydrochloric acid. After extracting with chloroform the aqueous solution was filtered and the pH raised to 6.5 with sodium hydroxide. The precipitate thus obtained was chromatographed (silica gel, chloroform/methanol, graded 1:0 to 20:1) and the required component recrystallised twice from ethanol to give 2-[3-(5-cyanopyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone 0.2H2O, (0.38 g; 25%) m.p. 175°-177° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-:13])=O)=[C:8]([CH:10]=1)[NH2:9])[CH3:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N+:11]([O-:13])=[N:14][C:15]([NH2:16])=[N:9][C:8]=2[CH:10]=1)[CH3:2]
Reactant: N#CN
Reactant: CCOc1ccc([N+](=O)[O-])c(N)c1
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc2c(c1)nc(N)n[n+]2[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
A mixture of 5-ethoxy-2-nitroaniline (15) (1.63 g, 9.0 mmol) and cyanamide (1.50 g, 35.8 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (15 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (100 mL), filtered, washed with water (3×20 mL), washed with ether (3×5 mL) and dried. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give amine 16 (1.26 g, 68%) as a yellow powder, mp (MeOH) 268-271° C.; 1H NMR [(CD3)2SO] δ 8.02 (d, J=9.4 Hz, 1 H, H-8), 7.19 (brs, 2 H, NH2), 6.92 (dd, J=9.4, 2.6 Hz, 1 H, H-7), 6.83 (d, J=2.6 Hz, 1 H, H-5), 4.17 (q, J=7.0 Hz, 2 H, CH2O), 1.37 (t, J=7.0 Hz, 3 H, CH3); 13C NMR [(CD3)2SO] δ 163.9, 160.7, 151.2, 124.8, 121.4, 117.1, 104.2, 64.2, 14.1. Anal. Calcd for C9H10N4O2: C, 52.4; H, 4.9; N, 27.2. Found: C, 52.4; H, 4.8; N, 27.0%.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CO.O.[NH2:16][NH2:17]>O>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:16][N:17]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NN
Reactant: CC(C)Cc1ccc(C=O)cc1
Solvent: O
Solvent: CO
Product: CC(C)Cc1ccc(C=NN=Cc2ccc(CC(C)C)cc2)cc1
Reaction time: 24 h

Procedure:
A 3-liter three-necked flask was charged with 638.5 g (3.94 mol) of 4-isobutylbenzaldehyde and 1 liter of methanol, which were stirred for mixing by a mechanical stirrer. While the reactor was cooled with water so as to maintain the temperature of the reaction solution below 50° C., 98.5 g (1.97 mol) of hydrazine monohydrate was slowly added dropwise. After the completion of addition, the reaction solution was heated under reflux for 30 minutes and then allowed to stand one day.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[K+].[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14]1>CO.O>[O:13]1[CH:17]=[CH:16][C:15]([CH:18]=[C:3]2[C:4](=[O:10])[CH:5]3[CH2:8][CH2:9][N:2]2[CH2:7][CH2:6]3)=[CH:14]1
Reactant: O=C1CN2CCC1CC2
Reactant: O=Cc1ccoc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccoc2)N2CCC1CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Furan-3-carboxaldehyde (2.83 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (2.1 g, 100 mmol) was dissolved in methanol (100 ml) and 10% palladium on charcoal (0.2 g) was carefully added under nitrogen. The suspension was hydrogenated at 50 psig in a Parr hydrogenation apparatus for 8 hrs followed by quenching of the catalyst with a small amount of chloroform. The entire slurry was filtered through a pad of Celite filter aid followed by additional washing of the pad with methanol. Rotary evaporation of the pooled solvents gave the desired product, 2-((3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octan-3-one, as a clear oil that solidified upon cooling (2.05 g, 96.7%).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH3:25])[CH:28]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1cccc(CN)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: COc1cccc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)c1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (3-methoxybenzyl)amine instead of (pyridin-2-ylmethyl)amine. The crude product was purified by crystallization from ethanol (10 mL) to afford the titled compound as the hydrochloride salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.15-1.28 (m, 5H), 1.60-1.80 (m, 5H), 1.87 (s, 3H), 2.21 (s, 3H), 3.72 (s, 3H), 3.86 (s, 1H), 4.48 (d, J=5.64 Hz, 2H), 6.75-6.89 (m, 3H), 7.23 (t, J=7.93 Hz, 1H), 7.56 (d, J=7.52 Hz, 1H), 8.40-8.55 (m, J=38.95 Hz, 1H), 12.56 (s, 1H); MS (ESI) m/z 341.5 (M+1)+.
Reaction SMILES: Cl.C(O[CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[NH2:6])C.[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([NH:35][NH2:36])=O)[CH2:28][CH2:27]1)(=[O:25])[CH3:24].C[O-].[Na+]>CO>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[NH:6][C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[C:10]4[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:36][N:35]=2)[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: CCOC(N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CC(=O)N1CCN(CC(=O)NN)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCN(Cc2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)CC1
Yield: 5.2 %

