Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (7.7 g, 21 mmol, HPLC=75%) and DMAP (1.27 g, 10 mmol, 0.5 eq) in dry CH2Cl2 (120 mL), Et3N (6.38 g, 8.45 mL, 63 mmol) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (8.1 mL, 104.5 mmol, 5 eq) in dry CH2Cl2 (50 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at 0-5° C. The reaction was quenched with water (80 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL), the combined organic layers were washed with 10% citric acid (2×80 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (4.4 g, HPLC≧98%, the total yield for five steps is 41%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:28]#[N:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:28]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:8][C:4]1[CH:3]=[C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)=[CH:17][C:16]([NH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[N:15][CH:14]=2)#[N:29]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 33.6 %

Procedure:
4-(3-aminophenylamino)-6-(2-morpholinoethylamino)-1,7-naphthyridine-3-carbonitrile (111 mg, 0.29 mmol, 1 eq) was suspended in methylene chloride (10 mL). Triethylamine (44 uL, 0.32 mmol, 1.1 eq) was added and the mixture was cooled to 0° C. Methylsulfonyl chloride (24 uL, 0.31 mmol, 1.1 eq) was added and the mixture was stirred at room temperature for 12 hr. Another 44 uL triethylamine (1.1 eq) and 48 uL methylsulfonyl chloride (2.2 eq) were added and reaction mixture was stirred for 12 hr. Work-up and preparative HPLC yielded 45.5 mg product (34% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 2.39-2.47 (m, 4 H) 2.56 (t, J=6.82 Hz, 2 H) 2.99-3.03 (m, 3 H) 3.27-3.42 (m, 2 H) 3.55-3.61 (m, 4 H) 6.63 (t, J=6.06 Hz, 1 H) 7.00-7.04 (m, 1 H) 7.04 (s, 1 H) 7.08 (d, J=8.59 Hz, 1 H) 7.12-7.16 (m, 1 H) 7.36 (t, J=8.34 Hz, 1 H) 8.26 (s, 1 H) 8.84 (s, 1 H) 9.69 (s, 2 H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][N:6]([CH3:23])[C:7]1[CH:12]=[CH:11][C:10]([CH:13](O)[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:9][CH:8]=1>C(O)(=O)C>[CH3:23][N:6]([CH3:5])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:1][C:2](=[O:3])[NH:4][C:14]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: NC(N)=O
Reactant: CN(C)c1ccc(C(O)C(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CN(C)c1ccc(-c2[nH]c(=O)[nH]c2-c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To acetic acid (2 mL) was added urea (0.6 g, 10 mmol) and 2-(4-dimethylaminophenyl)-2-hydroxy-l-phenylethanone (2.6 g, 10 mmol). After stirring for 2 hours at 120° C., the reaction was cooled to ambient temperature. The resulting solid was filtered, washed with ether, and dried in vacuo to give 4-(4-dimethylaminophenyl)-2,3dihydro-5-phenyl-1H-imidazol-2-one; NMR (CDCl3) 10.98 (s,2), 7.5 (m,4), 7.4 (m,5), 3.18 (s,6) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[C:17]=1[C:23]#[N:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:31](Cl)(=[O:34])(=[O:33])[NH2:32].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:31](=[O:34])(=[O:33])[NH2:32])[C:17]=1[C:23]#[N:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc(N)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl-2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 15d, 8.65 g, 26.1 mmol) in dimethyl acetamide (48 mL) were added pyridine (8.44 mL, 104 mmol) and sulfamoyl chloride (6.03 g, 52.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a clear oil, which was used immediately in the next step. MS 311 (MH+-boc).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[C:5](/Br)=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1(P([Pd-4](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)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:14])/[C:5](/[C:20]1[CH:21]=[CH:22][C:17]([S:16][CH3:15])=[CH:18][CH:19]=1)=[CH:6]/[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CCOC(=O)/C(Br)=C/C1CCCCC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)/C(=C/C1CCCCC1)c1ccc(SC)cc1
Yield: 87.6 %

