Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21](=[O:23])[CH3:22])=[C:6]([CH3:20])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18]C)[C:8]=1[CH3:9])(=[O:3])[CH3:2].C([S-])C.[Na+]>CN(C=O)C>[C:1]([C:4]1[C:5]([C:21](=[O:23])[CH3:22])=[C:6]([CH3:20])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[OH:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: COc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OC)c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(O)c1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of 1-[4-acetyl-1-(2,4-dimethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone prepared as in Example 70 (1580 mg, 0.5 mmol) in 2.0 mL of dry DMF at rt was added sodium ethanethiolate (80%, Aldrich; 210 mg, 2.0 mmol). After 20 min at rt, it was heated to 120° C. and stirred for an additional 2 h before it was quenched with 1N HCl (5 mL). It was extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with dried with MgSO4, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. This crude material was purified by automated chromatography on silica gel (using an 20-50% EtOAc/hexanes gradient) to give the major product 1-[4-acetyl-1-(2-hydroxy-4-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as pale yellow oil: MS (ESI) 302 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O[C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC)[CH2:16][CH3:17])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:16]([CH3:17])[C:4]2=[O:6]
Reactant: CCOC(CC)(OCC)c1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1c(-c2ccccc2)[nH]c2ccc(Cl)cc2c1=O
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a mixture of 2-amino-5-chloro-benzoic acid (0.82 g, 4.80 mmol) in Dowtherm A (20 mL), was added the compound of Step A (1.0 g, 4.80 mmol). The mixture was warmed to reflux for 15 hours, then cooled to room temperature. Upon cooling, a white precipitate formed which was collected by filtration. The solid was triturated with diisopropyl ether followed by methylene chloride to give the title compound (0.58 g, 45%), m.p. 296-302° C. Anal. calcd. for C16H12CINO: C, 71.25; H, 4.48; N, 5.19. Found: C, 70.92; H, 4.44; N, 5.04.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=[CH:33][C:34](Cl)=[O:35])[CH:23]=1>C(Cl)Cl>[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=[CH:33][C:34]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:35])[CH:23]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)C=Cc1cnc2ccccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cnc2ccccc2c1)NCCCSc1ccncc1
Yield: 83.8 %

Procedure:
To a solution of 396 mg (1.64 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 0.27 ml (1.97 mmol) of triethylamine in 20 ml of methylene chloride, 500 mg (1.96 mmol) of 3-quinolineacryloyl chloride hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain powder. The powder was washed with ether and dried to obtain the desired compound (480 mg, yield: 83.8%, pale yellow powder).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1C(=O)CCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:9]1[CH:10]=[CH:11][C:4]2[S:3][C:2]([CH:13]=[CH2:14])=[C:6]([CH3:7])[C:5]=2[CH:8]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)sc2ccc(Cl)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: C=Cc1sc2ccc(Cl)cc2c1C

Procedure:
A solution of 2-bromo-5-chloro-3-methylbenzthiophene (5 g, 19.1 mmol), vinyltributylstannane (5.59 mL, 19.1 mmol), Pd2dba3 (525 mg, 0.57 mmol), and tri(2-furyl)phosphine (532 mg, 2.29 mmol) in NMP (70 mL) at 90° C. was stirred for 18 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with hexanes to provide the desired product. MS (ESI(−)) m/e 207 (M−H)−.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:10][C:11]([NH:13][C:14]1[S:18][N:17]=[C:16](/[C:19](=[N:23]/[O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:20](O)=[O:21])[N:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:36][C@@H:37]1[C:62](=[O:63])[N:39]2[C:40]([C:46]([O:48][CH:49]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])=[C:41]([CH2:44][Cl:45])[CH2:42][S:43][C@H:38]12.C[Si](C)(C)NC(=O)C>O1CCCC1.O.C(OCC)(=O)C.CN(C)C=O>[C:6]([O:10][C:11]([NH:13][C:14]1[S:18][N:17]=[C:16](/[C:19](=[N:23]/[O:24][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH3:33])[CH3:34])/[C:20]([NH:36][C@@H:37]2[C:62](=[O:63])[N:39]3[C:40]([C:46]([O:48][CH:49]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[O:47])=[C:41]([CH2:44][Cl:45])[CH2:42][S:43][C@H:38]23)=[O:21])[N:15]=1)=[O:12])([CH3:7])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)ns1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A mixture of N,N-dimethylformamide (0.648 ml) and phosphoryl chloride (0.781 ml) was stirred at room temperature for 30 minutes. To the mixture were added tetrahydrofuran (4 ml) and (Z)-2-{5-[(tert-butoxy carbonyl)amino]-1,2,4-thiadiazol-3-yl}[(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)imino]ethanoic acid (3 g) at 4° C., and the reaction mixture was stirred at room temperature for 1 hour. Meanwhile, a mixture of benzhydryl 7β-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (3 g) and N-trimethylsilylacetamide (8.72 g) in tetrahydrofuran (15 ml) was warmed to make a clear solution. The solution was then cooled to −20° C. and added to the activated acid solution obtained above. The reaction mixture was stirred at a temperature of −10° C. to 0° C. for 1 hour and poured into a mixture of ethyl acetate and water. The aqueous layer was separated, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:2) to give benzhydryl 7β-[(Z)-2-(5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (4.79 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[CH3:34][O:33][C:29]1[CH:28]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:30]=1[O:31][CH3:32])[C:25]([N:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1)=[O:26]
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N2CCC3(CC2)Cc2ccccc2O3)cc(OC)c1OC

