Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1.I[CH:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH:13]([CH3:15])[CH3:14])[C:6]=2[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1cc2[nH]cnc2c(Cl)n1
Reactant: CC(C)I
Product: CC(C)n1cnc2c(Cl)nc(Cl)cc21

Procedure:
Following the procedure of Example 15b, 4,6-dichloro-1H-imidazo[4,5-c]pyridine (J. Het. Chem. 1965, 196-201) (0.19 g, 1.0 mmol) was reacted with 2-iodopropane. The residue was purified by silica gel chromatography (25 to 35% ethyl acetate in hexane eluant) to afford the title compound as a solid. MS m/z 230.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[F:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>C(OCC)C>[F:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH:17]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[OH:18]
Reactant: Cc1ccnc(Br)c1
Reactant: Cc1ccc(C=O)c(F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccnc(C(O)c2ccc(C)cc2F)c1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-4-methylpyridine (600 mg) in diethyl ether (20 mL) at −78° C. is added a 2.3M solution of butyllithium in hexanes (1.52 mL). After stirring at this temperature for 1 hour 2-fluoro-4-methylbenzaldehyde is added and the mixture allowed to warm at room temperature. The reaction mixture is then hydrolyzed with diluted aqueous hydrochloric acid, washed with diethyl ether, basified with concentrated sodium hydroxide and extracted with diethyl ether. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1) to afford (2-fluoro-4-methylphenyl)(4-methyl-pyridin-2-yl)methanol as a pale yellow oil which solidifies on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:16])=[O:15]
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccnc(NS(C)(=O)=O)c1
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of ethyl 2-aminoisonicotinate (1 g, 6.02 mmol) in dry pyridine (20 ml), methanesulfonyl chloride (0.938 ml, 12.04 mmol) was added at room temperature, and the resulting solution was stirred for 3 hours. Pyridine was evaporated and the residue was triturated with water (20 ml). The solid was collected by filtration and dried affording ethyl 2-(methylsulfonamido)isonicotinate as a light brown powder (1.3 g, 5.32 mmol, 88% yield, MS/ESI+ 245.2 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(Nc2ccc(Cl)cc2)nc(Cl)n1
Temperature: 90 °C
Yield: 9.6 %

Procedure:
2,4-Dichloro-6-methylpyrimidine (10 g, 61.3 mmol) and 4-chloroaniline (7.83 g, 61.3 mmol) were dissolved in acetonitrile (100 mL). Diisopropylethylamine (21.37 mL, 122.7 mmol) was added and heated to 90° C. for 4 days. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography with ethyl acetate-hexane as eluent to give (2-chloro-6-methyl-pyrimidin-4-yl)-(4-chloro-phenyl)-amine (1.5 g, 10%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:10]=2)[O:5][C:4]([CH3:18])([CH3:17])[CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][C:4]([CH3:17])([CH3:18])[CH2:3][CH:2]2[NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:14][CH2:15][CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCOc1ccc2c(c1)C(N)CC(C)(C)O2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1ccc2c(c1)C(NS(C)(=O)=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
A reaction mixture of 3.0 g (12 mmol) of 4-amino-6-butoxy-2,2-dimethylchroman, 4.9 g (48 mmol) of triethylamine and 1.65 g (14.4 mmol) of methanesulfonyl chloride in 25 ml of THF was stirred at RT for 3 h. After concentrating, the residue was taken up in water and extracted with EA. After drying and concentrating, the product was crystallized using PE and 2.25 g of 6-butoxy-4-(methylsulfonyl)amino-2,2-dimethylchroman were obtained; m.p. 123-127° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:34][C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)=[O:32])=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCC(O)CC2)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 82.9 %

