Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:17]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]([CH3:16])[C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:3]=2[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2cc(F)ccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2c3ccc(F)cc3-c3ccccc3C2C)cc1
Yield: 66.4 %

Procedure:
The title compound was prepared from N-[1-(2′,5′-difluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide (450 mg, 1.1 mmol), anhydrous N,N-dimethylformamide (2 mL), and potassium carbonate (304 mg, 2.2 mmol) according to the procedure and in the same manner as described in Example 105, step d. The product was purified by preparative column chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the desired compound (280 mg, 65%) as a white solid, m.p. 167-168° C.;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[OH-].[K+].CO.Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][C:24]([C:33](=[O:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>CN(C)C=O>[C:33]([C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:26][CH2:25]1)(=[O:35])[CH3:34]
Reactant: CC(=O)C1(c2ccccc2)CCN(CCCCl)CC1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccccc2)CCN(CCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 50 °C

Procedure:
1.65 Grams of 6-hydroxycarbostyril and 0.75 g of granular potassium hydroxide were mixed with 50 ml of methanol and concentrated under a reduced pressure to dryness. To the residue obtained was added 50 ml of dimethylformamide and mixed well, then 2.6 g of 1-(3-chloropropyl)-4-acetyl-4-phenylpiperidine was added and heated at 50° C. for 6 hours under stirring condition. The reaction mixture was concentrated under a reduced pressure to dryness and 20 ml of 5%-sodium hydrogencarbonate aqueous solution was added thereto and stirred. The insoluble matters were collected by filtration and washed with water. After dried the insoluble matters were recrystallized from ethanol to obtain 1.1 g of 6-[3-(4-acetyl-4-phenyl-1-piperidyl)propoxy]carbostyril as in the form of colorless prism-like crystals. Melting point: 192.5°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[N+:17]([O-])=O>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)c1cc(CCN2CCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CCN2CCCC2)ccc1N
Reaction time: 2 h

Procedure:
To a solution of 2-nitro-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid methyl ester in THF (16 mL) was added 10% palladium on charcoal (0.23 g). The resulting reaction mixture was hydrogenated under 40 psi for 2 hours, then the catalyst was filtered off and the filtrate concentrated under high vacuum to give 2-amino-5-(2-pyrrolidin-1-yl-ethyl)-benzoic acid methyl ester as a yellow oil. Yield: 1.04 g (89.6%). The crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.O>CN1CCCC1=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: Fc1ccccn1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc(C#CC=C2CCN(c3ccccn3)CC2)n1
Yield: 14.7 %

Procedure:
A solution of the Compound of Example 3 (100 mg, 0.47 mmol), 2-fluoropyridine (45.5 μL, 0.52 mmol), TEA (102 μL) in N-methylpyrrolidone was heated in a microwave oven at 160° C. for 20 min. Afterwards, the reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 7:93 to 40:60) affording the title product (0.02 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1.[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[CH:29][CH:28]=1.[ClH:37].CO.CCOC(C)=O>CCO.O.CCOC(C)=O>[ClH:26].[ClH:37].[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=[CH:29][CH:28]=4)=[CH:18][CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:25])[N:3]=1
Reactant: Cc1cc(Nc2ccc(C(=O)Nc3ccc(N)cc3)cc2)nc(N)n1
Reactant: Clc1ccnc2ccccc12
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2ccc(C(=O)Nc3ccc(Nc4ccnc5ccccc45)cc3)cc2)nc(N)n1
Temperature: 20 °C

