Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:31][CH2:32][CH2:33][NH:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>C(#N)C.C(N(CC)CC)C>[OH:31][CH2:32][CH2:33][N:34]([C:7]([C:5]1[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=1)=[O:9])[CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N(CCO)C2CCN(C(=O)OC(C)(C)C)CC2)c[nH]1
Yield: 17.9 %

Procedure:
2-Methylimidazole-4-carboxylic acid (2.0 g) was suspended in acetonitrile (150 ml). HOBt (3.7 g) and WSC (4.6 g) were sequentially added thereto, and then mixed at room temperature for 20 minutes. To the reaction solution was added a solution of tert-butyl 4-(2-hydroxyethyl)amino-1-piperidinecarboxylate (4.7 g) obtained in Example 91a) and triethylamine (8.0 ml) in acetonitrile (50 ml), and mixed at room temperature for 15 hours. Acetonitrile was distilled off under reduced pressure, and then to the residue were added chloroform and water. The organic layer was collected by separation and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with basic silica gel column (ethyl acetate:ethanol=5:1) to obtain the title compound as a colorless oil (1.0 g, 18%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:26]([CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:31][CH2:30][CH2:29][C:28]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([S:16][CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: CSc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(SC)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methylthiophenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a mixture of ethyl and isopropyl esters. The pure title compound was obtained by purification on a flash chromatogram.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:41]=[CH:42]/[CH2:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH2:45][CH3:46].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24]/[CH:41]=[CH:42]/[CH2:43][C:44]([CH2:55][CH3:56])([O:47][Si:48]([CH2:53][CH3:54])([CH2:49][CH3:50])[CH2:51][CH3:52])[CH2:45][CH3:46])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(CC)(C/C=C/Br)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(C/C=C/OC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Yield: 61.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (400 mg, 0.698 mmol), 1-bromo-4-ethyl-4-triethylsilyloxy-(2E)-hexene (0.897 g, 2.79 mmol), sodium hydride (60% in oil, 0.168 g, 4.188 mmol), 15-crown-5 (0.14 ml, 0.698 mmol) and tetrahydrofuran (12 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (3 hours), worked up and purified by column chromatography (hexane:toluene=2:1) to give the titled compound (0.35 g, 62%) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
The process of claim 86 wherein the 2-chloro-5-nitrobenzoic acid is contacted with phosphorus pentachloride to form the 2-chloro-5-nitrobenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[N+]=[N-])=[CH2:3].[F:7][C@:8]12[C@@H:28]([OH:29])[CH2:27][C@@:26]3([CH3:30])[C@@H:18]([CH2:19][C@@H:20]([OH:32])[C@:21]3([OH:31])[C:22](=[O:25])[CH2:23][OH:24])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:34])[CH2:10][CH2:11][C:12](=[O:33])[CH:13]=1>CCOCC.CO>[F:7][C@:8]12[C@@H:28]([OH:29])[CH2:27][C@@:26]3([CH3:30])[C@@H:18]([CH2:19][C@@H:20]([O:32][CH2:3][C:2]([CH3:4])=[CH2:1])[C@:21]3([OH:31])[C:22](=[O:25])[CH2:23][OH:24])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:34])[CH2:10][CH2:11][C:12](=[O:33])[CH:13]=1
Reactant: C=C(C)C=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Solvent: CCOCC
Solvent: CO
Product: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Temperature: 0 °C

Procedure:
A solution of 2-methyl-3-diazo-1-propene in 250 ml of ether (prepared from 0.2 mole of N-(2-methyl-2-propenyl)ethyl carbamate by the method of J. L. Brewbaker and H. Hart, J. Am. Chem. Soc., 91, 711 (1969) is diluted with 300 ml of methanol and cooled to 0°C. A total of 6.5 g of 9-fluoro-11β ,16α ,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions until the initial red color fades and nitrogen evolution ceases. The solvent is evaporated in vacuo and the residue dissolved in chloroform and chromatographed on a 100 g - silica gel column. Elution with chloroform and chloroform-ethyl acetate gives TLC homogeneous material which crystallizes from acetone-hexane to give 3.73 g of 9-fluoro-11β ,17,21-trihydroxy-16α-[(2-methyl-2-propenyl)oxy]pregn-4-ene-3,20-dione, melting point 213°-215°C, softening at 198°-200°C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:17][O:18][C:19]([CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25])=[O:20]>>[CH:1]1([CH2:4][N:5]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:19]([O:18][CH3:17])=[O:20])[CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(CCNCC3CC3)c[nH]c2c1
Reactant: COC(=O)CCCC(=O)Cl
Product: COC(=O)CCCC(=O)N(CCc1c[nH]c2ccccc12)CC1CC1
Yield: 60.2 %

