Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C[O-].[Na+].C(NC1C=CC(S)=CC=1)(=O)C.[Na].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Cl)[N:29]=1>CS(C)=O>[Cl:27][C:28]1[N:29]=[C:30]([S:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(Sc2cccc(Cl)n2)cc1
Temperature: 100 °C

Procedure:
4-Acetamidothiophenol (16.8 grams; 0.1 mole) was mixed with a solution of sodium methylate (prepared by mixing sodium metal (2.3 grams; 0.1 mole) in 90 ml. of methanol) and the resulting sodium 4-acetamidothiophenol solution added over a period of about one hour to a well-stirred solution of 2,6-dichloropyridine (14.8 grams; 0.1 mole) in 100 ml. of dimethylsulfoxide. The reaction mixture was distilled during the addition and the reaction temperature maintained at about 100° C. for this period and for a period of about 2 hours thereafter. The reaction mixture was then poured into 350 ml. of water and the resulting product precipitate recovered by filtration, washed several times and taken up in 300 ml. of hot benzene and dried and treated with Norite. About 350 ml. of hexane was added to precipitate the product from the bezene solvent which was recovered by filtration. As a result of such operations, the desired N-(4-((6-chloro-2-pyridinyl)thio)phenyl)acetamide compound was recovered as a crystalline solid which was found to have carbon, hydrogen, nitrogen, chlorine and sulfur contents of 56.2, 4.3, 9.9, 11.4 and 11.63 percent, respectively, as compared with the theoretical contents of 56.0, 3.96, 10.05, 12.7 and 11.45, respectively, calculated for the named structure.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25](S(C)=O)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH2:39][CH2:40][NH2:41])[CH3:38].C(O)(C(F)(F)F)=O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25]([NH:41][CH2:40][CH2:39][N:37]([CH3:38])[CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)c(-c2ccc(F)c(NC(=O)Nc3cc(C(C)(C)C)no3)c2)cc2cnc(S(C)=O)nc21
Reactant: CN(C)CCN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To a stirring solution of 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 43 (0.125 g, 0.251 mmol, 1.00 eq) in DMF (2.50 ml) at 0° C. was added unsym-dimethylethylenediamine (0.138 ml, 1.25 mmol, 5.00 eq). After 1 h, the completed reaction was diluted with brine (5 ml) and left to stir overnight. The solids were collected by filtration, rinsed well with H2O and dried on the filter to afford crude desired product (76 mg) as a pale pink solid. The crude product was purified by reverse phase chromatography (5-40% MeCN (w/0.1% TFA)/H2O (w/0.1% TFA)) to afford 1-(3-t-butylisoxazol-5-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea (37.3 mg, 0.059 mmol) as the TFA salt following lyophilization. The TFA salt thus obtained was treated with MP-Carbonate resin and certified 0.1N HCl (1.0 eq), frozen and lyophilized to afford the HCl salt. 1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.56 (brs, 1H), 8.85 (brs, 1H), 8.76 (brs, 1H), 8.41 (dd, J=2.0 and 7.6 Hz, 1H), 8.01 (brs, 1H), 7.95 (s, 1H), 7.37-7.28 (m, 2H), 6.05 (s, 1H), 3.73 (m, 2H), 3.58 (brs, 3H), 3.41 (brs, 2H), 2.85 (brs, 6H), 1.24 (s, 9H); MS (ESI) m/z: 523.2 (M+H+).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[C:12](=[C:13]([O:22][CH:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:35][C:31]6([CH2:34][O:33][CH2:32]6)[CH2:30]5)[CH2:25][CH2:24]4)[N:14]=[CH:15][N:16]=3)[C:11]1=2)(C(C)(C)C)(C)C.Cl>CO>[CH2:32]1[C:31]2([CH2:35][N:29]([CH:26]3[CH2:27][CH2:28][CH:23]([O:22][C:13]4[N:14]=[CH:15][N:16]=[C:17]5[C:12]=4[C:11]4[C@@H:10]([CH2:9][OH:8])[CH2:21][CH2:20][C:19]=4[S:18]5)[CH2:24][CH2:25]3)[CH2:30]2)[CH2:34][O:33]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Agent: Cl
Solvent: CO
Product: OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CC6(COC6)C5)CC4)c3c21
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
To a solution of (3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (360 mg, 0.70 mmol, 1.00 equiv) in methanol (65 mL) was added 0.04 M aqueous hydrochloric acid (13 mL) at 0° C. The resulting solution was stirred for 4 h at 0° C. and then quenched with saturated aqueous sodium bicarbonate. The resulting solution was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The solvents were evaporated under reduced pressure to yield 250 mg (crude) of the desired [(3S)-12-[(4-[2-oxa-6-azaspiro[3.3]heptan-6-yl]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]methanol as a colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([O:22]CC)=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>C(O)C.O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC(OC/C=C/C(=O)OCC)c1ccc(CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCC(OC/C=C/C(=O)O)c1ccc(CC(C)C)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of (E)-ethyl 4-[1-(4-isobutylphenyl)pentyloxy]-2-butenoate in ethanol and 1,4-dioxane was added a 4N aqueous solution of sodium hydroxide. After being stirred at 80° C. for 5 hours, the mixture was cooled, concentrated and acidified with diluted hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent and silica gel column chromatography of the residue afforded the object compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:28]1([C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:26]3[CH:22]([CH2:23][N:24]([C:8](=[O:10])[CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3)CC12
Reaction time: 1 h
Yield: 67 %

