Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1.N1C=CC=CC=1>[C:16]([NH:14][C:11]1[CH:12]=[CH:13][C:4]([C:3]([OH:2])=[O:15])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Reactant: CCCCCC(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ccc(C(=O)O)cc1C(=O)O
Yield: 94.9 %

Procedure:
Dimethyl-4-amino-isophthalate (9 g) in 60 ml of dioxane and 18 ml of pyridine is treated with hexanoyl chloride (8.8 g) at room temperature for 16 hours. After dilution with water and extraction with ethyl acetate, the solution is washed with 40% citric acid and 5% NaHCO3 and evaporated to dryness, so obtaining dimethyl-4-hexanoylamino-isophthalate (14.8 g) that is dissolved in 75 ml of dioxane and treated with 75 ml of 2 N NaOH at room temperature for 6 hours. After acidification with HCl the precipitate is collected under vacuum and washed until neutral. 4-hexanoylamino-isophthalic acid (11.4 g) is obtained, which is treated with 26 ml of acetic anhydride at reflux for 10'. After cooling, dilute with 30 ml of isopropyl ether and filter. 6-carboxy-2-pentyl-4H-3,1-benzoxazin-4-one (7.3 g; m.p. 185°-190° C.) is obtained, which is treated at room temperature first with 70 ml of 32% ammonium hydroxide for 16 hours and then with 50 ml of 2 N NaOH for 2 hours. After acidification with 2 N HCl, the precipitate is filtered off and crystallized from ethanol, so obtaining 6-carboxy-2-pentyl-3,4-dihydro-4-oxo-quinazoline (6.1 g; m.p. 311°-313° C.).
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][O:27][CH2:28][C:29]([NH:31][NH2:32])=O)=[CH:24][CH:23]=1>C(O)CCC>[Cl:1][C:2]1[S:19][C:5]2[N:6]3[C:29]([CH2:28][O:27][CH2:26][C:25]4[CH:33]=[CH:34][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)=[N:31][N:32]=[C:7]3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)sc2N1
Reactant: COc1ccc(COCC(=O)NN)cc1
Solvent: CCCCO
Product: COc1ccc(COCc2nnc3n2-c2sc(Cl)cc2C(c2ccccc2Cl)=NC3)cc1

Procedure:
1.5 g of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-thione are refluxed for 4 hours with 4 g of 2-(p-methoxybenzyloxy)acetic acid hydrazide in 100 ml of absolute butanol, a nitrogen stream being conducted through the solution. The mixture is evaporated, taken up in methylene chloride, washed with water and saturated sodium chloride solution, dried and evaporated. By recrystallization of the residue from ethyl acetate containing active carbon, there is obtained 2-chloro-4-(o-chlorophenyl)-9-[(p-methoxybenzyloxy)methyl]-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:11]=[CH:10][N:9]=1>C(O)C>[CH2:17]([N:14]([CH2:15][CH3:16])[C:12]1[CH:11]=[CH:10][N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:13]=1)[CH3:18]
Reactant: CCN(CC)c1ccnc(Cl)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: CCN(CC)c1ccnc(N2CCNCC2)n1
Yield: 63.3 %

Procedure:
A solution of piperazine (5.8 g, 67.33 mmol) and N-(2-chloro-4-pyrimidinyl)-N,N-diethylamine (5.0 g, 26.93 mmol; preparation see: L. Strekowski, Pol. J. Chem. 1980, 54, 1557–62) in ethanol (200 ml) is heated at 100° C. for 16 hours. The mixture is then concentrated under reduced pressure and extracted with water/ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Silica gel chromatography (mobile phase: dichloromethane/methanol) gives 4.01 g of the product (63%) as a yellow oil.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[CH3:21])[NH:17][C:16]([C:22]([OH:24])=O)=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[CH:25]1([C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([CH:2]([CH3:3])[CH3:4])[CH2:6][CH2:7]3)=[C:20]([CH3:21])[CH:19]=4)=[O:24])[CH2:32][CH2:31]2)=[O:29])[CH2:26][CH2:27]1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: Cc1cc2[nH]c(C(=O)O)cc2cc1OC1CCN(C(C)C)CC1
Agent: Cl
Product: Cc1cc2[nH]c(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2cc1OC1CCN(C(C)C)CC1
Yield: 56 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(1-isopropyl-piperidin-4-yloxy)-6-methyl-1H-indole-2-carboxylic acid hydrochloride and 1-(cyclopropanecarbonyl)piperazine to afford the title compound as a light-yellow foam (56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([C:16]([CH3:17])=[N:15][N:14]=2)[N:13]=1
Reactant: NNc1ncc(-c2ccccc2Cl)nn1
Reactant: CCOC(C)([O-])[O-]
Product: Cc1nnc2ncc(-c3ccccc3Cl)nn12