Procedure:
To a solution of C3 (218 mg, 0.54 mmol) in EtOH (20 mL) and H2O (10 mL) was added 4-chloroquinoline (96 mg, 0.59 mmol) and stirred until it dissolved, then 2 drops of c.HCl was added. The reaction mixture was refluxed for 3 h, diluted with EtOAc, brought to boil and cool to 20° C. The resulting precipitate was filtered and recrystallized from MeOH/EtOAc/Charcoal/Celite to give Cpd. GG1 (259 mg 98%) as a yellow solid.; M.P (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ13.75 (br. 2 H, 2×N+H), 11.07 (s, 1 H, NH), 10.99 (s, 1 H, NH), 10.52 (s, 1 H, NH), 8.83 (d, J=8.4 Hz, 1 H, ArH), 8.50 (d, J=7.0 Hz, 1 H, ArH), 8.11-7.99 (m, 10 H, ArH & NH2), 7.80 (dt, J=8.0, 1.1 Hz, 1 H, ArH), 7.48 (d, J=8.9 Hz, 2 H, ArH), 6.78 (d, J=7.0 Hz, 1 H, ArH), 6.35 (s, 1 H, ArH), 2.31 (s, 3 H, CH3); 13C NMR [(CD3)2SO] δ164.8, 161.6, 155.9, 155.0, 153.3, 142.5, 141.4, 138.4, 138.1, 133.7, 132.1, 129.6, 128.5 (2×C), 126.8, 125.8 (2×C), 123.5, 121.4 (2×C), 120.2, 120.1, 116.9, 99.6, 94.3, 18.4, one of the quaternary carbons were difficult to observe; HRMS FAB+ calc. for C27H25N7O (M+1) m/z, 462,2042 found 462.2047.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:17]([CH:21]=2)[C:18]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridyl) benzoic acid (73 mg, 0.1857 mmol) was dissolved in methylene chloride (5 ml), then p-anisidine (46 mg, 0.3739 mmol), triethylamine (75 mg, 0.7425 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (126 mg, 0.7455 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:4) to give the title compound (33 mg, 0.0662 mmol, 36%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=O)[CH2:11][C:12]1[N:13]([CH3:21])[C:14]3[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:2]2.B.Cl.[OH-].[Na+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1.C(OCC)(=O)C.CO>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][CH2:10][CH2:11][C:12]1[N:13]([CH3:21])[C:14]3[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:2]2
Reactant: Cn1c(CC(=O)NC2CN3CCC2CC3)cc2ccccc21
Agent: B
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(CCNC2CN3CCC2CC3)cc2ccccc21
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-1-methyl-1H-indole 2-acetamide (1.4 g) in dry THF (30 ml) under nitrogen was added borane (1M solution in THF; 30 ml), and the mixture was heated under reflux for 3 h and then cooled in ice. Methanol (10 ml) was added dropwise followed by 5M hydrochloric acid (50 ml), and the mixture was then heated at reflux for 4 h. The cooled solution was poured into 2M sodium hydroxide solution (200 ml), and the mixture was extracted with ethyl acetate (2x200 ml). The combined, dried organic extracts were evaporated in vacuo to give an oil which was dissolved in dry THF (45 ml). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.13 g) was added slowly in small portions over 15-20 min and the resulting suspension was stirred for 30 min. The mixture was diluted with ethyl acetate (250 ml) and washed with 2M sodium hydroxide solution (2x250 ml). The organic layer was dried and evaporated in vacuo to give a gum which was purified by FCC eluting with System A (75:8:1) to give the title compound (354 mg) as an oil, t.l.c. (System A,75:8:1) Rf 0.24.
Reaction SMILES: [NH2:1][C:2]1[S:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:22]=1[C:23](Cl)=[O:24]>>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:22]=1[C:23]([NH:1][C:2]1[S:13][C:5]2[C:6]([CH3:11])([CH3:12])[O:7][C:8]([CH3:9])([CH3:10])[C:4]=2[C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])=[O:24]
Reactant: CCCOC(=O)c1c(N)sc2c1C(C)(C)OC2(C)C
Reactant: O=C(Cl)c1c(F)cccc1C(F)(F)F
Product: CCCOC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 62A and commercially available 2-fluoro-6-(trifluoromethyl)benzoyl chloride using the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 0.90 (t, J=7.5 Hz, 3H), 1.49 (s, 6H), 1.54 (s, 6H), 1.62-1.74 (m, 2H), 4.20 (t, J=6.7 Hz, 2H), 7.74-7.88 (m, 3H), 11.61 (br s, 1H). MS (ESI+) m/z 474 (M+H)+. Anal. calcd. for C22H23F4NO4S: C, 55.81; H, 4.90; N, 2.96. Found: C, 56.11; H, 5.04; N, 3.01.
Reaction SMILES: FC(F)(F)C(O)=O.[Si:8]([O:15][C:16]1[CH:17]=[C:18]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C:19]2[CH2:30][S:29][CH2:28][C@@H:27]([C:31]([O:33][CH3:34])=[O:32])[NH:26][C:25](=[O:35])[C@@H:24]([NH:36]C(OC(C)(C)C)=O)[CH2:23][O:22][C:21](=[O:44])[C:20]=2[C:45]=1[CH3:46])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>>[NH2:36][C@H:24]1[CH2:23][O:22][C:21](=[O:44])[C:20]2[C:45]([CH3:46])=[C:16]([O:15][Si:8]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:10])[CH3:9])[CH:17]=[C:18]([O:47][Si:48]([C:51]([CH3:52])([CH3:53])[CH3:54])([CH3:49])[CH3:50])[C:19]=2[CH2:30][S:29][CH2:28][C@@H:27]([C:31]([O:33][CH3:34])=[O:32])[NH:26][C:25]1=[O:35]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c2C(=O)OC[C@H](N)C(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To 15 ml of trifluoroacetic acid, cooled to 0° C., were added 1.07 g of tert-butyl (4R, 7S)-12,14-bis (tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-4-methoxycarbonyl11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7carbamate. The solution was stirred at 0° C. for 30 minutes, and then the solvent was evaporated in vacuo. The residue was dissolved in 50 ml of ethyl acetate, and the solution was washed successively with saturated sodium carbonate solution and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material from hexane at -20° C. yielded 0.71 g of methyl (4R, 7S)-7-amino-12,14-bis-(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-11-methyl-6,10-dioxo-9,2,5-benzooxathiaazacyclododecine-4-carboxylate as white crystals of m.p. 135°-141° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.Cl.[OH-].[Na+:34]>O>[Na+:34].[Na+:34].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1
Temperature: 70 °C

