Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH2:3]Cl.[CH3:6][C:7]([CH3:13])([CH:10]=[C:11]=[CH2:12])[CH:8]=[O:9].[NH4+].[Cl-]>CCOCC>[CH3:1][C:2]([CH2:3][CH:8]([OH:9])[C:7]([CH3:13])([CH3:6])[CH:10]=[C:11]=[CH2:12])=[CH2:5]
Reactant: C=C=CC(C)(C)C=O
Reactant: C=C(C)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C=CC(C)(C)C(O)CC(=C)C
Temperature: 15 °C
Yield: 91 %

Procedure:
300 ml of absolute ether were added to 7.29 g (0.30 mole) of dry Mg, the mixture was cooled to 15±1° C., and 27.19 g (0.30 mole) freshly distilled β-methylallyl chloride were added. The mixture was stirred over night at the same temperature. The white suspension was cooled to 0° C., and 11.03 g (0.10 mole) 1a in 150 ml absolute ether were added dropwise during 1 hour. The mixture was stirred at 0° C. for 4 hours (reaction monitored on GC). 37 ml of saturated NH4Cl solution were added with vigorous stirring. The solution was decanted from the magnesium salts which were washed several times with ether. The combined ether phases were dried (MgSO4). Distillation gave 14.22 g (91%) 2a, b.p. 60°-1° C./1.5 mm Hg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13]([Cl:22])[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C1(C)C=CC=CC=1.O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:22][C:13]1[CH:14]=[C:15]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:3][CH:4]=3)[CH:23]=[C:11]2[N:12]=1
Reactant: C1COCCN1
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc(Br)cc3)cc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
There was dissolved, in toluene (2 mL), 2-(4-bromo-phenyl)-5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (41.7 mg, 0.106 mM) in an argon gas atmosphere and then there were added, to the resulting solution, sodium t-butoxide (15.3 mg, 0.159 mM), tris(dibenzylidene acetone) di-palladium (4.9 mg, 0.0053 mM), 2-biphenyl-di-t-butyl phosphine (4.7 mg, 0.016 mM) and morpholine (13.9 μL, 0.159 mM), followed by the stirring of the resulting mixture at 70° C. for 3 hours and the further stirring of the same at 90° C. for one hour. This reaction liquid was diluted with water and then extracted with ethyl acetate. The extracts thus obtained were combined, they were dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:4) to thus give the title compound (15.6 mg, yield: 39%).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[C:14]2[S:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]=1[CH3:33])=O>O>[CH2:4]([C:6]1[C:14]2[S:13][CH2:12][CH:11]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:7]=1[CH3:33])[CH3:1]
Reactant: C[Mg]Br
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CS2
Solvent: O
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
To methylmagnesium bromide (1.0 M, THF solution, 10 mL, 10 mmol) was added at 0° C. N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (600 mg, 1.42 mmol) obtained in Example 163 and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was added to water and the product was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the obtained residue in trifluoroacetic acid (3 mL) was added with ice-cooling triethylsilane (1.0 mL) and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, to the residue was added an aqueous saturated sodium hydrogen carbonate solution and the aqueous layer was made alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 345 mg (yield: 57%) of the title compound. Melting point: 172-173° C. (hexane-ethyl acetate).
Reaction SMILES: C(OC1N=CC=CC=1C(O)=O)CCC.C(N(CC)CC)C.COC(Cl)=O.Cl.[CH2:28]([O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35](CCN)=[CH:34][CH:33]=1)[CH3:29]>O1CCCC1>[CH2:28]([O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc(CCN)cc1
Agent: CCCCOc1ncccc1C(=O)O
Agent: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6.5 g of 2-butoxy-nicotinic acid (melting point= m.p. 54°-56° C., from acetic acid ethyl ester) are dissolved in 150 ml of tetrahydrofuran. After addition of 14.5 ml of triethylamine, the batch is cooled to 0° C., and 3.2 ml of chloroformic acid methyl ester are added dropwise. Agitation is continued for one hour at 0° C., 7.6 g of 4-(2-aminoethyl)-benzoic acid ethyl ester-hydrochloride are added, agitation is continued for a further hour at 0° C., and subsequently for 4 hours at room temperature. The batch is evaporated and the residue is combined with acetic acid ethyl ester. After washing with water, sodium bicarbonate solution, dilute hydrochloric acid and water, the acetic acid ethyl ester solution is dried and evaporated under reduced pressure. The 4-(2-<2-butoxy-nicotin-amido>-ethyl)-benzoic acid ethyl ester so obtained is refluxed for 3 hours in 25 ml of 2 N sodium hydroxide solution and 50 ml of ethanol. After having distilled off the solvent, the product is dissolved in water and acidified with dilute acetic acid, suction-filtered and recrystallized from acetic ester. The 4-(2-<2-butoxy-nicotin-amido>-ethyl)-benzoic acid has a melting point of 147°-149° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:25]2[C:26]([CH:31]=O)=[N:27][CH:28]=[CH:29][CH:30]=2)([CH3:24])[CH3:23])=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:31][C:26]1[C:25]([C:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)([CH3:24])[CH3:23])=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1C=O
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(CCCCNCc1ncccc1C(C)(C)c1ccc(Cl)cc1)C(=O)OC(C)(C)C