Procedure:
A mixture of 4.45 g. of 6-(o-chlorophenyl)-3-hydrazino-1,2,4-triazine and 50 ml. of ethyl orthoacetate is treated as described in Example 16, giving the desired product as yellow crystals, m.p. 172°-175° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([NH2:16])=[O:15].[C:17]([O:21][C:22]([N:24]1[CH2:27][CH:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH:30]([C:34](OC)=O)[CH2:29]2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(O)C>[CH3:13][C:4]1[C:3]2[C:14](=[O:15])[NH:16][C:34]([CH:30]3[CH2:31][CH2:32][CH2:33][N:28]([CH:26]4[CH2:25][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:23])[CH2:27]4)[CH2:29]3)=[N:1][C:2]=2[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1
Reactant: Cc1nn(-c2ccccc2)c(N)c1C(N)=O
Reactant: COC(=O)C1CCCN(C2CN(C(=O)OC(C)(C)C)C2)C1
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c2nc(C3CCCN(C4CN(C(=O)OC(C)(C)C)C4)C3)[nH]c(=O)c12

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of Na (128 mg, 5.57 mmol, 6.00 equiv) in ethanol (10 mL) at room temperature. To the resulting mixture was then added a solution of 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide (200 mg, 0.93 mmol, 1.00 equiv) in C4H10O (10 mL), in portions at room temperature, followed by a solution of methyl 1-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidine-3-carboxylate (1.66 g, 5.57 mmol, 6.00 equiv) in C4H10O (20 mL), in portions at room temperature. The resulting solution was heated to reflux overnight. The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with DCM (3×30 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride (2×30 mL). The mixture was dried over anhydrous sodium sulfate, the solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1) to yield tert-butyl 3-(3-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-1-yl)azetidine-1-carboxylate as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C>C(Cl)Cl.CCCCCC>[CH2:13]([O:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc2c(cc1O)CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A 2-liter, 3-neck flask equipped with a nitrogen inlet, internal thermometer, mechanical stirrer, and reflux condenser was charged with 5-hydroxy-2,3-dihydrobenzofuran-6-carboxaldehyde (50.00 g; 0.30 moles), benzylbromide (38.6 ml, 0.34 moles), and crushed anhydrous K2CO3 (165.84 g, 1.20 moles). The reaction mixture was refluxed for 16 hours, cooled to room temperature and suction filtered. The filtrate was concentrated in vacuo to afford a yellow solid. The solid was dissolved in methylene chloride (600 ml) and washed sequentially with 0.5N sodium hydroxide solution (3×250 ml) and brine (2×250 ml). The organic phase was dried over MgSO4, suction filtered, and the filtrate concentrated in vacuo to yield a crude solid (85 g). The solid was dissolved in methylene chloride (300 ml)/n-hexane (200 ml), treated with charcoal and suction filtered through a bed of celite. The filtrate was evaporated in vacuo to approximately 300 ml and slowly cooled to 0° C. to produce yellowish flat needles (60 g, 78%).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[OH:24])[CH2:4][CH3:5])[CH3:2].[Cl:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>C1COCC1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[O:24][C:27](=[O:28])[CH2:26][Cl:25])[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1OC(=O)CCl

