Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[C:31]([C:40]([NH:42][CH3:43])=[O:41])=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[C:31]([C:40]([NH:42][CH3:43])=[O:41])=[CH:30][C:29]4=[O:44])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To 2 mL of a dichloromethane solution containing 0.15 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-4-((methylamino)carbonyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred at room temperature for 30 min. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 11 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 88 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide as a pale yellow foam.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[C:30](#[N:32])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:18][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:7][C:3]=1[CH2:2][C:30]#[N:32]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
Tetrabutylammonium cyanide (18.5 g, 67 mmol) was added to a solution of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [15.0 g, 51 mmol; PCT Int. Appl. (2002), WO 0292590 A1] in acetonitrile (340 ml). The solution was stirred at ambient temperature for 16 h, saturated aqueous sodium bicarbonate solution/ice water 1/1 and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give a brown oil which was purified by column chromatography (silica gel, n-heptane/CH2Cl2) to yield 8.58 g (30 mmol, 59%) of the title compound as light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([CH3:52])[CH:51]=1)[C:36]([C:38]1[NH:43][C:42](=[O:44])[NH:41][C:40](=[O:45])[C:39]=1[CH:46]([CH3:48])[CH3:47])=[O:37].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[Br:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([CH3:52])[CH:51]=1)[C:36]([C:38]1[N:43]([CH2:8][C:6]2[CH:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:3]=[C:2]([F:1])[CH:7]=2)[C:42](=[O:44])[NH:41][C:40](=[O:45])[C:39]=1[CH:46]([CH3:47])[CH3:48])=[O:37]
Reactant: Cc1cc(Br)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1ccc(CNc2cc(CO)cc(F)n2)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(Br)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Yield: 57.1 %

Procedure:
[2-Fluoro-6-(4-methoxy-benzylamino)-pyridin-4-yl]-methanol (262 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with 6-(3-Bromo-5-methyl-benzoyl)-5-isopropyl-1 H-pyrimidine-2,4-dione (351 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:dichloromethane (1:9); Rf˜0.2 fraction was collected.) to afford 340 mg (57%) of a white solid.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:21][NH:22][O:23][CH3:24].O>ClCCl>[CH3:21][N:22]([O:23][CH3:24])[C:6]([CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:8]
Reactant: O=C(O)C1CC=CC1
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)C1CC=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a solution of cyclopent-3-ene-1-carboxylic acid (80.0 g, 0.71 mol) in dichloromethane (300 ml) was added 1,1′-carbonyldiimidazole (127.5 g, 0.78 mol) slowly and the reaction mixture was stirred at room temperature for 1 h. N,O-dimethylhydroxylamine (76.7 g, 0.78 mol) was added and stirred for 18 h at room temperature. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (100 ml). The organic extracts were washed with hydrochloric acid (1N, 2×200 ml) and then with brine before filtering through cotton wool, drying and concentrating. The product was purified by flash chromatography using silica gel eluting with dichloromethane to give the title compound (116.78 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[OH:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>C(OCC)(=O)C>[NH2:26]/[C:4](/[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Cl:1])=[C:6]1\[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: O=C(c1ccccc1Cl)c1sc2ccccc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1Cl
Yield: 33 %

