Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]([O-:35])([O-:34])=[O:33].[Na+:36].[Na+]>C(O)C.O>[C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:32]([O-:35])(=[O:34])=[O:33])[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:36]
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 32.1 %

Procedure:
2,4,5-Triphenyl-1-(7-bromoheptyl)imidazole (0.95 g) was dissolved in hot ethanol (10 ml) and a solution of sodium sulphite (0.38 g) in hot water (5 ml) was added. The white suspension was heated at reflux temperature for 20 hours then evaporated to dryness. The mixture was taken up in dichloromethane, filtered and the filtrate evaporated to an oil which was chromatographed on silica gel (dichloromethane/methanol). The resulting oil was dissolved in methanol and excess ether added giving an oil which slowly solidified to give sodium 7-(2,4,5-tri-phenylimidazol-1-yl)heptane-sulphonate (0.32 g; 32%) as a white solid, m.p. 310° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[S:32]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:38][CH2:37][C:34]5[CH:35]=[CH:36][S:32][CH:33]=5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: NCc1ccsc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNCc5ccsc5)c4)cc23)CC1
Yield: 10.1 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), 1-(3-thienyl)methanamine (9.83 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (4.7 mg, 7.8%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[Cl:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][NH:17][C:18]([C:20]2[C:21]([OH:31])=[C:22]3[CH:28]=[C:27]([CH2:29][OH:30])[S:26][C:23]3=[N:24][CH:25]=2)=[O:19])=[CH:14][CH:13]=1>CN(C=O)C.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]([C:20]2[C:21](=[O:31])[C:22]3[CH:28]=[C:27]([CH2:29][OH:30])[S:26][C:23]=3[N:24]([CH2:8][CH2:9][CH3:10])[CH:25]=2)=[O:19])=[CH:32][CH:33]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (0.91 g) and 1-iodopropane (0.64 mL) are added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (2.0 g, prepared as described in U.S. Pat. No. 6,239,142) in anhydrous DMF (60 mL). The reaction mixture is stirred at room temperature for 4 h. The mixture is diluted with water (150 mL) and filtered. The resulting white powder is washed with water (15 mL) followed by diethyl ether (15 mL) and dried in a vacuum oven to afford 1.73 g of the title compound as a white solid Physical characteristics. Mp 174-175° C. 1H NMR (300 MHz, DMSO-d6) δ 10.62, 8.72, 7.38, 7.29, 5.80, 4.69, 4.55, 4.27, 1.87, 0.89; Anal. Found: C, 58.20; H, 4.96; N. 7.13; Cl, 8.98; S, 8.16.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1>>[CH:31]1([C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]4[CH2:14][CH2:13][CH2:12][C@H:11]4[CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:9])=[C:4]([F:21])[CH:3]=3)=[CH:24][CH:25]=2)=[O:30])[CH2:32][CH2:33]1
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: O=C(c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cc1)C1CC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedures P′ and FF starting from (4-Bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone and commercially available (4-Bromo-phenyl)-cyclopropyl-methanone and bis(pinacolato) diboron. MS (M+H) 421.3
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[NH2:28])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:27]=3[NH:28][C:29]2=[O:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1Nc2ccncc2C(c2ccccc2)N1C1CCN(Cc2ccccc2)CC1
Yield: 338.7 %

Procedure:
To a solution of 8.0 g (21.5 mmol) of 3-[α-{(1-benzyl-piperidin-4-yl)amino}benzyl]-4-aminopyridine in 100 mL of tetrahydrofuran was added 5.0 g (3.1 mmol) of 1,1'-carbonyldiimidazole, and the mixture was heated under reflux for 8 hours. After being cooled, the reaction mixture was concentrated in vacuo, and the residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform). The resulting crude crystals were recrystallized from diethyl ether/ethanol to give 4.2 g (10.5 mmol) of the title compound.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C@@H:8]([CH2:15][C:16]([O:18]C)=[O:17])[N:7]([CH2:20][C:21]3[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=3)[C:6]=2[N:5]=1>CO.C1COCC1>[NH2:3][C:4]1[N:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[C@@H:8]([CH2:15][C:16]([OH:18])=[O:17])[N:7]([CH2:20][C:21]3[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=3)[C:6]=2[N:5]=1
Reactant: COC(=O)C[C@@H]1C(=O)Nc2cnc(N)nc2N1Cc1ncc(C)c(OC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C)cnc(CN2c3nc(N)ncc3NC(=O)[C@H]2CC(=O)O)c1C
Reaction time: 2 h