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol with chloroacetyl chloride /triethylamine in THF at 0° C. to rt. 1H NMR(CDCl3) d 6.84(s,2H), 6.15(s,1H), 4.3(s,2H), 4.0(d,1H), 3.3(m,1H), 2.28(s,3H), 2.17(s,3H), 2.08(s,6H), ⅙-1.7(m,4H), 0.9(t,6H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([NH:22][C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:40][CH:39]=3)[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(NC3CCCC3)c2C)c(=O)[nH]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) and Pd (PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide which was further purified using preparative HPLC which gave the TFA salt.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][CH:6]([CH3:15])[CH2:7][CH2:8][CH2:9][C:10]([O:13][OH:14])([CH3:12])[CH3:11].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>O.CCCCC>[C:16]([O:14][O:13][C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]([CH3:15])[CH2:5][CH2:4][OH:3])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(CCO)CCCC(C)(C)OO
Agent: [K+]
Agent: [OH-]
Solvent: CCCCC
Solvent: O
Product: CC(CCO)CCCC(C)(C)OOC(=O)C(C)(C)C
Temperature: 30 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
A jacketed reactor equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 9.3 g (0.075 mole) of 45% KOH, 4.7 g of water and 11.3 g (0.058 mole) of 97.3% 7-hydroxy-1,1,5-trimethylheptyl hydroperoxide. To this vigorously stirred solution at 30° C. was slowly added 6.4 g (0.050 mole) of 94.3% pivaloyl chloride over a period of 20 minutes. The resulting mixture was then vigorously stirred for one hour at 30° C. after which it was cooled to 15° C. and 100 ml of pentane and 25 ml of water were added. After separating and discarding the aqueous phase the product solution was washed at 10° to 15° C. with 20 g of buffered sodium sulfite solution (consisting of 0.8 g of acetic acid, 1.2 g of sodium acetate, 2.0 g of sodium sulfite and 16 g of water), with 15 ml of water and then with 20 g of 7.7% sodium hydrogen carbonate solution. The resulting pentane solution was then dried over anhydrous MgSO4 and after separation of the spent desiccant by filtration the pentane was removed in vacuo at 0° to 10° C. leaving 8.2 g of liquid product. The assay of the product according to peroxyester active oxygen was 69.6% and the corrected yield was 41.7%. An infrared spectrum of the product showed a strong, broad OH band centered at 3400 to 3500 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[Br:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1.[H-].[Na+]>O1CCOCC1>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][Br:20])[CH:23]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: BrCc1cccc(CBr)c1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cccc(CBr)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (2 g, 6.06 mmol) was suspended in 1,4-dioxane (250 mL). α,α′-Dibromo-m-xylene (8 g, 30.3 mmol) was added followed by sodium hydride (0.3 g, 7.5 mmol, 60% in mineral oil). The reaction was heated to 60° C. and stirred for 16 hours. The reaction was filtered through Celite® and the filtrate was concentrated to an oil that was partitioned between water and dichloromethane and extracted with dichloromethane (4×250 mL). The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (1.2 g, 38%). 1H NMR (400 MHz, CDCl3) δ 7.57 (app q, J=7.6 Hz, 1H); 7.28-7.25 (m, 2H); 7.17 (s, 1H); 7.08 (m, 1H); 6.94 (app dt, J=1.2, 9.6 Hz, 1H), 6.87-6.82 (m, 1H); 5.99 (s, 1H), 5.34 (s, 2H), 5.20 (s, 2H); 4.43 (s, 2H); 2.29 (s, 3H). ES HRMS m/z 511.9672 (M+H C21H17Br2F2NO2 requires 511.9667).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([O:10][C:11]([F:14])([F:13])[CH3:12])=[CH:8][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[OH:24]O>CO>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([OH:24])=[CH:8][C:9]=2[O:10][C:11]([F:14])([F:13])[CH3:12])[CH2:3][CH2:2]1
Reactant: OO
Reactant: CC(F)(F)Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C1CC1
Solvent: CO
Product: CC(F)(F)Oc1cc(O)cnc1C1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the crude 2-cyclopropyl-3-(1,1-difluoroethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 268, 412 mg, 1.27 mmol) was added methanol (20 mL), and the stirred solution cooled in an ice bath. To the solution was added hydrogen peroxide solution (35% in water) (0.15 mL, 1.52 mmol) over 2 minutes. The solution was allowed to warm slowly to room temperature over 18 hours. The reaction was quenched by addition of 1M aqueous sodium thiosulfate solution (50 mL), and rapidly stirred for 15 minutes. The organics were removed in vacuo, and brine (50 mL) was added. The aqueous was extracted into ethyl acetate (3×100 mL). The combined organics were dried over magnesium sulfate, filtered and the solvent removed to leave an orange oil. The oil was purified through a plug of silica, eluting with 1:1 ethyl acetate:heptane to provide the title compound a white solid (155 mg, 57%).
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30]>C(O)C>[CH3:35][Si:33]([CH3:36])([C:29]([CH3:32])([CH3:31])[CH3:30])[O:6][CH2:7][C@@H:8]1[C@@H:15]2[C@@H:11]([O:12][C:13](=[O:16])[CH2:14]2)[CH2:10][C@H:9]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC3CCCCO3)C[C@@H]2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105.4 %