Procedure:
10.5 g of N-cyclopropylmethyl-tryptamine (i.e., 3-(2-cyclopropylmethylaminoethyl)-indole) and 9.7 g of 4-methoxycarbonylbutyryl chloride were treated in the same manner as described in Example 1. 10.1 g of N-cyclopropylmethyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-cyclopropylmethyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. Yield: 60.3%
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][C:15]([NH:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CCOC(=O)CN=C=O
Reactant: Oc1c(Br)cc(Br)c2cccnc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Oc1c(Br)cc(Br)c2cccnc12
Temperature: 25 °C

Procedure:
5,7-Dibromo-8-hydroxyquinoline (19.7 g), ethyl isocyanatoacetate (13.0 g) and triethylamine (6.58 g) were mixed in 200 ml of toluene and heated at reflux temperature for about 47 hours. The solution was cooled to room temperature and the desired ethyl N-(((5,7-dibromo-8-quinolinyl)oxy)carbonyl)glycinate was obtained as a white, crystalline solid, m.p. 129.5° C. (decomposition).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[N+]([C:17]1[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=1)([O-])=O>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C:17]3[CH:22]=[CH:21][N+:20]([O-:23])=[CH:19][CH:18]=3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 57.9 %

Procedure:
A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.00 g, 0.019 mol) in N,N-dimethylformamide (50 mL) was reacted with 60% sodium hydride in oil (0.92 g, 0.023 mol) at ambient temperature. The mixture was stirred for 15 minutes, and 4-nitropyridine-N-oxide (5.37 g, 0.038 mol) was added. The mixture was heated at 100° C. for 18 hours. The precipitate which formed was filtered, washing with N,N-dimethylformamide and ethyl acetate to give 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (3.79 g, 0.011 mol) as a tan solid:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21])[N:10]=1.Cl.C(O[C:31](=[NH:33])[CH3:32])C.C(N(CC)CC)C>C(O)C>[C:31]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([C:20]([NH:22][CH2:23][CH2:24][O:25][CH3:26])=[O:21])[N:10]=1)(=[NH:33])[CH3:32]
Reactant: CCOC(C)=N
Reactant: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2N)c2cc(C)ccc2n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(C)=N)c2cc(C)ccc2n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of 450 mg of 4-{[(1S,2R)-2-aminocyclohexyl]amino}-N-(2-methoxyethyl)-6-methylquinazolin-2-carboxamide and 467 mg of ethylacetoimidate hydrochloride in 10 ml of ethanol, 764 mg of triethylamine was added, and the mixture was stirred at 80° C. for 8 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (chloroform:methanol=20:1), whereby 391 mg of a desired compound was obtained as a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]([CH:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12](OC)=[O:13])(=O)[CH3:9]>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:6]=[C:5]2[N:7]=[C:8]([CH3:9])[C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:12]([OH:13])[N:4]2[N:3]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1cc(Br)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)nc2cc(Br)nn2c1O
Yield: 54.2 %

