Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[NH2:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36]O)=[NH:35])=[CH:32][N:31]=1>>[F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:13][N:36]=[C:34]([C:33]4[CH:38]=[CH:39][C:30]([NH2:29])=[N:31][CH:32]=4)[N:35]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1ccc(N)nc1
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) (201 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (110 mg, 43%). MS (ISP) 518.1 [(M+H)+]; mp 250° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>C(#N)C>[CH3:20][N:21]([CH3:25])[C:22](=[O:23])[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OC(=O)N(C)C)nc(C(Cl)(Cl)Cl)n1
Yield: 48 %

Procedure:
A mixture of 5.7 g (0.025 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 5.1 g (0.05 mole) triethylamine, and 100 ml acetonitrile was stirred and 5.4 g (0.05 mole) dimethylcarbamoyl chloride was added to the mixture. The reaction mixture was stirred 2 hours under reflux, and allowed to cool. A solid was filtered out after cooling and washed with water to give 3.6 g (48% yield; mp 83.5°-84.5° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:36])[C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:32]([C:31]3[CH:34]=[CH:35][C:28]([N:27]([CH3:36])[CH3:26])=[CH:29][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CCc3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CCc5ccccc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 85 °C
Yield: 1.6 %

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-phenethylpiperazin-1-yl)pyridin-2-amine (0.058 g, 0.16 mmol) in EtOH (2.8 mL) and DMF (0.37 mL), 4-(dimethylamino)benzaldehyde (0.026 g, 0.18 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.48 mL, 0.48 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 99:1) to give the title compound as a solid (0.0012 g, 16%); 1H-NMR (500 Mz, DMSO-d6): δ 2.57-2.64 (m, 2H), 2.64-2.70 (m, 4H, piperazine N(CH2)2), 2.77-2.83 (m, 2H), 3.00 (s, 6H, NMe2), 3.65-3.70 (m, 4H piperazine N(CH2)2), 6.82 (d, J=9.0 Hz, 2H, ArH), 7.16-7.22 (m, 1H, ArH, C6H5), 7.25-7.32 (m, 4H, ArH), 7.98-8.04 (m, 3H, imidazo[4,5-b]pyridine 5-H and ArH), 13.09 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.59 min—461/463 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 461.2214, calculated for C26H30ClN6 (M+H)+: 461.2220;
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](O)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][OH:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
1H-benzo[d]imidazole-5-carboxylic acid (5.39 g, 33.3 mmol) was dissolved into anhydrous THF (100 ml) under argon. The solution was cooled in an ice bath and lithium aluminum hydride (70.0 ml of 1M solution in THF, 70.0 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was cooled to 0° C. and ethyl acetate (90 ml) was carefully added, followed by methanol (15 ml) and water (15 ml). The mixture was stirred for 1 h and filtered through celite. The Solution was concentrated and dissolved in THF (200 ml) and washed with brine (2×100 ml), dried over Na2SO4, filtered and concentrated to yield the title compound ((1H-benzo[d]imidazol-5-yl)methanol) (1.26 g, 26%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.54-7.47 (m, 2H), 7.13 (s, 1H), 5.14 (s, 1H), 4.58 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2C(=O)O[CH:17]([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[CH:11][CH:10]=1.Cl[C:26](=[CH2:31])[C:27]([O:29][CH3:30])=[O:28]>C(#N)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][C:17]([C:21]([F:22])([F:23])[F:24])=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:13][CH:14]=1
Reactant: O=C1OC(C(F)(F)F)N=C1c1ccc(Cl)cc1
Reactant: C=C(Cl)C(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
Triethylamine (5.58 g, 0.055 mol) is added dropwise to a mixture of 4-(p-chlorophenyl)-2-(tri-fluoromethyl)-5(2H)-oxazolone (15.6 g, 0.054 mol), methyl α-chloroacrylate (6.52. g, 0.054 mol) and acetonitrile (50 mL). The reaction mixture heats up to 55° C. during the addition. After the addition is complete, the reaction mixture is heated at reflux temperature for one hour, cooled to room temperature and filtered. The filtrate is poured into an ether/water mixture and extracted with ether. The combined organic extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give a black residue. Recrystallization of the residue from hexane gives the title compound as an orange solid (8.25 g, 50.2%). Indentified by NMR spectral analyses.
