Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:11]3[CH2:12][N:13](CC4C=CC=CC=4)[CH2:14][CH2:15][N:10]3[C:9](=[O:23])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OC(Cl)C)=O>ClCCCl>[C:24]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:23])[O:8]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CCN12
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Temperature: 60 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-7-(phenylmethyl)-3H-oxazolo[3,4-a]pyrazin-3-one (19 g, 48 mmol) in 1,2-dichloroethane (80 mL) was added 1-chloroethyl chloroformate (8.7 g, 61 mmol), and the mixture was stirred at 60° C. for 3 hours. 1-Chloroethyl chloroformate (1.7 g, 12 mmol) was further added thereto, and the resulting mixture was stirred at 60° C. for 2 hours. The reaction solution was concentrated under reduced pressure and methanol was added thereto, and the mixture was heated under reflux for 2.5 hours. The reaction solution was concentrated under reduced pressure, and crystallized by adding ethyl acetate and hexane. The precipitated crystals were collected by filtration. The crystals were dissolved by adding ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution. Then, the organic layer was washed with water and concentrated under reduced pressure. To the residue was added diisopropyl ether, and the precipitated crystals were washed with diisopropyl ether and dried to obtain the title compound (13 g, yield 92%). 1H NMR of the above obtained compound corresponded with the compound obtained in Reference Example 2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:30][CH3:31])[CH:15]=2)[N:10]=1.C(N(CC)CC)C.O>C(Cl)Cl.CS(C)=O>[CH:8]([C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:30][CH3:31])[CH:15]=2)[N:10]=1)=[O:7]
Reactant: COc1ccc2nc(CO)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2nc(C=O)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: -78 °C
Yield: 99.7 %

Procedure:
A solution of 1.5 ml of dimethyl sulfoxide in 5 ml of methylene chloride was dropped into a solution of 1.0 ml (11 mmol) of oxalyl chloride in 10 ml of methylene chloride under stirring at -78° C. The obtained mixture was stirred at -78° C. for 15 minutes, followed by the dropwise addition of a solution of 0.74 g (2.2 mmol) of 2-hydroxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline in 7 ml of dimethyl sulfoxide. After the mixture thus obtained had been stirred at -78° C. for 20 minutes, 5 ml of triethylamine was dropped into the resulting mixture. The mixture thus prepared was stirred for 30 minutes, while raising the temperature to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. Thus, 0.74 g of the title compound was obtained as a crude brown oil.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([NH:18][C:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH2:30]([NH2:32])[CH3:31]>O1CCOCC1>[CH2:30]([NH:32][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:19]([CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])=[CH:27][CH:28]=1)[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(NC(=O)C3CCOCC3)cc2)cc1
Reactant: CCN
Solvent: C1COCCO1
Product: CCNCCOc1ccc(NC(=O)C2CCOCC2)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
4′-[2-(p-Toluenesulfonyloxy)ethoxy]-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (1.7 g) solution in dioxane (20 ml) was added with 70% ethylamine aqueous solution (1.63 ml) and stirred for 6 hours at 90° C. The reaction mixture was concentrated under vacuum and dissolved into 2N HCl (20 ml). This solution was washed with ethyl acetate (20 ml) two times. Aqueous layer was neutralized with 2N sodium hydroxide (20 ml). Solid formed was extracted with ethyl acetate (50 ml), washed with water and then dehydrated with anhydrous magnesium sulfate. After filtration, filtrate was concentrated under vacuum and purified with silica-gel column chromatography to obtain 4′-[2-(ethylamino)ethoxy]-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (0.77 g) as white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[OH:15]O>C(O)(=O)C>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:15])[CH:3]=1
Reactant: OO
Reactant: Cc1cncc2cc([N+](=O)[O-])ccc12
Solvent: CC(=O)O
Product: Cc1c[n+]([O-])cc2cc([N+](=O)[O-])ccc12

Procedure:
A solution of 4-methyl-7-nitroisoquinoline (400 mg), and 30% hydrogen peroxide (0.65 ml) in acetic acid (2 ml) was refluxed for 3.5 hours. After removal of the solvent, the residue in ether (50 ml) was stirred to give yellow powder. The powder was collected and washed with ether and dried to give 4-methyl-7-nitroisoquinoline N-oxide (360 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:20][CH2:19][C:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:4]=2[CH2:3]1>C(O)(=O)C.O=[Pt]=O>[OH:1][CH:2]1[CH2:20][CH2:19][CH:5]2[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=3[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1
Reactant: O=C1CCC2=C(C1)c1ccccc1Oc1ccccc12
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: OC1CCC2c3ccccc3Oc3ccccc3C2C1
Reaction time: 3 h