Procedure:
0.5 g (0.00212 mol) of 1-(4-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.561 ml (0.00424 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.623 g (83%) of 1-(4-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals. MS: me/e=355 (C20H23N2 O4+).
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C>[C@H:1]1([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20]3=[O:28])[CH2:17][CH2:18]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=c1[nH]c2ncccc2n1C1CCN([C@@H]2Cc3cccc4cccc2c34)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(R)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1 g) was dissolved in DMF (30 ml). Sodium hydride (120 mg, 60%) was added, and the suspension was stirred at room temperature for 20 min. Ethyl bromoacetate (500 mg) was added, and the mixture was stirred for 2 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentration to give ethyl (R)-2-{1-[1-(acenaphthen-1-yl)piperidin-4-yl]-1,2-dihydro-2-oxo-imidazo[4,5-b]pyridin-3-yl}acetate. 40% Methylamine-methanol solution (20 ml) was added, the mixture was stirred at room temperature for 2 hr, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.86 g) as a white powder.
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][NH:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1>ClCCl>[N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][N:11]([CH2:12][C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[S:42]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)(=[O:44])=[O:43])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
A solution of isopropyl [3-({[4-(1H-pyrazol-1-yl)benzyl]amino}methyl)-phenoxy]acetate (0.28 g, 0.75 mmol), triethylamine (0.53 mL, 0.37 mmol) and pyridine-3-sulfonyl chloride (268 mg, 1.50 mmol) in dichloromethane (7 mL) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, and the combined organic layers were washed with water, brine and dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (0-5% methanol in dichloromethane) afforded the desired product (180 mg, 69% based on the recovered amine starting material) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=5.56 Hz, 6H) 4.37 (s, 2H) 4.42 (s, 2H) 4.50 (s, 2H) 5.06-5.25 (m, 1H) 6.49 (s, 1H) 6.65-6.75 (m, 2H) 6.77-6.84 (m, 1H) 7.17-7.23 (m, J=8.59 Hz, 3H) 7.46 (dd, J=7.83, 4.80 Hz, 1H) 7.60 (d, J=8.34 Hz, 2H) 7.74 (s, 1H) 7.92 (s, 1H) 8.08 (d, J=7.83 Hz, 1H) 8.83 (d, J=4.29 Hz, 1H) 9.09 (s, 1H). LRMS m/z calcd. for C27H28N4O5S ([M+H]+): 520.2. Found: 521.2.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)=[C:17]([CH3:28])[C:16]=1[CH3:29])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][NH:31]1>>[CH2:8]([C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([N:31]3[CH2:32][CH2:33][C:34]4[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:30]3)[CH2:23][CH2:22]2)=[C:17]([CH3:28])[C:16]=1[CH3:29])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(=O)CC2)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(N3CCc4ccccc4C3)CC2)c1C

Procedure:
This compound as a TFA salt is prepared from compound 24 and 1,2,3,4-tetrahydro-isoquinoline following a procedure used in example 56.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[Cl:9][C:10]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([C:24]([Cl:28])=[C:25]([Cl:27])[Cl:26])[CH:23]=1)[CH2:17][N:18]=[N+:19]=[N-:20])=[C:11]([Cl:13])[Cl:12].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[N:18]([CH2:17][C:16]2[CH:21]=[C:22]([C:24]([Cl:28])=[C:25]([Cl:27])[Cl:26])[CH:23]=[C:14]([C:10]([Cl:9])=[C:11]([Cl:12])[Cl:13])[CH:15]=2)[N:19]=[N:20][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=O)c1nnn(Cc2cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c2)c1N
Reaction time: 0.33 h
Yield: 48.9 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (0.692 g) in 25 ml of ethanol, 8.2 ml of a 1N methanolic solution of NaOH was added and the resulting mixture stirred for 20 minutes. 3,5-Di(trichlorovinyl)benzyl azide (1.5 g) was added in one portion and the resulting mixture stirred at 60° C. for 1 hour. The pH of the mixture was adjusted to 6 with acetic acid. The reaction mixture was then concentrated to a reduced volume and diluted with 100 ml of water. The aqueous mixture was extracted with CH2Cl2 (3×100 ml). The combined organic layers were washed with water, dried with MgSO4 and concentrated to give 1.5 g of crude product. This material was chromatographed on silica gel (95:5 CH2Cl2 :CH3OH) to give 890 mg of a solid. Recrystallization from 5 ml of ethanol provided pure triazole, m.p. 167°-169° C..
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:27].[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[N:3][C:2]([C:32]2[CH:33]=[C:28]([Cl:27])[C:29]([OH:44])=[C:30]([Cl:43])[CH:31]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, {6-chloro-4-[trans-4-(dimethylamino)cyclohexyl-amino]-1,5-naphthyridin-3-yl}(cyclopropyl)methanone (50 mg, 0.13 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (65 mg, 84%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.43 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.11 (s, 2H), 5.64-5.54 (m, 1H), 3.51-3.44 (m, 1H), 2.91 (s, 6H), 2.93-2.89 (m, 1H), 2.63-2.56 (m, 2H), 2.32-2.24 (m, 2H), 1.87-1.68 (m, 4H), 1.33-1.18 (m, 4H); ESI MS m/z 499 [M+H]+; HPLC>99% (AUC), tR=10.12 min.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[OH:14])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:34]([F:39])([F:38])C([O-])=O.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[S:3][C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[O:17])=[C:5]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[O:14][CH:34]([F:39])[F:38])[N:6]=1
Reactant: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1O)c1cnn2cccnc12
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1sc(Br)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [2-bromo-4-(5-chloro-2-hydroxy-phenyl)-thiazol-5-yl]-amide (1.1 g, 2.4 mmol) in DMF (20 mL) and water (2 mL) was added cesium carbonate (1.1 g, 3.4 mmol) and then sodium chlorodifluoroacetate (839 mg, 5.5 mmol). The mixture was stirred at 100° C. for 16 hours before further cesium carbonate (2.2 g, 6.8 mmol) and sodium chlorodifluoroacetate (1.7 g, 11 mmol) was added and stirring continued at 100° C. for 6 hours. The mixture was allowed to cool to room temperature and partitioned between ethyl acetate and water and the phases separated. The organic layer was washed with brine. The combined aqueous layer was extracted with ethyl acetate once and the combined organic layer dried (Na2SO4), filtered and evaporated. The resultant residue was purified by flash chromatography on silica eluting with 50% ethyl acetate in cyclohexane to give the title compound as a yellow solid (710 mg, 59%). LCMS (Method 3) [M+H]+=500.1, RT=3.97 min. 1H NMR (400 MHz, DMSO-d6) δ: 10.84 (s, 1H), 9.42 (dd, 1H, J=1.6, 6.9 Hz), 8.79 (s, 1H), 8.66 (dd, 1H, J=1.6, 4.3 Hz), 7.76 (d, 1H, J=2.8 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=4.2, 7.0 Hz), 7.22 (t, 1H, J=73.1 Hz).
Reaction SMILES: [Br:1]Br.[CH:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13]([O:15][C:16](=[O:17])[C:9]3=[CH:8][CH:7]=[CH:6]2)=[O:14])[CH:12]=1>[N+]([O-])(O)=O>[CH:3]1[CH:12]=[C:11]2[C:13]([O:15][C:16](=[O:17])[C:9]3=[C:10]2[C:5](=[CH:6][C:7]([Br:1])=[CH:8]3)[CH:4]=1)=[O:14]
Reactant: BrBr
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Solvent: O=[N+]([O-])O
Product: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Temperature: 70 °C
Reaction time: 2 h
Yield: 14.3 %