Procedure:
A stirred mixture of 5.0 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7, and 15 g of sodium bicarbonate in 75 ml of chloroform is treated with a mixture of 8.8 g of 3,4,5-trimethoxybenzoyl chloride in 125 ml of chloroform according to the procedure of Example 7 to provide a tan solid. The solid is sequentially recrystallized from ethyl alcohol, chromatographed through a silica gel column with a 2% methyl alcohol in chloroform eluant and recrystallized from ethyl alcohol to give the product, 2,3-dihydro-1'-(3,4,5-trimethoxybenzoyl)spiro[benzofuran-2,4'-piperidine], mp 148°-150° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([N:15]2[CH2:19][C@@H:18]([N:20]([C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[CH3:21])[C@H:17]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH2:16]2)=[O:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22](=[O:23])[N:20]([C@H:18]2[C@H:17]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH2:16][N:15]([C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[O:14])[CH2:19]2)[CH3:21])=[CH:26][CH:27]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)C2)C[C@H]1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNC2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 79.6 %

Procedure:
To a solution of 3-{(3R,4S)-3-(4-chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-methyl-amino]-pyrrolidine-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.17 g, 2.14 mmol) in dichloromethane (20 mL) was added at ambient temperature trifluoroacetic acid (1.64 mL, 21.4 mmol) and the reaction mixture was stirred for 3 h. It was treated with an aqueous solution of sodium carbonate (1M, 50 mL) and the organic layer was separated and washed with brine (40 mL). The aqueous layer was extracted with dichloromethane (40 mL) and the combined organic layers were dried over sodium sulfate. Concentration afforded the title compound (760 mg, 79%) as a white semi-solid. MS m/e: 446.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[OH:11])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[C:22]([O:21][C:19](=[O:20])[CH2:18][O:16][C:3]1[C:2]([Cl:1])=[C:14]([Cl:15])[C:6]2[S:7][C:8]([C:10]([OH:11])([CH3:13])[CH3:12])=[CH:9][C:5]=2[CH:4]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)COc1cc2cc(C(C)(C)O)sc2c(Cl)c1Cl

Procedure:
To a mixture of 6,7-dichloro-5-hydroxy-α,α-dimethylbenzo[b]thiophene-2-methanol in 250 ml of 2-butanone is added a solution of 7.7 g of t-butyl bromoacetate in 50 ml 2-butanone and the resultant mixture is placed in a preheated oil-bath at 95°. To the mixture is added 6.7 g of potassium carbonate and 3 ml of dimethylformamide and the reaction mixture is refluxed at 95° for 21/2 hrs. The cooled mixture is filtered and 100 ml of water is added. The layers are separated and the aqueous phase is extracted two times with ethyl ether. The organic extracts are washed, dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. Recrystallization from ethyl ether and pentane gives 11.5 g of t-butyl[ [6,7-dichloro-2-(1-hydroxy-1-methylethyl)benzo[b]thien-5-yl]oxy]acetate, mp 137°-138°.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:42][CH2:43][NH:44][S:45]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[Cl:55])(=[O:47])=[O:46])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:42][CH2:43][NH:44][S:45]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[Cl:55])(=[O:46])=[O:47])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 83 %