Procedure:
Prepared as in Example 1 from 2-(2-chlorobenzoyl)-benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 33% of theory; m.p. 167°-168° C. (ethyl acetate)
Reaction SMILES: C([O-])(=O)C.[Ca+2].C([O-])(=O)C.[CH2:10]([O:17][C:18]([NH:20][CH:21]([C:33](O)=[O:34])[CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([OH:25])=[O:24])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:36][O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:40].[OH-].[Na+]>CN(C)C=O>[CH3:36][O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:40][C:33](=[O:34])[C@H:21]([CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](=[O:24])[OH:25])[NH:20][C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(NC(C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
A 100 mg amount of Thermoase and 100 mg of an inhibitor for proteolytic enzyme obtained from the potato were admixed with 10 ml of tris-hydrochloric acid buffer solution (pH 8.0) containing 2.0 × 10-2M of calcium acetate. The mixture was stirred at 30° C. for 10 minutes. The insoluble material was removed by filtering the solution through a glass filter (G-3). The filtrate was mixed with 715 mg (2.00 mmol) of N-benzyloxycarbonyl-(β-benzyl)-D,L-aspartic acid and 215 mg (1.00 mmol) of L-phenylalanine methyl ester and then 1N NaOH was added to the filtrate to adjust the pH to 7.5. The reaction was carried out with stirring at 39° C. for 17 hours. The resulting white precipitate was treated in accordance with the process of Example 1 whereby 411 mg (yield of 79.2%) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartyl-L-phenylalanine methyl ester having an [α]D23 = -12.5 (C=1.0 dimethylformamide)
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].O=[CH:24][CH2:25][C:26]1([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(C1(C(OC)=O)CCCC1)=O>>[CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C:26]4([C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1cccc2onc(OCC3CCNCC3)c12
Reactant: COC(=O)C1(CC=O)CCOCC1
Agent: COC(=O)C1(C=O)CCCC1
Product: COC(=O)C1(CCN2CCC(COc3noc4cccc(OCC(C)C)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-isobutoxy-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 10, Step 1) and methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (WO 2004/043958) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclopentanecarboxylate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][CH:10]=1.[C:15]([NH:18][C:19]1[CH:28]=[CH:27][C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16].CO>N1C=CC=CC=1.C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:23]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1=CC=Nc2ccccc2S1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a mixture of 2-(2-hydroxyethyl)-1,5-benzothiazepine as prepared in Example 2 (3 g, 14.4 mM) in pyridine (30 ml) was slowly added N-acetylsulfanilyl chloride (6.7 g, 28.7 mM). The resulting mixture was stirred at room temperature for 16 hours and the excess pyridine was removed under reduced pressure. The residual semi-solid was diluted with H2O (80 ml) and extracted with CH2Cl2 (2×80 ml). The combined methylene chloride extracts were dried (MgSO4), filtered and evaporated in vacuo to give a crude oil. Flash column chromatography (EM silica gel 60; 2% MeOH in CH2Cl2) gave the desired product as a white solid (2.9 g, 50%). m/z (MH+)407
Reaction SMILES: [CH:1]([N-:3][CH:4]=[O:5])=[O:2].[Na+].C(#N)C.CN(C)C=O.Cl[CH2:16]/[C:17](=[CH:27]/[F:28])/[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>O>[F:28]/[CH:27]=[C:17](\[CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)/[CH2:16][N:3]([CH:4]=[O:5])[CH:1]=[O:2]
Reactant: O=C[N-]C=O
Reactant: F/C=C(/CCl)CCc1ccc(F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: O=CN(C=O)C/C(=C/F)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Combine sodium diformylamide (28.8 g, 0.31 mol), acetonitrile (360 g), and N,N-dimethylformamide (48 g). Add (E)-1-chloro-2-(fluoromethylene)-4-(p-fluorophenyl)butane (50.6 g, 0.23 mol). Heat to reflux. After 5 hours, cool to ambient temperature. Add water (466 g) and stir for 15 minutes. After 30 minutes, the aqueous layer is removed. Evaporate the organic layer in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.28 (m, 2H), 2.72 (m, 2H), 4.07 (d, J=3 Hz, 2H), 6.74 (d, J=81 Hz, 1H), 6.94 (m, 2H), 7.13 (m, 2H), 8.73 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[NH:5][CH:6]=1>[Pd].C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[NH:5][CH:6]=1
Reactant: Cc1c[nH]c(Cc2ccccc2[N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: Cc1c[nH]c(Cc2ccccc2N)n1
Reaction time: 4 h

Procedure:
A mixture of 23.44 g of 4-methyl-2-(2-nitrobenzyl)imidazole, 2.34 g of 10% palladium on charcoal and 234 ml of ethanol is hydrogenated at 42 psi (3 atmospheres) at room temperature for 4 hours. The catalyst is filtered and the filtrates are evaporated to dryness to give 4-methyl-2-(2-aminobenzyl)imidazole showing signals in the NMR spectrum at δ2.09, 3.78, 6.08.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][N:20]2[C:24]3[N:25]=[CH:26][CH:27]=[C:28]([OH:29])[C:23]=3[C:22]([I:30])=[N:21]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:24]3=[N:25][CH:26]=[CH:27][C:28]([O:29][C:6]4[CH:7]=[C:2]([Cl:1])[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]=4[F:9])=[C:23]3[C:22]([I:30])=[N:21]2)=[CH:31][CH:32]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Reactant: COc1ccc(Cn2nc(I)c3c(O)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 50 °C
Yield: 40.3 %

