Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)[C:16]1=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>C(OC(=O)C)(=O)C.O>[CH2:5]([O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][N:17]([C:20]2[C:24]([N+:1]([O-:4])=[O:2])=[CH:23][N:22]([CH3:25])[N:21]=2)[C:16]1=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cn1ccc(N2CCN(CCOCc3ccccc3)C2=O)n1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cn1cc([N+](=O)[O-])c(N2CCN(CCOCc3ccccc3)C2=O)n1
Reaction time: 0.08 h

Procedure:
To acetic anhydride (22 mL) was added fuming nitric acid (2.76 mL) under ice-cooling, and the mixture was stirred for 5 min. The obtained solution was added dropwise to a solution of 1-(2-(benzyloxy)ethyl)-3-(1-methyl-1H-pyrazol-3-yl)imidazolidin-2-one (10 g) in acetic anhydride (44 mL) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water, and the mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (8.20 g).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[C:23]([OH:24])=[N:22][C:21]2[C:16]1=[N:17][CH:18]=[N:19][C:20]=2[NH2:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:27]([O:29][CH3:30])=[O:28]>C1COCC1>[CH2:8]([N:15]1[C:23]([O:24][C:27]([O:29][CH3:30])=[O:28])=[N:22][C:21]2[C:16]1=[N:17][CH:18]=[N:19][C:20]=2[NH2:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ncnc2c1nc(O)n2Cc1ccccc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1nc2c(N)ncnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Triethylamine (202 mg, 2 mmol) and N,N-dimethylaminopyridine (111 mg 0.5 mmol) were added to 9-benzyl-8-hydroxyadenine (241 mg, 1 mmol) dissolved in anhydrous THF (20 ml). After stirring at room temperature for 1 h, methyl chloroformate (113 mg, 1.2 mmol) was added thereto, and the mixture was stirred overnight at room temperature. The resulting reaction mixture was extracted by ethyl acetate (50 ml) and water (50 ml), and the resulting organic layer was concentrated under vacuum followed by addition of ether (20 ml) to obtain the desired compound as crystals (300 mg, Yield: 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH:31]=O)([CH2:18][CH2:19][CH2:20][CH2:21][B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:31][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH2:18][CH2:19][CH2:20][CH2:21][B:22]1[O:23][C:24]([CH3:30])([CH3:29])[C:25]([CH3:27])([CH3:28])[O:26]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OCc1ccccc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CN1CCCCC1)NC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A solution of ethyl 2-(benzyloxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.503 g, 1.13 mmol), piperidine (0.39 mL, 4 mmol) and acetic acid (0.23 mL, 4 mmol) in 1,2-dichloroethane (20 mL) was stirred for 15 minutes then treated with sodium triacetoxyborohydride (0.85 g, 4 mmol). After stirring for 2 h at 65° C. the solution was cooled to room temperature and concentrated. The resulting residue was purified using a combiflash system (12 g silica gel column, 10-100% ethyl acetate in heptanes) to give ethyl 2-(benzyloxycarbonylamino)-2-(piperidin-1-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (300 mg, 52%). 1H NMR (CDCl3) δ: 7.36 (m, 5H), 6.05 (bs, 1H), 5.14 (d, 1H), 5.03 (d, J=11.2 Hz, 1H), 4.19 (m, 2H), 3.06 (d, J=13.8 Hz, 1H,), 2.59 (d, J=13.8 Hz, 1H), 2.34 (m, 4H), 2.15 (m, 1H), 1.78-1.70 (m, 1H), 1.45-1.25 (m, 12H), 1.22 (s, 12H), 1.02 (m, 1H), 0.73 (t, J=7.8 Hz, 2H). MS found for C28H45BN2O7 m/z[517(M+1)].