Procedure:
To a solution of 3-bromo-1H-pyrazol-5-amine (0.2 g, 1.235 mmol) and dimethyl 2-acetylsuccinate (0.697 g, 3.70 mmol) in xylene (10 mL) was added p-toluenesulfonic acid monohydrate (2 mg, 10.51 μmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 8 h. The solid was filtered and washed with hexanes to afford the title compound (0.201 g, 54.2%). 1H NMR (400 MHz, MeOD) δ 2.37 (3H, s), 3.65 (2H, s), 3.71 (3H, s), 6.20 (1H, s).
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH:3]=[CH2:4].Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1.ClCCl>CO>[CH2:2]([O:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)[CH:3]=[CH2:4]
Reactant: C=CCO
Reactant: COc1ccc2nccc(Br)c2c1
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: C=CCOc1ccnc2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
Sodium (1.22 g, 52.9 mmol, 2.1 eq) is added portionwise at 0° C. to a stirred solution of allyl alcohol (117.1 g, 201.6 mmol, 80.0 eq). After 30 minutes stirring at 0° C., 4-bromo-6-methoxy-quinoline (6.0 g, 25.2 mmol, 1.0 eq) is added to the reaction mixture that is heated under reflux for 5 hours. The reaction mixture is then cooled down to room temperature, and filtered. The filtrate is evaporated under reduced pressure to give a residue that is extracted with ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 60:1, v/v) to afford 4-allyloxy-6-methoxy-quinoline as a white solid (4.0 g, 74% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[O:26][C:25]([NH2:27])=[N:24][N:23]=5)[CH:20]=4)[N:15](S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1>[OH-].[K+].C1COCC1>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[O:26][C:25]([NH2:27])=[N:24][N:23]=5)[CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(N4CCOCC4)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nnc(-c2ccc3[nH]cc(-c4cccc(N5CCOCC5)n4)c3c2)o1
Yield: 40.9 %

Procedure:
The solution of 5-(3-(6-morpholinopyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (0.07 g, 0.135 mmol) in 10% KOH (0.7 mL) and THF (0.7 mL) was heated at 100° C. for 5 h. Then the reaction mass was evaporated to dryness and ice cold H2O (5 mL) was added and extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated. The crude product was recrystallized with 10% MeOH in CHCl3 to give 5-(3-(6-morpholinopyridin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (0.02 g, 40.8%) as a pale yellow solid. MS (ESI, pos. ion) m/z: 363 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ 11.74 (s, 1H), 8.91 (s, 1H), 8.11 (s, 1H), 7.64-7.52 (m, 3H), 7.19 (d, J=7.6 Hz, 1H), 7.04 (s, 2H), 6.65 (d, J=8.4 Hz, 1H), 3.79 (s, 4H), 3.58 (s, 4H).
Reaction SMILES: [N+:1](=[CH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N-].B(F)(F)F.CCOCC.[Cl:22][CH2:23][C:24]#N>ClCCl>[Cl:22][CH2:23][C:24]1[O:12][C:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:3][N:1]=1
Reactant: [N-]=[N+]=CC(=O)Cc1ccccc1
Reactant: N#CCCl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: ClCc1ncc(Cc2ccccc2)o1
Yield: 61.6 %

Procedure:
1-Diazo-3-phenyl-2-propanone (0.8 g, 5 mmol) in dichloromethane (5 ml) was added to a mixture of boron triflouride diethyl etherate (1.2 ml, 10 mmol), chloroacetonitrile (6.4 ml, 100 mmol) and dichloromethane (5 ml) at 20° C. After 0.5 h at 20° C. the solution was washed with cold aqueous 20% sodium hydroxide, dried (MgSO4), and evaporated under reduced pressure to give an oil which was purified by chromatography (10 g silica, dichloromethane) to give 2-chloromethyl-5-benzyl oxazole as a yellow oil (0.64 g, 62%); δH (CDCl3) 7.2(5H, S, aryl), 6.7(1H, S, het-H), 4.5(2H, S, CH2Cl), 4.2(2H, S, CH2Ar), 2-Chloromethyl-5-benzyloxazole (0.6 g, 3 mmol) and triethyl phosphite (0.7 ml, 4.5 mmol) were heated together for 1 h at 160° C. and then cooled. Direct chromatography (10 g silica, 0 to 5% methanol in dichloromethane) then gave diethyl 5-benzyl-2-oxazolylmethyl phosphonate as a light brown oil (0.65 g, 70%); δH (CDCl3) 7.2(5H, S, aryl), 6.7(1H, S, het-H), 4.1(4H, m, OCH2), 3.9(2H, S, CH2Ar), 3.3(2H, d, CH2P), 1.3(6H, t, Me).
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[C:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:27]=[C:26]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]3[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH3:20]
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)c1

Procedure:
Compound (117) was prepared from compound (26) and (3-acetyl-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt=1.69 mins, m/z (ES−)=349 (M−H for C21H18O5).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([O:28][CH3:29])=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:22])=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([O:28][CH3:29])=[CH:23][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:45][CH2:44][CH2:43][N:40]3[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:36])[CH2:38][CH2:39]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1
Reactant: COc1cc(Nc2ncnc3cc(O)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Product: COc1cc(Nc2ncnc3cc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc(OC4CCOCC4)c23)c(Cl)cc1Cl
Yield: 72.5 %