Procedure:
The procedure described for Example 283 B was followed using ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methaneamine hydrochloride (600 mg, 1.88 mmol), 2-(4-acetylpiperazinyl)-N-aminoacetamide (1.12 g, 5.64 mmol), sodium methoxide (1.3 mL, 5.64 mmol), and methanol (8 mL) to yield the title compound (41 mg, 5% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.6 (s, 1H), 8.0 (m, 5H), 7.6 (m, 2H), 7.4 (t, 3H), 4.6 (m, 2H), ES-MS (m/z) 420 [M+1]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]([O:13][C:14]([N:16]([C:24]1[NH:25][CH:26]=[C:27]([CH:29]=[O:30])[N:28]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:15])([CH3:12])[CH3:11]>CN(C=O)C.CCOC(C)=O>[CH3:12][C:10]([O:13][C:14]([N:16]([C:24]1[NH:28][C:27]([CH:29]=[O:30])=[C:26]([Br:8])[N:25]=1)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:15])([CH3:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C=O)c[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C=O)[nH]1
Temperature: 50 °C
Yield: 40.9 %

Procedure:
NBS (0.206 g, 1.156 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-formyl-1H-imidazol-2-yl)imidodicarbonate (0.300 g, 0.964 mmol) in DMF (3 mL). The mixture was heated at 50° C. for 3 hrs. The reaction mixture was diluted with EtOAc and washed 2× with water. The organic layer was dried over sodium sulfate and concentrated. Chromatography (EtOAc:hexane) gave the desired product (0.154 g, 41%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 10.54 (br. s., 1H), 9.54 (s, 1H), 1.50 (s, 18H). ES MS: m/z 390.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:6]([NH:8][CH:9]1[CH2:12][N:11]([CH3:13])[CH2:10]1)=[O:7]>[Pd].CO.C1COCC1>[NH2:17][C:16]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH:9]2[CH2:10][N:11]([CH3:13])[CH2:12]2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)NC2CN(C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 3-methoxy-N-(1-methylazetidin-3-yl)-4-nitrobenzamide (1 equiv) and 10% palladium on carbon was stirred in a mixture of MeOH/THF under a hydrogen atmosphere. The mixture was stirred at 50° C. for 2 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the desired product (99% yield) as a white solid. MS (ESI) m/z 236.1 [M+H]+.
Reaction SMILES: [CH2:1]1COC[CH2:2]1.C([Mg]Cl)=C.[Cl:10][C:11]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].Cl>C#C>[Cl:10][C:11]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]([OH:14])[C:1]#[CH:2]
Reactant: C1CCOC1
Reactant: CC(C)c1cccc(C=O)c1Cl
Agent: C#C
Agent: C=C[Mg]Cl
Agent: Cl
Product: C#CC(O)c1cccc(C(C)C)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
30 ml of absolute THF is saturated under a nitrogen blanket at from 0°-10° C. with acetylene. While passing in further acetylene, 81.7 ml of vinylmagnesium chloride solution (1.47 molar) is dripped in and the mixture is stirred for 30 minutes at 0° C. Subsequently, 18.5 g of 2-chloro-3-isopropylbenzaldehyde is dripped in. The mixture is stirred for 15 hours at room temperature and then poured into 300 ml of ice water. The mixture is acidified with dilute hydrochloric acid and extracted by shaking three times with ether. The combined ether extracts are washed with water, dried and concentrated. There is obtained 22 g of crude product. Purification by column chromatography over silica gel with toluene/acetone (95/%) as eluant gives 9 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:19]=4[O:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:28][CH3:29].Cl[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][O:25][C:23]1[CH:22]=[CH:21][C:20]2[N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:28][CH3:29])[CH:4]=4)[CH2:13][CH2:12]3)=[O:27])[C:17](=[O:26])[O:18][C:19]=2[CH:24]=1)[CH3:36]
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(O)ccc43)CC2)ccc1Cl
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)oc(=O)n2CC(=O)N1CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (44) (300 mg, 0.72 mmol, 1 eq), ethyl chloroacetate (132 mg, 1.08 mmol, 1.5 eq), cesium carbonate (467 mg, 1.43 mmol, 2 eq) in DMF (2 ml) was stirred at rt overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and purified by flash chromatography to provide (3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-2-oxo-2,3-dihydro-benzooxazol-6-yloxy)-acetic acid ethyl ester (45).
Reaction SMILES: [Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.Cl>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([NH:6][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]([F:10])[CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCc1ccncc1
Yield: 67.8 %