Procedure:
1.0 g of 2-keto-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine is added to a suspension of 10 mg PtO2 (Adams catalyst) in 50 ml glacial acetic acid. The mixture is put in a hydrogenation apparatus under hydrogen atmosphere and shaken for 3 hours. After that time the theoretical quantity of hydrogen has been absorbed. The mixture is then filtered to remove the catalyst, whereupon the filtrate is evaporated in vacuo, yielding a light yellow oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:15]C([O-])(C)C.[K+].IC.O>O1CCCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:13])([F:12])[F:14])=[CH:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: FC(F)(F)c1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cn1nc(I)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of 3-iodo-6-(trifluoromethyl)-1H-indazole (650 mg, 2.09 mmol) in dry tetrahydrofuran (20 mL) was added potassium 2-methylpropan-2-olate (0.35 mL, 3.13 mmol) at 0° C. under N2 atmosphere. After 30 minutes, iodomethane (445 mg, 3.13 mmol) was added dropwise at 0° C., then it was warmed to room temperature for 2 h. Water (2 mL) was added and product extracted with dichloromethane (150 mL), then organic phase washed with water (2×20 mL), brine (2×20 mL) then dried over Na2SO4, filtered and concentrated. The residue was washed with petroleum ether (2 mL) and filtered to afford 3-iodo-1-methyl-6-(trifluoromethyl)-1H-indazole (491 mg, 72%) as a white solid. LCMS: (M+H)+=327.
Reaction SMILES: C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CC1(C)C(C)(C)OB([C:45]2[CH:54]=[CH:53][C:52]3[C:51]([CH3:56])([CH3:55])[CH2:50][CH2:49][C:48]([CH3:58])([CH3:57])[C:47]=3[CH:46]=2)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:54]3[CH:45]=[CH:46][C:47]4[C:48]([CH3:58])([CH3:57])[CH2:49][CH2:50][C:51]([CH3:56])([CH3:55])[C:52]=4[CH:53]=3)[N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
2.6 ml of toluene/ethanol (4:1) and 335 μl of 2N potassium carbonate solution are added to 100 mg (0.33 mmol) of 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (preparation analogous to US 2005/176722) and 147 mg (0.47 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane. The reaction mixture is degassed a number of times, 16 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium(0) are added under nitrogen atmosphere, the mixture is treated in an ultrasound bath for 10 min and subsequently irradiated in the microwave at 140° C. for 10 min. Water and dichloromethane are added to the reaction mixture. The organic phase is separated off, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by means of flash chromatography on silica gel.
Reaction SMILES: C([O-])(=O)C.[K+].[F:6][C:7]1[C:12](B(O)O)=[CH:11][CH:10]=[CH:9][N:8]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:18]=1.CCO>C(Cl)Cl.O>[F:6][C:7]1[C:12]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH2:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[N:18]=2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: OB(O)c1cccnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
A mixture of potassium acetate (0.38 g, 3.87 mmol), 2-fluoro-3-pyridineboronic acid (0.28 g, 1.987 mmol) and 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.60 g, 1.559 mmol) in DCM (8.0 mL) was evaporated under nitrogen to dryness. THF (5.0 mL) was added followed by the addition of bis[4-(di-tert-butylphosphino)-N,N-dimethylaniline]palladium dichloride (Am-phos) (0.060 g, 0.085 mmol). The mixture was heated in an oil bath at 80° C. After 1 h, EtOH (5 mL) was added and heating was continued overnight. The mixture was cooled to rt. Water (10 mL) and DCM (10 mL) were added. The organic layer was separated. The aqueous layer was extracted with CH2CL2 and the organic layer was dried over MgSO4. The solution was filtered and concentrated in vacuo. The orange oil was adsorbed onto a plug of silica gel and purified by chromatography eluting with 2:1 hexane-acetone to provide 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (80 mg, 0.180 mmol, 11.52% yield) as a white foam. LCMS (ES, pos.): calcd for C25H24FN5O2: 445.2. found: 446.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.49-8.62 (m, 1H); 7.86-7.99 (m, 1H); 7.27-7.36 (m, 1H); 7.23 (dd, J=8.31, 4.99 Hz, 4H); 6.87 (t, J=8.51 Hz, 4H); 3.81 (s, 3H) 4.81 (s, 4H); 3.80 (s, 3H); 2.55 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15](O)[C:16]([Cl:20])=[C:17]([F:19])[F:18].C(N(S(F)(F)[F:35])CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:5]=[C:6]([Cl:22])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14]/[CH:15]=[C:16](\[Cl:20])/[C:17]([F:35])([F:19])[F:18]
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(Cl)=C(F)F
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)/C(Cl)=C/COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
A solution of 0.36 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-chloro-4,4-difluoro-2-hydroxy-3-butenyloxy)butyloxy)benzene in 5 ml of dichloromethane was slowly added dropwise to a solution of 0.12 g of diethylaminosulfur trifluoride (DAST) in 10 ml of dichloromethane with stirring at -78° C. After complement of the dropwise addition, the reaction mixture was returned to room temperature over 30 minutes and poured into water. The dichloromethane layer was separated, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.20 g of (Z)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-chloro-4,4,4-trifluoro-2-butenyloxy)butyloxy)benzene (yield, 55%), nD23.7 1.5160.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:8][CH2:7][C:6]([CH2:11][OH:12])([CH2:9][OH:10])[CH2:5][CH2:4]1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1.CCOC(C)=O>[CH3:22][C:21]1[CH:23]=[CH:24][C:18]([S:15]([O:12][CH2:11][C:6]2([CH2:9][O:10][S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:5][CH2:4][C:3]([O:2][CH3:1])([O:13][CH3:14])[CH2:8][CH2:7]2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: COC1(OC)CCC(CO)(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1(OC)CCC(COS(=O)(=O)c2ccc(C)cc2)(COS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of (4,4-dimethoxycyclohexane-1,1-diyl)dimethanol (3.6 g, 17.62 mmol) in pyridine (20 mL) was added tosyl chloride (7.39 mL, 38.8 mmol). The reaction mixture was stirred at rt for 18 h and then diluted with EtOAc (50 mL). The organic mixture and washed with 10% aq. citric acid, dried (Na2SO4) and concentrated in vacuo to afford the title compound (5.4 g, 60% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=8.3 Hz, 4H), 7.35 (d, J=8.2 Hz, 4H), 3.84 (s, 4H), 3.09 (s, 6H), 2.45 (s, 6H), 1.54-1.45 (m, 4H), 1.42-1.34 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncccc2C(F)(F)F)cc1
Temperature: 140 °C
Yield: 83.1 %