Procedure:
Dissolve (Z)-2-bromo-3-cyclohexyl-acrylic acid ethyl ester (76.4 g, 300 mmol) and 4-(methylthio)benzene boronic acid (60.5 g, 360 mmol) in a mixture of 1500 mL toluene, 500 mL ethanol and 2M aqueous sodium carbonate solution (500 mL). Add tetrakis(triphenylphosphino)palladium(0) (10.4 g, 3mol %) and heat the mixture at reflux for 5 h. Cool and remove the ethanol under vacuum. Partition the residue between water (250 mL) and dichloromethane (4×250 mL). Combine the extracts and dry over magnesium sulfate, filter and concentrate. Pass through a silica gel pad with a mix of iso-hexane:dichloromethane:diethyl ether (92:4:4) to give the title compound as a hazy oil (80 g). GC-MS (m/e): 304 (M+).
Reaction SMILES: [C:1]([C:8]1NC=CN=1)([C:3]1[NH:4][CH:5]=[CH:6]N=1)=O.[C:13](O)(=[O:23])[C:14]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][O:17][C:16]=2[CH:15]=1.C(Cl)(=O)C1C=CC2OCOC=2C=1.N1CC=CCC1>>[O:19]1[C:20]2[CH:21]=[CH:22][C:14]([C:13]([N:4]3[CH2:5][CH:6]=[CH:8][CH2:1][CH2:3]3)=[O:23])=[CH:15][C:16]=2[O:17][CH2:18]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: C1=CCNCC1
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Product: O=C(c1ccc2c(c1)OCO2)N1CC=CCC1

Procedure:
The product amide is made by the method employed for the preparation of Invention Compound V, which uses carbonyl diimidazole in order to activate piperonylic acid, or piperonyloyl chloride (available from Aldrich) can be combined with 1,2,3,6-tetrahydropyridine either in a suitable anhydrous solvent or without solvent. In either case, the isolation of product is performed in the same manner as done for Invention Compound V to give Invention Compound III as a white solid. EIMS m/z=231 (parent, 149 (base), and 121. 1H NMR δ 2.21 (br s, 2), 3.4-4.3 (br m, 4), 5.87 (m, 2), 6.00 (s, 2), 6.83 (d, 1, J=7.84 Hz), and 6.92-6.96 (dd and d, 2). 13C NMR δ 101.3 (--OCH2O--) and 169.9 ppm (carbonyl).
Reaction SMILES: [N:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)=[N+]=[N-].Cl.[NH2:12][N:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>C(O)C.C(O)C.O>[O:15]=[C:14]1[NH:16][C:17](=[O:18])[CH2:19][N:13]1[N:12]=[CH:9][C:7](=[O:8])[CH:6]=[CH:5][C:4]#[N:1]
Reactant: [N-]=[N+]=Nc1ccc(C=O)o1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: N#CC=CC(=O)C=NN1CC(=O)NC1=O
Temperature: 60 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
A solution of 5-azido-2-furaldehyde (240 mg, 1.75 millimole (mmole)) in 20 milliliters (ml) of ethanol was added dropwise over 10-20 minutes to a solution of 1-aminohydantoin hydrochloride (320 mg, 2.1 mmole) in 25 ml of ethanol:water (4:1) and the mixture was chilled in an ice bath. The reaction mixture turned into a yellow-orange suspension within thirty minutes and was gradually heated to about 60° C. to form a complete solution. The heating continued for another 24 hours after which time it was allowed to cool and evaporated to dryness. The dark residue was triturated with 4-5 portions (15 ml each) of acetonitrile to obtain a suspension which was then filtered through a filter paper. The filtrate was evaporated to dryness. The residue was dissolved in 3 ml of acetone and streaked on two preparative silica gel TLC plates (EM Science, Cat # 5717-7) and developed with ethyl acetate: petroleum ether (3:1). The fast moving major band (Rf around 0.51) detected under UV light was stripped, and the silica gel was ground to a fine powder and eluted with acetone. The acetone eluent was evaporated to give a pale yellow solid which showed a homogeneous single spot on TLC (137 mg, 0.67 mmole, 38% yield). Alternatively the crude reaction product can be purified by silica gel column chromatography and further recrystallized from 30% ethyl acetate/hexanes to give the pure desired product (mp 171-173° C.). Elemental analysis supported a molecular formula of C8H6N4O3. 0.15 EtOAc. The structure of compound 1 was established by 1H and 13C NMR analysis as shown in FIGS. 1-4. 1H NMR analysis of 1 revealed that the acrylonitrile moiety has a trans (E)-configuration (coupling constant J=16.5 Hz). MALDI-TOF mass spectral analysis confirmed structure 1 with the M+1 peak of 207.22
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:16][C:17]1[N:18]=[N:19][C:20]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH2:32])=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.O1CCCC1>[CH2:9]([O:16][C:17]1[N:18]=[N:19][C:20]([C:31]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:4][CH2:32]2)=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1ccc(COc2cc(C3(c4ccccc4)CC3)nnc2OCc2ccccc2)cc1
Yield: 23 %

