Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+].C(N(CC)CC)C.C(O)(=O)C(C1C=CC=CC=1)O>CC(C)=O.C([C@H]([C@@H](C(OCC)=O)O)O)(OCC)=O.ClCCl.C(=O)(O)[O-].[Na+].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 0.75 h

Procedure:
Omeprazole sodium (500 grams) was suspended in acetone (6.0 liters) and diethyl D-tartrate (280 grams), titanium (IV) isopropoxide (325 grams) and triethylamine (410 grams) were added sequentially at a temperature of 35-40° C. L (+) mandelic acid (207 grams) was then added and further stirred for 30-60 minutes. The separated solid was filtered, washed with acetone (500 ml) and suck dried under vacuum. The wet solid thus resulting was suspended in a mixture of dichloromethane (2.0 liters) and 5% sodium bicarbonate solution (2.0 liters) and stirred for 15-30 minutes. The dichloromethane layer was separated from the resulting solution and the solvent was distilled off up to substantial completion to get the title compound in residual mass. [Weight: 180 grams, Chiral Purity: 99.93% (S-Isomer)].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:5]2[S:10](=[O:11])[CH2:9][CH2:8][C:6]=2[N:7]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21].C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[C:5]3[S:10](=[O:11])[CH2:9][CH2:8][C:6]=3[N:7]=[C:2]([N:32]3[CH2:33][CH2:34][N:29]([C:26]4[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=4)[CH2:30][CH2:31]3)[N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S1CCc2nc(Cl)nc(Nc3cccc(Cl)c3)c21
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(c3nc4c(c(Nc5cccc(Cl)c5)n3)S(=O)CC4)CC2)cc1
Temperature: 160 °C
Yield: 100 %

Procedure:
1.60 g (2-chloro-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-(3-chloro-phenyl)-amine (prepared from 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine and 3-chloroaniline as described in Example 28, see scheme 2), 2.30 g 1-(4-nitro-phenyl)-piperazine and 1.00 ml diisopropylethylamine are placed in 10 ml dioxane, then heated to 160° C. in the microwave for 0.75 hours. Then the reaction mixture is mixed with water, the precipitate formed is suction filtered. The precipitate is extracted first with water, then with ethanol. 2.47 g of the product are obtained as a powder.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([S:14]([OH:17])(=O)=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na]>>[CH2:7]([S:14]([Cl:2])(=[O:17])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCS(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na]
Product: CCCCCCCS(=O)(=O)Cl
Reaction time: 8 h

Procedure:
To phosphorous pentachloride (3.3 g, 16 mmol) was added solid heptanesulfonic acid, sodium salt monohydrate (1.75 g, 8 mmol) and the mixture was left to stir overnight under nitrogen. Phosphorous oxychloride was removed by distillation at 150° C. for 3 h. The residue was distilled under reduced pressure (ca. 5 mm Hg) at 135° C. to give ca. 1 g of material which was allowed to cool to room temperature. The precipitated free acid was removed by filtration to afford the title compound as an oil (500 mg, 31%) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:12]1(=[O:21])[N:11]([CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1CCOc1ccncc1
Temperature: 25 °C
Reaction time: 32 h
Yield: 3.1 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 13.97 g (55 mmol) of N-(2-bromoethyl)phthalimide in 80 ml of DMF, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added. The mixture was stirred at room temperature for 32 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by-column chromatography (eluent: ethyl acetate) to obtain 0.41 g of the desired compound (yield: 3.1%, colorless crystal).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[CH3:16].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].CC(O)=O>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[CH2:16][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(Br)cncc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(Br)cncc1Br
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 31.8 %

Procedure:
To a solution of LDA (0.308 mol) [generated from N,N-diisopropylamine (31.2 g, 0.308 mol) and n-BuLi (123 mL, 0.308 mol, 2.5M in hexane) in 800 mL THF] was added slowly a solution of 3,5-dibromo-4-methylpyridine (70 g, 0.28 mol) in THF (300 mL) while the inner temperature was maintained below −70° C. After the addition, the resulting mixture was stirred for another 30 min at −78° C. before ethyl bromoacetate (116.9 g, 0.7 mol) was slowly added and the reaction mixture was stirred at −78° C. for another 1.5 h. 10% aq. AcOH was added (resulting pH=4-5), and the reaction was allowed to warm up to room temperature. After evaporation of solvent, the residue was poured into sat. aq. NaHCO3 solution, and was extracted with EtOAc (1 L×3). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by column chromatography (n-pentane:EtOAc=15:1˜5:1) to afford the title compound (30 g, 32%) as a gray solid. MS: 337.7 (M+H+, 2 Br).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:29])([F:28])[C:14]1[N:19]=[CH:18][C:17]([C:20]2([CH2:26][NH2:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:20]1([C:17]2[CH:18]=[N:19][C:14]([C:13]([F:29])([F:28])[F:12])=[N:15][CH:16]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=418.1, tR (minutes, Method F)=2.24
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1.S(=O)(=O)(O)O.O>O1CCOCC1>[O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1
Reactant: CCOC(=O)C(C)c1ccc(C=C2CCSC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc(C=C2CCSC2=O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58 %

