Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:13]([O:15]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:14]>C1(C)C=CC=CC=1.[Pd].CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:13]([C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:15])[CH3:14]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=Cc1cc(Br)cc2ccoc12
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C=O)c2occc2c1
Reaction time: 6 h
Yield: 72.4 %

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (2.00 g), 1-ethoxy-1-tributylstannanylethene (3.53 g)and bis(triphenylphosphine)palladium (II) chloride (63 mg) in dry toluene (4 ml) was heated at reflux under nitrogen for 18 h. A further portion of palladium catalyst (63 mg) was added and heating at reflux continued for a further 6 h. The reaction was allowed to cool, diluted with ether (40 ml) and filtered through a plug of Hyflo. The filtrate was washed successively with hydrochloric acid (50 ml; 2M) and brine (50 ml), then dried, and concentrated in vacuo to give an orange oil. Purification by FCC eluted with hexane to hexane:ethyl acetate (4:1) gave the title compound as a yellow powder (1.21 g), m.p. 91-93°.
Reaction SMILES: [CH2:1]([N:3]1[CH2:22][CH2:21][C:5]2([CH2:9][N:8]([C:10]3[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH2:19])=[C:12]([CH3:20])[CH:11]=3)[CH2:7][CH2:6]2)[CH2:4]1)[CH3:2].C(O)(=O)C.[Cl:27][C:28]1[C:33]([CH:34]=O)=[C:32]([I:36])[CH:31]=[CH:30][N:29]=1>CO.[Pd]>[Cl:27][C:28]1[C:33]([C:34]2[NH:16][C:14]3[CH:15]=[C:10]([N:8]4[CH2:7][CH2:6][C:5]5([CH2:21][CH2:22][N:3]([CH2:1][CH3:2])[CH2:4]5)[CH2:9]4)[CH:11]=[C:12]([CH3:20])[C:13]=3[N:19]=2)=[C:32]([I:36])[CH:31]=[CH:30][N:29]=1
Reactant: O=Cc1c(I)ccnc1Cl
Reactant: CCN1CCC2(CCN(c3cc(C)c(N)c([N+](=O)[O-])c3)C2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCC2(CCN(c3cc(C)c4nc(-c5c(I)ccnc5Cl)[nH]c4c3)C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a solution of 4-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-2-methyl-6-nitro-phenylamine (304 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and then filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (5:1, CH2Cl2/MeOH) to afford the title compound (450 mg, 86%). 1H NMR (MeOH-d4) δ 1.38 (t, J=8 Hz, 3H), 2.10-2.21 (4H), 2.56 (s, 3H), 3.28-3.57 (10H), 6.55 (s, 1H), 6.57 (s, 1H), 8.03 (d, J=6 Hz, 1H), 8.13 (d, J=6 Hz, 1H). ESI-MS m/z 522 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)c1
Yield: 27 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (108 mg, 0.197 mmol) was deprotected in TFA/toluene (5/5 ml). This afforded 30 mg (27% yield) of the titled. 1H NMR (CD3OD, 300 MHz): δ 8.627-8.622 (d, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.75-7.71 (m, 3H), 7.44-7.42 (d, 2H), 7.25-7.20 (t, 1H), 7.13-7.07 (m, 3H), 5.37 (s, 2H), 3.55-3.51 (d, 2H), 3.21-3.13 (m, 2H), 3.03-2.94 (m, 1H), 2.31 (s, 3H), 2.14-2.10 (d, 2H), 2.03-1.89 (qd, 2H). MS: m/z=448.4 (M+1), HPLC: 98.27% in method A.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C@@H:6]1[CH2:10][NH:9][C@@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH3:14]O>>[CH3:14][O:12][C:11]([C@H:8]1[CH2:7][C@H:6]([OH:5])[CH2:10][NH:9]1)=[O:13]
Reactant: CO
Reactant: O=C(O)[C@H]1C[C@H](O)CN1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Add thionyl chloride (5.8 mL, 79.4 mmol) to an ice-cold suspension of 4-(S)-hydroxypyrrolidine-2-(R)-carboxylic acid (4.97 g, 31.9 mmol) in methanol (70 mL). Stir 10 min, then warm to room temperature and stir 3.5 h. Concentrate, add methanol and concentrate again to give the title compound as a white solid (7.18 g, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].C[N:17]1[C:22]([SH:23])=[C:21]([C:24]#[N:25])[C:20]([CH3:26])=[CH:19][CH2:18]1.[C:27](O)(=O)C>>[CH3:26][C:20]1[CH:19]=[C:18]([CH3:27])[N:17]=[C:22]([S:23][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:12]([Cl:15])([Cl:14])[Cl:13])[C:21]=1[C:24]#[N:25]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: CC1=CCN(C)C(S)=C1C#N
Reactant: CC(=O)O
Product: Cc1cc(C)c(C#N)c(SSc2ccc([N+](=O)[O-])cc2C(Cl)(Cl)Cl)n1
Reaction time: 2 h
Yield: 67 %