Procedure:
Using General Procedure B, (4-amino-butyl)-methyl-carbamic acid tert-butyl ester, 3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 were reacted to give [4-({3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-butyl]-methyl-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.24-1.32 (m, 2H), 1.33-1.42 (m, 11H), 1.65 (s, 6H), 2.20-2.24 (m, 2H), 2.79 (s, 3H), 3.08-3.12 (m, 2H), 3.26 (s, 2H), 7.05-7.08 (m, 2H), 7.21-7.26 (m, 3H), 7.84-7.87 (m, 1H), 8.46-8.48 (m, 1H).
Reaction SMILES: O1CCOCC1.[ClH:7].C(OC([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=3[Br:39])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1)=O)(C)(C)C>>[ClH:7].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=3[Br:39])[CH2:28][CH2:29]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(Br)c(CC2CCN(CCc3ccc(NC(=O)OC(C)(C)C)cc3)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Br)c(CC2CCN(CCc3ccc(N)cc3)CC2)c1
Reaction time: 2 h
Yield: 93 %

Procedure:
To a 4N hydrogen chloride-1,4-dioxane solution (5 ml) was added 2-(4-tert-butoxycarbonylaminophenyl)ethyl-4-(2-bromo-5-methoxybenzyl)piperidine (580 mg, 1.15 mmol) in small portions at room temperature, and the reaction mixture was stirred as it was for 2 hours. After the solvent was distilled off under reduced pressure, the residue was suspended in ethyl acetate-diethyl ether, and the precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (509 mg, 93%) as light-brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:12])[CH:9]([CH3:11])[CH3:10].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)C(O)c1ccccc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: CC(C)C(=O)c1ccccc1Cl
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of 1-(2-chlorophenyl)-2-methylpropan-1-ol (1.5 g in 15 mL DCM) was added is to a suspension of PCC (2.62 g in 30 mL DCM) at 25° C., monitoring the reaction by TLC. After 2 h, Et2O (120 mL) was added and the reaction mixture was stirred for 15 min. The supernatant was decanted, dried (Na2SO4) and concentrated under vacuum. Purification by flash chromatography (SiO2, 0-10% EtOAc in hexanes) gave the title compound as a clear colorless oil (1.24 g, 82%). 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.27 (m, 4H), 3.37-3.30 (m, 1H), 1.19 (d, J=6.8 Hz, 6H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[Cl:28][C:29]1[N:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([N:39]3[C:47](=[O:48])[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]3[CH2:49][C:50](O)=[O:51])=[N:36]2)=[C:31]([CH3:53])[CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[N:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([N:39]3[CH:40]([CH2:49][C:50]([N:8]4[CH2:9][CH2:10][C:5]5([O:4][CH2:3][CH2:2][O:1]5)[CH2:6][CH2:7]4)=[O:51])[C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:47]3=[O:48])=[N:36]2)=[C:31]([CH3:53])[CH:30]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1cc(Cl)nc2nc(N3C(=O)c4ccccc4C3CC(=O)O)ccc12
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)nc2nc(N3C(=O)c4ccccc4C3CC(=O)N3CCC4(CC3)OCCO4)ccc12
Temperature: 0 °C
Yield: 90.2 %

Procedure:
With ice-cooling and stirring, 1.6 g of 1,4-dioxa-8-azaspiro[4.5]decane, 2 ml of triethylamine and 2.2 g of diethyl phosphorocyanidate were successively added to a solution of 3.5 g of 2-(7-chloro-5-methyl-1,8-naphthyridin-2-yl)-3-oxoisoindoline-1-acetic acid in 30 ml of dimethylformamide. The mixture was stirred with ice-cooling for an additional 2 hours and 200 ml of ice-water was added thereto. The mixture was allowed to stand, and the resulting crystalline precipitate was collected by filtration, washed with water and dried. Recrystallization from dichloromethane-ether (1:4) gave 4.23 g of colorless crystals melting at 259°-262° C.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20]C(=O)C)=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[CH:16][CH:17]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)NCCc1ccc(-c2csc(-c3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCc1ccc(-c2csc(-c3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 84.6 %

