Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>COC(C)(C)C.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (1) (50.50 g, 195.6 mmol) in t-butyl methyl ether (750 ml), lithium hydroxide monohydrate (7.94 g, 189 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate (2) (52.00 g, 130.5 mmol) in t-butyl methyl ether (150 ml) and water (27 ml) were added thereto, and the mixture was heat refluxed for approximately 49 hours (internal temperature: approximately 53° C.). After cooling to room temperature, water (300 ml) was added and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (200 ml). The organic layers were combined, washed twice with saturated aqueous sodium chloride (300 ml), and dried with anhydrous magnesium sulfate (50 g). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 1805 g; ethyl acetate:hexane=1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 580 g; ethyl acetate:hexane=1:4), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (62.38 g; 117.6 mmol; yield: 90.1%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(#N)C>[CH2:16]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCBr
Reactant: Nc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.6 %

Procedure:
In 100 ml of acetonitrile was dissolved 5.90 g of 4-aminothiophenol. To the solution were added 6.57 ml of triethylamine and 8.44 g of n-heptylbromide, followed by stirring at room temperature for 18 hours. The precipitated crystals were collected by filtration, followed by removing the solvent. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N sodium hydroxide aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous potassium carbonate. After removing the solvent, the residue was purified by silica gel column chromatography using 50 g of silica gel and using chloroform as eluent to obtain 6.06 g of the titled compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:23][CH3:24]
Reactant: BrCCBr
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCBr
Temperature: 85 °C
Yield: 63 %

Procedure:
1,2-Dibromoethane (1.6 ml, 18.6 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (0.5 g, 1.86 mmol), (prepared as described for the starting material in Example 16), and potassium carbonate (1.2 g, 8.7 mmol) in DMF (60 ml) and the mixture was heated at 85° C. for 2 hours, and was then allowed to cool. The insolubles were removed by filtration, and the volatiles were removed from the filtrate by evaporation to give a residue which was purified by column chromatography eluting with methylene chloride/methanol (97/3) to give 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (440 mg, 63%).
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[OH:11])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:12]1[C:17](=[O:18])[N:16]([O:19][C:20](ON2C(=O)CCC2=O)=[O:21])[C:14](=[O:15])[CH2:13]1.CCN(CC)CC>CC#N>[CH2:1]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[O:11][C:20]([O:19][N:16]1[C:17](=[O:18])[CH2:12][CH2:13][C:14]1=[O:15])=[O:21])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: C=CCCC[C@@H]1CCC[C@H]1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCCC[C@@H]1CCC[C@H]1OC(=O)ON1C(=O)CCC1=O
Reaction time: 20 h

Procedure:
To a solution of (1R,2R)-2-pent-4-en-1-ylcyclopentanol (105 mg, 0.68 mmol) in MeCN (1.4 mL) was added N,N′-disuccinimidyl carbonate (174 mg, 0.68 mmol) and Et3N (0.19 mL, 1.36 mmol) and the mixture was stirred at 40 C for 20 hours. The reaction mixture was cooled, concentrated and purified by silica chromatography (gradient elution 0 to 100% EtOAc in hexane). LCMS (M+Na)+=318.1.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl.C(N(CC)CC)C.[O:30]=[C:31]1[N:35]([S:36](Cl)(=[O:38])=[O:37])[CH2:34][CH2:33][O:32]1.Cl>ClCCl>[C:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][S:36]([N:35]1[CH2:34][CH2:33][O:32][C:31]1=[O:30])(=[O:38])=[O:37])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C1OCCN1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCC[C@H](NS(=O)(=O)N1CCOC1=O)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A suspension of 5.39 g of H-Lys(Boc)-OtBu hydrochloride (15.9 mmol, 1.0 eq) and 7.1 ml of triethylamine (50.9 mmol, 3.2 eq) in dichloromethane (70 ml) was added to the solution obtained in Example 143d), in such a way that the temperatures did not exceed 10° C. After the addition was complete, the mixture was allowed to reach RT and was stirred for a further 2 h. The reaction mixture was then mixed with 200 ml of 0.2 M hydrochloride acid, and the organic phase was separated off and washed with 100 ml of 0.2 M hydrochloric acid and concentrated. 5.5 g of the desired material were obtained as a colorless oil, which crystallized on standing.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)=[N:26][OH:27])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(CC(c1ccccc1)c1ccc(Br)cc1)c1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: ON=C(CC(c1ccccc1)c1ccc(Br)cc1)c1ccnc(Cl)c1

