Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: COCCOCCOCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCCOCCc1ccc(N)cc1
Reaction time: 3 h
Yield: 103.4 %

Procedure:
A portion of 14 (5.77 g, 20.2 mmol) was dissolved in 40 mL of acidic ethanol, and a catalytic amount of 10% palladium on carbon was added. The mixture was hydrogenated on a Parr apparatus (60 psi, 70° C.) for 3 hours. The mixture was then filtered over Celite, washing with ethanol. Solid sodium bicarbonate was added, and the mixture was stirred for 2 hours and, then filtered. The solvent was removed by distillation at reduced pressure, leaving a brown oil (5.0 g, 98% yield). IR (neat) 3441.82, 3349.64, 2893.88, 2238.41, 1634.41, 1516.36, 1449.79, 1234.71, 1101.56, 906.97, 722.62 cm−1. 1H NMR (400 MHz, CDCl3) δ 6.65 (ABq, J=8.7 Hz, Δν=51.5 Hz, 4H), 4.01 (t, J=5.4 Hz, 2H), 3.77 (t, J=4.6 Hz, 2H), 3.69 (app t, J=5.6 Hz, 2H), 3.65 to 3.59 (m, 4H), 3.51 (app t, J=4.9 Hz, 2H), 3.34 (s, 3H), 3.0 (brs, 2H). 13C NMR (100 MHz, CDCl3) δ 152.30, 140.58, 116.75, 116.24, 72.31, 71.14, 71.02, 70.93, 70.30, 68.49, 59.44.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O.O>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: COCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCCCCCCOC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (9.5 g) in N,N-dimethylformamide (200 ml) was added portionwise sodium hydride (abt. 60% oil suspension) (2.6 g) under ice-cooling and nitrogen atmosphere. After stirring for 2 hours at room temperature, the reaction mixture was stirred for 1 hour at 60° C. To the reaction mixture was added a solution of 7-methoxyheptyl 4-methylbenzenesulfonate (15.0 g) in N,N-dimethylformamide (50 ml) at 60° C. and then the reaction mixture was stirred for 2 hours at 60° C. After being cooled to room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (10:1→5:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 8-(7-methoxyheptyloxy)-1,4-dioxaspiro[4.5]decane (9.77 g).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6](O)(=[O:10])[C:7]([CH3:9])=[O:8].N1C=CC=CC=1.COC(Cl)Cl>C(Cl)Cl>[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:10])[C:7]([CH3:9])=[O:8]
Reactant: CC(=O)C(=O)O
Reactant: CC(C)(C)O
Agent: COC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl pyruvate was prepared as follows: tert-butyl alcohol (444 mg, 6 mmol) and pyruvic acid (528 mg, 6 mmol) were dissolved in methylene chloride (30 mL) and cooled on an ice bath. Pyridine (948 mg. 0.97 mL, 12 mmol) was added, followed by addition of 1,1-dichloromethyl methyl ether (690 mg, 0.53 mL, 6 mmol). The reaction mixture was stirred for 1 h on an ice bath, warmed to room temperature and washed with 30 mL of 5% aqueous HCl, 30 mL of saturated aqueous NaHCO3, and 30 mL of saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator to give tert-butyl pyruvate in quantitative yield, slightly contaminated with methylene chloride (as 1H NMR). Aliquots used for biological analyses were cleared of methylene chloride by short path vacuum distillation.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][CH:8]([Cl:13])[C:9]([F:12])([F:11])[F:10].[CH:14](=[O:19])[CH:15]=[C:16]([CH3:18])[CH3:17]>O1CCCC1>[Br:7][C:8]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH3:17]
Reactant: CC(C)=CC=O
Reactant: FC(F)(F)C(Cl)Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Temperature: -60 °C
Yield: 73.8 %

Procedure:
Tetrahydrofuran (230 ml) and sodium t-butoxide (57.6 g; 40% w/v solution in dimethylformamide) was charged to a split-neck reaction flask, and cooled to -60° C. with stirring. 1-Bromo-1-chloro-2,2,2-trifluorethane (47.6 g) and senecialdehyde (20.9 g) were charged simultaneously over 25 minutes, then the mixture was stirred at -60° C. for a further 30 minutes. On completion of reaction, the mass was quenched by controlled addition of saturated ammonium chloride solution (120 ml). Hexane (500 ml) was added to the mixture, then the aqueous phase was separated and extracted with further hexane (2×500 ml). The combined organics were washed with brine (2×100 ml) and then water (3×20 ml). Drying (sodium sulphate) and concentration in vacuo then gave the product 5-bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene as a mobile yellow oil (50.1 g, 70% yield).