Procedure:
A mixture of 4-chloro-2-fluoro-3-hydroxyaniline (118 mg, 0.7 mmol), (EP 061741 A2), and 4-chloro-6-methoxy-7-((4-pyridyl)methoxy)quinazoline (200 mg, 0.7 mmol), (prepared as described for the starting material in Example 13), in isopropanol (10 ml) and ethereal hydrogen chloride (5 ml) was heated at 80° C. for 2 hours and the mixture was allowed to cool. The precipitated product was collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline hydrochloride (110 mg, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](Cl)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:26]([N+:31]([O-:33])=[O:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Reactant: COc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
880 mg of 4-methoxyphenol was dissolved in 10 ml of N,N-dimethylformamide. 790 mg of potassium t-butoxide was added thereto. Then, 1.7 g of 4-benzyloxy-2-nitro-chlorobenzene was added thereto. The mixture was stirred for 1 hour at 110°-120° C. The reaction mixture was introduced into a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: toluene) to obtain 1.92 g of 5-benzyloxy-2-(4-methoxyphenoxy)nitrobenzene.
Reaction SMILES: [C:1]([O:11][CH2:12][CH2:13][OH:14])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(CCCCCCC[O-])C.CC(CCCCCCC[O-])C.CC(CCCCCCC[O-])C.CC(CCCCCCC[O-])C.[Ti+4].C1(C)C(C)=CC=CC=1>[C:1]([O:11][CH2:12][CH2:13][O:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)CCCCC(=O)OCCO
Agent: [Ti+4]
Agent: CC(C)CCCCCCC[O-]
Solvent: Cc1ccccc1C
Product: CC(C)(C)CCCCC(=O)OCCOC(=O)c1ccccc1

Procedure:
Following the procedure of Example 3, 443 gms of ethylene glycol mononeononanoate prepared as in Example 2C and 222 gms of benzoic acid was added to the reaction flask together with 1.5 gms of tetraisodecyl titanate as catalyst. No ortho-xylene entrainer was used in this Example. With continuous stirring the reaction mixture was heated from room temperature to 221° C. at a rate of about 5° to 6° C. per minute for a total heating time of about 150 minutes, employing an initial reaction vessel pressure of about 500 mmHg. During the course of the reaction, the reaction vessel was further depressured to maintain continuous liquid reflux (with the final reaction pressure being about 100 mmHg). After about 150 minutes of reaction, corresponding to a benzoic acid conversion of about 99.2 mol %, ethylene glycol benzoate neononanoate was recovered and analyzed by gas chromatography, and was found to have the following characteristics:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=O.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[N:13][OH:14]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)=CCCC(C)CC=NO

Procedure:
(Compound 8). 3,7-Dimethyloct-6-enal (15.4 g) in 50 ml ethyl alcohol was added to a solution of hydroxylamine hydrochloride (7 g) and sodium carbonate (5 g) in 25 ml of water. The mixture was heated on the steambath for 15 minutes and then allowed to cool. Addition of an excess of water yielded 3,7-dimethyl-oct-6-enal oxime as an oil. The oil was extracted with ether and the organic layer dried and evaporated. The residue was added dropwise to a solution of lithium aluminum hydride (3.8 g) in 380 ml anhydrous ethyl ether. After refluxing overnight an additional quantity of lithium aluminum hydride (0.78 g) was added to complete the reduction. Decomposition of the reaction mixture with excess aqueous sodium hydroxide (200 ml of 10 percent solution), separation of the ether layer, and distillation yielded 3,7-dimethyloct-6-enyl amine (10 g) bp 60°/0.5 mm). To an ice cold solution of this amine (1.5 g) and triethylamine (1.1 g) in ether (25 ml) was added dropwise a solution of ethyl chloroformate (1.1 g) in ether (10 ml). The reaction mixture was allowed to stand overnight at room temperature. The triethylamine hydrochloride was filtered off and the ether solution washed with water, dilute hydrochloric acid, and again with water. The ether solution was dried and evaporated and the residue distilled to yield 2 g carbamic acid (3,7-dimethyl-6-octenyl)-, ethyl ester (Compound 7), bp 102°-103°/0.1 mm. The ester was epoxidized as described in the previous examples to yield VII. The crude reaction product can be readily purified by chromatography using neutral activated alumina.