Procedure:
In analogy to example 1, step 2, from 3-(4-bromo-phenyl)-1-(2-chloro-pyridin-4-yl)-3-phenyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.6:1) as a colorless oil, MS (ESI−): m/z=413.0 ([M−H]−, 1Br,1Cl).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:38])([F:37])[C:11]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[CH2:34]([N:33]([CH2:32][C:11]([CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)([OH:31])[C:10]([F:9])([F:37])[F:38])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:35][CH3:36]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1cccs1
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.CN(C)C=O.Cl[CH2:28][C:29]#[N:30]>C(N(CC)CC)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:28][C:29]#[N:30])[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CC#N)C[C@H]1OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a stirred solution of 12.55 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide in 180 parts of N,N-dimethylformamide were added 5.05 parts of N,N-diethylethanamine and 3.4 parts of 2-chloroacetonitrile. The whole was stirred for 18 hours at 50° C. The solvent was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was triturated in 1,1'-oxybisethane. The product was filtered off and dried, yielding 12.21 parts (86.5%) of cis-4-amino-5-chloro-N-[1-(cyanomethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 130.4° C. (interm. 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 101 mg of 4-methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.75 (s, 3H), 6.76 (m, 2H, 7.45 (m, 2H), 7.63 (m, 2H), 7.71 (d, 1H, J=8.8 Hz), 7.78 (m, 1H), 7.88 (m, 2H), 8.64 (m, 1H), 10.24 (s, 1H). MS: m/z 403.9 (M++1).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)=[O:8])=[CH:5][N:6]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:22][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:21])[C:11]([CH2:10][NH:9][C:7]([C:4]3[S:3][C:2]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:6][CH:5]=3)=[O:8])=[CH:12][N:13]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(Br)s1
Reactant: C1COCCN1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnc(N2CCOCC2)s1

Procedure:
2-Morpholin-4-yl-thiazole-5-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate F and morpholine. MS calcd. for C24H21ClN4O3S [(M+H)+] 481.1, obsd. 481.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Cl.ClCC1C=C(C=CC=1)O[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1O
Temperature: 50 °C

Procedure:
2′,4′-Dihydroxy-acetophenone (912 mg, 6 mmol) and 2-chloromethyl-quinoline hydrochloride (856 mg, 4.0 mmol, example 49) are dissolved in acetonitrile (20 mL). K2CO3 (1.12 g, 8.0 mmol) is added and the contents are heated to 50° C. for 16 hrs. The reaction is cooled to room temperature, and the solvent is removed by rotary evaporation. The contents are partitioned between ethyl acetate (100 mL) and water (100 mL), the aqueous layer is acidified with 2 N HCl to ˜pH 2 and further extracted with ethyl acetate (2×50 mL). All organic fractions are combined and washed with brine (3×150 mL), dried over MgSO4 and concentrated. The crude material is preadsorbed onto silica gel and purified by flash chromatography (silica, 15% ethyl acetate in hexanes) to give the title compound; MS (ion spray) 294 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:13][NH:14][C:15](=N)[CH:16]([CH3:18])[CH3:17]>>[CH:16]([C:15]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[O:13][N:14]=1)([CH3:18])[CH3:17]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC2(CC1)OCCO2
Product: CC(C)c1noc(N2CCC3(CC2)OCCO3)n1