Procedure:
N,N'-Carbonyldiimidazole (1.7 g) is added to a solution of phenylacetic acid (1.34 g) in dry dichloromethane (30 cc) cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.27 g) and triethylamine (1.7 cc) in dichloromethane (30 cc) is then added. The reaction mixture is stirred for 1 hour at +5° C. and then for 1 hour at 20° C. The reaction mixture is washed with a saturated aqueous solution (50 cc) of sodium bicarbonate, dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (15 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-(phenylacetyl)-4-perhydroisoindolone (2.7 g) melting at 216° C. is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]3[CH2:18][CH2:17][O:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[C:19]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])([CH3:22])([CH3:21])[CH3:20]>>[CH2:26]([CH:25]([CH2:17][CH2:18][CH:15]([OH:16])[C@H:12]1[CH2:11][CH2:10][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[CH2:14][CH2:13]1)[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:29])[CH2:27][CH3:28]
Reactant: CCCCC(=O)OC(C)(C)C
Reactant: CCc1ccc([C@H]2CC[C@H](C3CCO3)CC2)cc1
Product: CCCC(CCC(O)[C@H]1CC[C@H](c2ccc(CC)cc2)CC1)C(=O)OC(C)(C)C

Procedure:
Reaction operations were carried out according to the first step of Example 1 by using 2-(trans-4-(4-ethylphenyl)cyclohexyl)oxetane (42) (7.5 g, 30.9 mmol) and tert-butylpentanoate (43) (15.6 g, 98.9 mmol) as starting materials to obtain tert-butyl 2-propyl-5-hydroxy-5-(trans-4-(4-ethylphenyl)cyclohexyl)pentanoate (44) (11.6 g, 28.8 mmol). The yield based on the compound (42) was 93%.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH:4]=[C:3]1[S:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25]([NH2:28])(=[O:27])=[O:26]>Cl[Ti](Cl)(Cl)Cl.C(N(CC)CC)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:28][S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])[CH:4]=[C:3]1[S:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NS(=O)(=O)c1cccs1
Reactant: CCOC(=O)CSC1=CC(=O)c2ccccc2C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Yield: 60.4 %

Procedure:
63 mg (0.228 mmoles) ethyl 2-(1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)acetate (7a) was mixed with 37 mg (0.228 mmoles) thiophene-2-sulfonamide in 2.5 ml dichloromethylene, to which at 0° C. was added 76 mg TiCl4.2THF followed by 70 μl triethylamine. The mixture was heated at 60° C. with microwave synthesizer (Initiator 8, Biotage) for 20 min. Diluted with dichloromethylene to 60 ml, the reaction mixture was washed with H2O and brine and dried over Na2SO4. After removal of Na2SO4, the filtrate was concentrated and the residue was purified with flash column (EtOAc/Hexane) affording title compound 58 mg (60.4%) as orange oil which was solidified on standing, m.p.: 110-112° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:22])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[CH3:26][S:23]([O:22][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:19])[F:20])[N:8]=1)(=[O:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(O)nc1Nc1ccccc1OC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc([N+](=O)[O-])c(Nc2ccccc2OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
5-Nitro-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-ol (1.5 g, 4.8 mmol) was taken up in CH2Cl2 (25 mL). TEA (1.3 ml, 9.5 mmol) was added followed by mesylchloride (0.45 ml, 5.7 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and quenched with 1 N HCl. The layers were separated and the aqueous layer was back extracted with additional CH2Cl2. The combined organic portions were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (1.8 g). 1H NMR (400 MHz, CDCl3) δ ppm 3.26 (s, 3H), 6.54 (d, J=8.8 Hz, 1H), 7.26 (m, 1H), 7.39 (m, 2H), 8.22 (m, 1H), 8.67 (d, J=8.8, 1H), 10.46 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.Cl>C1COCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[Br:12]
Reactant: BrCc1ccccc1Br
Reactant: OCc1ccccc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccccc1COCc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79.8 %