Procedure:
A mixture of 1-chloro-4,5-difluoro-2-nitrobenzene (2.23 g, 11.5 mmol), 1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-ol (4.00 g, 10.5 mmol), K2CO3 (1.60 g, 11.5 mmol) and DMF (100 mL) was heated to 50° C. for 18 hours. The reaction was cooled to ambient temperature, diluted with water (500 mL), extracted with EtOAc, dry over sodium sulfate, filter and concentrate. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to provide a light pink solid. The solid was triturated with hot MeOH to afford the product (2.35 g, 40% yield) as a white solid. LRMS (APCI pos) m/e 554.8 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][NH:23][C:22](=[O:26])[CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12].[F:27][CH2:28][CH2:29]I>CN(C=O)C.C1COCC1>[F:27][CH2:28][CH2:29][N:23]1[CH2:24][CH2:25][N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:7]3[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:5]([O:4][CH3:3])[CH:6]=3)[CH2:15][CH2:16]2)[CH2:21][C:22]1=[O:26]
Reactant: FCCI
Reactant: COc1cc(N2CCC(N3CCNC(=O)C3)CC2)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCF)C(=O)C3)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 75.6 %

Procedure:
NaH (60% dispersion in mineral oil, 0.174 g, 4.35 mmol) was washed two times with hexanes. 10 mL of DMF and 5 mL of THF was added via syringe. 4-{1-[3-(Methyloxy)-4-nitrophenyl]-4-piperidinyl}-2-piperazinone (0.970 g, 2.90 mmol) in 20 mL of DMF and 10 mL of THF was added slowly via syringe. The reaction was stirred for 45 min, and 1-fluoro-2-iodoethane (0.28 mL, 3.4 mmol) was added via syringe. The reaction was stirred overnight and quenched by the addition of H2O. The mixture was poured into EtOAc and H2O, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.834 g (76%) of the title compound of step B. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=9.0 Hz, 1H), 6.55 (dd, J=9.4, 2.5 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 4.55 (t, J=4.9 Hz, 1H), 4.44 (t, J=4.9 Hz, 1H), 4.07-3.94 (m, 2H), 3.86 (s, 3H), 3.58 (t, J=4.9 Hz, 1H), 3.51 (t, J=5.1 Hz, 1H), 3.34-3.22 (m, 2H), 3.11 (s, 2H), 2.99-2.86 (m, 2H), 2.68 (t, J=5.2 Hz, 2H), 2.57-2.46 (m, 1H), 1.89-1.76 (m, 2H), 1.49-1.32 (m, 2H).
Reaction SMILES: NC1C(F)=CC(Cl)=C(O[C:9](=O)[O:10][C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([F:18])=[CH:13][C:12]=2[Cl:19])C=1.CS(O[CH:28]1[CH2:32]C[CH2:30][CH2:29]1)(=O)=O.[OH-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:19][C:12]1[C:11]([O:10][CH:9]2[CH2:30][CH2:29][CH2:28][CH2:32]2)=[CH:16][C:15]([NH2:17])=[C:14]([F:18])[CH:13]=1
Reactant: Nc1cc(OC(=O)Oc2cc(N)c(F)cc2Cl)c(Cl)cc1F
Reactant: CS(=O)(=O)OC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 80 °C
Yield: 191.3 %

