Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(#N)C>[Br-:20].[CH2:25]([O:24][C:22]([CH2:21][N+:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=1)=[O:23])[CH3:26]
Reactant: c1ccc(C(c2ccccc2)c2cccnc2)cc1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Product: CCOC(=O)C[n+]1cccc(C(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Yield: 97 %

Procedure:
A mixture of 0.490 g (2 mmol) 3-diphenylmethylpyridine (Sigma-Aldrich Library of Rare Chemicals) and 0.334 g (4 mmol) ethyl bromoacetate (Aldrich) in 2 ml acetonitrile was heated under reflux for 1 hour. The solvent was evaporated, the residue suspended in diethyl ether and filtered to give 0.8 g 1-ethoxycarbonylmethyl-3-diphenylmethylpyridinium bromide as a yellow powder. 1H NMR (CD3OD, 300 MHz) δ 8.87 (d, 1 H), 8.77 (s, 1 H), 8.42 (d, 1 H), 8.10 (dd, 1 H), 7.50-7.10 (m, 10 H), 5.96 (s, 1 H), 5.55 (s, 2 H), 4.28 (q, 2 H), 1.29 (t, 3 H).
Reaction SMILES: C(OCC)(=O)C.[CH3:7][NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].C(N(CC)CC)C>O>[CH3:7][N:8]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Cl:15]
Reactant: CNC1CCCCC1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C(=O)CCCCl)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl acetate (400 ml) is added N-methylcyclohexylamine (26 ml), and to the mixture are added dropwise with stirring 4-chlorobutyryl chloride (25 ml) and triethylamine (33.5 ml) over a period of 20 minutes with keeping the inner temperature at 10° to 20° C. by ice-cooling. The mixture is further stirred at room temperature for one hour. After the reaction, water is added to the reaction mixture. The organic layer is separated and washed with water and aqueious saturated potassium carbonate solution, 10% hydrochloric acid and water in order, and then dried over anhydrous sodium sulfate. After filtering off sodium sulfate, the mother liquor is concentrated and distilled under reduced pressure to give N-methyl-N-cyclohexyl-4-chlorobutyramide (41.5 g), b.p. 133°-136° C./2 mmHg.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:31]=[N+:32]=[N-:33])(C)C.[N-]=[N+]=[N-].[Na+].C[Sn](Cl)(C)C>C1(C)C=CC=CC=1>[NH:31]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[N:2][N:33]=[N:32]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: C[Sn](C)(C)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)OCC
Reaction time: 16 h
Yield: 73.9 %

