Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[CH2:10][CH2:11][N:12]([CH2:35][CH2:36]Cl)[C:13]1[CH:33]=[C:32]([Cl:34])[C:16]2[O:17][C:18]3[C:27]([CH3:28])=[CH:26][C:25]([C:29]([OH:31])=[O:30])=[CH:24][C:19]=3[S:20](=[O:23])(=[O:22])[CH2:21][C:15]=2[CH:14]=1.[CH3:38]O>>[CH3:38][O:31][C:29]([C:25]1[CH:26]=[C:27]([CH3:28])[C:18]2[O:17][C:16]3[C:32]([Cl:34])=[CH:33][C:13]([N:12]4[CH2:11][CH2:10][N:1]([CH2:2][CH2:3][N:4]5[CH2:8][CH2:7][CH2:6][CH2:5]5)[CH2:36][CH2:35]4)=[CH:14][C:15]=3[CH2:21][S:20](=[O:23])(=[O:22])[C:19]=2[CH:24]=1)=[O:30]
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: CO
Reactant: NCCN1CCCC1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(CCN4CCCC4)CC3)cc(Cl)c1O2
Temperature: 70 °C

Procedure:
1-(2-Aminoethyl)pyrrolidine (1.60 mL, 12.6 mmol) was added to a solution of Example 102j (0.75 g, 1.50 mmol) in methanol (5 mL), in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 110° C. for 5 h. The reaction mixture was brought to room temperature, concentrated, treated with methanolic HCl solution, and refluxed at 70° C. for 2 h. The reaction mixture was concentrated, treated with aqueous sodium bicarbonate solution to neutral pH and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 5% methanol/chloroform) to obtain the title compound. Yield: 0.320 g, (30.5%); 1H NMR (DMSO-d6): δ 1.90-1.95 (m, 4H, 2CH2), 2.62 (s, 6H, 2CH3), 2.70 (s, 3H, CH3), 3.10-3.15 (m, 8H, 4CH2), 3.20-3.25 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.20 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar); MS : m/e (CI+) 534 (M+).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Br:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[C:20](F)[N:19]=2)[N:16]=[CH:15][C:14]=1[N+:30]([O-:32])=[O:31].O1CCCC1>C(Cl)Cl>[Br:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[C:20]([NH:4][CH2:1][CH:2]=[CH2:3])[N:19]=2)[N:16]=[CH:15][C:14]=1[N+:30]([O-:32])=[O:31]
Reactant: C=CCN
Reactant: O=[N+]([O-])c1cnn(-c2nc(F)c(C(F)(F)F)cc2Cl)c1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNc1nc(-n2ncc([N+](=O)[O-])c2Br)c(Cl)cc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
0.3 g (0.00565 mol) of allylamine and 0.6 g (0.00565 mol) of triethylamine were added to a mixture of 2.2 g (0.00565 mol) of 5-bromo-4-nitro-1-(3-chloro-6-fluoro-5-trifluoromethyl-2-pyridyl)pyrazole and 50 ml of tetrahydrofuran at 22° C. with stirring in the course of 5 minutes and the mixture was subsequently stirred for 21/2 hours. After working up according to the above example and chromatographing with methylene chloride on silica gel, 0.9 g (37% of theory) of the title compound was obtained as a colorless resin. 1H-NMR (CDCL3 /TMS) δ (ppm) allyl 3.95 (s/2), 5.05 (tr/2), 5.85 (m/1); NH 7.6 (tr/1); pyrid 8.4 (s/1); pyraz. 8.8 (s/1) (Active Compound Example No. 9.022).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH2:8])[CH2:5][CH2:6][CH3:7].[N:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])=[C:10]=[O:11]>>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[NH:9][C:10]([NH:8][CH:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])=[O:11]
Reactant: CCCC(N)CCC
Reactant: COc1ccc(N=C=O)c(OC)c1
Product: CCCC(CCC)NC(=O)Nc1ccc(OC)cc1OC
Yield: 88 %

Procedure:
Prepared in a similar manner to example 158 using heptan-4-amine and 1-isocyanato-2,4-dimethoxybenzene. Yield: 88%. mp: 172-173° C. 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 6H), 1.45 (m, 8H), 3.82 (s, 3H), 3.83 (m, 1H), 3.84 (s, 1H), 4.32 (br s, 1H), 6.34 (br s, 1H), 6.49 (d, 1H), 6.50 (s, 1H), 7.71 (d, 1H). MS (M+H, 295).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:25])([O:23][CH3:24])[CH3:22])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:65][CH2:66]I)(=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61].Cl>O.CN(C)C=O>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:29][CH:30]=3)=[N:19][O:20][C:21]([CH3:22])([O:23][CH3:24])[CH3:25])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([O:13][CH2:66][O:65][C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])=[O:12])=[N+:2]=[N-:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A suspension of 739 mg of the syn isomer of 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxyethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid, 76 g of potassium carbonate and 3 ml of dimethylformamide was stirred for 10 minutes at 20° C. and after cooling the mixture to 0° to 5° C., the suspension of Step A was slowly added thereto. The mixture was stirred at 0° to 5° C. for 30 minutes and then at 20° C. for one hour and a mixture of 40 ml of water and 1.5 ml of N hydrochloric acid was added thereto. The mixture was vacuum filtered and the recovered product was washed with water and dried to obtain 850 mg of the syn isomer of pivaloyloxymethyl 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxy-ethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[O:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:16][C:15]=1[O:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccc(O)cc1OC)C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)C(=CNc1ccc(OC(=O)c2ccccc2)cc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Ethyl 2-butyryl-3-(4-hydroxy-2-methoxyphenylamino)acrylate (34.5 g) and pyridine (100 ml) were stirred in dichloromethane (500 ml) at 0°-5°. Benzoyl chloride (20 ml) in dichloromethane (100 ml) was added dropwise (below 10°) and the mixture was stirred overnight at room temperature. The reaction mixture was washed successively with water, 2M HCl (×2) and sodium hydrogen carbonate solution (×2). The organic layer was dried, filtered and evaporated to an oil which crystallized on standing to give ethyl 2-butyryl-3-(4-benzoyloxy-2-methoxyphenyl-amino)acrylate (24 g, 52%) m.p. 85°-87°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][C:14]#[N:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CO.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1nc(-c2ccc(F)cc2)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
2-(4-(4-fluorophenyl)thiazol-2-yl)acetonitrile (400 mg, 1.83 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. Borane tetrahydrofuran complex solution (1M in tetrahydrofuran, 9.16 mL, 9.16 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was cooled to 0° C. and quenched with methanol (5 eq., 0.4 mL). The reaction was allowed to warm to room temperature and 2N HCl was added until the reaction mixture was confirmed acidic by a pH paper. The reaction mixture was then refluxed at 65° C. for 30 min. The reaction mixture was then allowed to cool to room temperature and was concentrated under reduced pressure. The solid obtained was triturated with ether (2×20 mL) and dichloromethane (2×20 mL). The remaining solid was dissolved in water (50 mL) and basified to pH ˜11 with NaOH pellets. The aqueous mixture was then extracted with ether (2×100 mL). The organic layer was dried over anhdrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was used directly without any purification in the next step (100 mg, 25% yield). MS (ESI) m/z: Calculated for C11H11FN2S: 222.06. found: 223.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][C:26]#[N:27])[C:5]2=3)[CH:14]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:25][CH2:26][NH2:27])[C:5]2=3)[CH:14]=1