Procedure:
Ethyl 2-[4-(2-oxothiolan-3-ylidenemethyl)phenyl]propionate (124 mg) obtained in Example 34 was dissolved in 1,4-dioxane (4.0 ml), and then to the solution was added 30% aqueous sulfuric acid (4.0 ml). The reaction mixture was stirred at room temperature for 4 days, then added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the title compound (65 mg, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21][NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a 500 mL three-necked round-bottom flask was added 8-benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl]-1H-quinolin-2-one (43 g, 0.124 mol, about 95% chiral purity), 1-methyl-2-pyrrolidinone (210 mL) and benzylamine (28.3 g, 0.37 mol). The resulting mixture was flushed with nitrogen and then stirred at 90° C. for 6 hours. The mixture was then cooled to room temperature and water (300 mL) and ethyl acetate (300 mL) were added. The layers were separated and the organic layer was washed with water (200 mL), a 1:1 mixture of water and aqueous saturated sodium chloride solution (200 mL), and water (200 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an orange oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[C:17]([CH:22]=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([CH:22]([C:17]2[C:16]([C:15]([F:25])([F:14])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:23])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=Cc1ncccc1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC(c1cccc(Br)c1)c1ncccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
25 mL of anhydrous THF was placed under nitrogen and cooled to −78° C. 2.2 ml (5.5 mmol) of a 2.5 M solution of n-butyl lithium in hexanes were added. To the resulting solution was slowly added 0.7 mL (1.4 g, 5.8 mmol) of 1,3-dibromobenzene. Upon complete addition the resulting solution was stirred at −78° C. for 90 min. 1.00 g (5.71 mmol) of 3-trifluoromethyl-pyridine-2-carbaldehyde was added rapidly. The dark solution was warmed to −20° C. and stirred for 20 min at that temperature. The resulting mixture was distributed between 10% aqueous citric acid and dichloromethane. The phases were separated and the aqueous layer extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent completely evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 1.053 g (3.171 mmol, 58%) of (3-bromo-phenyl)-(3-trifluoromethyl-pyridin-2-yl)-methanol as a yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (m, 1H), 8.18 (dd, 1H), 7.63 (m, 1H), 7.53 (dd, 1H), 7.42 (m, 1H), 7.26-7.24 (m, 2H), 6.31 (d, 1H), 6.02 (d, 1H); MS: m/z 332.0+334.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(OCC)(=O)C>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Nc1ccc(O)c2ccccc12)c1cccs1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(NS(=O)(=O)c2cccs2)c2ccccc12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
61.1 mg 3 was dissolved in 1 ml DMF, to which was added 60 μl tert-butyl bromoacetate followed by 0.4 ml DBU solution (1M in NMP) and catalytic amount of KI. The mixture was heated with microwave initiator (biotage) to 90° C. and reacted for 20 min. TLC indicated the reaction didn't go complete. Additional 13.5 eq. of tert-butyl bromoacetate was added. The mixture was continued at 90° C. for 30 min. The mixture was diluted with ethyl acetate to 40 ml and washed with 0.5 M NaHSO4, H2O and brine. Dried over Na2SO4, the organic phase was concentrated and the residue was purified via flash chromatography (5 g silica gel, Hex/EtOAc) affording 43 mg (51.3%) solid. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=7.8 Hz, 1H), 7.80 (dd, J=8.1, 1.2 Hz, 1H), 7.61 (dd, J=5.0, 1.3 Hz, 1H), 7.56 (dd, J=3.8, 1.3 Hz, 1H), 7.46-7.36 (m, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.99 (dd, J=5.0, 3.8 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 3.92 (s, 2H), 1.52 (s, 9H).; LRMS (ES+) 420 (M+H)+; HRMS (ES+) m/z calculated for C20H22NO5S2 (M+H)+ 420.0934, found 420.0932.
Reaction SMILES: O[N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>CCO.[Pd]>[C:12]([NH:2][CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:14])[CH3:13]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)C(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.6 %

Procedure:
To a mixture of ethyl 2-(hydroxyimino)-3-oxobutanoate (compound 8, 9.32 g, 58.5 mmol), Pd/C (400 mg, palladium on carbon, 10 wt %, support activated carbon, wet, Degussa type E101 NE/W) in EtOH was added acetic anhydride (compound 9, 11.0 mL, 117.0 mmol) at room temperature. The reaction mixture was stirred at room temperature under H2 for 15 hrs. The palladium was filtered off (filter aid, Celite 521 AW), then the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage SP1™ FLASH Purification System was used for normal phase column chromatography with tetrahydrofuran and hexane) to provide the title compound (9.48 g, 86%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:32][CH2:31][C:30]5([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[N:29]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:32][CH2:31][C:30]5([CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:39])[CH2:34][CH2:33]5)[N:29]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6(CCNCC6)CO5)cc34)cc2C)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)COC(Nc1ccc3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(C)c4)c3c1)=N2