Procedure:
N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid from Example 7 was dissolved in 3.8 mL of water and 2.2 ml of 1N sodium hydroxide. The pH of the mixture was adjusted to 7.5-8.5 using dilute hydrochloric acid and 1N sodium hydroxide. The solution was heated to 70° C. and 40 mL of 3A alcohol were added. The solution was allowed to cool to room temperature during which time a thick slurry developed. The solids were filtered and washed with 4:1 ethanol:water. The solids were dried at 50° C. in a vacuum oven. 640 milligrams of the title compound were recovered as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O.[NH:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-butoxybezenesulfonyl chloride and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 22 as an off-white solid; 1H NMR (CDCl3) δ 0.98 (t, J=7.38 Hz, 3H), 1.44-1.54 (m, 4H), 1.75-1.84 (m, 4H), 2.54 (t, J=6.24 Hz, 2H), 3.37 (t, J=6.18 Hz, 2H), 4.02 (t, J=6.48 Hz, 2H), 6.99 (dt, J=2.91 Hz, 4.77 Hz, 2H), 7.72(dt, J=2.91 Hz, 4.86 Hz, 2H); MS (ES) m/z 311.9 (MH+); HRMS for C15H21NO4S: 311.1196; Anal. Calcd. for C15H21NO4S: C, 57.86; H, 6.80; N, 4.50. Found: C, 57.69; H, 6.50; N, 4.25.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCCC1>CO>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]2([O:1][C:2]3[C:3](=[N:4][N:5]([CH2:7][C:8]4[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=4)[CH:6]=3)[C:16](=[O:18])[CH2:17]2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Cn2cc(O)c(C(C)=O)n2)cc1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc(Cn2cc3c(n2)C(=O)CC2(CCN(Cc4ccccc4)CC2)O3)cc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Suspended 1-(4-hydroxy-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)ethanone (350 mg, 1.42 mmol) in 10 mL methanol and added N-benzyl-4-piperidone (0.25 mL, 1.42 mmol) and pyrrolidine (0.036 mL, 0.3 eq). The mixture was then heated at reflux for 18 h. The reaction was then cooled to room temperature and methanol was removed under reduced pressure. The resultant orange oil was partitioned between 50 mL ethyl acetate and 50 mL water. The aqueous phase was extracted with an additional 50 mL ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered and concentrated. The resultant oil was flash chromatographed (50-100% ethyl acetate/heptane gradient, 25 g silica) to yield 428 mg (72%) of 1-benzyl-2′-(4-methoxybenzyl)-2′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.25-7.37 (m, 6H), 6.95 (s, 1H), 6.81-6.92 (m, 2H), 5.20 (s, 2H), 3.79 (s, 3H), 3.49 (s, 2H), 2.63 (s, 2H), 2.57 (d, J=11.3 Hz, 2H), 2.25-2.44 (m, 2H), 2.02 (d, J=12.5 Hz, 2H), 1.62-1.77 (m, 2H); m/z (M+1)=418.5.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.O1CCCC1.O.O.[OH-].[Li+]>C(OCC)(=O)C>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1CCN(C2CCN(C(=O)OCC)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(N2CCC(C(=O)O)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a stirred mixture of [1,4′]Bipiperidinyl-4,1′-dicarboxylic acid diethyl ester (5.51 grams, 17.67 mmol), tetrahydrofuran (34 mL) and water (34 mL) cooled at 0° C., lithium hydroxide monohydrate (742.0 mg, 17.67 mml) was added. The reaction mixture was stirred at room temperature for 16 hours, diluted with Ethyl acetate. The two layers were separated, the aqueous layer was acidified with 2N hydrochloric acid to pH: 3-4 and the volatiles were removed under reduced pressure to obtain [1,4′]Bipiperidinyl-4,1′-dicarboxylic acid 1′-ethyl ester (5.0 grams).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:13][C:7]=3[C:6]=2[CH:21]=1.[ClH:22].[C:23]([Cl:31])(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[ClH:31].[ClH:22].[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[CH:12]1[CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:21][C:6]=3[C:7]=2[CH2:13]1)[CH2:16][CH3:17]
Reactant: CCCN(CCC)C1CCc2oc3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: CCCN(CCC)C1CCc2oc3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 80.7 %