Procedure:
Sodium hydroxide (1 mL, 2M, 2 mmol) was added to a solution of methyl {(7R)-2-amino-8-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-6-oxo-5,6,7,8-tetrahydropteridin-7-yl}acetate (272 mg, 0.26 mmol)(Example 7[3]) in methanol (1 mL) and THF (3 mL). The mixture was stirred for 2 hours and then concentrated under reduced pressure. The solution was diluted with water (1 mL) and made acidic by the addition of acetic acid. This solution was loaded onto an SCX column, washed with water and then methanol and the product was eluted with 2M ammonia in methanol. Thus, the title compound was obtained as a cream solid (169 mg, 65%); 1H NMR spectrum (400 MHz, DMSO-d6) δ 2.18 (6H, s), 2.29 (1H, d), 2.38 (1H, d), 3.72 (3H, s), 4.13-4.15 (1H, m), 4.41 (1H, d), 5.49 (1H, d), 5.55 (2H, s), 7.27 (1H, s), 8.13 (1H, s), 9.91 (1H, s); Mass spectrum: (M+H)+ 373.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.CO[CH:17]([O:20][CH3:21])[O:18][CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:21][O:20][CH:17]([O:18][CH3:19])[C:6]1[CH:9]=[C:2]([F:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]=1[O:10][CH3:11]
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C=O
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc([N+](=O)[O-])c(F)cc1C(OC)OC

Procedure:
A mixture of 0.210 g (1.06 mmole) of 5-fluoro-2-methoxy-4-nitro-benzaldehyde (IV.46c), 1 mL of trimethylorthoformate, 0.025 g of p-toluenesulfonic acid monohydrate and 5 mL of methanol was heated at reflux for one hour. The mixture was cooled, neutralized by addition of saturated sodium bicarbonate solution and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.243 g of 1-dimethoxymethyl-5-fluoro-2-methoxy-4-nitro-benzene (IV.46d) as a yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](Cl)=[O:36])=[CH:29][CH:28]=1>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:35](=[O:36])[CH2:34][CH2:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(CCC(=O)Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CCC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 72 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 3-(4-methoxyphenyl)propionyl chloride, the title compound was synthesized according to Example 1b. Yield: 72%. Melting point: 188-191° C. (Ethyl acetate-hexane)
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH:18]=[C:19]2[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:28])[C@:7]1([CH3:27])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:26])[CH:9]=[CH:8]1)(=[O:3])[CH3:2].[CH2:29]([SH:33])[CH2:30][CH2:31][CH3:32]>>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2([S:33][CH2:29][CH2:30][CH2:31][CH3:32])[S:23][CH2:24][CH3:25])[C@H:15]2[C@@:6]1([F:28])[C@:7]1([CH3:27])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:26])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Reactant: CCCCS
Product: CCCCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@@]21C
Temperature: 10 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A solution of 11β-acetyloxy-17-(ethylthio)-9-fluoroandrosta-1,4,16-triene-3-one (700 mg; see example 11c) and n-butanethiol (271 mg) is cooled and stirred in a bath at -40° to -45° C. and distilled boron trifluoride etherate (0.3 ml) is added. After 2.0 hours at -40° to -45° C., the solution is gradually warmed to 10° C. in the course of 1.5 hours. The mixture is then diluted with dichloromethane, washed successively with a saturated sodium bicarbonate solution and brine, dried (MgSO4 anh.) and is evaporated to afford the crude title compound. This material is chromatographed over a column of silica gel (20 g), eluting the column with chloroform-hexane mixtures (1:1, 1:4), chloroform and chloroform-ethyl acetate (95:5) to afford the title compound (700 mg). Examination of the nmr spectrum and tlc behavior shows that this material is contaminated with a significant amount of the starting steriod which is not readily separable from the more polar isomer of the product under the tlc systems examined. Partial separation of the two 17-isomers is achieved under these tlc conditions.
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.Br[C:9]1[C:10]([Cl:33])=[C:11]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:16][N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:12]2=[N:13][CH:14]=1.C(O[B:38]([O:43][CH:44]([CH3:46])[CH3:45])[O:39][CH:40]([CH3:42])[CH3:41])(C)C.OC(C(O)(C)C)(C)C.[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Cl:33][C:10]1[C:9]([B:38]2[O:39][C:40]([CH3:41])([CH3:42])[C:44]([CH3:45])([CH3:46])[O:43]2)=[CH:14][N:13]=[C:12]2[N:15]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:11]=12
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(F)cc2)c2c(Cl)c(Br)cnc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnc3c(c(-c4ccc(F)cc4)cn3COCC[Si](C)(C)C)c2Cl)OC1(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 48.5 %

