Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH3:21][C:22]1([CH3:45])[CH2:27][CH2:26][C:25]2[CH:28]=[C:29]([CH2:32][CH2:33]C3C=C(C)C=CC=3S([O-])(=O)=O)[CH:30]=[CH:31][C:24]=2[O:23]1>O>[CH3:21][C:22]1([CH3:45])[CH2:27][CH2:26][C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][O:1][C:2]3[CH:3]=[C:4]([NH:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=3)[CH:30]=[CH:31][C:24]=2[O:23]1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCc2ccc3c(c2)CCC(C)(C)O3)c1
Reactant: CN(C)C(=O)Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1cccc(OCCc2ccc3c(c2)CCC(C)(C)O3)c1
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
1.8 g of 1-(3-hydroxyphenyl)-3,3-dimethylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.4 g of 60% sodium hydride was added thereto. After the mixture was stirred for 15 minutes, 3.6 g of 3-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)ethyl]-p-toluene sulfonate was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into iced water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous sodium sulfate and ethyl acetate was distilled off. The residue was purified by silica gel column chromatography using n-hexane/ethyl acetate (1/1) as a developer to obtain 2.4 g of Compound No. 94 shown in Table 5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J35) (347 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K25) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (320 mg, 57%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH2:32])[C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[C:21]([F:29])[CH:20]=3)=[N:16][C:15]=2[CH:30]=1)(=O)C.O1CCOCC1.Cl>O>[F:29][C:21]1[CH:20]=[C:19]([C:17]2[O:18][C:14]3[C:13]([CH:31]=[CH2:32])=[CH:12][C:11]([OH:10])=[CH:30][C:15]=3[N:16]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
Potassium carbonate (55 mg) was added into a solution of 2-[4-(acetyloxy)-3-fluorophenyl]-7-vinyl-1,3-benzoxazol-5-yl acetate (0.14 g, 0.39 mmol) and 1,4-dioxane (3 mL). The mixture was stirred at 90° C. for 1 h, poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from EtOAc/hexanes, gave a white solid (0.06 g, 46% yield, m.p. 250–252° C.); MS m/e 272 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[OH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([OH:24])[CH:26]=2)[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Reactant: O=C(O)c1cccc(O)c1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 3-hydroxybenzoic acid as brown solid (49%). MS 438 (MH+).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[Li]N([Si](C)(C)C)[Si](C)(C)C.[OH:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1>C1COCC1>[CH:41]([C:40]1[CH:43]=[CH:44][C:37]([OH:36])=[CH:38][CH:39]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCCCC=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a suspension of pentyl triphenylphosphonium bromide (4.76 g, 11.5 mMol) in freshly distilled THF (40 ml) was added LiN(SiMe3)2 (1N in THF, 23 ml). The red solution was stirred at ambient temperature for 30 minutes then a solution of p-hydroxybenzaldehyde (1.06 g, 10 mMol) in THF (10 ml) added. The reaction was stirred at ambient temperature for 4 days, then partitioned between ethyl ether and dilute aqueous HCl (1N). The combined etherial extracts were washed with brine, dried (MgSO4) and evaporated. The crude oil was purified by chromatography (eluant: ethyl ether/hexane) to give 4-(1-hexenyl)phenol as a pale yellow solid (1.5 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH:6]=O)[CH3:2].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]=1.C(#N)C.C(O)C>C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]([C:5]1[N:11]2[CH:12]=[C:13]([I:16])[CH:14]=[CH:15][C:10]2=[N:9][CH:6]=1)=[O:8])[CH3:2]
Reactant: Nc1ccc(I)cn1
Reactant: CCOC(=O)CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(I)cn12
Yield: 78 %