Procedure:
Bromine (8.2 g, 51.3 mmol) was added to a solution of 1,8-naphthalic anhydride (10.0 g, 50.5 mmol) in 70% nitric acid (200 mL) at 25° C. The mixture was stirred at 70° C. for 2 hours and cooled overnight. The solids that separated were filtered, washed with water, and dried to give 2.0 g of the title compound (Reference: J. C. S., 1938:1764-1767).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20](=[O:27])[NH:21][CH:22]1[CH2:26][CH2:25][N:24]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[O:13])[CH2:23]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate and racemic pyrrolidin-3-yl-carbamic acid tert butyl ester by a method analogous to Example 1B. MS: 382/384 (MH+); HPLC Rf: 5.21 min.; HPLC purity 99%.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.COC1C=CC=CC=1O.[CH:22]([Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])Cl)([CH3:24])[CH3:23]>C1(C)C(C)=CC=CC=1>[C:1]([O:5][Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:22]([CH3:24])[CH3:23])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=CC(=O)O
Agent: COc1ccccc1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: C=CC(=O)O[Si](C(C)C)(C(C)C)C(C)C

Procedure:
72.1 g (1 mol) of glacial acrylic acid, 101.2 g (1 mol) of triethylamine 0.072 g of methoxyphenol and 300 ml of xylene is added to a four-neck, round bottom flask equipped with a stirrer, condenser, nitrogen inlet, thermometer and dropping funnel. Under a nitrogen blanket, a solution of 192.8 g (1 mol) of triisopropylchlorosilane in 100 ml of xylene is slowly added to the rapidly stirred reactants at room temperature. The temperature is permitted to rise to a maximum temperature of 55° C. and this temperature is maintained with cooling if necessary.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[CH3:9][C:10]1[N:11]([C@H:16]2[CH2:20][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17]2)[C:12]([CH3:15])=[CH:13][CH:14]=1.C(I)C.[NH4+].[Cl-]>O1CCCC1>[CH3:15][C:12]1[N:11]([C@H:16]2[CH2:20][C@@:19]([CH2:2][CH3:3])([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17]2)[C:10]([CH3:9])=[CH:14][CH:13]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@H]1C=C[C@@H](n2c(C)ccc2C)C1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CC[C@]1(C(=O)OC)C=C[C@@H](n2c(C)ccc2C)C1
Reaction time: 0.67 h
Yield: 82 %