Procedure:
580 mg (13.69 mmol) of vacuum dried anhydrous lithium chloride was dissolved in 30 mL of anhydrous THF under nitrogen. The mixture was cooled to 0° C. and 1.5 mL (3.0 mmol) of a 2 M solution of iso-propylmagnesium chloride in anhydrous THF was added. To this mixture was added at 0° C. a solution of 1.064 g (2.33 mmol) of 5-bromo-4-chloro-3-(4-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine in 20 mL of anhydrous THF under nitrogen. The resulting mixture was stirred at 0° C. for 2 h before 1.0 mL (4.3 mmol) of tri-iso-propylborate was added at 0° C. The resulting mixture was allowed to stir at that temperature for 2.5 h. 990 mg (8.38 mmol) of pinacol was added and the mixture stirred for 24 h, allowing to warm to room temperature. The resulting reaction mixture was distributed between diethyl ether and a saturated aqueous solution of ammonium chloride. The organic phase was separated, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate and hexanes to afford 569 mg (1.13 mmol, 48%) of 4-chloro-3-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine as a beige solid. 1H-NMR [500 MHz, d6-DMSO] δ: 8.46 (s, 1H), 7.83 (s, 1H), 7.50 (dd (m), 2H), 7.27 (t (m), 2H), 5.68 (s, 2H), 3.57 (t, 2H), 1.32 (s, 12H), −0.09 (s, 9H); MS [MH+] m/z: 503
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([N:18]1[CH2:19][C:20]2[C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[C:21]=2[CH2:22][CH2:23]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: O=C=Nc1ccccc1
Product: O=C(c1ccccc1)N1CCc2c(c(=O)[nH]c3ccccc23)C1

Procedure:
In the same way as described in example 2, the title product was prepared starting from phenylisocyanate and the pyrrolidine enamine of N-benzoyl-4-piperidone. Crystallization from methanol afforded analytical material, mp 275°-277° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].[H][H]>CO.O=[Pt]=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[NH2:12]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(F)c(N)c1
Yield: 111.7 %

Procedure:
A mixture of 4-fluoro-3-nitrophenyl methyl sulfone (Acros; 1.00 g; 4.56 mmol) and PtO2 (100 mg) in MeOH (150 ml) was placed in a PARR reactor and treated with a pressure of 20 atm of hydrogen for 3 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated to dryness affording the title compound (964 mg) as a dark green oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][NH:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[O:8]1)=[O:6])[CH3:3].C(=O)(O)[O-].[Na+].[O-]CC.[Tl+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:11]1[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[O:8][CH:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:12]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CNc2ccccc2O1
Agent: CC[O-]
Agent: Cl
Agent: O=C([O-])O
Product: CCOC(=O)C1CN(Cc2ccccc2)c2ccccc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1A was treated with sodium bicarbonate to prepare the free base (1B). A mixture of 5.3 g of 1B and 8.23 g of thallium ethoxide in 50 ml of dimethylformide was stirred at room temperature for 16 hours. 5.64 g of benzyl bromide then was added and the resulting mixture was stirred at room temperature for 5 hours. Thallium bromide precipitated and was filtered. The filtrate was stripped of solvent under reduced pressure and the residue was dry column chromatographed through silica gel using a 4:16:80 by volume mixture of tetrahydrofuran, ethyl acetate and hexane as eluent. The product was recrystallized from ether/hexane to give 1, as a solid, m.p.: 83.5°-84.5°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].[NH:17]1[CH:21]=[N:20][N:19]=[N:18]1>CN(C)C=O>[NH:20]1[CH:21]=[N:17][NH:18][N:19]1[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C(NCCCBr)c1ccccc1[N+](=O)[O-]
Reactant: c1nnn[nH]1
Solvent: CN(C)C=O
Product: O=C(NCCCN1NC=NN1)c1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 18.2 %