Procedure:
A mixture of 69.9 g of ethyl 2-[(2'-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate, prepared according to Example 5, 700 ml of anhydrous toluene and 47.5 g of trimethyltin azide, prepared from sodium azide and trimethyltin chloride, is refluxed for 24 h. A further 47.5 g of trimethyltin azide are added and reflux is continued for 16 h. The mixture is concentrated to 50%. The orange solution obtained is purified by chromatography twice in succession (eluent: chloroform 90%/methanol 10%, then chloroform 95%/methanol 5%) to give 58 g of an orange oil, which crystallizes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([NH2:11])=[NH:10])=[C:4]([F:12])[CH:3]=1.O=[C:14]1[CH2:18][S:17][CH2:16][CH:15]1[C:19](OCC)=[O:20].C[O-].[Na+]>CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[NH:11][C:14]3[CH2:18][S:17][CH2:16][C:15]=3[C:19](=[O:20])[N:10]=2)=[C:4]([F:12])[CH:3]=1
Reactant: CCOC(=O)C1CSCC1=O
Reactant: N=C(N)c1cc(F)c(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1nc(-c2cc(F)c(Cl)cc2F)[nH]c2c1CSC2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-chloro-2,5-difluorobenzenecarboxamidine, ethyl 4-oxotetrahydrothiophene-3-carboxylate, NaOMe, and MeOH was stirred at ambient temperature for 19 hours and then at 60° C. for 5 hours to yield 2-(4-chloro-2,5-difluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4(1H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[S:31][N:30]=[C:29]([CH3:32])[C:28]=1[Cl:33]>ClC(Cl)C>[Cl:33][C:28]1[C:29]([CH3:32])=[N:30][S:31][C:27]=1[NH:26][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: Cc1nsc(N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1nsc(NC(=O)Cc2ccc(O)c([N+](=O)[O-])c2)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
4-Hydroxy-3-nitrophenylacetic acid (10 g, 0.05 mol) was suspended in dichloroethane (50 ml) and stirred at room temperature under a nitrogen atmosphere. N,N-Dimethylformamide (0.1 ml) was added followed by dropwise addition of oxalyl chloride (6.77 g, 0.05 mol) over 20 minutes. The mixture was stirred at room temperature for 25 minutes and then at 40° C. for 20 minutes. The reaction mixture was then heated under reflux while a solution of 5-amino-4-chloro-3-methylisotiazole (7.54 g, 0.05 mol) in dichloroethane (30 ml) was added over 30 minutes. The resultant pale orange suspension was stirred at reflux for 2 hours and then cooled to room temperature, to give a precipitate, which was collected by filtration and washed with dichloromethane. The solid was suspended in water (150 ml), treated with 10% (w/v) sodium hydroxide (50 ml) and the resulting red solution was washed with dichloromethane (2×50 ml). The combined washings were extracted with water (50 ml) and the combined aqueous layers were acidified to pH4-5 by addition of concentrated hydrochloric acid (approximately 10 ml). The resultant yellow suspension was filtered and the solid was washed with water and dried under suction to give N-(4-chloro-3-methyl-5-isothiazolyl)-4-hydrox-3-nitrophenylacetamide (14.6 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:16][C:17]#[C:18][CH3:19]>>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][S:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:16][C:17]#[C:18][CH3:19])[CH:3]=1)[CH3:14]
Reactant: CCOC(=O)CSc1cccc(O)c1
Reactant: CC#CCBr
Product: CC#CCOc1cccc(SCC(=O)OCC)c1
Yield: 100 %

Procedure:
Ethyl{[3-(2-butynyloxy)phenyl]sulfanyl}acetate was prepared according to the general method as outlined in example 1 (step 2), starting from ethyl [(3-hydroxyphenyl)sulfanyl]acetate (3.87 g, 18.3 mmol) and 4-bromo-2-butyne (2.66 g, 20 mmol); 5.16 g yellow oil. Yield 100%; MS(EI): 264.1 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11]>O>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCO2
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
1,3-Benzodioxole (10.0 g, 82 mmol) was added dropwise to a solution of con. HNO3 (65%˜68%, 18 g) in H2O (39 g) at 60˜65° C. The mixture was then heated to 90° C. and stirred for 2 h at this temperature. The mixture was cooled to room temperature and poured into ice/water, filtered to give compound 5-nitrobenzo[d][1,3]dioxole (12.0 g, 87%) as a yellow solid. LCMS: 168 [M+1]+; 1H NMR (DMSO-d6) δ 6.27 (s, 2H), 7.12 (d, 1H, J=12 Hz), 7.76 (d, 1H, 3.2 Hz), 7.91 (dd, 1H, J1=12 Hz, J2=3.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1Br.[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16]>C1C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:16][CH:15]=[CH2:14]
Reactant: COC(=O)c1cc(OC)ccc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: C=CCc1ccc(OC)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To an ambient temperature solution of 2-Bromo-5-methoxy-benzoic acid methyl ester (750 mg, 3.02 mmol) in benzene (2 mL) are added allyltri-n-butyl tin (1.16 mL, 3.73 mmol) and tetrakis(triphenylphosphine)palladium (0) (174 mg, 0.157 mmol, 5 mol %). The reaction mixture is heated in a sealed tube to 100° C. After 3 h, the reaction is concentrated under reduced pressure and the residue is chromatographed (0% to 10% EtOAc/Hex) to yield the title compound (451 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, 1H, J=2.6 Hz), 7.18 (d, 1H, J=8.4 Hz), 7.00 (dd, 1H, J=8.6, 2.9 Hz), 6.04-5.93 (m, 1H), 5.03-4.94 (m, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 3.70-3.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:20]=[C:19](Cl)[CH:18]=[C:17](Cl)[CH:16]=2)=[C:6]1[C:23]([O-:25])=[O:24].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Cl.FC(F)(F)OC1C=CC(CBr)=CC=1>>[Cl:1][C:2]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([O:34][CH3:33])[CH:36]=3)=[CH:11][CH:12]=2)[C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[C:23]([OH:25])=[O:24]
Reactant: O=C([O-])c1c(-c2cc(Cl)cc(Cl)c2)c2cc(O)ccc2n1Cc1cc2c(cc1Cl)OCO2
Reactant: COc1cccc(CCl)c1
Agent: FC(F)(F)Oc1ccc(CBr)cc1
Product: COc1cccc(COc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2cc3c(cc2Cl)OCO3)c1