Procedure:
In a round-bottomed flask, N-{2-[4-(2-phenyl-thiazol-4-yl)-phenyl]-ethyl}-acetamide (838 mg, 2.60 mmol) was added to 5.0 ml of concentrated HCl and the resulting solution was heated to about 120° C. for about sixteen hours. The solution was then cooled to about 0° C., brought to pH 12 with 5M sodium hydroxide, and extracted with four portions of methylene chloride. The combined organic extracts were then washed with brine, dried over magnesium sulfate, and concentrated in vacua. The crude material was purified by column chromatography (silica gel; methylene chloride to 20% methanol/methylene chloride) to afford the product (617 mg, 85% yield). LRMS ([M+H]+)=281.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:45][CH2:46][C:47]1[N:48]=[CH:49][NH:50][CH:51]=1>CN(C=O)C>[NH:50]1[CH:51]=[C:47]([CH2:46][NH:45][C:8]([C:4]2[N:5]([CH3:7])[CH:6]=[C:2]([Cl:1])[CH:3]=2)=[O:10])[N:48]=[CH:49]1
Reactant: Cn1cc(Cl)cc1C(=O)O
Reactant: NCc1c[nH]cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(Cl)cc1C(=O)NCc1c[nH]cn1
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of 4-chloro-1-methyl-1H-pyrrole-2-carboxylic acid (55 mg, 0.34 mmol) and triethylamine (0.100 mL, 0.72 mmol) in DMF (2 mL), BOP (217 mg, 0.49 mmol) was added. After 5 min of stirring, a solution of 4-aminomethylimidazole 11-2 (100 mg, 1.03 mmol) in DMF (2 mL) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to give N-((1H-imidazol-4-yl)methyl)-4-chloro-1-methyl-1H-pyrrole-2-carboxamide (81 mg).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)C.C[O-].[Na+].CI>C1COCC1.CO>[CH3:1][S:4][CH2:5][C:6]1[CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cc(CSC(C)=O)cc(C(=O)OCC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CO
Product: CCOC(=O)c1cc(CSC)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To diethyl 5-(acetylthiomethyl)isophthalate (1.02 gm, 3.30 mmol) in THF (10 ml) and MeOH (10 ml), sodium methoxide (207 mg, 3.63 mmol) was added and stirred at rt for 2 h. Then methyl iodide (0.69 ml, 10.9 mmol) were added in two portions. After stirring at rt for 4 h, THF and MeOH were removed in vacuum and the reaction mixture was diluted with ethyl acetate. Organic layer was washed with water, brine and dried. Column purification of the crude residue yielded diethyl 5-(methylthiomethyl)isophthalate in 55% yield.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[CH2:31][CH2:30]1)[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:35]1(=[O:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([C:35]2([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:30]1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](C2(O)CCCCC2)C(=O)O1
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
1.43 ml (3.58 mmoles) of butyllithium (as a 2.5M hexane solution) was added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 0.50 ml (3.57 mmoles) of diisopropylamine in 10 ml of anhydrous tetrahydrofuran. The mixture was then stirred for 30 minutes, after which a solution of 500 mg (1.61 mmoles) of (5S)-5-[(1S)-1-(N-t-butoxycarbonylamino)-2-cyclohexylethyl]dihydrofuran-2(3H)-one (prepared as described in Preparation 5) in 5 ml of anhydrous tetrahydrofuran was added thereto. The mixture was then stirred for a further 1 hour, and then 0.24 ml (3.55 mmoles) of distilled cyclohexanone was added to the mixture and stirred for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a 10% w/v aqueous solution of citric acid, with water and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (using a 1:1 by volume mixture of hexane and diethyl ether as eluent), followed by recrystallization from hexane, to give 410 mg (yield 62%) of the title compound as white crystals, melting at 133°-134° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)=[CH:4][C:3]=1[C:21]([NH:23][C:24]1[CH:29]=[C:28]([C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[CH:27]=[CH:26][C:25]=1[CH3:36])=[O:22].[CH2:37](OC(OCC)OCC)C>>[CH:33]1([NH:32][C:30]([C:28]2[CH:27]=[CH:26][C:25]([CH3:36])=[C:24]([N:23]3[C:21](=[O:22])[C:3]4[C:2](=[CH:20][CH:19]=[C:5]([O:6][C@@H:7]5[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8]5)[CH:4]=4)[N:1]=[CH:37]3)[CH:29]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)ccc1N
Reactant: CCOC(OCC)OCC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@@H]3CCN(C(=O)OC(C)(C)C)C3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (C) in the portion of Example 18 which is concerned with the preparation of starting material, tert-butyl (3R)-3-{4-amino-3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]phenoxy}pyrrolidine-1-carboxylate was reacted with triethylorthoformate to give tert-butyl (3R)-3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]pyrrolidine-1-carboxylate; NMR Spectrum: (DMSOd6) 0.54 (m, 2R), 0.68 (m, 2H), 1.39 (s, 9H), 2.15 (m, 5H), 2.85 (m, 1H), 3.50 (m, 4H), 5.19 (m, 1H), 7.54 (m, 3H), 7.72 (d, 1H), 7.83 (s, 1H), 7.89 (d, 1H), 8.19 (s, 1H), 8.41 (s, 1H); Mass Spectrum: M+Na+ 527.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[C@@H:11]([O:23]CC1C=CC(OC)=CC=1)[C:12]([O:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:34])[C@@H:11]([OH:23])[C:12]([O:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(CO[C@@H](C(=O)O[C@@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: C[C@H](OC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCCl)c1ccccc1
Yield: 93.1 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19, (1S)-1-phenylethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (35a) (0.42 g, 0.82 mmol), dissolved in a mixture of dichloromethane (DCM) and water (10:1) (3 mL), was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (220 mg, 0.98 mmol). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:1) to provide 300 mg (93% yield) of the title compound (35b) as a colorless oil. Rf=0.39 (EtOAc/Hex=1:2). 1H NMR (400 MHz, CDCl3): δ=1.02 (s, 3H), 1.19 (s, 3H), 1.64 (d, J=6.4 Hz, 3H), 2.30-2.37 (m, 2H), 3.01 (d, J=5.6 Hz, 1H), 3.30-3.33 (m, 2H), 3.67-3.70 (m, 2H), 4.02-4.04 (m, 2H), 4.20 (d, J=9.2 Hz, 1H), 6.02 (q, J=6.8 Hz, 1H), 7.36-7.38 (m, 5H) ppm. MS (ESI) m/z: 414.09 (M+Na)+. The analytical data was consistant with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH3:22].CO.CCOC(C)=O>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[CH3:21][C:22]1[N:12]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Reactant: COC(C)(OC)OC
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1nc2cnc3ccccc3c2n1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A solution of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (11.67 g, 42.5 mmol) in 400 mL of anhydrous toluene was treated with trimethyl orthoacetate (5.96 mL, 46.8 mmol) and pyridine hydrochloride (100 mg) under an atmosphere of N2 and heated to reflux. After stirring for 3 h, the reaction mixture was concentrated under reduced pressure to give a red solid. Chromatography (SiO2, 0–10% MeOH/EtOAc) gave tert-butyl N-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (10.7 g) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:19]2[N:20]=[C:21]([CH2:26][CH3:27])[C:22]([N+:23]([O-])=O)=[C:18]2[CH:17]=[CH:16][CH:15]=1>[C].[Pd].CO>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH2:9][O:10][CH3:11])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:14]1[N:19]2[N:20]=[C:21]([CH2:26][CH3:27])[C:22]([NH2:23])=[C:18]2[CH:17]=[CH:16][CH:15]=1
Reactant: CCc1nn2c(-c3c(OC)cc(COC)cc3OC)cccc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCc1nn2c(-c3c(OC)cc(COC)cc3OC)cccc2c1N
Temperature: 50 °C
Reaction time: 13 h
Yield: 439.4 %