Reaction SMILES: CO.[Cl:3][C:4]1[CH:25]=[C:24]([F:26])[C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])=[CH:22][C:5]=1[O:6][CH2:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[O:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15]C)=[O:13].C[O-].[Na+]>Cl>[Cl:3][C:4]1[CH:25]=[C:24]([F:26])[C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[N:29]([CH3:38])[C:28]2=[O:39])=[CH:22][C:5]=1[O:6][CH2:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[O:10][CH:11]([CH3:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CCOC(=O)C(C)Oc1ccccc1COc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)Oc1ccccc1COc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Yield: 91.7 %

Procedure:
Into 10 ml of methanol was dissolved 0.216 g of ethyl 2-[2-({2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy}methyl)phenoxy]propionate obtained in the above-described Production Example 3; a catalytic amount of sodium methoxide was added under ice-cooling and stirring and the mixture was stirred for 6 hours at room temperature. The reaction solution was poured into IN hydrochloric acid and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed once with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure to give 0.193 g of methyl 2-[2-({ 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidine-1-yl]phenoxy}methyl)phenoxy]propionate [Compound 3-1].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:26][OH:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>C(#N)C.[Ag-]=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:26][O:27][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)cc(CO)n2-c1ccc(OCc2ccccc2)cc1
Reactant: CI
Agent: O=[Ag-]
Solvent: CC#N
Product: COCc1cc2cc(OC)ccc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
[1-(4-Benzyloxyphenyl)-5-methoxy-1H-indol-2-yl]methanol (0.2 g, 0.56 mmol) was dissolved in acetonitrile (2 mL), and iodomethane (0.35 mL, 5.6 mmol) and silver(I) oxide (0.39 g, 1.68 mmol) were added. The mixture was stirred overnight at 40° C., then cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated. SiO2 chromatography with 3-50% ethyl acetate/hexanes gave 0.16 g (77% yield) of the desired product. LC-MS (C24H23NO3 calc'd 373) m/z 374 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32]C)=[O:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:14]1([C:11]2[S:12][CH:13]=[C:9]([CH2:8][O:7][C:6]3[CH:20]=[CH:21][C:3]([CH2:2][O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([OH:32])=[O:31])=[CH:4][CH:5]=3)[N:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Reactant: COC(=O)Cc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccccc1OCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole (1.95 g), methyl 2-(2-hydroxyphenyl)acetate (1.00 g), anhydrous potassium carbonate (0.85 g) and N,N-dimethylformamide (15 mL) was stirred overnight at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. To a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 mL) was added a 1N aqueous sodium hydroxide solution (10 mL) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to the residue. The precipitated solid was collected by filtration and dried with air to give crystals (0.76 g, 29%) of 2-[2-[4-[(2-phenyl-4-thiazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:20]([NH:22][C:23](=O)[O:24]C1C=CC=CC=1)[CH3:21]>CN(C)C=O>[CH2:20]([NH:22][C:23]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:24])[CH3:21]
Reactant: CCNC(=O)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