Procedure:
To a suspension of sodium hydride (0.487 g, 12.17 mmol, 60% in mineral oil) in DMSO (33.8 ml) stirring under nitrogen was added trimethyl sulfoxonium iodide (2.68 g, 12.17 mmol) in 4 portions over 20 minutes. A solution of 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 25; 3.2 g, 8.11 mmol) in tetrahydrofuran (50.7 ml) was added via a dropping funnel over 90 minutes before the reaction was left to stir at room temperature for 18 hours. The resulting mixture was concentrated, poured into ice water and extracted with ethyl acetate (×3). The organics portion was dried (MgSO4), filtered and concentrated to give a brown oil. The crude oil was purified by silica chromatography (eluting with 0-50% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-(1-phenylcyclopropyl)pyridazine as a yellow oil (yield=23%).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:11])[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCCNC(=O)Nc1nc2ccc(Br)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCNC(=O)Nc1nc2ccc(Br)cc2s1
Temperature: 20 °C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
To a solution of ethyl 4-([(6-bromo-1,3-benzothiazol-2-yl)amino]carbonylamino)-butanoate (175 mg, 0.453 mmol) in THF/EtOH (1/1, 3 mL) was added 2 M NaOH (2.26 mL, 4.53 mmol). The reaction mixture was stirred at about 20° C. for about 3 hrs then 2 M HCl was added until pH<6 and a white precipitate was formed. The precipitate was filtered off and washed with H2O. 25 mg (15%) pure product was isolated.
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1.[C:39]([O:43][C:44]([NH:46][CH2:47][C:48](O)=[O:49])=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[CH2:31]([C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:48](=[O:49])[CH2:47][NH:46][C:44]([O:43][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:45])=[CH:36][CH:37]=1)[C:28]1[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(Cc2ccccc2)cc1
Reaction time: 17.5 h
Yield: 83.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.90 g) and N,N-diisopropylethyl-amine (1.5 mL) were added to a solution of 4-aminodiphenylmethane (0.52 g) and N-tert-butoxycarbonylglycine (0.50 g) in dichloromethane (30 mL) at 0° C. After stiriing at 0° C. for 10 min and at room temperature for 17.5 hr, the solvent was removed in vacuo. The residue was diluted with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1, v/v) to afford the title compound (0.81 g) as a colorless powder: 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 3.90 (d, 2H), 3.94 (s, 2H), 7.12-7.21 (m, 5H), 7.28 (d, 2H), 7.41 (d, 2H).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12]
Reactant: CI
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Temperature: 0 °C
Yield: 14.4 %

Procedure:
Cytidine (100 g, 0.41 mol) was dissolved in warm dimethylformamide (65° C., 1125 mL). The solution was cooled with stirring to 0° C. A slow, steady stream of nitrogen gas was delivered throughout the reaction. Sodium hydride (60% in oil, washed thrice with hexanes, 18 g, 0.45 mol) was added and the mixture was stirred at 0° C. for 45 min. A solution of methyl iodide (92.25 g, 40.5 mL, 0.65 mol) in dimethylformamide (400 mL) was added in portions over 4 h at 0° C. The mixture was stirred for 7 h at 25° C. and then filtered. The filtrate was concentrated to dryness under reduced pressure followed by coevaporation with methanol (2×200 mL). The residue was dissolved in methanol (350 mL). The solution was adsorbed on silica gel (175 g) and evaporated to dryness. The mixture was slurried in dichloromethane (500 mL) and applied on top of a silica gel column (1 kg). The column was eluted with a gradient of dichloromethane-methanol (10:1®2:1). The less polar 2′,3′-dimethyl side product was removed and the coeluting 2′ and 3′-O-methyl product containing fractions were combined and evaporated under reduced pressure to a syrup. The syrup was dissolved in a minimum of hot ethanol (ca. 150 mL) and allowed to cool to 25° C. The resulting precipitate (2′ less soluble) was collected, washed with ethanol (2×25 ml) and dried to give 15.2 g of pure 2′-O-methylcytidine; mp 252–254° C. (lit. mp 252–254° C.); TLC homogenous (Rf 0.50, dichloromethane-methanol 3:1, (Rf of 3′ isomer is 0.50 and the dimethyl product is 0.80). The filtrate was evaporated to give 18 g of a mixture of isomers and sodium iodide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>ClCCl>[CH3:21][S:22]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)[CH:8]=2)[CH2:3][CH2:2]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)NCC4)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)N(S(C)(=O)=O)CC4)c2n1