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C>CC(O)=O.O.[Pd]>[NH2:22][C@@:10]1([C:12]([OH:14])=[O:13])[C@H:9]([OH:25])[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1O)[C@@H]2C(=O)O
Temperature: 23 °C
Yield: 86.8 %

Procedure:
A solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1) (1.55 g, 4.49 mmol) in HOAc (20 mL) and H2O (5 mL) was hydrogenated in the presence of Pd/C (100 mg, 10% Pd/C) at 23° C. for 18 h. The catalyst was removed by filtration, the filter cake washed with 50% aqueous acetic acid. After removal of the solvent in vacuum, the beige residue was refluxed in 10% HCl (55 mL) for 4 h. The solution was cooled to 23° C., filtered, washed with water and evaporated to dryness. The remaining pale yellow solid was dissolved in EtOH (45 mL) and propylene oxide (24 mL) and refluxed for 15 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid (I-A) (784 mg, 87%) as a white solid. 1H-NMR (250 MHz, D2O) □1.87 (1H, t, J=3.1 Hz), 2.15-2.26 (3H, m), 2.38 (1H, dd, J=13.0, 7.6 Hz), 3.97 (1H, dd,J=8.6,7.4 Hz); MS[ISP]202 (M+H+); mp>250° C.; □D20 +7.41° (c=1.01, H2O).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([C:21]3([CH3:24])[CH2:23][CH2:22]3)[C:12]3[C@@H:25]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)[O:26][C:27]4([CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C.C(OC(=O)C)(=O)C.[Pt](=O)=O>[C:21]([C:13]1[C:12]2[C@@H:25]([C:33]3[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:38]=3)[O:26][C:27]3([CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:11]=2[C:10]2[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=2[N:14]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1(C)Cc2nc(C3(C)CC3)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(C)Cc2nc(C(C)(C)C)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
30 mg (3R,9S)-9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-4-(1-methylcyclopropyl)-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran] are dissolved in 3 ml acetic acid and 1 ml acetic acid anhydride. 30 mg Platinum-(IV)-oxide are added and the mixture is hydrogenated for 2 hours at 60° C. and 3 bar. The catalyst is filtered off and washed with methanol. The liquid phases are combined and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 90:10).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:19](=O)[CH2:18][O:17][CH:16]([CH2:21][N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]2=3)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][O:17][CH:16]([CH2:21][N:22]2[C:23]3[CH:36]=[CH:35][CH:34]=[CH:33][C:24]=3[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]2=3)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COC(CN2c3ccccc3CCc3ccccc32)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CCOC(CN3c4ccccc4CCc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium aluminum hydride (0.03 g) in tetrahydrofuran (5 ml) was added a solution of 5-(4-benzyl-5-oxo-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz-[b,f]azepine (0.5 g) in tetrahydrofuran (15 ml) under ice cooling, and the resulting mixture was stirred at room temperature for 1 hour and refluxed for 10 hours with stirring. The reaction mixture was cooled, admixed with water (2 ml) and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-benzyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 139°-140° C (oxalate).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6].C([BH3-])#N.[Na+]>CO>[C:5]([N:10]1[CH2:15][CH2:14][CH:13]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]([CH3:17])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: NC1CC1
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC2CC2)C(C)C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Cyclopropylamine (10 g, 169.5 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (7.0 g, 37.83 mmol) obtained as described in Preparation 1, in methanol (50 ml) and stirring was continued for 12 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.0 g, 46.0 mmol) was added to it. Cooling was removed after 10 min. and stirring was continued for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford 1-carbethoxy4-cyclopropylamino-3-methylpiperidine. Yield 6.0 g (70%), C12H22N2O2, m/z 227 (M+1), PMR (CDCl3): 0.38 (m, 4H), 0.88 (dd, 3H), 1.28 (t, 3H), 1.54 (m, 1H), 2.06 (m, 2H), 2.32 (m, 1), 2.48 (m, 1H), 2.84 (m, 1H), 3.06 (m, 1H), 3.72 (m, 1H), 3.88-4.24 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:18][CH2:19][CH2:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:18][CH2:19][CH2:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-propoxypiperidin-1-yl)benzoate obtained in Example (178b) (42.4 mg, 0.14 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (24.1 mg, 0.14 mmol), WSC hydrochloride (79.4 mg, 0.41 mmol) and HOBt (18.7 mg, 0.14 mmol), to obtain 35.5 mg of the title compound as a yellow oily substance (67%).