Reactant: Cc1cc2c3c(c1)c1c(OCC#N)cccc1n3C(c1ccccc1)CO2
Solvent: C1CCOC1
Product: Cc1cc2c3c(c1)c1c(OCCN)cccc1n3C(c1ccccc1)CO2
Temperature: 85 °C
Yield: 66.6 %

Procedure:
To a mixture of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile (0.66 g, 1.86 mmol) in dry THF (120 mL) is added borane-methylsulfide complex (0.53 mL, 5.6 mmol). The mixture is refluxed at 85° C. for 18 h. The mixture is removed from heat and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added and again removed. The residue is dissolved in CH2Cl2/CH3OH (1:2 15 mL). Conc. HCl (2 mL) is added and the mixture heated at 65° C. for 1 h. The mixture is removed from heat and neutralized with aqueous potassium carbonate then partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. Column chromatography (70 g silica gel) using CH3OH/CH2Cl2 (4:96) as eluent gave 0.444 g (67%) of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[C:18]([OH:19])=[CH:17][N:16]=[C:15]2[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:21]=[CH:22][C:14]=12>CN(C=O)C>[F:12][C:13]1[C:18]([O:19][CH2:2][CH2:3][O:4][CH3:5])=[CH:17][N:16]=[C:15]2[NH:20][CH:21]=[CH:22][C:14]=12
Reactant: COCCBr
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cnc2[nH]ccc2c1F
Temperature: 65 °C
Yield: 49.7 %

Procedure:
1-Bromo-2-methoxyethane (0.586 g, 4.21 mmol) and potassium carbonate (1.16 g, 8.43 mmol) to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (1.3 g, 4.21 mmol; Example 119, Step A) in DMF (13 mL). The reaction was heated to 65° C. in a sealed tube for 18 hours, cooled down and then filtered. The filtrate was concentrated and purified by reverse chromatography (SP4, 25M, water/ACN 90/10→0/100, 30CV) to yield 4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridine (440 mg, 49.7% yield) as an oil.
Reaction SMILES: CC1(C)[O:6][C:5](=O)[C@H:4]([C@@H:8]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[O:3]1.[NH2:28][OH:29]>CC(O)C>[OH:29][NH:28][C:5](=[O:6])[C@@H:4]([OH:3])[C@@H:8]([C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@@H]1OC(C)(C)OC1=O
Reactant: NO
Solvent: CC(C)O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
To a solution of (5S)-2,2-dimethyl-5-((1S)-3-methyl-1-{[4-(2-pyridinyl)-1-piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-one (250 mg; 0.67 mmol; 1.0 eq.) in iPrOH (5 mL) was added an aqueous solution of hydroxylamine (50%; 0.195 mL; 3.35 mmol; 5.0 eq.) and the resulting reaction mixture was stirred at RT for 2.5 h. After evaporation of the solvents, the crude mixture was purified by reverse-phase chromatography to give the title compound (1) as a white powder (74 mg; 31%). M−(ESI): 349.2; M+(ESI): 351.1. HPLC: Rt: 1.3 min (HPLC purity: 100%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:13][CH2:14][C@@H:15]1[O:19][C:18]([C:20]2[NH:24][C:23]([C:25]3[CH:26]=[C:27]([OH:37])[CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)=[CH:22][CH:21]=2)=[N:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(OCC)(=O)C>[OH:13][CH2:14][C@@H:15]1[O:19][C:18]([C:20]2[NH:24][C:23]([C:25]3[CH:26]=[C:27]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[O:37][C:2]3[N:3]=[CH:4][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=3)=[CH:22][CH:21]=2)=[N:17][CH2:16]1
Reactant: CNS(=O)(=O)c1cnc(Br)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CNS(=O)(=O)c1cnc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](CO)O4)[nH]3)c2)cn1
Reaction time: 4 h
Yield: 53.6 %

Procedure:
5-Bromo-N-methylpyrazine-2-sulfonamide (147 mg, 0.58 mmol) synthesized in Example (128b) and 3-{5-[(5R)-5-(Hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (262 mg, 0.76 mmol) synthesized in Example (125g) were dissolved in acetonitrile (6 mL), and potassium carbonate (161 mg, 1.17 mmol) was added, followed by stirring for 4 hours under nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-3.5%) to afford the desired compound (161 mg, yield 54%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>CS(C)=O>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:13][CH:15]3[O:17][CH2:16]3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: c1cc(OCC2CO2)c2cc[nH]c2c1
Temperature: 45 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
The solvents used in reactions were dried prior to use. All other reagents were used as received without purification. All moisture-sensitive reactions were performed in flame-dried and/or oven-dried glassware under a positive pressure of nitrogen unless otherwise noted. Thin-layer chromatography was carried out with glass TLC plates precoated with silica gel 60 F254. Flash column chromatography was accomplished with silica gel BW820MH. Proton nuclear magnetic resonance spectra were recorded in deuterated solvents at 270 or 600 MHz. To a solution of 4-hydroxy indole (1) (0.50 g, 3.8 mmol) in dimethylsulfoxide (10 mL) at 45° C. was added potassium hydroxide (0.4 g, 7.6 mmol) followed by epichlorohydrin (1.4 g, 15.2 mmol). The reaction mixture was stirred at 45° C. for 4 h. The reaction was quenched with a saturated solution of NH4Cl, extracted with diethyl ether (3×50 mL). The combined organics were dried with MgSO4, and concentrated. The product was purified by elution from silica gel column with benzene/acetone mixtures to give the glycidyl 4-indolyl ether (2) (0.75 g, 3.8 mmol, 99%) as a clear oil. To a solution of glycidyl 4-indolyl ether (2) (215 mg, 1.14 mmol) in methanol (2 mL) was added isobutyl amine (160 mg, 2.28 mmol). The solution was heated to 100° C. and stirred for 32 h. The product was purified by elution from silica gel column with benzene/acetone mixtures to give the corresponding amine (3) (120 mg, 0.46 mmol, 40%) as a clear oil. To a solution of 4,4′-bipiperidine (420 mg, 5.0 mmol) and triethylamine (2 mL) in 150 mL of CHCl3 was added a solution of 1-adamantanecarbonyl chloride (4) (500 mg, 2.5 mmol) in 50 mL of CHCl3. The resulting mixture was refluxed for 0.5 h, diluted with brine, and dried over MgSO4. The solution was then concentrated in vacuum and purified by elution from silica gel column with CHCl3/methanol mixtures to give the corresponding amide (5) (750 mg, 2.3 mmol, 90%) as a clear oil. See FIG. 11 and FIG. 13.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[OH:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cnc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
4-Hydroxymethylimidazole hydrochloride (10 g) was suspended in dichloromethane (200 ml). ρ-Toluenesulfonyl chloride (15.58 g) was added and triethylamine (25.8 ml) was added dropwise to the stirred reaction mixture which was allowed to stir at room temperature overnight. The mixture was washed with water (2×100 ml) and brine (1×100 ml) and the organic layer was dried and evaporated to leave a clear oil which was recrystallised from ethyl acetate/hexane to afford the title compound as a white crystalline solid (15 g, 80%). 1H NMR (360 MHz, CDCl3) δ2.44 (3H, s), 4.55 (2H, s), 7.21 (1H, s), 7.35 (2H, d, J=8.0 Hz), 7.62 (2H, d, J=8.0 Hz 7.98 (1H, s). MS (CI+) m/z 253 (M+H, 100%).