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1([CH3:19])[C@@H:11]([CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:10]1[C:16](Cl)=[O:17].[CH3:20][C:21]1([CH3:31])[C@@H:23]([CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:22]1[C:28]([OH:30])=[O:29]>N1C=CC=CC=1>[CH3:8][C:9]1([CH3:19])[C@@H:11]([CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:10]1[C:16]([O:30][C:28]([C@H:22]1[C@H:23]([CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]1([CH3:31])[CH3:20])=[O:29])=[O:17]
Reactant: CC(C)=C[C@H]1[C@H](C(=O)O)C1(C)C
Reactant: CC(C)=C[C@H]1[C@H](C(=O)Cl)C1(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)=C[C@H]1[C@H](C(=O)OC(=O)[C@H]2[C@H](C=C(C)C)C2(C)C)C1(C)C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
In a 500 ml flask were placed 200 g of toluene, 27.8 g of (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid chloride and 25.0 g of (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid. Into the mixture was added drop-wise 11.9 g pyridine, while stirring under nitrogen at a temperature of 20° to 25° C. After 5 hours, the reaction mixture was washed sequentially with an aqueous 10% hydrogen chloride solution, an aqueous 5% sodium hydroxide solution, and water, and then concentrated in vacuo. The residue was distilled in vacuo at boiling point 130° to 135° C./0.2 mmHg, to obtain 46.1 g of (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid anhydride, with [α]D -17.3° (C=1, CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]([OH:17])(=O)[CH3:15].Cl[C:19]1[N:20]=C(NC2C=C(C=CC=2)C(O)=O)C2[S:27][CH2:26][CH2:25][C:23]=2[N:24]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:19]3[N:20]=[C:14]([OH:17])[C:15]4[S:27][CH2:26][CH2:25][C:23]=4[N:24]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cccc(Nc2nc(Cl)nc3c2SCC3)c1
Solvent: O
Product: Oc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Temperature: 180 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
1.9 g (9.66 mmol) of 1-(4-chlorophenyl)piperazine is placed in 0.55 mL (9.62 mmol) of glacial acetic acid and heated to 180° C. in the heating block. 0.800 g (3.73 mmol) of 2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (I) is added, then the mixture is left to stand for 1.5 hours at 180° C. and 16 hours at ambient temperature. Then the reaction mixture is combined with water and treated in the ultrasound bath. The precipitate is suction filtered, washed, and dried. 1.25 g of product II is obtained and used further in the crude state.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C1C=CC(C2(C[O:32][S:33]([CH3:36])(=O)=[O:34])CCCC2)=CC=1>>[CH3:36][S:33]([O:15][CH2:14][C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:34])=[O:32]
Reactant: OCC1(c2cccc(C(F)(F)F)c2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: CS(=O)(=O)OCC1(c2cccc(C(F)(F)F)c2)CCCC1

Procedure:
(1-(3-(Trifluoromethyl)phenyl)cyclopentyl)methyl methanesulfonate (471) was synthesized from ((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methanol (470) following the procedure described for methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.Cl.[C:16](=N)([O:18][CH2:19][CH3:20])[CH3:17]>O>[CH2:16]([O:18][C:19](=[N:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:20])[CH3:17]
Reactant: CCOC(C)=N
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(C)=NNc1ccc([N+](=O)[O-])cc1
Yield: 85 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 15 parts of 1-(4-nitrophenyl)hydrazine and 160 parts of absolute ethanol were added 13.5 parts of ethyl ethanimidate hydrochloride. After stirring for 3 hours while cooling, the reaction mixture was poured into water. The precipitated product was filtered off, washed with water and dried, yielding 19 parts (85%) of 1-(1-ethoxyethylidene)-2-(4-nitrophenyl)hydrazine; mp. 101.8° C. (int. 18).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:41]([O:45][C:46]([N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CN(C=O)C.O>[C:41]([O:45][C:46]([N:48]1[CH2:54][CH2:53][CH2:52][N:51]([C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[Br:10])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccccc2Br)CC1