Procedure:
A mixture of commercially available 2-chloro-3-trifluoromethylpyridine (64.83 g, 357 mmol), 4-methoxybenzylamine (56 mL, 429 mmol) and DIPEA (73.4 mL, 429 mmol) in n-butanol (100 mL) was refluxed (oil bath temp. 140° C.) for 3.5 days. Concentrated in vacuum, partitioned between 25% HCl and TBME, reextracted the organic layer twice with 25% HCl, the aqueous layer was made alkaline with 32% NaOH, extracted with TBME, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil (105.21 g, >100%). Vacuum distillation gave the product as a colorless liquid (83.766 g, 83%, bp 139–141° C. at 1.4 mbar). MS (ISP) 283.1 [(M+H)+].
Reaction SMILES: C([O:4][C:5](=O)[C:6]1[C:11]([O:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:9]=[CH:8][N:7]=1)CC.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(Cl)Cl.O=[Mn]=O>[CH2:13]([O:12][C:11]1[C:6]([CH:5]=[O:4])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:14][CH3:15]
Reactant: CCCOC(=O)c1ncccc1OCCC
Agent: O=[Mn]=O
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: ClCCl
Product: CCCOc1cccnc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 113.5 %

Procedure:
To a stirred solution of 3-n-propoxypicolinic acid n-propyl ester (0.1209 g, 0.541 mmol) in dry CH2Cl2 (5 mL) at −78° C. was added DIBAL-H (1.0 M, 2.5 mL, 2.5 mmol). The mixture was stirred at −78° C. for 1 hr, then at room temperature for 3 hrs. The mixture was poured into saturated aqueous sodium potassium tartrate (15 mL), diluted with CH2Cl2 (15 mL) and stirred vigorously for 65 hrs. The phases were separated and the aqueous phase extracted with CH2Cl2 (3×20 mL). The combined organic phases were dried (Na2SO4) and concentrated to give a yellow oil. The yellow oil was dissolved in CH2Cl2 (5 mL) and treated with MnO2 (˜85%, 0.4549 g, 4.45 mmol). The mixture was stirred for 19 hrs then filtered through celite. The filtrate was concentrated to give 0.1014 g of 3-n-propoxypyridine-2-carboxaldehyde as an orange oil. 1H NMR (CDCl3) d 1.09 (t, 3H, J=7.4 Hz), 1.91 (sextet, 2H, J=7.1 Hz), 4.07 (t, 2H, J=6.6 Hz), 7.38–7.47 (m, 2H), 8.39 (dd, 2H, J=4.4, 1.4 Hz), 10.43 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][S:40](=[O:44])(=[O:43])[CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCNCC1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCS(=O)(=O)CC1
Yield: 23.6 %