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[Cl:10].[H-].[Na+].CS(O[CH2:18][CH2:19][O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)(=O)=O>CN(C)C=O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:18][CH2:19][O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)=[CH:4][C:3]=1[Cl:10]
Reactant: Oc1cc(Cl)c(Br)c(Cl)c1
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(OCCOc2ccc3ccccc3c2)cc(Cl)c1Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
A stirred mixture of 4-bromo-3,5-dichlorophenol (1.9 g) in dimethylformamide (20 mL) under argon was treated with 55% sodium hydride (0.345 g), stirred for 30 minutes and treated with 2-(2-naphthalenyloxy)ethyl methanesulfonate (2.1 g). The mixture was heated at 60° C. overnight and evaporated to dryness. The residue was mixed with water and excess sodium hydroxide solution, the product was extracted twice with dichloromethane, and the organic layers were washed with water. The combined organic layers were dried (Na2SO4), filtered, evaporated and crystallized from dichloromethane-diethyl ether to provide 3.3 g of 2-[2-(4-bromo-3,5-dichlorophenoxy)ethoxy]naphthalene as a colorless solid, mp 140°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.Cl.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=[NH:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:23][C:22]([C:21]([CH3:26])([CH3:25])[CH3:20])=[N:24][C:7]=3[C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Product: CC(C)(C)c1ncc2c(n1)-c1cc(Cl)ccc1NC(=O)C2
Yield: 88 %

Procedure:
Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2,2-dimethylpropionamidine hydrochloride. Yield: 88%. Off-white solid, m/z (ISP) 302 (MH)
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[O:13][CH3:14].[N+:15]([O-])([OH:17])=[O:16].C(OCC)C.CCCCCC>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([F:11])=[C:9]([N+:15]([O-:17])=[O:16])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[O:13][CH3:14]
Reactant: O=[N+]([O-])O
Reactant: COc1c(F)c(C(=O)O)cc(F)c1Br
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1c(F)c(C(=O)O)c([N+](=O)[O-])c(F)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 8 ml of sulfuric acid was dissolved 2.0 g of 4-bromo-2,5-difluoro-3-methoxybenzoic acid, and 4 ml of nitric acid was dropwise added to the solution with ice-cooling, after which the resulting mixture was stirred at room temperature for one hour. The reaction mixture was added to a mixed solvent of 50 ml of diethyl ether and 50 ml of ice water, and the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. To the residue thus obtained was added n-hexane, and the resulting crystals were collected by filtration to obtain 1.9 g of pale yellow, crystalline 4-bromo-2,5-difluoro-3-methoxy-6-nitrobenzoic acid.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:14]=[CH:15][CH:16]=2)=[C:8]([N+:26]([O-:28])=[O:27])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([N+:26]([O-:28])=[O:27])=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH:14]=[CH:15][CH:16]=3)[CH:24]=[CH:25][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2cccc(NC(=O)C(F)(F)F)c2)c([N+](=O)[O-])c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)c([N+](=O)[O-])c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.6 %

Procedure:
Potassium thiocyanate (4.3 g, 44.2 mmol) was suspended in acetic acid (40 mL), and the mixture was stirred at room temperature for 10 min. N-[3-(4-Amino-2-nitrophenoxy)phenyl]-2,2,2-trifluoroacetamide (3.02 g, 8.85 mmol) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (1.98 g, 12.4 mmol) in acetic acid (10 mL) was slowly added dropwise to the obtained solution, and the mixture was stirred at room temperature for 16 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (400 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (400 mL). The aqueous layer was extracted with ethyl acetate (200 mL), and the combined organic layer was washed with saturated brine (400 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (1.29 g, 37%) as a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[N+:1]([C:4]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:21])=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Nc2ccc(O)cc2)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