Procedure:
The title compound is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile and N-hydroxy-isobutyramidine following a procedure analogous to that described in Intermediate 2. LC (method 17): tR=1.56 min; Mass spectrum (ESI+): m/z=254 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:10](=[CH:11][CH2:12][C@@H:13]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:23])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:9]1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].N1C=CN=C1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:33]([O:22][CH2:21][CH2:20][CH2:19][C@H:18]([C@@H:17]1[C@:24]2([CH3:32])[C@H:14]([C@H:13]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:31])[C:10]([CH2:9][C@@H:8]([O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[CH2:30][CH2:29]2)=[CH:11][CH2:12]3)[CH2:15][CH2:16]1)[CH3:23])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Compound 2002 (7.6 g, 17 mmol) in dry CH2Cl2 (300 ml) was treated with a solution of t-butyldimethylsilylchloride (TBDMSCl, 1.0M) and imidazole (0.5M) in dry CH2Cl2 (38.0 ml, 38.0 mmol TBDMSCl). The solution was stirred at room temperature under argon overnight. The resultant solution was poured into an aqueous saturated NaHCO3 solution and the mixture extracted with CH2Cl2 (3×). The combined organic layers were washed with saturated sodium chloride, dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. The resultant solid was purified by flash chromatography (SiO2, hexanes:EtOAc gradient from 20:1 to 5:1) giving compound 2003 (9.4 g, 17 mmol, 98%). 1H NMR (500 MHz, CDCl3) δ: 5.38-5.32 (m, 1H, C-6 H), 4.72 (brs, 1H, THP methine H), 3.95-3.88 (m, 1H, THP CH2O), 3.60-3.46 (m, 4H THP CH2O & C-3 H & C-24 H), 1.01 (S, 3H, C-19 H), 0.93 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.67 (s, 3H, C-18 H), 0.05 (s, 6H, TBDMS CH3); IR (CHCl3) 2900 cm-1 ; MS (CI/isobutane) m/z 559 (M-1, 1%), 474 (M+1-THP, 12%), 457 (M+1-THPOH, 18%), 343 (M+1-THP-TBDMSOH, 6%), 325 (M+1-THPOH-TBDMSOH, 100%); m.p. 116°-118° C.; Anal. calcd. for C35H62O3Si: C=75.21, H=11.18; Found: C=75.37, H=11.24.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][CH3:24])[C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:31][CH2:32][CH2:33]CCC>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:23][CH3:24])[C:16]2[C:21]([NH:22][CH:32]([CH3:33])[CH3:31])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC
Reactant: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1N
Solvent: CCOC(C)=O
Product: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1NC(C)C

Procedure:
Following the general procedure of EXAMPLE 201 and making non-critical variations, but using 1-benzyll-4-[N-ethyl-N-(3-amino-2-pyridinyl)amino]methylpiperidine (EXAMPLE 177, 8.78 g, 27.06 mmol), and chromatographing the crude product (silica gel; ethyl acetate/hexane (50/50)) gives the title compound, NMR (300 MHz, CD3OD) 7.52, 7.21, 6.93, 3.56, 3.42, 2.90, 2.81, 1.86, 1.64, 1.33, 1.22, 1.+w and 0.95δ.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([NH:6][C:7](OC1C=CC([N+]([O-])=O)=CC=1)=[O:8])[CH3:5].Cl.[C:22]1([C@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]([CH3:19])([NH:6][C:7]([N:30]1[CH2:31][CH2:32][C@H:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:29]1)=[O:8])[CH3:5]
Reactant: c1ccc([C@H]2CCNC2)cc1
Reactant: COC(=O)C(C)(C)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)NC(=O)N1CC[C@H](c2ccccc2)C1