Procedure:
61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride, dissolved in 500 ml of glacial acetic acid, are reacted with 33 g of 1,4-dimethyl-5-cyano-6-mercaptopyridine at 20° C. After 2 hours, the solution is filtered, 500 ml of water are added and the precipitate formed is filtered off, washed with 10% strength sodium carbonate solution and with ether, and dried over potassium hydroxide. 58 g (67% of theory) of 4,6-dimethyl-3-cyano-pyridin-2-yl-dithio-(4-nitro-2-trichloromethylbenzene), of melting point 132° C., are obtained.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:15][NH:16][C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([O:32]CCC)=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3>>[CH3:15][N:16]([C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C@H:17]1[CH2:36][N:21]2[C:22]3[C:27]([C:28]([CH2:29][C:30]([OH:32])=[O:31])=[C:20]2[CH2:19][CH2:18]1)=[CH:26][CH:25]=[CH:24][CH:23]=3
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1cccc2ccccc12
Product: CN(C(=O)Cc1cccc2ccccc12)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-naphthylacetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 427
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([B:12]([OH:14])[OH:13])=[CH:6][C:5]=1[O:15][CH3:16])[CH3:2].[CH2:17]([O:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([I:28])=[CH:22][C:21]=1[O:29][CH3:30])[CH3:18]>>[CH3:17][O:19][CH2:2][CH2:1][O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([B:12]([OH:13])[OH:14])=[CH:6][C:5]=1[O:15][CH3:16].[I:28][C:23]1[CH:22]=[C:21]([O:29][CH3:30])[C:20]([O:19][CH2:17][CH2:18][O:3][CH3:1])=[C:25]([O:26][CH3:27])[CH:24]=1
Reactant: CCOc1c(OC)cc(I)cc1OC
Reactant: CCOc1c(OC)cc(B(O)O)cc1OC
Product: COCCOc1c(OC)cc(B(O)O)cc1OC
Product: COCCOc1c(OC)cc(I)cc1OC

Procedure:
Applying the synthetic procedure of 4-ethoxy-3,5-dimethoxyphenylboronic acid from 4-ethoxy-1-iodo-3,5-dimethoxybenzene in Reference Example 3, the title compound was obtained as a colorless amorphous powder (276.0 mg, yield: 54%) from 1-iodo-3,5-dimethoxy-4-(2-methoxyethoxy)benzene (673.0 mg, 2.00 mmol).
Reaction SMILES: CN(C=O)C.[NH2:6][CH:7]([CH3:20])[CH2:8][C:9]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=1)[CH:25]([OH:29])[C:26](O)=[O:27].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH2:8][CH:7]([NH:6][C:26](=[O:27])[CH:25]([C:24]1[CH:30]=[CH:31][CH:32]=[C:22]([Cl:21])[CH:23]=1)[OH:29])[CH3:20]
Reactant: COc1cccc2c(CC(C)N)c[nH]c12
Reactant: O=C(O)C(O)c1cccc(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc2c(CC(C)NC(=O)C(O)c3cccc(Cl)c3)c[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
To a DMF solution (80 ml) containing 3-(2-aminopropyl)-7-methoxyindole (12.24 g) and 3-chloromandelic acid (7.46 g) is added benzotriazole-N-oxytris(dimethylamino)phosphonium hexafluorophosphate (17.68 g), and then thereto is added dropwise triethylamine (9.8 ml). The mixture is stirred at room temperature for five hours, and to the reaction mixture is added ethyl acetate. The mixture is washed successively with water, 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is evaporated to remove the solvent under reduced pressure, and the residue is purified by silica gel column chromatography (eluent; ethyl acetate/n-hexane=1:1→2:1) to give N-[3-(7-methoxyindol-3-yl)-2-propyl]-3-chloromandelamide (14.02 g) as an oily product.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH2:28]([N:30]([CH2:34][CH3:35])[C:31](Cl)=[O:32])[CH3:29]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:31]([N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[O:32])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 18 h
Yield: 31.5 %