Sodium hydride (573 mg, 14.32 mmol) was suspended in N,N-dimethylformamide (30 ml) under nitrogen atmosphere. 4-(1H-5-Indolyloxy)-2-pyridinamine (3.00 g, 13.32 mmol, CAS No. 417722-11-3) described in WO 02/32872 was gradually added thereto while stirred at room temperature. After 10 minutes, the reaction mixture was cooled with an ice water bath, and phenyl N-ethylcarbamate (2.31 g, 13.98 mmol) was added. The reaction mixture was heated to room temperature and was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, then the crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (3.168 g, 10.69 mmol, 80.3%) as pale brown crystals.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[O:17]([C:18]1[CH:19]=[CH:20][C:21]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:22][CH:23]=1)[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: Ic1ccc(Oc2ccccc2)cc1
Reactant: OC1CN2CCC1CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1
Temperature: 110 °C

Procedure:
3-Hydroxy quinuclidine (Aldrich, 254 mg, 2 mmol) was treated with 1-iodo-4-phenoxy-benzene (Aldrich, 296 mg, 1 mmol), Cul (Strem Chemicals, 19 mg, 0.1 mmol), 1,10-phenanthroline (Aldrich, 36 mg, 0.2 mmol), and Cs2CO3 (660 mg, 2.0 mmol) in toluene (anhydrous, Aldrich, 10 mL) and heated at 110° C. for two days. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×10 mL). The organic phase was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:1, Rf. 0.20) as oil (220 mg, yield, 75%). 1H NMR (MeOH-d4, 300 MHz) δ 1.45–1.58 (m, 1H), 1.64–1.85 (m, 2H), 2.00–2.15 (m, 1H), 2.20–2.30 (m, 2.70–3.10 (m, 5H), 3.34–3.40 (m, 1H), 4.52 (m, 1H), 6.83–6.98 (m, 6H), 7.03 (tt, J=7.5, 1.0 Hz, 1H), 7.20–7.41 (m, 2H) ppm. MS (DCl/NH3) m/z 296 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:35][C@H:36]([O:63][Si:64]([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65])/[CH:37]=[CH:38]\[C@H:39]([CH3:62])[C@H:40]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C)[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CN=CC=1.F.CCOC(C)=O.CCCCCC>N1C=CC=CC=1>[Si:55]([O:54][C@@H:40]([C@@H:39]([CH3:62])/[CH:38]=[CH:37]\[C@@H:36]([O:63][Si:64]([C:67]([CH3:68])([CH3:69])[CH3:70])([CH3:65])[CH3:66])[CH2:35][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]([CH3:34])/[CH:11]=[CH:12]/[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:41]([CH3:53])[CH2:42][CH2:43][CH2:44][OH:45])([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56]
Reactant: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@@H](/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: C[C@H](/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C[C@@H](/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 70964.2 %

Procedure:
The procedure for 36 was used with 67 (1.82 g, 1.77 μmol) and HF-pyridine in pyridine (100 mL) to yield 68 (1.15 g, 71%) by flash column chromatography (EtOAc/Hexane 1:9) as a colorless oil: IR (CHCl3) 3349, 2956, 2929, 2856, 1471, 1448, 1254, 1060, 836, 773, 705 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.58-7.55 (m, 6H), 7.39-7.27 (m, 9H), 5.81-5.65 (m, 2H), 5.56 (t, J=10.7 Hz, 1H), 5.41 (dd, J=11.0, 8.4 Hz, 1H), 4.67 (m, 1H), 4.05 (m, 1H), 3.69-3.63 (m, 4H), 3.53 (m, 1H), 2.73 (m, 1H), 2.52 (m, 1H), 1.64 (m, 3H), 1.58-1.48 (m, 2H), 1.30-1.20 (m, 2H), 1.11 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 1.03-0.92 (m, 30H), 0.23-0.14 (m, 18H); 13C NMR (75 MHz, CDCl3) δ 144.3, 134.3, 132.9, 132.0, 128.6, 127.7, 126.8, 86.7, 80.1, 72.3, 66.4, 65.0, 63.1, 42.4, 41.7, 38.2, 35.5, 31.2, 29.5, 26.2, 25.95, 25.89, 19.6, 18.4, 18.1, 18.0, 15.1, 13.3, −2.9, −3.7, −3.8, −4.17, −4.24, −4.3; LRMS (ESI) 937.6 [M+Na]+; HRMS (ESI) calcd for C55H90O5Si3Na 937.5994 [M+Na]+, found 937.6035; [α]20D−10.8 (c 0.84, CHCl3).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](O)=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[C:24](=[O:37])[N:25]([CH2:34][CH2:35][CH3:36])[C:26](=[O:33])[N:27]([CH2:30][CH2:31][CH3:32])[C:28]=1[NH2:29]>C(Cl)Cl>[CH2:34]([N:25]1[C:24](=[O:37])[C:23]2[NH:22][C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[N:29][C:28]=2[N:27]([CH2:30][CH2:31][CH3:32])[C:26]1=[O:33])[CH2:35][CH3:36]
Reactant: O=C(O)C1CCOCC1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C3CCOCC3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.2 %