Procedure:
Combine 2-methyl-2-(4-nitro-phenoxycarbonylamino)-propionic acid methyl ester (500 mg, 1.77 mmol) and (R)-3-phenyl-pyrrolidine hydrochloride (325 mg, 1.77 mmol) in 1,4-dioxane (5 mL). Add TEA (494 uL, 3.54 mmol) and heat to 130° C. for 5 min by microwave irradiation. Dilute the reaction mixture with DCM (100 mL) and extract with 1 N NaOH (30 mL) followed by 1 N HCl (30 mL). Dry the organic layer over MgSO4 and concentrate. Purify the concentrate by silica gel chromatography (40-60% EtOAc/HEP) to afford the title compound: 1H NMR (400 MHz, DICHLOROMETHANE-d2) 1.51 (d, J=1.77 Hz, 6H) 1.98-2.14 (m, 1H) 2.22-2.38 (m, 1H) 3.31 (t, J=9.28 Hz, 1H) 3.35-3.48 (m, 2H) 3.53-3.65 (m, 1H) 3.70 (s, 3H) 3.80 (dd, J=9.41, 7.52 Hz, 1H) 7.15-7.40 (m, 5H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH:21](Br)[CH2:22][CH3:23])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13].[SH:26][C:27]1[N:28]=[N:29]C=[CH:31][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(OCC)(=O)C.CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[CH:21]([S:26][C:27]2[NH:28][N:29]=[CH:31][N:32]=2)[CH2:22][CH3:23])=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: Sc1nccnn1
Reactant: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(Sc1ncn[nH]1)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-Benzothien-2-yl)-5-[(2-bromobutanoyl)amino]benzamide (Example 9A; 50 mg) is introduced into DMF (1 ml) and, after addition of 3-mercapto-1,2,4-triazine (15 mg) and cesium carbonate (78 mg), stirred at RT overnight. The reaction mixture is mixed with ethyl acetate (50 ml) and 0.5N hydrochloric acid (50 ml), the aqueous phase is extracted with ethyl acetate (twice 50 ml), and the combined organic phases are washed with saturated sodium chloride solution (twice 100 ml). The organic phase is dried over magnesium sulfate and concentrated in a rotary evaporator. The residue is purified on a preparative HPLC. 14 mg (26% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CC1C=CC(C2[O:21]C=CN=2)=CC=1>>[O:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH:1]=[O:21])=[CH:7][CH:6]=2)=[N:9][CH:10]=[N:11]1
Reactant: Cc1ccc(-c2ncno2)cc1
Reactant: Cc1ccc(-c2ncco2)cc1
Product: O=Cc1ccc(-c2ncno2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Step B of Reference Example 73 by substituting the 5-(4-methylphenyl)-1,2,4-oxadiazole from Step A above for the 2-(4-methylphenyl)oxazole of Step B of Reference Example 73. MS 175 (M+H)+.
Reaction SMILES: CO[C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8])=O.[CH3:64]OC(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:3][N:5]([CH3:64])[CH:6]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52](=[O:55])[O:53][CH3:54])[CH:48]([CH3:50])[CH3:49])=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:57]=2)=[CH:17][N:18]=1)=[O:8]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]3)cc2CO4)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c4c(ccc3c2)-c2ccc(-c3cnc([C@@H]5CCCN5C(=O)C(c5ccccc5)N(C)C)[nH]3)cc2CO4)[nH]1)C(C)C

Procedure:
This compound was made in an analogous manner to methyl (S)-1-((S)-2-(5-(8-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (R)-2-(methoxycarbonylamino)-2-phenylacetic acid in the second amide coupling. LCMS-ESI+: calculated for C48H52N8O5: 820.41; observed [M+1]+: 821.25.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:36])[NH:15][C:16](=[O:35])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=5)[CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:35])[NH:15][C:14]2=[O:36])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COc1ccc(-c2ccc3[nH]cc(C4=C(c5cn6c7c(cccc57)CCC6)C(=O)NC4=O)c3c2)cc1
Solvent: CO
Product: COc1ccc(-c2ccc3[nH]cc([C@@H]4C(=O)NC(=O)[C@H]4c4cn5c6c(cccc46)CCC5)c3c2)cc1

Procedure:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-(4-methoxyphenyl)-1H-indol-3-yl) pyrrole-2,5-dione, prepared as in Example 33, was reduced with Mg in methanol as described in Example 2, Procedure C, to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-(4-methoxyphenyl)-1H-indol-3-yl)pyrrolidine-2,5-dione. 1H NMR (CD3OD) a: 2.03-2.22 (m, 2H), 2.98 (t, J=6.0 Hz, 2H), 3.80 (s, 3H), 3.97-4.06 (m, 1H), 4.06-4.14 (m, 1H), 4.38 (d, J=6.8 Hz, 1H), 4.67 (d, J=6.8 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.91-7.00 (m, 2H), 7.08 (s, 2H), 7.17-7.27 (m, 4H), 7.31 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H).