Procedure:
Following the procedure of Example 26(c)-26(d), except substituting ethyl 1-(2-chloro-4,5-methylenedioxybenzyl)-5-hydroxy-3-phenylindole-2-carboxylate for 1-(2-chloro-4,5-methylenedioxybenzyl)-3-(3,5-dichlorophenyl)-5-hydroxyindole-2-carboxylate and 3-methoxybenzyl chloride for 4-trifluoromethoxybenzyl bromide in step (c), the title compound was prepared as a white solid (64% overall). MS (MH+): 542.4
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11]C(OCC2C=CC=CC=2)=O)=[CH:5][C:4]=1[F:22])#[N:2].C(Cl)Cl.[H][H]>C1COCC1.[Pd]>[NH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:22])[CH:5]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(CCNC(=O)OCc2ccccc2)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(CCN)cc1F
Yield: 100 %

Procedure:
Into a 100 mL single neck flask were placed N-[2-(4-cyano-3-fluorophenyl)ethyl](phenylmethoxy)carboxamide (2 g, 6.7 mmol) in THF: MeOH (25:25 mL). The mixture was treated with a 10% palladium on carbon (0.5 g, 25 mol%) and stirred under the hydrogen balloon for 12 hour. The reaction mixture was filtered through a Celite® cake. The filtrate was concentrated under reduced vacuum to provide the intermediate title compound, 4-(2-aminoethyl)-2-fluorobenzenecarbonitrile, (1.1 g, 100%) as a white solid. Electron spray M.S. 165 (M*+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:30])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH:17]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:30][C:20]1[CH:19]=[C:16]([C:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=3[CH3:12])[N:1]=2)[CH:15]=[C:14]([CH3:13])[C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1cc(C)c(C(N)=O)c(N)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCC4)c(C)c3)nc2c1
Temperature: 110 °C

Procedure:
To a solution of 2-amino-4,6-dimethyl-benzamide (0.20 g, 1.22 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (0.36 g, 1.46 mmol) in N,N-dimethylacetamide (10 mL) was added NaHSO3 (58.5 wt %, 0.55 g, 3.05 mmol) and p-TSA (0.46 g, 2.44 mmol). The reaction mixture was heated to 110° C. for 2 hours, then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with sodium bicarbonate solution (50 mL), and the solid separated was filtered and dried under vacuum. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 6% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.145 g (30%). MP 181-182° C. 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 7.75 (s, 2H), 7.44 (s, 1H), 7.03 (s, 1H), 3.95 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H), 2.85 (s, 3H), 2.65 (s, 4H), 2.44 (s, 3H), 2.39 (s, 6H), 1.84 (s, 4H). MS (ES+) m/z: 392.13 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:29]([N:36]1[C:44]2[CH:43]=[CH:42][C:41]([Cl:45])=[C:40]([NH2:46])[C:39]=2[C:38]([CH2:47][CH3:48])=[N:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([N:36]1[C:44]2[C:39](=[C:40]([NH:46][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[C:41]([Cl:45])=[CH:42][CH:43]=2)[C:38]([CH2:47][CH3:48])=[N:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Reactant: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(N)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(NC(=O)c3cnc4cc(OCCOC)ccn34)c12
Temperature: 25 °C
Yield: 37.5 %