Reaction SMILES: [C:1]1([C:6]2[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C1(C2C=CN([Si](C(C)C)(C(C)C)C(C)C)C=2)CCCC=1.[C:41]([O:50][CH2:51][CH3:52])(=[O:49])/[CH:42]=[CH:43]/[C:44]([O:46][CH2:47][CH3:48])=[O:45].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[CH:12]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[N:7]1[C:6]2[C:10](=[C:42]([C:41]([O:50][CH2:51][CH3:52])=[O:49])[C:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:2]3[CH2:3][CH2:4][CH2:5][C:1]3=2)[CH:9]=[CH:8]1)([CH3:13])[CH3:14]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1C1=CCCC1
Agent: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C2=CCCC2)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CCOC(=O)c1c2c(c3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c1C(=O)OCC)CCC2
Temperature: 150 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A 2:1 mixture of 2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole and 3-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole (1.16 g, 4.01 mmol) and diethyl fumarate (0.75 g, 4.36 mmol) was heated under nitrogen to 150° C. for 64 h, affording the crude Diels-Alder adduct as an amber oil. The pure Diels-Alder adduct could be isolated by chromatography on silica gel (hexanes-ether 90:10). NMR (CDCl3) δ 6.68 (d, 1H), 6.16 (d, 1H), 4.20 (m, 4H), 3.95 (d, 1H), 2.91 (t, 2H), 2.49 (m, 1H), 2.09 (m, 1H), 1.73 (m, 2H), 1.48 (septet, 3H), 1.30 (2t, 6H), 1.27 (d, 9H), 1.07 (d, 9H). MS m/e 462 (M+H)+. DDQ (2.2 g, 9.7 mmol) was added in three portions to a benzene solution (16 mL) of the crude Diels-Alder adduct at 50° C. until no starting material remained (TLC and NMR). After 8 h, the mixture was filtered through Celite®. The precipitate was rinsed with benzene, and the filtrate was evaporated to give 1.52 g of a black solid. This was chromatographed on silica gel (hexanes-ether 15:85 to 20:80) to give the product (380 mg, 21% yield, 35% yield from 2-isomer) as a colorless oil. NMR (CDCl3) δ 7.42 (d, 1H), 7.05 (d, 1H), 4.40 (2q, 4H), 3.20 (t, 2H), 3.12 (t, 2H), 2.17 (quintet, 2H), 1.67 (septet, 3H), 1.39 (t, 3H), 1.36 (t, 3H), 1.20 (d, 18H). MS m/e 458 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[N:4]=[CH:3][CH:2]=1.[NH2:17]/[C:18](/[C:23]#[N:24])=[C:19](\[NH2:22])/[C:20]#[N:21].C(O)C.O>C1C=CC=CC=1>[N:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]1[N:17]=[C:18]([C:23]#[N:24])[C:19]([C:20]#[N:21])=[N:22][C:9]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: O=C(C(=O)c1ccccn1)c1ccccn1
Reactant: N#C/C(N)=C(/N)C#N
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: N#Cc1nc(-c2ccccn2)c(-c2ccccn2)nc1C#N
Yield: 45.7 %

Procedure:
Into a 250 mL round bottomed flask are placed, 2,2'-pyridil (8.48 g, 40 mmol), diaminomaleonitrile (4.32 g, 40 mmol) and 125 mL of ethanol. The flask is fitted with a magnetic stirrer and a condenser, and refluxed for 30 minutes. The mixture is allowed to cool, and 10 mL of water is added. Filtration yielded 8.9 g of crude product as a beige solid. The solid is boiled in benzene (400 mL) and filtered hot. The red filtrate is discarded giving 5.2 g of the title compound as a pale beige solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li]CCCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCOCC>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1cc(Br)ccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2,5-dibromobenzoic acid (27.8 g, 100 mmol, 1.00 equiv) in THF/Et2O (450/50 mL) under nitrogen at −78° C. was added dropwise n-BuLi (2.5M) (88 mL, 2.20 equiv). After 2 h at −78° C., was added 1-benzylpiperidin-4-one (26.5 g, 140 mmol, 1.40 equiv). The resulting solution was stirred for 0.5 h at −78° C. and then warmed to room temperature, and stiffed overnight. The reaction was quenched by carefully adding 200 mL of water. The pH of the mixture was adjusted to 2-3 with hydrogen chloride (aq., 2 M). The aqueous phase was extracted with 3×500 mL of ethyl acetate and 3×500 mL of tetrahydrofuran. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 38.9 g (crude) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:25][CH2:26][CH2:27][CH2:28]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[O:10][CH2:28][CH2:27][CH2:26][CH2:25][N:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[C:5]=12)=[O:23]
Reactant: BrCCCCBr
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cccc2c1N(S(=O)(=O)c1ccc(OC)cc1)CCCCO2
Yield: 29.9 %

Procedure:
In the same manner as described in Example 159, 0.400 g (1.187 mmol) of the product of Example 31 and 0.198 mL (1.662 mmol) of 1,4-dibromobutane provided 0.139 g (30%) of the desired product as a white solid. Electrospray Mass Spec: 392 (M+H).