Procedure:
To 1 ml of pyridine were added 0.2 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.18 g of N,N-diethylcarbamoyl chloride was added at room temperature. After stirring for 18 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.09 g of 3-(4-trifluoromethylpyridin-2-yl)-N,N-diethyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (16)).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].N1C=CN=C1.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].CCOCC>CN(C)C=O.CCCCCC>[Si:16]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)CCO
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(O)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
In N,N-dimethylformamide (30 ml) was dissolved 1,3-butanediol (3.00 g, 33.3 mmol), followed by the dropwise addition of an N,N-dimethylformamide solution (30 ml) of imidazole (2.72 g, 40.0 mmol) and t-butylchlorodimethylsilane (5.29 g, 35.0 mmol). After stirring at room temperature for 24 hours, ether was added to the reaction mixture and the white solid thus precipitated was filtered off. The resulting ether solution was washed with water and brine, dried over magnesium sulfate and then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=5:1 eluate was concentrated, whereby the title compound (5.43 g, 26.6 mmol, 80%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][S:36]([NH:39][C:40]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[CH:42][C:41]=1[C:55]1[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][CH:56]=1)(=[O:38])=[O:37].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:13]1[CH:14]=[CH:15][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:44]4[CH:43]=[CH:42][C:41]([C:55]5[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][CH:56]=5)=[C:40]([NH:39][S:36]([CH3:35])(=[O:37])=[O:38])[CH:45]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:26])=[O:27])[CH:9]=2)=[N:12]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2NS(C)(=O)=O)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 83.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 63B) (200 mg, 0.368 mmol) was coupled with tert-butyl 4-(2-(methylsulfonamido)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 65E) (210 mg, 0.44 mmol) using Pd(PPh3)2Cl2 (13 mg, 0.018 mol) and sodium carbonate (117 mg, 11 mmol) in DME/water (10/1 mL) to afford 250 mg (83.3% yield) of the titled compound. MS: m/z=814.7 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.[CH3:22]NC.C=O.Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[C:17](=[CH2:22])[CH2:18][CH3:19]
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Product: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl

Procedure:
A mixture of 8.9 g. (0.03 mole) of 1-[2-chloro-4-(2-diethylaminoethoxy)phenyl]-1-butanone, 2.7 g. (0.033 mole) of dimethylamine hydrochloride, 1.8 g. (0.06 mole) of paraformaldehyde and 5 ml. of concentrated hydrochloric acid is heated on the steam bath for 2 hours. The mixture is digested on the steam bath with 700 ml. of water, filtered and the filtrate added to 350 ml. of 10% aqueous sodium bicarbonate. The solution is heated on the steam bath for 1 hr., cooled and extracted with ether. The ether extract is washed with water, dried over sodium sulfate, filtered and evaporated to dryness on the steam bath. The product is obtained upon distillation in vacuo (0.3 mm.) as a pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:18]=[C:19]([N:20]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])[C:12]2=[N:11][C:10]=1[C:33]1[NH:34][C:35]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([Cl:46])[CH:40]=2)=[CH:36][N:37]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl-:46].[Cl:46][C:41]1[CH:40]=[C:39]([CH:44]=[CH:43][C:42]=1[F:45])[CH2:38][C:35]1[NH:34][C:33]([C:10]2[N:11]=[C:12]3[C:19]([N:20]4[CH2:24][CH2:23][N:22]([CH3:25])[C:21]4=[O:26])=[CH:18][C:17]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[OH:8])=[NH+:37][CH:36]=1
Reactant: CN1CCN(c2cc(N3CCOCC3)cn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)c(Cl)c5)[nH]4)nc23)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cc(N3CCOCC3)cn3c(=O)c(O)c(-c4[nH]c(Cc5ccc(F)c(Cl)c5)c[nH+]4)nc23)C1=O
Product: [Cl-]
Yield: 112.9 %

Procedure:
The solution of the product of Example 76 (80 mg, 0.12 mmol) in trifluoroacetic acid (2 ml) was refluxed for 3 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 ml) and then a drop of HCl solution (37%) was added. The precipitates were collected by filtration and washed with ethyl acetate to give the title compound (40 mg, 56%).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Br[C:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][N:32]=1.IC1C=CC=CC=1>>[N+:37]([C:36]1[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])=[N:32][CH:33]=[CH:34][CH:35]=1)([O-:39])=[O:38]
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: O=[N+]([O-])c1cccnc1Br
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ncccc3[N+](=O)[O-])c(=O)c2)cc1

Procedure:
4-[3-(3'-Nitro-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-bromo-3-nitropyridine for the iodobenzene in Step 3.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][C:16]#[N:17]>CO>[ClH:7].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][C:16]([NH:2][OH:3])=[NH:17]
Reactant: N#CNc1c(Cl)cccc1Cl
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(NO)Nc1c(Cl)cccc1Cl
Reaction time: 3 h