Procedure:
Solution of 2-bromobenzylalcohol (3.8 g) in THF (10 ml) was delivered by drops over 15 minutes to suspension of sodium hydride (0.88 g; 60% in oil) in THF (30 ml) cooled to −0° C. in argon atmosphere, and the reaction mixture was further stirred for 20 minutes. Solution of 2-bromobenzyl bromide (6.0 g) in THF (10 ml) was added thereto and the reaction solution was stirred for one hour at room temperature. The reaction mixture was poured to water and neutralized with 1N hydrochloric acid and extracted with hexane. The organic layer was dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (hexane:ethyl acetate=1:0 to 100:1 to 10:1) to obtain the title compound (5.77 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:33])[CH2:14][CH2:15][CH2:16][S:17]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH:37]([CH3:39])[CH3:38]>CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:33])[CH2:14][CH2:15][CH2:16][S:17]([N:20]([CH:37]([CH3:39])[CH3:38])[C:21]2[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN(C)CCCS(=O)(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1OC
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCS(=O)(=O)N(c2cc(OC)c(OC)c(OC)c2)C(C)C)cc1OC
Yield: 46.6 %

Procedure:
3-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]-N-(3,4,5-trimethoxyphenyl)-1-propanesulfonamide (6.7 g, 0.0139 mol) in dry dimethylformamide (100 mL) was treated with sodium hydride, 60% in mineral oil, (0.555 g, 0.0139 mol) and the reaction stirred 1 hour at which point 2-bromopropane (1.71 g, 0.0139 mol) was added and the solution warmed overnight. The reaction was then stripped, dissolved in methylene chloride, filtered and evaporated to a gum. Preparative high pressure chromatography provided the title compound (3.40 g).
Reaction SMILES: COC1C=CC(N2C[C@H](C[N:15]3[CH2:20][CH2:19][CH:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)OC2=O)=CC=1>CS(C)=O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(N2C[C@H](CN3CCC(Oc4ccc(Cl)cc4)CC3)OC2=O)cc1
Solvent: CS(C)=O
Product: Clc1ccc(OC2CCNCC2)cc1

Procedure:
3-p-methoxyphenyl-5(S)-[(4-p-chlorophenoxypiperidino)methyl]-2-oxazolidinone (hydrochloride), m.p. 249°-251°; [α]D =-29.9° (DMSO);
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:5]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH2:24].Cl.C(N=C=NCCCN(C)C)C.ON1C(=O)C2C=CC=CC=2N=N1>>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([CH2:25][CH2:26][S:27][CH3:28])[NH:24][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: Cc1ccccc1-c1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Yield: 98 %

Procedure:
4-Nitro-2-(2-methylphenyl)benzoic acid (2.31 g, 9 mmol), prepared as in Example 178B, was coupled with L-methionine methyl ester (1.0 eq) in the presence of ethyl dimethylaminopropyl carbodiimide hydrochloride (EDCI, 1.0 eq) and 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOBT, 1.0 eq) to give [4-nitro-2-(2-methylphenyl)benzoyl]methionine methyl ester as a pale yellow oil (3.54 g, 98% yield); 1H NMR showed diastereomers due to restricted carbon-carbon bond rotation; 1H NMR (CDCl3) δ 8.26-8.30 (d, J=8.5 Hz, 1H), 8.10 (s, 1H), 8.03-8.09 (m, 1H), 7.27-7.42 (m, 3.5H), 7.18 (d, J=7.4 Hz, 0.5H), 6.03 (br, 1H, amide), 4.59-4.67 (m, 1H), 3.67 (s, 3H), 2.23 (s, 1.5H, PhCH3), 2.06 (s, 1.5H, PhCH3), 1.98-2.03 (m, 5H), 1.81-1.93 (m, 1H), 1.59-1.69 (m, 1H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]#[N:32])[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:36].[NH4+].OO.O>CO>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]([NH2:32])=[O:36])[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [OH-]
Reactant: N#Cc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Agent: OO
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile (45 mg, 0.097 mmol) was dissolved in hot methanol (2 mL). Subsequently, the solution was cooled down to room temperature and 30% ammonium hydroxide (2 mL) was added. The reaction mixture was then cooled to 0° C., and 30% hydrogen peroxide was added. After stirring at room temperature for 8 hours, water was added and the resulting mixture extracted with ethyl acetate. The organics were dried over magnesium sulfate. Filtration and concentration, followed by purification with flash chromatography (95:5 dichloromethane:methanol), gave 3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzamide (18 mg, 39% yield) as a yellow solid. 1H NMR (CDCl3): δ 8.12 (s, 1H), 7.99 (d, 1H), 7.92 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.32 (t, 1H), 6.28 (d, 1H), 6.18 (broad, 1H), 6.05 (d, 1H), 6.02 (d, 1H), 5.82 (broad, 1H), 5.25 (d, 1H), 4.30 (m, 1H), 4.00 (m, 1H), 2.15 (m, 2H), 2.03 (m, 2H), 1.81–1.50 (m, 12H). MS m/z 482 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH2:11][OH:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([C:5]1[C:6]([CH:11]=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cccnc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)Cc1cccnc1C=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 90.8 %