Procedure:
To a magnetically stirred, ice cooled, suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (6.76 mg, 0.0286 mmol) (prepared as in Example 1, steps A-D) in dichloromethane (1 mL) was added N,N-dimethylformamide (1 μL) followed by oxalyl chloride (18.3 μL, 0.0365 mmol; 2M solution in dichloromethane). The mixture was allowed to warm to ambient temperature with occasional venting to allow gases to evolve. After stirring for 30 minutes, 1-benzyl-5-chloro-3-ethyl-1H-indazol-4-amine (8.70 mg, 0.0304 mmol) was added as a solution in dichloromethane (0.5 mL). The mixture was stirred for 60 minutes and then concentrated under reduced pressure. The material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol in dichloromethane to give N-(1-benzyl-5-chloro-3-ethyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (5.4 mg). MS (APCI), positive scan, m/z=504.3 (M+H).
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]2)=[CH:36][CH:35]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)=[O:22])=[CH:14][C:13]=1[Cl:32])=O)(C)(C)C.C(OCC)C>O1CCOCC1.C(#N)C>[ClH:32].[ClH:1].[Cl:32][C:13]1[C:12]([CH2:11][CH2:10][NH:9][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[CH:36][CH:35]=2)=[CH:17][C:16]([O:18][CH3:19])=[C:15]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)=[O:22])[CH:14]=1
Reactant: COc1cc(CCN(Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cc(CCNCc2ccc(N3CCNCC3)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A 3 N HCl solution in 1,4-dioxane (0.4 mL) was slowly added to a solution of tert-butyl 4-(4-((tert-butoxycarbonyl (2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)-5-methoxy-phenethyl)amino)methyl)phenyl)piperazine-1-carboxylate (0.1 g) in acetonitrile (5 mL) at 0° C. The mixture was allowed to warm to room temperature and then stirring continued for one hour. Diethyl ether (25 mL) was added and after stirring continued for 15 minutes then the supernatant was decanted and the resulting solid was triturated with diethyl ether (25 mL) and dried under reduced pressure to yield a yellow solid. The solid was further triturated with methanol followed by diethyl ether and dried under reduced pressure to give the title compound (0.05 g, 60%) as an off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:23]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:24]C([O-])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(OCC)(=O)C>[O:9]=[C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:24][C:23]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C(O)c1ccncc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of 4-pyridinecarboxylic acid (50.0 g, 406 mmol) in tetrahydrofuran (250 ml) was added 1,1′-carbonylbis-1H-imidazole (72.5 g, 447 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added monoethyl malonate magnesium salt (82.9 g, 487 mmol), and the mixture was heated under reflux for 30 min. To the reaction solution were added ethyl acetate (200 ml) and water (200 ml), and citric acid was added until the pH of the aqueous layer became 7. The reaction solution was extracted with ethyl acetate (400 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was washed with diisopropyl ether-hexane and recrystallized from diisopropyl ether-hexane to give ethyl 3-oxo-3-(4-pyridyl)propionate (13.3 g, 17%).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[C:12]([CH:40]=1)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:24]3[CH:32]=[CH:33][C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:35][C:23]=3[N:22]=2)=[CH:17][CH:16]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[ClH:47].[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[C:12]([CH:40]=1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:24]3[CH:32]=[CH:33][C:34]([C:36]([O:38][CH3:39])=[O:37])=[CH:35][C:23]=3[N:22]=2)=[CH:19][CH:20]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(C(=O)OC(C)(C)C)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(C(=O)O)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 194.4 %