Procedure:
3.2 g (0.025 mol) of tetrahydropyran-4-carboxylic acid, 4.0 g (0.025 mol) of carbonyldiimidazole and 85 ml of absolute methylene chloride are stirred for 30 minutes at ambient temperature. After the addition of 5.7 g (0.025 mol) of 5,6-diamino-1,3-dipropyluracil, the mixture is stirred for 4 hours at ambient temperature and then evaporated down in vacuo. The residue is combined with 130 ml of water and 11.6 g of calcium hydroxide, stirred for 30 minutes at 80° C. and, after cooling, acidified with conc. HCl whilst cooling with ice. The mixture is extracted with ethyl acetate and the organic phase is dried and evaporated. Chromatography of the crystalline residue on silica gel (CH2Cl2CH3OH 99:1) yields 1.7 g of the title compound in the form of white crystals (15% of theory), m.p. 171°-172° C.
Reaction SMILES: [C:1]([CH2:3][C:4](=S)[NH2:5])#[N:2].BrCC.[O-]CC.[Na+].[NH2:14][C:15]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:21]1[CH:20]=[C:16]2[C:15](=[CH:23][CH:22]=1)[NH:14][C:4]([CH2:3][C:1]#[N:2])=[N:5][C:17]2=[O:19]
Reactant: N#CCC(N)=S
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCBr
Product: N#CCc1nc(=O)c2cc(Cl)ccc2[nH]1
Reaction time: 6 h
Yield: 28.6 %

Procedure:
2-cyanoethanethioamide (501 mg, 5.00 mmol) and bromoethane (448 μL, 6.00 mmol) were added an ethanolic solution of sodium ethoxide (6.00 mmol, 3 mL). The resulting mixture was stirred for 6 hours, 2-amino-5-chlorobenzoic acid (858 mg, 5.00 mmol) was added, and the reaction was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with ethanol, water, ethanol, and diethyl ether. The solid was then dried to yield 2-(6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (314 mg, 29%). 1H NMR (500 MHz, DMSO-d6) δ ppm 4.18 (s, 2H), 7.70 (d, J=8.8 Hz, 1H), 7.85 (dd, J1=8.7 Hz, J2=2.0 Hz, 1H) 8.03 (d, J=2.4 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Br:9]Br>C(O)(=O)C>[Br:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]cc(Br)c(=O)[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
39.4 g (0.35 mol) of uracil are dissolved in 200 ml of acetic acid, and the mixture is warmed to 70° C. The mixture is added dropwise over the course of 2 hours to a solution of 20 ml (0.38 mol) of bromine dissolved in 200 ml of acetic acid. The orange suspension is held at 70° C. overnight and then cooled to 0°-5° C. The precipitate obtained is filtered off, washed with 200 ml of cold water and dried, giving 60.2 g of 5-bromouracil (89.7% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:25]([N:26]([C:28](=[O:46])[CH2:29][NH:30][C:31](=[O:45])[CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([O:42]CC)=[O:41])=[CH:36][CH:35]=2)[CH3:27])=[CH:24][CH:23]=[C:22]([Cl:47])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[OH-].[Na+]>C(O)C>[C:40]([C:37]1[CH:36]=[CH:35][C:34]([CH:33]=[CH:32][C:31]([NH:30][CH2:29][C:28]([N:26]([C:25]2[C:2]([Cl:1])=[C:3]([C:22]([Cl:47])=[CH:23][CH:24]=2)[CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]3[N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH3:27])=[O:46])=[O:45])=[CH:39][CH:38]=1)([OH:42])=[O:41]
Reactant: CCOC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(-n5ccnc5)cc(C)nc34)c2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)O)cc4)c3Cl)c2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
A mixture of 8-[2,6-dichloro-3-[N-(4-ethoxycarbonylcinnamoylglycyl)-N-methylamino]benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (64 mg), 1N sodium hydroxide solution (0.12 ml) in ethanol was stirred for 4 hours at 60° C. The mixture was concentrated in vacuo, and water was added to the residue. The solution was washed with diethyl ether, and the aqueous layer was adjusted to pH 5 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water and diethyl ether to give 8-[3-[N-(4-carboxycinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (44 mg) as amorphous powder.