Procedure:
A solution of 34.7 g (0.5 mol) of hydroxylamine hydrochloride in methanol and a solution of 27 g (0.5 mol) of sodium methylate in methanol is mixed whilst cooling by means of an ice bath. The NaCl is filtered off and the filtered solution is introduced into a 2,000 ml Erlenmeyer flask with magnetic stirring and cooling by means of an ice bath. A solution of 39.6 g (0.21 mol) of 2,6-dichlorophenyl-cyanamide in CH3OH is run into the preceding solution and the mixture is stirred at ambient temperature (15°-25° C.) overnight. A small amount of insoluble matter is filtered off. To the methanol solution is added twice its volume of distilled water. An insoluble material is filtered off and discarded. The filtrate is placed in a freezer for 3 hours and an insoluble material is filtered off and discarded. The filtrate is evaporated to dryness. The residue is taken up in 1,000 ml of water and the medium is rendered acid with concentrated HCl. An insoluble material is filtered off and discarded. The liquid phase is washed with ether and the pH is brought to 8 with NaOH, taking care not to exceed this value. The mixture is extracted with ether. The ether is dried over MgSO4 and the hydrochloride of the product is precipitated from the ether by bubbling-in HCl gas.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN1C(=O)N(C)CCC1.I[C:38]1[C:51](I)=[CH:50][C:49]2[C:40](=[C:41]([CH2:56][CH2:57][CH3:58])[C:42]3[C:47]([C:48]=2[CH2:53][CH2:54][CH3:55])=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=1>C1COCC1.Cl[Cu]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:44]3[C:45](=[CH:46][C:47]4[C:42]([CH:43]=3)=[C:41]([CH2:56][CH2:57][CH3:58])[C:40]3[C:49](=[CH:50][CH:51]=[CH:38][CH:39]=3)[C:48]=4[CH2:53][CH2:54][CH3:55])[C:15]([C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[C:14]3[C:9]=2[CH2:10][CH2:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: CCCc1c2ccccc2c(CCC)c2cc(I)c(I)cc12
Reactant: Brc1ccc(C#CCCCCC#Cc2ccc(Br)cc2)cc1
Agent: Cl[Cu]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCCc1c2ccccc2c(CCC)c2cc3c(-c4ccc(Br)cc4)c4c(c(-c5ccc(Br)cc5)c3cc12)CCCC4
Temperature: 50 °C
Yield: 57 %

Procedure:
1,8-Bis(p-bromophenyl)-1,7-octadiyne (0.191 g, 0.459 mmol) was added at −78° C. to a THF solution of bis(η5-cyclopentadienyl)dibutylzirconium in THF, which was prepared from bis(η5-cyclopentadienyl)dichlorozirconium (0.161 g, 0.551 mmol) and n-butyl lithium (0.7 ml, 1.6 M, 1.1 mol/l). The mixture was then allowed to stand at room temperature for an hour. CuCl (0.095 g, 0.964 mmol), DMPU (0.17 ml, 1.38 mmol) and 2,3-diiodo-9,10-dipropylanthracene (0.236 g, 0.459 mmol) were added to the mixture. After heating at 50° C. for an hour, the solvent in the mixture was removed in vacuum. Column chromatography (chloroform) was performed. By recrystallization in chloroform/methanol, the title compound (0.177 g) was obtained as orange red. The isolation yield was 57%.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:5]=2[CH:6]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1.CCOCC.[NH4+].[Cl-]>CCOC(C)=O.O1CCCC1>[Br:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)([OH:11])[C:5]=2[CH:6]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C1CCCc2sc(Br)cc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC1(c2ccc(Cl)cc2)CCCc2sc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In a 250 mL round bottomed flask was placed 2-bromo-6,7-dihydro-1-benzothiophen-4(5H)-one (1.9 g, 8.2 mmol) and tetrahydrofuran (30 mL). To the solution was added 4-chlorophenylmagnesium bromide in ether (1 M, 8.2 mL, 8.2 mmol) and the mixture was stirred for 30 min at rt. To the mixture were added 10% NH4Cl aq (50 mL) and EtOAc (50 mL). The mixture was vigorously stirred for 10 min and then the aqueous phase was discarded. The organic phase was dried over anhydrous MgSO4 and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified pre-packed silica gel (40 g) column chromatography eluted with 0% to 50% EtOAc/hexane to yield the title compound (2.4 g; 85%) as a colorless syrup. 1H NMR (300 MHz, d-chloroform) δ ppm 7.26-7.29 (m, 4H), 6.56 (s, 1H), 2.68-2.86 (m, 2H), 1.81-2.17 (m, 5H).
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1)([O-:23])=[O:22].Cl>CN(C)C1C=CN=CC=1.ClCCl>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:32])=[CH:28][CH:29]=1)([O-:23])=[O:22]
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-nitrophenyl isocyanate (0.33 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 24 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield an orange oil, which was crystallized from 95% ethanol to yield the title compound as an off-white solid (0.20 g, 30% yield), mp=168–170° C.; MS (−) ESI m/z=343 (M−H)−; [α]D25=+29.4° (c=1, DMSO).