Procedure:
1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3-oxa-1,8-diaza-spiro[4.5]dec-1-en-8-yl)-ethanone is prepared from N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(3-oxa-1,8-diaza-spiro[4.5]dec-1-en-2-yl)-quinazoline-4,6-diamine by standard acetylation methods using acetic anhydride in a mixture of pyridine and methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:6]([C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([Cl:18])[C:3]=1[CH3:19].C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]([C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:2]([N:1]([C:30]([O:32][CH3:33])=[O:31])[C:30]([O:32][CH3:33])=[O:31])[C:3]([CH3:19])=[C:4]([Cl:18])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cccc(F)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a mixture of 1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.094 mL, 0.54 mmol) followed by methyl chloroformate (0.033 mL, 0.43 mmol). The mixture was stirred at room temperature for 30 min. To the reaction mixture was added a catalytic amount of DMAP and another equivalent of methyl chloroformate. The reaction was stirred at room temperature over a weekend, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the bis-acylated product (67 mg, 50%). LCMS calculated for C19H18ClFNO5 (M+H)+: m/z=394.1. found: 394.1.
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32]C)=[CH:25][CH:24]=2)=[N:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(OC1C=NC(C2C=CC(CCCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCCCC.C(OC1C=NC(C2C=CC(CCCCCCCCC)=CC=2)=NC=1)CCCCCCCCCCCCCC>>[CH2:1]([O:16][C:17]1[CH:22]=[N:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH3:32])=[CH:25][CH:24]=2)=[N:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCC)cc2)nc1
Agent: CCCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCCCCCCCC)cc2)nc1
Product: CCCCCCCCCCCCCCCOc1cnc(-c2ccc(CCCC)cc2)nc1

Procedure:
5-pentadecyloxy-2-(4-pentylphenyl)pyrimidine ##STR15## 5-pentadecyloxy-2-(4-heptylphenyl)pyrimidine ##STR16## 5-pentadecyloxy-2-(4-nonylphenyl)pyrimidine 5-pentadecyloxy-2-(4-decylphenyl)pyrimidine
Reaction SMILES: [Na].[F:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][CH:4]=1.[CH2:10]([P:12](Cl)(Cl)=[S:13])[CH3:11]>Cl[Hg]Cl.C(#N)C>[CH2:10]([P:12](=[S:13])([O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([F:2])[N:8]=1)[O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([F:2])[N:8]=1)[CH3:11]
Reactant: CCP(=S)(Cl)Cl
Reactant: Oc1cccc(F)n1
Agent: Cl[Hg]Cl
Agent: [Na]
Solvent: CC#N
Product: CCP(=S)(Oc1cccc(F)n1)Oc1cccc(F)n1
Reaction time: 5 h
Yield: 60 %

Procedure:
Into a 500 milliliter (ml) flask were placed 22 grams (g) (0.15 mole (m)) of the sodium salt of 6-fluoro-2-pyridinol, 1 gram HgCl2 and 200 milliliters of acetonitrile. The mixture was stirred while 9.5 grams (0.075 mole) of ethylphosphonothioic dichloride was added. An exotherm from 24° C. to 38° C. was obtained. The mixture was stirred at 40°-45° C. for five hours and allowed to cool. The insolubles were filtered off and the liquid phase distilled under reduced pressure until all the solvent was removed. The resulting oil was taken up in 300 milliliters of methylene chloride and washed once with 200 milliliters of water, once with 200 milliliters of aqueous 2% NaOH and twice with 200 milliliters portions of water. The product layer was dried over sodium sulfate, filtered and distilled under reduced pressure at 45° C. until the solvent was removed. The resulting oil was mixed in 150 mls of n-hexane and cooled to dry ice/acetone bath temperatures. The resulting solids were filtered off and dried to give a 60% yield of O,O-bis(6-fluoro-2-pyridinyl) ethylphosphonothioate, a solid, m.p. 47°-49° C. Product was confirmed by N.M.R. and I.R. spectra (compound No. 1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.O=C1CCC(=O)N1[O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN1C(=O)CCC1>[C:38]([O:37][C:35]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:19])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To 4-(Aminomethyl)benzoic acid (0.2 g, 1.32 mmol) was added in NMP (5 mL). Hexadecanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.58 g, 1.32 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into water (100 mL), the precipitate was isolated by filtration and dried in vacuo. The crude material was recrystalized from toluene to give 4-[(15-tert-butoxycarbonylpentadecanoylamino)methyl]benzoic acid (413 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CS(C)=O>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[N:3]=2)(=[O:34])=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2cccs2)nc1Cl
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2cccs2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
A solution of 0.353 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(thiophen-2-yl)-pyrimidine in 5 ml of DMSO was heated to 150° C. with 0.376 g of p-tert-butylbenzenesulphonamide for 30 minutes. The solution was concentrated in a high vacuum and the oily residue was poured on to ice, made acid (pH=3) and the suspension was extracted with ethyl acetate. The organic extracts were combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel with toluene-ethyl acetate 9:1 and yielded 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulphonamide as a white foam.