Procedure:
Methyl 2-{4-[5-tert-butoxycarbonyl-2-(4-chlorophenyl)-benzyloxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylate (3.5 g) obtained in Example 245 was dissolved in dichloromethane (35 ml), and trifluoroacetic acid (35 ml) was added. The mixture was stirred for 1 hr at room temperature and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and 4N hydrochloric acid-ethyl acetate was added. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (3.3 g, yield 97%).
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][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=1.[N:31]([C@@H:34]1[C@@H:38]([CH2:39][OH:40])[O:37][C@@H:36](N2C=C(C)C(=O)NC2=O)[CH2:35]1)=[N+:32]=[N-:33]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:36]2[O:37][C@H:38]([CH2:39][OH:40])[C@@H:34]([N:31]=[N+:32]=[N-:33])[CH2:35]2)=[C:17]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: Nc1nc(Oc2ccccc2)c2nc[nH]c2n1
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(Oc4ccccc4)nc(N)nc32)O[C@@H]1CO
Temperature: 50 °C
Yield: 54 %

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-phenoxy-9H-purine (0.181 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 (Example 2b) with an activity of 1500 units/mL was added. The reaction was heated at 50° C. Six days later, 0.181 g, 0.8 mmol, of 2-amino-6-phenoxypurine was added to the reaction. Fifteen days after the reaction was started, another 0.181 g, 0.8 mmol, of 2-amino-6-phenoxypurine and 0.428 g, 1.6 mmol, of 3'-azido-3'-deoxythymidine were added to the reaction. The reaction was stopped after thirty-three days, by heating to 80° C. to precipitate the enzyme, and filtered. The aqueous solution was extracted with ethyl acetate 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 (99:1, v/v). The fractions containing product were combined and the solvent removed in vacuo to give the product as a foam, 0.48 g, 54% yield.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26][CH:25]=4)=[N:23][C:16]=23)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.Cl[S:37]([NH2:40])(=[O:39])=[O:38].Cl.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.O>[S:37](=[O:39])(=[O:38])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26][CH:25]=4)=[N:23][C:16]=23)[CH2:13][C@@H:9]1[OH:8])[NH2:40]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2ccnc3[nH]c(-c4cccc5ccccc45)nc23)C[C@H]1CO
Reactant: NS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](Oc2ccnc3[nH]c(-c4cccc5ccccc45)nc23)C[C@@H]1O
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To a solution of ((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{[2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]oxy}cyclopentyl)methanol (0.0624 g, 0.000127 mol) in DMA (2.00 mL) was added chlorosulfonamide (0.0736 g, 0.000637 mol) and the mixture was stirred for 10 min. To this was added 12 M of hydrochloric acid in water (2.00 mL) dropwise at 0° C. and the mixture was stirred for 10 min. The mixture was added dropwise to 50 mL of a 2N Na2CO3 solution, and was extracted by CH2Cl2 (3×30 ml). The combined organic layers were concentrated and the residue was purified by flash chromatography (0 to 10% MeOH/EtOAc) to provide the title compound (14.5 mg, 25%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ: 8.49 (m, 1H,), 8.28 (m, 1H), 8.06 (d, 1H, J=8.3 Hz), 7.97 (m, 1H), 7.87 (dd, 1H, J=7.0 Hz, J=1.0 Hz) 7.63-7.54 (m, 3H), 6.89 (d, 1H, J=5.8 Hz) 5.40 (bs, 1H), 4.45 (dt, 1H, J=4.9 Hz, J=1.9 Hz), 4.35 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 4.19 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 2.62 (m, 1H), 2.44-2.39 (m, 1H), 2.31-2.25 (m, 1H), 2.18-2.14 (m, 2H). LC/MS: Rt=1.55 min, ES+ 455 (AA standard).