Procedure:
MnO2 (2.01 g, 23.2 mmol) was added to a flask containing a solution of (3-isobutyl-pyridin-2-yl)-methanol (383 mg, 2.32 mmol) in CH2Cl2 (15 mL). The black mixture was stirred at room temperature for 22 hours and then filtered through celite. The filtrate was concentrated in vacuo to give a yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 97.5:2.5, v/v) afforded 3-isobutyl-pyridine-2-carbaldehyde as an orange oil (344 mg, 91%). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.0 Hz), 1.87 (m, 1H), 2.94 (d, 2H, J=6.0 Hz), 7.39 (dd, 1H, J=9.0, 3.0 Hz), 7.60 (d, 1H, J=9.0), 8.67 (d, 1H, J=6.0 Hz), 10.18 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:9][CH:8]=1>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([S:22]([C:25]3[CH:26]=[C:27]4[C:32](=[C:33]([CH3:35])[CH:34]=3)[N:31]=[CH:30][C:29]([C:36]([NH2:38])=[O:37])=[C:28]4[NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=3)(=[O:23])=[O:24])[CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:11][CH:12]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C#CCCCO)cc5)c4)cc23)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCCO)cc5)c4)cc23)c1
Reaction time: 5 h
Yield: 104.8 %

Procedure:
Pd(OH)2 (20% on activated carbon, 250 mg) was added to a solution of Intermediate 72 (250 mg, 0.38 mmol) in MeOH/THF (1:1) (10 mL). The solution was hydrogenated via balloon for 5 h. The Pd was filtered through a plug of celite. The filtrate was then concentrated in vacuo to afford the title compound as a yellow solid (260 mg). ES/MS calcd. for C36H37N4O6S+ 653.2. Found m/z=653.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:10]([CH3:14])([CH3:13])[CH:11]=[CH2:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:34])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][C:10]([CH3:13])([CH3:14])[CH:11]=[CH2:12])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: C=CC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Solvent: c1ccccc1
Product: C=CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Yield: 81.9 %

Procedure:
Using the procedure of Step B of Example 15, 450 mg of the product of Step A were reacted to obtain 370 mg of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[Z-2-(1,1-dimethylallyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+40° (c=0.5% in benzene).
Reaction SMILES: ClC1C=C2C(=CC=1)N([C:11]1[C:20]3[C:15](=[CH:16][C:17]([O:23]C)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=1)CC2.Cl.[NH+]1C=CC=CC=1>>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[OH:23])[N:14]=[CH:13][N:12]=[CH:11]2
Reactant: COc1cc2ncnc(N3CCc4cc(Cl)ccc43)c2cc1OC
Agent: Cl
Agent: c1cc[nH+]cc1
Product: COc1cc2cncnc2cc1O
Temperature: 170 °C
Reaction time: 0.75 h
Yield: 106.6 %

Procedure:
4-(5-Chloro-2,3-dihydro-indol-1-yl)-6,7-dimethoxy-quinazoline (1.00 g, 2.93 mmol; from Example 3) was added to molten pyridinium hydrochloride (10.14 g, 88 mmol) at 170° C. The mixture was stirred at 170° C. for 0.5-1.0 hours (until <5% starting material remained by anal. RP-HPLC), and then poured into ice/water (110 mL). The precipitated orange solid was recovered by filtration, dried by azeotropic removal of H2O with CH3CN at 40° C. in vacuo, dissolved in 15% i-PrOH/CHCl3 (75 mL) and washed with saturated aqueous NaHCO3 (2×). The organic phase was dried over Na2SO4(s), filtered and concentrated in vacuo. The residue (~800 mg) was triturated with CHCl3 (60 mL) and filtered to recover the 6,7-diol (typically 200 mg, 94% purity; used without further purification)(M.P. 200° C. (dec); LC-MS: 314 (MH+); anal. RP18-HPLC RT: 4.07 min.). The filtrate was flash chromatographed on silica (40 to 80% acetone/CH2Cl2) to afford ~550 mg of the pure 6-methoxy-quinazolin-7-ol product (M.P. 175° C. (dec); LC-MS: 328 (MH+); anal. RP18-HPLC RT: 4.07 min.).