Procedure:
The title compound was prepared as described in Example 57B by using 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea from Example 65A (200 mg, 0.38 mmol), thiomorpholine 1,1-dioxide (154 mg, 1.14 mmol), tetrabutylammonium iodide (140 mg, 0.38 mmol) and N,N′-diisopropylethylamine (135 μL, 0.76 mmol) in N,N′-dimethylformamide (2 mL) to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-7-methoxy-quinazolin-4-ylsulfanyl}-phenyl)-urea (56.27 mg, 24%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.01 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.52-7.27 (m, 5H), 6.49 (s, 1H), 4.30 (bs, 2H), 3.99 (s, 3H), 3.12-3.04 (m, 10H), 1.27 (s, 9H); LC-MS (ESI) m/z 627 (M+H)+.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Si:39]([O:46][C:47]1[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])=[C:53]([CH2:63][CH3:64])[CH:52]=[CH:51][C:48]=1[CH:49]=O)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].[NH4+].[Cl-]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:63]([C:53]1[C:54]([O:55][Si:56]([C:59]([CH3:60])([CH3:62])[CH3:61])([CH3:57])[CH3:58])=[C:47]([O:46][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[C:48](/[CH:49]=[CH:7]\[C:6]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:4]([O:3][CH3:2])[CH:5]=2)=[CH:51][CH:52]=1)[CH3:64]
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Reactant: CCc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 21.5 %

Procedure:
A suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (3.9 g, 7.5 mmol) in tetrahydrofuran (40 mL) was cooled to 0° C. and butyllithium (4.7 mL of a 1.6 N solution in hexane, 7.5 mmol) was added dropwise. The brick red solution was stirred at 0° C. for 20 min, then a solution of 12 (2 g, ca 5 mmol) in tetrahydrofuran (15 mL) was added dropwise. The temperature was allowed to rise to room temperature over 4 hours, than the reaction was poured into ethyl acetate (ca 150 mL) and NH4Cl sat (ca 100 mL) the phases separated and the organic layer re-extracted with AcOEt. The combined organic extracts were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure to give a crude which was purified by column (cyclohexane:AcOEt 9:1) to give 0.6 g of 13:
Reaction SMILES: [C:1]([C:3]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:4]=1[N:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])#[N:2]>CO.[Pd]>[C:1]([C:3]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:4]=1[N:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])#[N:2]
Reactant: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CO
Product: CCCCCCN(CCCCCC)c1ccc(N)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A mixture of 2-cyano-N,N-dihexyl-4-nitroaniline (2.89 g, 8.72 mmol) and Pd/C (0.30 g) in MeOH (30 mL) under H2 was stirred at rt overnight. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=5:1) to give the title compound as colorless oil (1.55 g, 59%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][Al](C)C.C[Si](Cl)(C)C.Cl>CCCCCC.C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1
Reactant: CC1=CC(=O)CCC1
Reactant: C[Al](C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)CCCC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
1.1 g (10 mmol) of 3-methyl-cyclohex-2-en-1-one and 28 mg (0.2 mmol) of CuBr are introduced into 15 ml of THF. 11 ml (11 mmol) of a 10% trimethylaluminum solution in hexane and 2.16 g (20 mmol) of trimethylsilyl chloride are added at 0° C. and stirred for 3 hours at room temperature. It is hydrolyzed with 10 ml of 1N hydrochloric acid, extracted with ethyl acetate, and the solvent is evaporated. 1.21 g (97% of theory) of 3,3-dimethylcyclohexanone is obtained.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:1]1([C:11]2[S:12][CH:13]=[C:14]([Br:16])[N:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1csc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A flask containing 238 mg of tetrakis(triphenylphosphine)palladium, 0.55 g of phenyl boronic acid and 1.00 g of 2,4-dibromothiazole was subjected to nitrogen substitution. To this flask, 30 ml of toluene, 6.1 ml of ethanol, and 9.1 ml of a 2 M sodium carbonate aqueous solution were added, and the obtained mixture was then stirred under reflux for 6 hours. Thereafter, the reaction solution was cooled to a room temperature, and 50 ml of water was then added thereto, followed by extraction with 50 ml of ethyl acetate twice. The organic layer was washed with 30 ml of a saturated brine, and it was then dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The residue was then purified by column chromatography (Wako Gel C-200; hexane:ethyl acetate=14:1), so as to obtain 0.71 g of 2-phenyl-4-bromothiazole.