Reaction SMILES: C([C@@H]1C[C@@H]([C@@](N=C=O)(OC(C)(C)C)CC(C)(C)CCOCC2C=CC=CC=2)[O:5]C1=O)C.C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(COCC=C)C1)=O)CCC.[CH2:75]([NH:79][C:80](=[O:113])[C@H:81]([CH2:111][CH3:112])[CH2:82][C@@H:83]1[O:87][C:86]([CH3:89])([CH3:88])[N:85]([C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])[C@H:84]1[CH2:97][C:98]([CH3:110])([CH3:109])[CH2:99][CH2:100][O:101]CC1C=CC=CC=1)[CH2:76][CH2:77][CH3:78].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(NC(C2CC2)=O)C1)=O)CCC>>[CH2:75]([NH:79][C:80](=[O:113])[C@H:81]([CH2:111][CH3:112])[CH2:82][C@@H:83]1[O:87][C:86]([CH3:89])([CH3:88])[N:85]([C:90]([O:92][C:93]([CH3:94])([CH3:95])[CH3:96])=[O:91])[C@H:84]1[CH2:97][C:98]([CH3:109])([CH3:110])[CH2:99][C:100]([OH:101])=[O:5])[CH2:76][CH2:77][CH3:78]
Reactant: CCCCNC(=O)[C@H](CC)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCOCc1ccccc1
Reactant: CC[C@@H]1C[C@@H]([C@@](CC(C)(C)CCOCc2ccccc2)(N=C=O)OC(C)(C)C)OC1=O
Agent: C=CCOCC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC)C1
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(NC(=O)C2CC2)Cc2ccccc21)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](CC)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O

Procedure:
Starting from 200 mg of 3(R)-ethyl-5(S)-[5-benzyloxy-1(S)-tert-butoxy- carbonylamino-3,3-dimethyl-pentyl]-2-oxo-tetrahydrofuran via 2(R)-ethyl-9-benzyloxy-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7,7-dimethyl-nonanoic acid (N-butyl)amide (Rf (A)=0.28; FAB-MS: (M+H)+ =507), 3-[N-tert-butoxycarbonyl-4(S)-(4-benzyloxy-2,2-dimethylbutyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-ethyl-propionic acid (N-butyl)amide (Rf (B)=0.46; FAB-MS: (M+H)+ =547) and 3-[N-tert-butoxycarbonyl-4(S)-(2,2-dimethyl-4-hydroxybutyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-ethyl-propionic acid (N-butyl)amide (Rf (A)=0.24; FAB-MS: MS:(M+H)+ =457) in a manner analogous to that described in Examples 74a,74b and 74c), as the pure diastereomer: Rf (P)=0.58; FAB-MS:(M+H)+ =471.