Procedure:
Ethyl 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoic acid (light-brown solid) in 83% yield.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[N:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:9][CH:8]=1.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([F:27])=[C:23]([CH:26]=1)[CH:24]=[O:25].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O.O>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([F:27])=[C:23]([CH:24]([C:9]2[CH:8]=[C:7]([Cl:6])[N:12]=[C:11]([F:13])[C:10]=2[O:14][CH2:15][O:16][CH3:17])[OH:25])[CH:26]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COCOc1ccc(Cl)nc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1c(C(O)c2cc(Br)ccc2F)cc(Cl)nc1F
Temperature: -78 °C

Procedure:
DIPA (0.750 mL, 5.35 mmol) was dissolved in dry THF (20 mL) under nitrogen and cooled in a dry ice bath to −78° C. Butyllithium solution (2.5 M in hexanes, 2.0 mL, 5.00 mmol) was added and the solution was stirred for a few minutes. A solution of 6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (0.864 g, 4.51 mmol) in dry THF (10 mL) was added slowly and the resulting solution stirred for 40 minutes. A solution of 5-bromo-2-fluorobenzaldehyde (1.02 g, 5.05 mmol) in dry THF (1 mL) was added dropwise. After 10 minutes saturated ammonium chloride (10 mL), water (100 mL) and EtOAc (100 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to EtOAc gradient) gave the desired (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl)methanol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.[CH3:62][N:63]1[CH2:68][CH2:67][N:66](C2C=CC(C=O)=CC=2)[CH2:65][CH2:64]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:66]4[CH2:67][CH2:68][N:63]([CH3:62])[CH2:64][CH2:65]4)=[CH:22][CH:23]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cc2)CC1
Yield: 88 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-(4-Methyl-piperazin-1-yl)-benzaldehyde were reacted to produce the title compound (88%). 1H NMR (d-chloroform): 15.58 (br s, 1H) 8.36 (d, J=9 Hz, 1H), 8.00 (d, J=9 Hz, 2H), 7.78 (s, 1H), 7.02 (d, J=9 Hz, 2H), 6.48 (m, 1H), 6.41 (m, 1H), 5.99 (s, 1H), 5.61 (s, 1H), 5.35 (t, J=9 Hz, 1H), 3.38-3.93 (m, 8H), 3.17 (s, 1H), 3.04 (m, 1H), 3.02 (s, 1H), 2.91 (s, 3H), 2.69 (d, J=9 Hz, 1H), 2.31 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H). MS: 479.11 (M+H). HPLC retention time: 1.81 minutes (G Method).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[O:32])=[CH:24][C:23]=3[F:43])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[N-:44]=[N+]=[N-].[Na+]>CN(C=O)C>[NH2:44][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[O:32])=[CH:24][C:23]=3[F:43])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCCCl)c4)sc23)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCCN)c4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
To a solution of 366 (0.19 g, 0.31 mmol) in DMF (5 mL) was added sodium azide (0.050 g, 0.77 mmol) and the reaction mixture was heated to 100° C. for 1 h. The mixture was then cooled, partitioned between ethyl acetate and water, the organic phase was collected, washed with water, brine, dried (anhydrous MgSO4), filtered, and concentrated. The residue was filtered through a short plug of silica, eluting with ethyl acetate, and the eluate was concentrated. The residue was dissolved in 1:1 ethyl acetate/methanol (30 mL) mixture; to this solution was added palladium (10% on carbon), and the suspension was stirred under an atmosphere of hydrogen for 3 h. It was then filtered through celite and concentrated. The residue was purified by flash chromatography (eluent 95:3:2 chloroform/methanol/NH4OH) to afford 367 (0.097 g, 52% yield): LRMS (M+H): 601.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH:29]1[CH:34]=[CH:33][C:32]([O:35][C:36](OC2C=CC=CC=2)=[N:37][C:38]#[N:39])=[CH:31][CH:30]=1>CC#N>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:36](=[N:37][C:38]#[N:39])[O:35][C:32]2[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Temperature: 40 °C