Procedure:
Reflux a solution of 3-oxo-propionic acid ethyl ester (J. Med. Chem. 2001, 44(12), 1193-2003; 3.4 g, 23.7 mmol) and 2-amino-5-iodopyridine in 1:1 acetonitrile/ethanol (100 mL) overnight. Dilute with saturated aqueous sodium bicarbonate, extract into dichloromethane (4×100 mL), combine organics, and concentrate. Flash chromatography using appropriate ethyl acetate/hexane mixtures gives 3.7 g (78%) of the subtitled compound as an off-white solid. ES+ m/e 316.7 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[S:20]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21].N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:39]/[C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:22])=[O:21])[CH:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1
Reactant: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1ccc(S(=O)(=O)n2cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C)CC4)C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.525 g, 2.00 mol) in methanol (10 mL) was added with 1-tosyl-1H-indole-3-carboxaldehyde (0.599 g, 2.00 mmol) and piperidine (0.017 g, 0.200 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol, and the solid was suspended in methanol and thereby washed to obtain the objective (Z)-6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]-2-[(1-tosyl-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (0.887 g, 81%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:17](=[O:19])[O:15][CH2:14][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OCC2CN(Cc3ccccc3)CCN12
Temperature: 50 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a stirred solution of (4-benzyl-piperazin-2-yl)methanol (250 mg, 1.21 mmol) in anhydrous DCE (8.0 mL) was added triphosgene (133 mg, 0.45 mmol, 0.37 eq) followed by diisopropylethylamine (0.25 mL, 1.45 mmol, 1.2 eq). The mixture was stirred at 50° C. under N2 for 16 h. The mixture was cooled to rt, quenched with aqueous, saturated NH4Cl solution (2.0 mL), and poured into EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®, gradient elution 80 to 100% EtOAc/hexane) to give the product (91.2 mg, 32%) as a clear oil, 1H-NMR (300 MHz, CD3OD) 7.35 to 7.24 (m, 5H), 4.38 (t, 1H), 3.96 to 3.87 (m, 2H), 3.71 to 3.66 (m, 1H), 3.57 (q, 2H), 3.14 to 3.07 (m, 1H), 2.97 to 2.93 (m, 2H), 2.04 (dt, 1H), 1.93 (t, 1H); ES-MS m/z 233.2 [M+H]+, RT (min) 0.29.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=1.Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+]>CN(C)C=O>[Cl:7][C:8]1[C:13]([O:14][CH:16]([F:21])[F:20])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)Oc1cccnc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
This reaction was carried out 3 times. A mixture of potassium carbonate (282 g, 2.04 mol) and N,N-dimethylformamide (750 mL) was heated to 100° C. and slowly treated, in a drop-wise manner over 1 hour, with a solution of 2-chloropyridin-3-ol (66.7 g, 515 mmol) and sodium chloro(difluoro)acetate (200 g, 1.31 mol) in N,N-dimethylformamide (750 mL). After completion of the addition, the reaction mixture was stirred at 100° C. for 1 hour, then cooled to 25° C. and partitioned between water (10 L) and tert-butyl methyl ether (5 L). The aqueous layer was extracted with ethyl acetate (4×2.5 L), and the combined organic layers were washed with saturated aqueous sodium chloride solution (6×2.5 L), dried over sodium sulfate, filtered, and concentrated in vacuo. The combined crude products from the three reactions were purified via distillation at reduced pressure (30-40° C., 1-5 mm Hg) to provide the product as a colorless oil. Yield: 192 g, 1.07 mol, 69%. LCMS m/z 180.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.26-8.30 (m, 1H), 7.60 (br d, J=8.2 Hz, 1H), 7.28 (br dd, J=8.0, 4.8 Hz, 1H), 6.60 (t, JHF=72.5 Hz, 1H).
Reaction SMILES: C(OC([N:6]=[S:7]([CH3:35])([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[S:29][CH:30]=[N:31][N:32]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:33][CH3:34])=[CH:11][CH:10]=1)=[O:8])=O)C.ClCCl.CO>CO>[CH3:34][O:33][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:17]=1[O:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([S:7]([CH3:35])(=[NH:6])=[O:8])=[CH:14][CH:13]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:27][C:28]1[S:29][CH:30]=[N:31][N:32]=1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc3ncnc(Nc4nncs4)c3cc2OC)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3nncs3)ncnc2cc1OCc1ccc(S(C)(=N)=O)cc1
Yield: 74 %

Procedure:
According to GWP 6, the conversion of (RS)-N-(ethoxycarbonyl)-S-methyl-S-[4-({[6-methoxy-4-(1,3,4-thiadiazol-2-ylamino)quinazolin-7-yl]oxy}methyl)-phenyl]sulphoximide (33 mg, 0.064 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 74% yield (21 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([NH:19][CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)CCC>[CH2:12]([N:19]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: OCCNCc1ccccc1
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Br)ccc1N(CCO)Cc1ccccc1