Procedure:
A solution of 24.5 g (0.085 mol) of N-(3-bromopropyl)-2-nitrobenzamide in 75 ml of dimethylformamide was slowly added to a solution of 7.00 g (0.10 mol) of tetrazole. The resulting solution was heated to 50° C. and allowed to react overnight. When the reaction was complete, as determined by thin layer chromatography, most of the dimethylformamide was removed under reduced pressure. The resultant residue was diluted with water, causing a precipitate to form. The precipitate was isolated by filtration and dried under vacuum. Thin layer chromatography and nuclear magnetic resonance spectroscopy indicated the presence of two isomers; namely, the N-1 and N-2 alkylated tetrazoles (75:25 ). The N-2 alkylated compound was isolated by column chromatography to provide 4.3 g of the desired subtitled intermediate. The N-1 alkylated compound was isolated by twice crystallizing the precipitate from cyanomethane to provide 3.72 g of that compound. (m.p. 148°-150° C.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>O1CCOCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][C:18]=3[C:4]=2[CH:3]=1
Reactant: NNc1ccc(I)cc1
Reactant: CN1CCC(=O)CC1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(I)cc3c2C1
Temperature: 70 °C

Procedure:
To a solution of compound 4-iodophenylhydrazine (1 equiv.) in 1,4-dioxane (50 mL) is added conc. sulfuric acid, followed by dropwise addition of 1-methyl-4-piperidone (1 equiv.) at RT. The reaction mixture is heated at 70° C. for 90 min., evaporated, diluted with water and the pH is adjusted to 12 with 40 mL of 15% aq. KOH solution. The reaction mixture is extracted with EtOAc, followed by brine wash, dried over sodium sulfate and evaporated under vacuum. The crude product is column purified over 230-400 silica gel using a gradient of 0-5% of MeOH in EtOAc. Note 1: The reaction temperature should be 70° C. Higher temperature results in the de-iodo carboline.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:33]([O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]I)=[CH:43][CH:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([O:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:42][CH:43]=2)[CH2:18]1)[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: ICc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1) c), 30.9 g (99.26 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-dihydrofuran-2-(3H)-one are reacted with 200 ml (200 mmol) of lithium bis(trimethylsilyl)amide 1M in THF and 34 g (104.8 mmol) of 4-benzyloxybenzyl iodide to yield the title compound. The title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1 to 1/1) and crystallisation (hexane/ethyl acetate); TLC Rf (C)=0.33; tRet (IV)=20.41 min; FAB-MS (M+H+)=508.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:19]=[C:18]([Cl:20])[C:11]3[O:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][C:10]=3[C:9]=2[Cl:21])=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:19]=[C:18]([Cl:20])[C:11]3[O:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][C:10]=3[C:9]=2[Cl:21])=[N:25][OH:26])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Cl)c2c(c1Cl)CC(C(=O)O)O2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1Cc2c(Cl)c(C(=NO)c3ccc(Cl)cc3)cc(Cl)c2O1
Yield: 97.9 %

Procedure:
A mixture of 5-(4-chlorobenzoyl)-4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid (10.8 g), hydroxylamine hydrochloride (20.7 g) and pyridine (100 ml) was refluxed for 13 hours. After distilling off the solvent, water was added to the mixture which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. By distilling off the solvent, 11.0 g of 5-(4-chloro-α-hydroxyiminobenzyl)4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid was obtained. This compound (11 g) was dissolved in anhydrous dimethylformamide (140 ml), and to the ice-cooled solution, 4.0 g of 60% sodium hydride was added in small portions under agitation. After continuing the agitation for 5 hours at room temperature, the mixture was left to stand overnight. Water was added to the mixture, which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 6.5 g of 5-chloro-3-(4-chlorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 240°-243° C. (with decomposition). This compound exhibited a mass spectrum having a molecular ion peak at m/e 349.
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[N:26]1>>[N:25]1([CH2:2][C:3]2[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:11]=3)=[O:8])=[CH:5][CH:4]=2)[CH:29]=[CH:28][N:27]=[N:26]1
Reactant: c1c[nH]nn1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cn2ccnn2)cc1

Procedure:
88 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 40 μL of 1H-1,2,3-triazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield 4-((1H-1,2,3-triazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 390.1 (M)+.