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-6-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (Intermediate 16.1) (1.10 g, 4.19 mmol), methanesulfonyl chloride (0.65 ml, 8.39 mmol), and triethylamine (3.49 ml, 25.16 mmol) in dichloromethane (50 ml) is stirred for 15 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 1.40 g (98%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 99% purity, tR 7.03 min (tR(SM) 7.06 min). MS (ESI) m/z (C17H16N4O2S) 341.0 (M+1, 100) Finnegan LCQ.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c(C(=O)O)c1-c1ccc(Cl)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c[nH]c(C(=O)N2CCOCC2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a solution of 3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylic acid (1.71 g, 7.26 mmol) and DIPEA (1.39 mL, 7.98 mmol) in DCM (50 mL) were added morpholine (664 μL, 7.62 mmol), HOAt (99 mg, 726 μmol) and EDCI (1.53 g, 7.98 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was washed with brine (100 mL) and the organic layer was dried (Na2SO4) and concentrated. Purification by column chromatography (silica, DCM/(7 M NH3 in MeOH), 98:2) afforded the desired product (1.73 g, 78%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:22]3[CH:23]=[CH:24][S:20][CH:21]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccsc1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1ccsc1
Yield: 90 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-thiophenecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 90% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[C:20]12([CH2:30][CH:31]=O)[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C(Cl)Cl>[C:20]12([CH2:30][CH:31]3[C:12]4[NH:13][C:14]5[C:19]([C:11]=4[CH2:10][CH2:9][NH:8]3)=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2
Reactant: O=CCC12CC3CC(CC(C3)C1)C2
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2c3c([nH]c2c1)C(CC12CC4CC(CC(C4)C1)C2)NCC3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (443 μl, 5.8 mmol) was added to a solution of tryptamine (5.76 g, 36 mmol) and 1-adamantylacetaldehyde (6.52 g, 36.6 mmol) in dry DCM (450 ml) wth 3A molecular sieves (46.5 g) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, followed by the addition of trifluoroacetic acid (5.76 ml, 74.8 mmol) then allowed to warm to room temperature and stirring continued for a further 16 hours. The resultant suspension was concentrated in vacuo, taken up in ethyl acetate (200 ml), filtered, washed successively with saturated NaHCO3 solution (200 ml), brine (2×200 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product as an orange foam which was used without further purification. (10.95 g, 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(O)C>[F:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][C@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1F
Yield: 91 %

Procedure:
Method 1 of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl(3R,4R)-4-fluoropiperidin-3-ylcarbamate and triethylamine in ethanol yielding tert-butyl(3R,4R)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (91%). LCMS (m/z): 341.0 (MH+); LC Rt=2.37 min.
Reaction SMILES: [C:1]1([CH2:7][O:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:22][N:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(OCc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
A mixture of 110.6 g of the product of Example 32, 49.8 g of anhydrous potassium carbonate, 55.8 g of methyliodide and 500 ml of acetone was stirred at ambient temperature for 20 hours. The solvent was evaporated and the residue partitioned between methylene chloride and water. Concentration of the organic extract afforded 88.9 g of N-methyl-N-(phenylmethoxy)-2-nitrobenzenesulfonamide as a yellow oil. [NMR:δ 2.8(s, 3H, NCH3)].