Procedure:
Beginning with 0.072 gm (0.20 mMol) 8-amino-1,2,3,4-tetrahydro-2-dipropylaminodibenzofuran and 0.054 gm (0.30 mMol) isonicotinoyl chloride hydrochloride, 0.075 gm (81%) of the title compound were recovered as a yellow solid by the procedure described in Example 17.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:24][C:25]([O:28][C:29]([NH:31][C:32](N1C=CC=N1)=[N:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])([CH3:27])[CH3:26]>CO>[CH3:27][C:25]([O:28][C:29]([NH:31][C:32]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[N:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])([CH3:24])[CH3:26]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a solution of piperidine-4-carboxylic acid trifluoroacetate salt (0.20 g, 0.82 mmol) in methanol (10 mL), triethylamine (0.20 mL, 1.6 mmol) and N,N′-bis{[(2-methyl-2-propanyl)oxy]carbonyl}-1H-pyrazole-1-carboximidamide (0.30 g, 0.98 mmol) was added and the reaction mixture stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure and the resulting residue dissolved in ethyl acetate and washed with brine. The organic layer was dried and concentrated to dryness to obtain the title compound (200 mg, 76%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.[H-].[Na+].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C)C=O>[C:15]([Si:12]([CH3:14])([CH3:13])[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: c1cnc2c(c1)CCN2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)N1CCc2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a 0° C. solution of 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (24.0 g, 200 mmol) in N,N-dimethylformamide (68 mL) was added a 60% dispersion of sodium hydride in mineral oil (12.0 g, 300 mmol) portionwise. The mixture was stirred at 0° C. for 30 min and then a solution of tert-butyldimethylsilyl chloride (46 g, 300 mmol) in N,N-dimethylformamide (100 mL) was added to the above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 3 h and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 5% ethyl acetate/hexanes) to afford 1-(tert-butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (31 g, 66%) as a yellow oil: LC/MS m/e calcd for C13H23N2Si [M+H]+ 235.42, observed 235.3; 1H NMR (400 MHz, CDCl3) δ ppm 0.35 (s, 6H), 0.98 (s, 9H, 3×CH3), 3.02 (t, J=8.6 Hz, 2H), 3.68 (t, J=8.6 Hz, 2H), 6.40 (dd, J=5.2 Hz, 7.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.80 (d, J=5.2 Hz, 1H).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35]([O:37][CH2:38][CH:39]([CH2:44][O:45][C:46](=[O:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:40][C:41](O)=[O:42])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C1C=CC=CN=1)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(O)(=O)C.ClCCl>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:41](=[O:42])[CH2:40][CH:39]([CH2:38][O:37][C:35](=[O:36])[C@H:31]([CH:32]([CH3:33])[CH3:34])[NH:30][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:44][O:45][C:46](=[O:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Reaction time: 48 h

Procedure:
To a solution of 2′,3′-dideoxy-3′-fluoroguanosine (113 mg, 0.42 mmol) and 3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyric acid (140 mg, 0.21 mmol) in DMF (2 ml) were added dimethylaminopyridine (3 mg, 0.02 mmol) and DCC (52 mg, 0.25 mmol). After two days, dichloromethane (10 ml) and a few drops of acetic acid were added and the organic phase was filtered through Celite. The filtrate was washed with aqueous sodium hydrogen carbonate solution and the product 2′,3′-dideoxy-3′-fluoro-5′-O-[3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butanoyl]guanosine was isolated by silica gel column chromatography to yield 51 mg.