Procedure:
A mixture of 7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (850 mg, 2.3 mmol), 10% palladium-carbon (50% wet, 330 mg) and methanol (19 mL) was stirred for 13 hours at 50° C. under a hydrogen atmosphere at atmospheric pressure. After cooling the reaction mixture to room temperature, the reaction mixture was filtered through celite to remove the catalyst. The solvent of the obtained filtrate was evaporated under reduced pressure to afford 3.45 g of the title compound (84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1.[H][H]>C(O)C.[Pt]=O>[NH2:8][C:4]1[C:3]([CH2:11][N:12]2[C:16](=[O:17])[C:15]([CH3:18])([CH3:19])[CH2:14][O:13]2)=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC1(C)CON(Cc2c(Cl)cccc2[N+](=O)[O-])C1=O
Agent: O=[Pt]
Solvent: CCO
Product: CC1(C)CON(Cc2c(N)cccc2Cl)C1=O
Yield: 59.5 %

Procedure:
Under an argon atmosphere, platinum oxide (0.3 g) was added to a Parr bottle (500 ml), followed by a solution of 2-[(2-chloro-6-nitrophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (9.4 g, 0.033 mole) in ethanol (150 ml). The Parr bottle was placed on a Parr hydrogenation apparatus and charged with hydrogen. The reaction mixture was allowed to shake until the calculated amount of hydrogen was absorbed. The catalyst was removed by vacuum filtration. The filtrate was concentrated under reduced pressure to a residue. The residue was chromatographed on silica gel, eluting with 1:4 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield 5.0 g of 2-[(6-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone as a white solid.