Procedure:
Using an analogous procedure to that described in Example 12, 4-(2,4-dichloro-5-methoxyanilino)-7-hydroxy-5-tetrahydropyran-4-yloxyquinazoline (0.109 g) was reacted with 1-tert-butoxycarbonyl-4-(3-hydroxypropyl)piperazine (0.074 g) to give 4-(2,4-dichloro-5-methoxyanilino)-7-[3-(4-tert-butoxycarbonylpiperazin-1-yl)propoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.12 g).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[NH:5][CH:4]=[C:3]1[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:45][C:46]1[C:47]([C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:48][C:49]([C:53]([CH3:56])([CH3:55])[CH3:54])=[C:50]([OH:52])[CH:51]=1>C1COCC1>[C:57]([C:47]1[CH:48]=[C:49]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:50]([OH:52])=[CH:51][C:46]=1[NH:45][C:11]([C:3]1[C:2](=[O:1])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[NH:5][CH:4]=1)=[O:13])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)cc1N
Reactant: O=C(O)c1c[nH]c2ccnn2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(C)(C)C)c(NC(=O)c2c[nH]c3ccnn3c2=O)cc1O
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a vial charged with 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid (50 mg, 0.28 mmol) and HATU (117 mg, 0.31 mmol) was added 2 mL of THF followed by triethylamine (85 mg, 0.84 mmol). The reaction mixture was allowed to stir for 10 minutes at room temperature, upon which 5-amino-2,4-di-tert-butylphenol (62 mg, 0.28 mmol) was added and the reaction was heated at 65° C. for 16 h. After 16 h, the reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2 0 (0.05% TFA)). LC/MS (10-99% CH3CN/0.05% TFA in H2O/0.05% TFA gradient over 3 min) to give N-(2,4-di-tert-butyl-5-hydroxyphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide; M+H m/z 383.3, retention time 1.71 minutes. 1H NMR (400.0 MHz, DMSO) δ 13.48 (s, 1H), 10.68 (s, 1H), 9.24 (s, 1H), 8.78 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.17 (s, 1H), 7.13 (s, 1H), 6.41 (d, J=2.0 Hz, 1H), 1.36 (d, J=4.5 Hz, 18H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1cc(Cl)nc(Cl)c1C(=O)Cl

Procedure:
A solution of 2,6-dichloro-4-methyl-nicotinic acid (3.94 g, 19.1 mmol) in thionyl chloride (18 mL) was heated to 80° C. for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-4-methyl-nicotinoyl chloride as yellow oil. It was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)=[CH:13][CH:12]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl>[Cl:29][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH+:8]([O-:38])[C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH2:25][CH:26]2[CH2:27][CH2:28]2)=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OCC2CC2)c2oc3ccccc3c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCC2CC2)c2oc3ccccc3c12)[NH+]([O-])c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
A suspension of N-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide (370 mg, 0.936 mmol) (example 26) and m-chloroperbenzoic acid (50-55%) (1.0 gm, 4.68 mmol) in chloroform (20 ml) was stirred at room temperature for 12 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 30% acetone-chloroform as the eluent to give 200 mg of N-(3,5-dichloropyrid-4-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 263-265° C.
Reaction SMILES: [N:1]#[N:2].C(OC([NH:13][C@@H:14]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:24])[CH3:23])=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:1]#[N:2].[NH2:13][C@@H:14]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccc2ccccc2c1)NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@@H](N)Cc1ccc2ccccc2c1)C(N)=O
Yield: 98.8 %

Procedure:
A solution of 0.725 g of N2 -[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-(2-naphthyl)butyl]-N1 -tert.butyl-L-prolinamide was dissolved in 25 ml of ethanol and hydrogenated at room temperature and under atmospheric pressure over 0.5 gof 10% palladium-on-carbon for 20 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.54 g of N2 -[3(S)-amino-2(R)-hydroxy-L-(2-naphthyl)butyl]-N1 -tert.butyl-L-prolinamide as a white foam which was used without further purification.