Procedure:
A mixture of 2,5-dibromonitrobenzene (40 g) and N-benzylethanolamine (40.4 ml) in 1-butanol (160 ml) was heated at reflux for 18 hours then a further portion (20.2 ml) of N-benzylethanolamine was added and refluxing was continued for a further hour. The reaction mixture was evaporated under reduced pressure (2.7 kPa) at 40° C. and the residue was treated with water (500 ml) and the mixture was then extracted three times with diethyl ether (250 ml). The combined organic extracts were washed with hydrochloric acid (180 ml, 1N), then with an aqueous sodium hydrogen carbonate solution (20 ml, 5%), then twice with distilled water (50 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting brown oil (47.1 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting with dichloromethane to give the title compound (19.66 g) as a red oil. 1H NMR, 400 MHz, (CD3)2SO: δ3.1 (t, 2H); 3.5 (q, 2H); 4.5 (s, 2H); 4.6 (t, 1H); 7.3 (m, 6H); 7.6 (dd, J=8 Hz and J=1.5 Hz, 1H); 8 (d, J=1.5 Hz, 1H). MS (EI): M+ 352 and 350 (5%), 321 and 319 (20%), 91 (100%).
Reaction SMILES: [BrH:1].C(O)(=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14](=O)[CH2:15][S:16][C:17]#[N:18])[CH:11]=[CH:12][CH:13]=1.O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)[N:18]=1
Reactant: Br
Reactant: COc1cccc(C(=O)CSC#N)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
A 25% hydrogen bromide/acetic acid (65 ml) solution was added to a solution of 2-(3-methoxyphenyl)-2-oxoethyl thiocyanate (6.50 g, 31.4 mmol) in acetic acid (65 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 3.80 g (44.8%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([Br:12])=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5].C(N(C(C)C)CC)(C)C.[CH:23]1([C:26](Cl)=[O:27])CC1>C(OCC)(=O)C>[C:26]([O:10][C:9]1[C:8]([F:11])=[C:7]([Br:12])[C:6]([CH3:13])=[C:3]([C:4]#[N:5])[C:2]=1[NH2:1])(=[O:27])[CH3:23]
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(N)c(C#N)c(C)c(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
2-Amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (7.86 g, 32.08 mmol) and diisopropylethylamine (19.5 ml, 112.2 mmol) were dissolved in ethyl acetate (300 ml), and at 0° C., cyclopropanecarbonyl chloride (4.4 ml, 48.12 mmol) was dropwise added, followed by stirring at room temperature for 16 hours under nitrogen atmosphere. After the reaction, ethyl acetate was added to the reaction liquid, followed by washing with water and saturated brine. The organic layer was concentrated under reduced pressure, the resulting residue was recrystallized with diisopropyl ether/ethyl acetate to obtain the entitled compound (8.96 g, 89%) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)C.[C:11](=O)([O:13]CC)[NH2:12].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:13])[NH:12][CH:1]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: CCOC(N)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1[nH]cnc2ccccc12

Procedure:
From acetanilide. Acetanilide reacts with ethyl carbamate in the presence of phosphorous pentoxide to produce 4-quinazolone. For unsymmetrical 4-quinazolones this reaction produces a mixture of regioisomers, thereby complicating the isolation and lowering the yield. ##STR7##
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=O)[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2].[CH2:33]([P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([N:3]1[CH:7]=[C:6](/[CH:8]=[CH:33]/[P:42](=[O:49])([O:43][CH2:44][CH3:45])[O:46][CH2:47][CH3:48])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCn1cc(C=O)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(CC)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 62.8 %

Procedure:
To a mixture of 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.35 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (9:1, v/v) to give diethyl (E)-2-{1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.41 g, yield 65%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 82-84° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[F:32][C:33]([F:38])([F:37])[C:34](=O)[CH3:35].CO>C(Cl)(Cl)Cl>[F:32][C:33]([F:38])([F:37])[CH:34]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH3:35]
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: CC(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 40 mg (0.098 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 1 mL chloroform was treated with 1 mL (large excess) trifluoracetone and 62 mg (0.29 mmol) NaBH3(CN), followed by addition of 1 mL methanol. The mixture was stirred at ambient temperature for 15 h when it was quenched before complete conversion to product. The reaction mixture was diluted with 20 mL DCM, washed with 20 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a mixture of diasteriomers (9:1 by HPLC). MS (ES+): 508 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C.[Pt]=O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CCNC1
Reactant: Cc1cccc(C=O)n1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cccc(CN2CCCC2)n1
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A mixture of 6-methylpyridine-2-carboxaldehyde (1.2 g), pyrrolidine (0.78 g) and platinum oxide (0.15 g) in ethanol (50 ml) was hydrogenated at atmospheric pressure for 30 min. The catalyst was filtered off and the filtrate was evaporated. The residue (1.6 g) was purified by chromatography on alumina (60 g, Type UGI), eluting with ether-hexane (1:1) to give the title compound as a colourless mobile oil (1.15 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH2:14])[C:8]2=[CH:7][N:6]=1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].N1C=CC=CC=1>O1CCOCC1>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH:14][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[C:8]2=[CH:7][N:6]=1
Reactant: Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Reactant: CCS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To 6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-ylamine (60 mg, 0.228 mmol) in 2 mL dioxane was added ethanesulfonyl chloride (22.0 uL, 0.228 mmol) and pyridine (18.5 uL, 0.228 mmol). The reaction mixture was heated to reflux with stirring for two hours, then cooled and chromatographed through silica (0%-40% EtOAc in hexanes) to give 31 mg of ethanesulfonic acid [6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-amide, MP=226.0-226.9° C., MS(M+H)=356.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.[CH:16](C1NC=CN=1)=[O:17]>>[CH:16]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)=[O:17]
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Reactant: O=Cc1ncc[nH]1
Product: CC1CCC2(O1)C(C)(C)CCCC2(C)OC=O
Reaction time: 48 h

Procedure:
0.4 g (0.002 M) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol -- isomer A; see Example 1 -- were intimately mixed with 0.5 g (0.005 M) of freshly sublimated formylimidazole and then kept for 2 days at room temperature. The reaction mixture was then extracted with ether and the organic layer washed, dried, evaporated and finally subjected to a fractional distillation to give 0.3 g of a product having b.p. 70°-80°/0.5 Torr and containing 60% of the desired ester. An analytical sample was purified by vapour phase chromatography.