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.50 g, 1.26 mmol) and diphenyl cyanocarbonimidate (0.60 g, 2.51 mmol) were combined in MeCN (5 mL) and stirred at 40° C. until no starting material was seen by analytical LCMS. The mixture was concentrated and purified by silica gel chromatography (10-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 38 g of p-hydroxyphenylacetic acid, 39.4 g of 4-nitrochlorobenzene and 69 g of anhydrous potassium carbonate in 275 ml of N,N-dimethylacetamide is heated to 155°-160° C over 2 hours, and maintained at that temperature, under Argon atmosphere for 4 hours with vigorous stirring. On cooling, an orange solid separated. A 1000 g solution of 5% NaHCO3 is added, resulting in a red brown solution. The solution is extracted with 4 × 100 ml of ether. The aqueous layer is acidified by the dropwise addition of 150 ml of concentrated HCl. A light yellow solid precipitates and is filtered and washed with 1500 ml of H2O to give the product, mp 132°-136° C. A sample is recrystallized from 19:1 methanol-water, to give the product, mp 135°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH:14]([CH3:19])[CH2:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[CH:14]([CH3:19])[CH2:13][N:12]([CH3:11])[CH2:17][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CC1CN(C)CCC1=O
Product: CC1CN(C)CC=C1c1c[nH]c2cc(Cl)ccc12
Yield: 62.9 %

Procedure:
Beginning with 0.97 gm (6.4 mMol) 6-chloro-1H-indole and 1.6 gm (13.0 mMol) 1,3-dimethyl-4-piperidone, 1.05 gm (63%) of the title compound were recovered as a crystalline solid.
Reaction SMILES: O[C@H]1CCCC[C@@H]1N1C[C:15]2[C:14]3C=CC=C[C:13]=3[C:12](CC3C=NC(SC)=CC=3)=[CH:11][C:10]=2[C:9]1=[O:30].BrC1C2C=CC=CC=2C2CN([C@H]3CCCC[C@@H]3O)C(=O)C=2C=1.CS[C:55]1[CH:64]=[CH:63][C:58]([C:59]([O:61][CH3:62])=[O:60])=[CH:57][N:56]=1>>[CH2:9]([O:30][C:55]1[N:56]=[CH:57][C:58]([C:59]([O:61][CH3:62])=[O:60])=[CH:63][CH:64]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(SC)nc1
Reactant: CSc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Agent: O=C1c2cc(Br)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Product: COC(=O)c1ccc(OCc2ccccc2)nc1

Procedure:
The title compound was prepared employing the procedures described for the construction of 2-[(1S,2S)-2-hydroxycyclohexyl]-5-{[6-(methylthio)pyridine-3-yl]methyl}-1,2-dihydro-3H-benzo[e]isoindol-3-one in Example 10, substituting 5-bromo-8-[(1S,2S)-2-hydroxycyclohexyl]-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one for 5-bromo-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one, and substituting methyl 6-(benzyloxy)pyridine-3-carboxylate for methyl 6-(methylthio)nicotinate. The resultant white solid gave a proton NMR spectra consistent with theory: 1H NMR (400 MHz, CDCl3) δ 9.00-8.98 (m, 1H), 8.43-8.41 (m, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.54-7.51 (m, 1H), 7.45-7.42 (m, 2H), 7.38-7.28 (m, 4H), 6.70 (d, J=8.5 Hz, 1H), 5.33 (s, 2H), 5.30-4.87 (m, 2H), 4.38 (s, 2H), 4.23-4.17 (m, 1H), 3.79-3.73 (m, 1H), 2.22-2.19 (m, 1H), 2.01-1.98 (m, 1H), 1.86-1.83 (m, 2H), 1.73-1.63 (m, 1H), 1.54-1.31 (m, 3H) ppm.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1>CS(C)=O>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][O:10][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCCc2ccc(Cl)cc2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of NaH (0.77 g) and DMSO is slowly added 4-chlorophenethyl alcohol (5 g) in DMSO (20 ml) while maintaining the temperature at or below 32°. After gas evolution stops, 2-chloro-5-nitropyridine (4 g) is added in small portions while maintaining temperature below 25°. After stirring about 1 hour, the reaction is poured onto about 300 g ice and then filtered. The solid is dissolved in ether, washed with water, dried (sodium sulfate) and solvent evaporated to give 2-(4-chlorophenethoxy)-5-nitropyridine, a grey solid.