1.43 g of 4-(2,4-dinitroanilino)phenol, 500 mg of potassium carbonate and 0.32 ml of methyl iodide were stirred in 5 ml of N,N-dimethylformamide for 2 days at 20° C. The mixture was poured onto water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: P(=O)(O)(O)O.[Cl-].[Na+].[CH2:8]([OH:30])[C@H:9]1[O:14][C@H:13]([O:15][C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H:12]([OH:27])[C@@H:11]([OH:28])[C@@H:10]1[OH:29]>O>[O:15]=[CH:13][C@@H:12]([C@H:11]([C@@H:10]([C@@H:9]([CH2:8][OH:30])[OH:14])[OH:29])[OH:28])[OH:27]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
To 1 ml of a buffer solution (pH 6.5) containing 20 mM phosphoric acid and 6.7 mM sodium chloride, 300 mg of maltose (Wako Pure Chemical Industries Ltd. product) was dissolved, and then, 10 mg of α-amylase (saccharification type, Seikakagaku Corporation product by using Bacillus subtilis) and 1 mg of ε-poly-L-lysine were added and dissolved. The spores of Bacillus cereus (equivalent to 103 colony-forming units) were inoculated to the solution and allowed to react at 60° C. for 24 hrs. After the reaction was completed, the reaction solution was heated in a boiled water to stop the enzyme reaction, and filtered through a 0.45 μm membrane filter. The quantity of glucose in the filtrate was measured by a high speed liquid chromatographic method (column: Showa denko K.K. product, #SC1011). The quantity of glucose thus obtained was 260 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]([NH:25]C(=O)OC(C)(C)C)[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C@H:21]([CH:22]([CH3:24])[CH3:23])[C:19]([NH:18][C:15]1[CH:14]=[N:13][C:12]([O:11][C:7]2[C:6]3[C:2]([CH3:1])([CH3:33])[CH2:3][O:4][C:5]=3[CH:10]=[CH:9][CH:8]=2)=[N:17][CH:16]=1)=[O:20]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-[({2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]-2-methylpropyl}carbamate (Intermediate 144, 52 mg, 0.114 mmol) in dry Dichloromethane (DCM) (2 mL) at 0° C. TFA (0.5 ml, 6.49 mmol) was slowly added and the reaction mixture was stirred for 1 h at the same temperature. The solvent and the excess of TFA were evaporated end the residue was dissolved in DCM (5 ml) and an aqueous saturated solution of NaHCO3 was added while the pH was allowed to reach ˜8-9. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (40 mg) as a white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[CH2:18]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.S(Cl)([Cl:29])=O>ClCCl>[C:4]([Si:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1[CH2:18][Cl:29])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(F)(F)F)sc1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cc(C(F)(F)F)sc1CCl
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of [3-(tert-butyldimethylsilanyloxy)-5-trifluoromethylthiophen-2-yl]methanol in anhydrous dichloromethane (100 mL) was added triethylamine (4.05 g, 40.0 mmol) followed by thionyl chloride (2.38 g, 20.0 mmol) at 0° C. The reaction mixture was stirred for 30 min and quenched with water (50.0 mL). After separation, the organic layer was washed with water (3×50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with hexane to afford the title compound (2.31 g, 70%) as a yellow oil, which was directly used.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.[OH-].[Li+]>C1COCC1>[C:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][CH:4]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:3]([OH:23])=[O:2])=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C(CCNC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 4-tert-butoxycarbonylamino-2-(3,4-dichlorophenyl)-butyric acid methyl ester (12.3 g, 34 mmol) in THF (80 mL)/water (20 mL) was added lithium hydroxide (1.63 g, 68 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the residue diluted with water. After extraction with EtOAc, the aqueous phase was acidified to pH 5 by the addition of 2M aqueous hydrochloric acid solution. The aqueous phase was extracted with EtOAc and the extracts dried over magnesium sulfate. Concentration gave the title compound as a pale brown foam (11.54 g, 98%); 1H NMR (400 MHz, DMSO) δ 1.35 (9H, s), 1.74–1.81 (1H, m), 2.03–2.10 (1H, m), 2.81 (2H, m), 3.61 (1H, t), 6.86 (1H, m), 7.28 (1H, dd), 7.54 (1H, dd), 7.59 (1H, d), 12.60 (1H, brs); MS (ES−) m/e=346.