Reaction time: 0.03 h
Yield: 277.6 %

Procedure:
DIPEA (460 mg, 0.63 mL, 3.68 mmol) was added dropwise to 2-bromo-benzoic acid (370 mg, 1.84 mmol) in DMF (4 mL). This was followed by the addition of EDCI (423 mg, 2.2 mmol) and HOBT (298 mg, 2.2 mmol). After 2 minutes of stirring, [1,4]diazepane-1-carboxylic acid tert-butyl ester (150 mg, 0.47 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 500 mg (71.12% yield) of 4-(2-bromo-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)=[CH2:18])=[CH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][C:34](=[CH2:37])[CH:35]=[O:36].B(F)(F)F>C(Cl)Cl>[CH3:33][C:34]1([CH:35]=[O:36])[CH2:37][CH2:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:24]=2)[CH2:18]1
Reactant: C=C(C)C=O
Reactant: C=C(C(=C)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Agent: FB(F)F
Solvent: ClCCl
Product: CC1(C=O)CCC(c2ccc(OCc3ccccc3)cc2)=C(c2ccc(OCc3ccccc3)cc2)C1
Reaction time: 3 h

Procedure:
To a solution of 2,3-di(4-benzyloxy-phenyl)-1,3-butadiene (1.2 g, 2.8 mmol) and 2-methyl-propenal (0.602 g, 8.4 mmol) in DCM (10.5 mL) was added BF3.OCH2CH3 (0.596 mL, 4.2 mmol) at −10° C. After 3 h at −10° C., the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL). The reaction mixture was then extracted with ethyl acetate (2 10 mL), dried over MgSO4 and purified by SiO2 twice (15% ethyl acetate/hexane) to yield 1-methyl-3,4-di(4-benzyloxy-phenyl )-cyclohex-3-ene carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[OH:14].CC(C)([O-])C.[K+].Cl[C:22]1C=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C[N:39](C)C(=O)C>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][C:26]1[CH:27]=[CH:22][N:39]=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:25]=1
Reactant: CNC(=O)c1cccc(Cl)c1
Reactant: CC(=O)N(C)C
Reactant: CNc1cc(OC)c(O)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-methoxy-4-(methylamino)-5-nitrophenol (1 eq) in N,N-dimethylacetamide was added potassium-t-butoxide (1.2 eq) and continued stirring at ambient temperature utility solidified. To it was then added (3-chlorophenyl)-N-methylcarboxamide (1 eq) and anhydrous potassium carbonate (1 eq) and the resulting mixture was heated to 50° C. whereby the solid liquified. It was then heated to 110° C. for 12 h. After cooling to ambient temperature the solvent was distilled off and the resulting solid was extracted using ethyl acetate in a soxhlet apparatus for 48 h. The organic layer was cooled to 0° C., when the product crystallized from the ethyl acetate to give {4-[2-methoxy-4-(methylamino)-5-nitrophenoxy](2-pyridyl)}-N-methylcarboxamide. MS: MH+ 332
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:17]1([C:23]2[O:27][N:26]=[CH:25][C:24]=2[CH2:28][CH2:29][C:30](O)=[O:31])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:24]2[CH:25]=[N:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (1.25 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (1.00 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.80 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (1.89 g, yield 93%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 139–140° C.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)=[CH:5]OCC.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([C:4]2[C:3](=[O:20])[C:26]3[C:25](=[CH:24][CH:23]=[C:22]([CH3:21])[N:27]=3)[NH:28][CH:5]=2)=[O:19])=[CH:11][C:12]=1[CH3:18]
Reactant: CCOC=C(C(=O)OC)C(=O)c1ccc(OC)c(C)c1
Reactant: Cc1ccc(N)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1C
Yield: 56.9 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (1.88 mmol) of 3-ethoxy-2-(4-methoxy-3-methyl-benzoyl)-acrylic acid methyl ester, 0.20 g (1.88 mmol) of 6-Methyl-pyridin-3-ylamine, and 10 mL of diphenyl ether to yield 0.33 g of 3-(4-Methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one.