Procedure:
A −40° C. solution of 2M (in THF/ethylbenzene/heptane) LDA (68 ml, 138 mmol) in tetrahydrofuran (120 ml) was treated with methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate (14.02 g, 63.9 mmol) while keeping the temperature less than −33° C. The cold reaction was stirred for 40 minutes and then a solution of ethyl iodide (13.63 g, 87.4 mmol) in tetrahydrofuran (5 ml) was added slowly while keeping the temperature less than −33° C. The reaction was stirred with the cold bath in place for four hours and allowed to slowly warm. The reaction was poured into NH4Cl soln (300 ml), then extracted with ethyl acetate (2×200 ml), washed with brine dried over MgSO4, and concentrated under reduced pressure. The resulting brown oil was passed through a column of silica gel with 10% ethyl acetate/hexanes to give methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-ethylcyclopent-2-ene-1-carboxylate as a brown oil (12.96 g, 82%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON(C)[C:8]([C:10]1[S:14][C:13]2[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:12]=2[CH:11]=1)=[O:9]>O1CCCC1>[CH3:20][O:19][C:15]1[C:13]2[S:14][C:10]([C:8](=[O:9])[CH2:1][CH3:2])=[CH:11][C:12]=2[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2cc(C(=O)N(C)OC)sc12
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1cc2cccc(OC)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide (1M solution in tetrahydrofuran; 6.4 ml) was added to a solution of N,7-dimethoxy-N-methylbenzo[b]thiophene-2-carboxamide (1.5 g) in tetrahydrofuran, then the mixture was stirred at ambient temperature for 1 hour and at reflux temperature for 1 hour. Further ethylmagnesium bromide (1M solution in tetrahydrofuran; 6.4 ml) was added, the mixture was stirred at ambient temperature for 1 hour and at reflux temperature for 2.5 hour, then it was cooled to ambient temperature and quenched by the addition of 5M hydrochloric acid (10 ml) and water (150 ml). The product was extracted into dichloromethane (3×60 ml), then the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane followed by a 99:1 mixture of dichloromethane and methanol as eluants. Appropriate fractions were combined, and the solvents were removed in vacuo to give 1-(7-methoxybenzo[b]thiophen-2-yl)propan-1-one (0.7 g) as an oil which was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2].[C:18]([C@@:21]1([OH:36])[C@@H:25]([CH2:26][OH:27])[O:24][C:23](Cl)([C:28](=[O:30])[CH3:29])[C@:22]1([C:33](=[O:35])[CH3:34])[OH:32])(=[O:20])[CH3:19]>>[C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@:23]2([C:28](=[O:30])[CH3:29])[O:24][C@H:25]([CH2:26][OH:27])[C@@:21]([C:18](=[O:20])[CH3:19])([OH:36])[C@@:22]2([C:33](=[O:35])[CH3:34])[OH:32])=[C:7]([NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1(Cl)O[C@H](CO)[C@](O)(C(C)=O)[C@]1(O)C(C)=O
Reactant: CC(=O)Nc1nc(NC(C)=O)c2[nH]cnc2n1
Product: CC(=O)Nc1nc(NC(C)=O)c2ncn([C@]3(C(C)=O)O[C@H](CO)[C@](O)(C(C)=O)[C@]3(O)C(C)=O)c2n1

Procedure:
Generally speaking, compounds of this invention are prepared from 2-acetamido-adenosine-5'-carboxylic acid or from the corresponding 2',3'-isopropylidene derivatives. 2-acetamido-adenosine-5'-carboxylic acid is obtained by reacting 2,6-diaminopurine sulfate with sodium hydroxide to obtain 2,6-diaminopurine which is then reacted with acetic anhydride to yield 2,6-diacetamidopurine, which in turn is converted to a mercuri chloride complex. The mercuri chloride complex of 2,6-diacetamidopurine is then reacted with triacetyl D-ribofuranosyl chloride to obtain 2,6diacetamido-9-(triacetyl-β-D-ribofuranosyl) purine, which is then converted to the corresponding 2-acetamido adenosine by treatment with methanol in the presence of ammonia. Preparation of 2-acetamido adenosine from 2,6-diaminopurine sulfate has been described by J. Davoll & B. A. Lowy [J.A.C.S., 73, 1650 (1951)]. The corresponding isopropylidene compound is obtained by reacting 2-acetamido adenosine with acetone. Potassium permanganate oxidation affords the corresponding 5'-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13](O)([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2nn[nH]n2)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnc(-c2ccc(Br)cc2)n1
Yield: 70.9 %

Procedure:
5-(4-Bromophenyl)-2H-tetrazole (19.0 g. 81.9 mmol), t-butanol (12.1 g. 164 mmol). trifluoroacetic acid (80 mL) and concentrated sulfuric acid (4.6 g, 41 mmol) were stirred at ambient temperature for 24 hours. The mixture was concentrated and dissolved in ethyl acetate (200 mL). After washing with water (3×25 mL), 1M NAOH (3×25 mL) and brine (25 mL) the organic layer was dried (Na2SO4), filtered and concentrated. The oil was purified by chromatography on a Waters Prep 500 liquid chromatograph fitted with two silica gel cartridges eluting with a mixture of hexanes and ethyl acetate (9:1) to provide 5-(4-bromophenyl)-2-(1,1-dimethylethyl)-2H-tetrazole (17.1 g. 58.1 mmol) as a yellow oil in 71% yield.