Procedure:
A round-bottomed flask (300 cc) was charged with bis(5-amino-2-chloro-4-fluorophenyl)carbonate (10.0 g, 28.6 mmol), cyclopentyl methanesulfonate (10.1 g, 61.3 mmol) and tetrabutylammonium bromide (463 mg, 1.43 mmol) to prepare a solution in toluene (55 mL). Subsequently, 48% sodium hydroxide in aqueous solution (28 mL) was added slowly and the mixture was stirred under heating at 80° C. for 30 min. Subsequently, 48% sodium hydroxide in aqueous solution (27 mL) was added slowly over 30 min and the mixture was stirred under heating at 80° C. for an additional 1.0 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (100 mL) was added, followed by extraction with toluene (50 mL×2). The organic layers were combined and washed with water (100 mL×2). The solvent was distilled off under vacuum from the resulting toluene solution, thereby giving 4-chloro-5-cyclopentyloxy-2-fluoroaniline (12.6 g, 54.7 mmol; yield=95.4%; purity on HPLC=83.8%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:28]([C:31]1[CH:36]=[C:35]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])[CH:34]=[CH:33][CH:32]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCc1nc(CC)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 47.4 %

Procedure:
To a suspension of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 3-acetylphenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.1 mL) and molecular sieves 4 A (2 g) in dichloromethane (20 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 47%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5]CC)[CH3:4].Cl.[NH2:9][C@@H:10]([CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[C:23]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]2=3)[CH2:19][CH2:18]1)=[O:16])[CH2:11][OH:12].C(Cl)(=O)C>O.C(OCC)(=O)C>[CH:33]1[C:28]2[CH:27]=[CH:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[C:23](=[C:20]3[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C@H:10]([NH:9][C:3](=[O:5])[CH3:4])[CH2:11][OH:12])[CH2:22][CH2:21]3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CCOCC
Reactant: N[C@H](CO)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N[C@H](CO)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of 1 N aqueous sodium hydroxide solution, 3 ml of diethyl ether and 2 ml of ethyl acetate were added to 151 mg (0.36 mmol) of (S)-2-amino-5-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-5-oxo-1-pentanol hydrochloride. 0.04 ml (0.56 mmol) of acetyl chloride was added dropwise to the obtained solution under vigorous stirring, and they were stirred at room temperature for 2 hours. Water was added to the reaction mixture. After extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (chloroform:methanol-200:1 to 50:1) to obtain the title compound.
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[C:17]([O:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:16]=1.[N:29]([C@@H:32]1[C@@H:36]([CH2:37][OH:38])[O:35][C@@H:34](N2C=C(C)C(=O)NC2=O)[CH2:33]1)=[N+:30]=[N-:31]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:34]2[O:35][C@H:36]([CH2:37][OH:38])[C@@H:32]([N:29]=[N+:30]=[N-:31])[CH2:33]2)=[C:17]([O:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[N:16]=1
Reactant: Nc1nc(OC2CCC2)c2nc[nH]c2n1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(OC4CCC4)nc(N)nc32)O[C@@H]1CO
Temperature: 50 °C
Yield: 32 %

Procedure:
To 800 mL of an aqueous pH 6.0, 50 mM citrate buffer, prepared as described in Example 2c, was added 2-amino-6-(cyclobutoxy)-9H-purine (0.164 g, 0.8 mmol) and 3'-azido-3'-deoxythymidine (1.069 g, 4.0 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 40 mL solution of trans-N-deoxyribosylase with an activity of 1500 units/mL was added. The reaction was heated at 50° C. Five days later 0.164 g, 0.8 mmol, of 2-amino-6-cyclobutoxypurine was added to the reaction. Ten days after the reaction was started, another 0.164 g, 0.8 mmol, of 2-amino-6-cyclobutoxypurine and 0.428 g, 1.6 mmol, of 3'-azido-3'-deoxythymidine were added to the reaction. Twenty-one days after the reaction was started, 0.164 g, 0.8 mmol, of 2-amino-6-cyclobutoxypurine was added to the reaction. The reaction was stopped after twenty-six days by heating to 80° C. to precipitate the enzyme. After chilling to 0° C. the mixture was filtered. The aqueous filtrate was extracted with ethyl acetate (3 times) to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered and the solvent removed in vacuo to give a foam. The foam was chromatographed on basic alumina grade 1 eluted with chloroform/methanol (95.5, v/v). The product containing fractions were combined and the solvent removed in vacuo to give the product as a foam, 0.334 g, in 32% yield.