Reaction SMILES: [CH3:1][C:2](O[Si](C)(C)C)=[CH:3][C:4]([O:6][Si](C)(C)C)=[CH2:5].[CH2:16]([NH:18][S:19](Cl)(=[O:21])=[O:20])[CH3:17].Cl>O1CCCC1>[CH2:16]([N:18]1[C:2]([CH3:1])=[CH:3][C:4](=[O:5])[CH2:6][S:19]1(=[O:21])=[O:20])[CH3:17]
Reactant: CCNS(=O)(=O)Cl
Reactant: C=C(C=C(C)O[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCN1C(C)=CC(=O)CS1(=O)=O
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A solution, cooled to -75°, of 24.5 g of 1-methyl-1,3-bis(trimethylsiloxy)-1,3-butadiene and 10.1 g of triethylamide in 100 ml of dry tetrahydrofuran was treated dropwise at -80° to -70° under argon with a solution of 14.4 g of N-ethyl-sulfamoyl chloride in 50 ml of dry tetrahydrofuran and the mixture was subsequently stirred at the same temperature for 2 hours. The temperature was then allowed to rise to room temperature, the mixture was stirred for 1 hour, acidified at 15°-20° with 110 ml of 2N hydrochloric acid and stirred for a further 15 minutes. The mixture was extracted with ether and the extracts, dried over sodium sulfate, were evaporated to dryness. The residual oil was dissolved in 250 ml of toluene, 0.4 g of methanesulfonic acid was added thereto and the mixture was heated to reflux for 15 hours with a water separator. The solution obtained was cooled, concentrated to dryness under reduced pressure and the residual oil was chromatographed on 280 g of silica gel with methylene chloride/ethyl acetate (9:1) as the elution agent. The uniform fractions were combined and evaporated. After triturating the residue with ether there were obtained 13.8 g of 2-ethyl-3-methyl-1,2-thiazin-5-(6H)-one 1,1-dioxide in the form of almost colorless crystals, m.p. 90°-92°. Recrystallization from ethanol did not increase the melting point.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[C:6]=1[O:17][CH3:18].C([Li])CCC.CN([CH:27]=[O:28])C.O>CCOCC>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([O:17][CH3:18])=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[C:10]=1[CH:27]=[O:28]
Reactant: COCOc1cc(OC)c(OC)c(OC)c1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COCOc1c(C=O)c(OC)c(OC)c(OC)c1OC
Temperature: -20 °C

Procedure:
6.2 g of 1-methoxymethyloxy-2,3,4,5-tetramethoxybenzene prepared in Referential Example 13 was dissolved in 50 ml of anhydrous ether, and 18 ml of n-butyllithium (1.6M n-hexane solution) was dropwise added thereto at -20° C. while stirring. After the mixture was stirred at 0° C. for 30 min, the temperature was returned to -20° C. and 3.5 ml of DMF was dropwise added thereto. After 100 ml of water was added thereto, the mixture was extracted with ethyl acetate, and the organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=7:3) to prepare 5.6 g of the product compound as a light yellow oleaginous substance.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.Cl>COCCOCCOC.C(OCC)(=O)C>[ClH:12].[ClH:14].[C:1]([C:5]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=1[N:7]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCNCCCl
Reactant: CC(C)(C)c1cc(Cl)ccc1N
Agent: Cl
Solvent: COCCOCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Cl)ccc1N1CCNCC1
Temperature: 170 °C
Reaction time: 72 h
Yield: 14.7 %

Procedure:
A mixture of 2-tert-butyl-4-chloroaniline (Reference Example 19, 16.7 g, 90.8 mmol) and bis(2-chloroethyl)amine hydrochloride (17.8 g, 99.9 mmol) in diglyme (170 mL) was stirred at 170° C. for 3 days under nitrogen atmosphere. After this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 1 M NaOH. The organic layer was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash column chromatography (NH-silica gel, 1:1-0:100 hexane/ethyl acetate, 10:1 ethyl acetate/MeOH) to provide an impure brown oil and a brown solid. The solid was dissolved in ethyl acetate and the solution was treated with 4 M HCl in ethyl acetate to give the title compound (2.17 g) as a brown solid. The impure brown oil was partitioned between ethyl acetate and 1 M HCl and the resulting white precipitate was collected by filtration, and washed with diethyl ether to give the title compound (2.98 g) as a white solid.
Reaction SMILES: CN1C(=O)CCC1.Cl[C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[CH:17]=2)[C:12]([C:24]([NH2:26])=[O:25])=[CH:11][N:10]=1.Cl.[Cl:28][C:29]1[CH:30]=[C:31]([CH2:36][CH2:37][NH2:38])[CH:32]=[CH:33][C:34]=1[OH:35].C(N(C(C)C)CC)(C)C>O>[Cl:28][C:29]1[CH:30]=[C:31]([CH2:36][CH2:37][NH:38][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[CH:17]=3)[C:12]([C:24]([NH2:26])=[O:25])=[CH:11][N:10]=2)[CH:32]=[CH:33][C:34]=1[OH:35]
Reactant: NCCc1ccc(O)c(Cl)c1
Reactant: CCc1cccc(Nc2nc(Cl)ncc2C(N)=O)c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(Nc2nc(NCCc3ccc(O)c(Cl)c3)ncc2C(N)=O)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
A 6 ml portion of NMP solution containing 533 mg of 2-chloro-4-[(3-ethylphenyl)amino]pyrimidine-5-carboxamide was mixed with 624 mg of 2-(3-chloro-4-hydroxyphenyl)ethylamine hydrochloride and 0.87 ml of diisopropylethylamine, followed by stirring at 80° C. for 4 hours. The reaction mixture was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, the solvent was evaporated, and then the resulting residue was recrystallized (methanol-THF) to obtain 460 mg of 2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}-4-[(3-ethylphenyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[C:16]1([CH2:22][CH2:23][CH2:24]CBr)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.O1CCC[CH2:29]1>>[CH3:8][C:7]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)([CH2:24][CH2:23][CH:22]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:29])[CH3:9]
Reactant: C1CCOC1
Reactant: CC(C)c1ccncc1
Reactant: BrCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(CCC(C)(C)c1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 5.2 %

Procedure:
In a flask, 0.61 g (18 mmol) of lithium aluminum hydride and 50 ml of dried tetrahydrofuran were placed. While cooling with ice-cold water under a nitrogen atmosphere, a solution of 10.0 g (82.6 mmol) of 4-isopropylpyridine dissolved in tetrahydrofuran was added dropwise. After stirring for 24 hours at room temperature, a solution of 3.41 g (16.0 mmol) of 4-phenylbutyl bromide dissolved in tetrahydrofuran was added. The resulting mixture was stirred for 2 hours. Subsequently, water was added, tetrahydrofuran was distilled away under reduced pressure, and then the residue was extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, ethyl acetate was distilled away under reduced pressure. The resulting oily substance was purified by silica gel column chromatography, to obtain 0.21 g (yield: 5.2%) of the desired compound.