Procedure:
To a dimethylformamide (hereinafter, abbreviated as DMF in some cases) (100 mL) solution of (3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one (50 g), imidazole (29.22 g), and tert-butyldimethylchlorosilane (30.87 g) were sequentially added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, a small amount of ethanol was added; the reaction solution was poured into ice water; and this was extracted with ethyl acetate:hexane (2:3). The extract was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution, water and a saturated saline, dried with sodium sulfate, and concentrated under reduced pressure to obtain a titled compound (76.2 g) having the following physical property values.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]#[N:18])=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.O.O.[Sn](Cl)Cl>C(O)C>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:16])[C:7](=[O:15])[NH:8]2)=[C:3]([C:17]#[N:18])[C:2]=1[Cl:1]
Reactant: N#Cc1c(Cl)c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: N#Cc1c(Cl)c(N)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A suspension of 6-chloro-5-cyano-7-nitroquinoxaline-2(1H),3(4H)-dione (0.100 g, 0.38 mmol, as prepared above) and tin (II) chloride dihydrate (0.508 g, 2.25 mmol, Aldrich) in ethanol (4.0 mL) was refluxed for 24 h. The resulting suspension was then cooled to room temperature and the yellow solid was filtered, washed with ethanol (2.0 mL), and dried under vacuum to obtain 0.078 g (88%) of 7-amino-6-chloro-5-cyanoquinoxaline-2(1H),3(4H)-dione as a yellow powder; 1H NMR (DMSO-d6): δ5.762 (br s, 2H), 6.818 (s, 1H), 11.69 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]1[O:22][C:21](=[O:23])[C:20]2([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:19]=1.O>CN(C)C=O>[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]([NH:19][C:20]1([C:21]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Reactant: CSCC[C@H](N)CO
Solvent: CN(C)C=O
Solvent: O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
284 mg (2.1 mmol) of L-methioninol was added to a solution of 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of N,N-dimethylformamide, and the mixture was stirred overnight. Water was slowly added and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain 722 mg (98%) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[C:8]2[C:19]([CH3:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:9]=2[O:10][CH:11]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[C:25]([Si:22]([CH3:23])([CH3:24])[O:21][C:12]1[C:9]2[O:10][CH:11]=[C:7]([CH2:6][CH2:5][CH:4]=[O:3])[C:8]=2[C:19]([CH3:20])=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[CH:17]2)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)CCc1coc2c(O[Si](C)(C)C(C)(C)C)c3ccccc3c(C)c12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1c2ccccc2c(O[Si](C)(C)C(C)(C)C)c2occ(CCC=O)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A solution of 67.0 mg (0.162 mmol, 1.0 eq) of ester 17 in 1.60 mL of dry CH2Cl2 was stirred in a dry 5 mL round bottom flask at room temperature under argon. The solution was then cooled to −78° C. in a dry ice/acetone bath. Once cooled, 162 μL (1.2 M in toluene, 0.195 mmol, 1.2 eq) of Diisobutylaluminum hydride was added dropwise and the resulting solution was stirred at −78° C. for 30 minutes. While still cold, the solution was then quenched via the dropwise addition of 170 μL of MeOH followed by 670 μL of saturated aqueous sodium potassium tartrate (Rochelle's salt) added at once. The dry ice/acetone bath was then removed and the solution was diluted with Et2O and stirred for 20 minutes. The colorless solution was then filtered through CELITE. The CELITE was washed with Et2O and the combined organic fractions were washed with brine. The aqueous layer was further extracted with Et2O and the combined organic fractions were dried over MgSO4. Concentration yielded 58.8 mg (98%) of 18 as a colorless solid, Rf 0.72 (1:1 hexane:EtOAc). Mp: 152.5-153.6° C. 1H-NMR (500 MHz, CDCl3): 9.92 (1H, s), 8.31 (1H, m), 8.09 (1H, m), 7.47 (2H, m), 7.44 (1H, s), 3.29 (2H, t, J=7.3 Hz), 2.93 (2H, t, J=7.4 Hz), 2.91 (3H, s), 1.15 (9H, s), 0.27 (6H, s). 13C-NMR (500 MHz, CDCl3): 201.35, 143.46, 143.26, 130.19, 127.88, 125.80, 124.12, 123.86, 123.79, 122.72, 119.76, 118.44, 43.76, 26.24, 18.93, 18.85, 14.45, −3.85. IR (cm−1): 2927 (m), 2856 (m), 1724 (s), 1628 (m), 1461 (m), 1390 (s), 1247 (m), 1191 (m), 1117 (s), 988 (s), 826 (s), 786 (s), 760 (s). Anal. Calcd. for C22H28O3Si: C, 71.70; H, 7.66. Found: C, 71.34; H, 7.68.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]1)=[O:16])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl>[CH2:12]([O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH:19]([O:22][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:18]1)=[O:16])[CH3:13]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)C1CCC(O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(Oc2ccc(Cl)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of 1,4-dichloro-2-nitro-benzene (190 mg, 1.1 mmol), 3-hydroxy-cyclopentanecarboxylic acid ethyl ester (180 mg, 1.14 mmol), triphenylphosphine (448 mg) and DIAD (345 mg) in dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was then evaporated under reduced pressure and the crude residue was purified by flash chromatography to afford 280 mg of 3-(4-chloro-2-nitro-phenoxy)-cyclopentanecarboxylic acid ethyl ester.