Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)[CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:31])[C:29]#[CH:30])[CH3:26]>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH:30]([CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:31])[O:17][C:12]=2[CH:11]=1)=[O:18])[CH2:5][CH2:6][CH3:7]
Reactant: C#CC(=O)OCC
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(CCC)NC(=O)c1ccc2c(c1)OC(CC(=O)OCC)O2
Yield: 71 %

Procedure:
N-(heptan-4-yl)-3,4-dihydroxybenzamide (example 18a) (0.29 mmol, 75 mg) was dissolved in dry acetone with 6 eq excess (242 mg) of potassium carbonate then 1.2 eq excess (36 μl) of propynoic acid ethyl ester was added and a mixture was refluxed for 24 h. The solvent was evaporated and a solid was dissolved in dichloromethane and extracted with 10% NaHCO3 and water. The crude product was purified by chromatography on silica gel to give 72 mg of desired product (71%). 1H NMR (500 MHz, CDCl3): δ 0.91-0.94 (t, 6H), 1.23-1.30 (m, 4H), 1.37-1.41 (4H), 2.97-2.98 (d, 2H), 3.70-3.74 (dd, 2H), 4.12-4.17 (m, 1H), 4.2-4.24 (m, 3H), 5.61-5.64 (d, 1H), 6.58-6.60 (t, 1H), 6.79-6.81 (d, 1H), 7.23 (s, 1H), 7.60-7.85 (b, 1H). MS (M+H, 350.1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][C:5]1([CH3:17])[CH3:16].[C:18]([N:22]=[C:23]=[O:24])([CH3:21])([CH3:20])[CH3:19].O.C(OCC)(=O)C>C1COCC1>[C:18]([NH:22][C:23](=[O:24])[NH:1][CH2:2]/[CH:3]=[C:4]1/[C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][C:8]2[C:13]/1=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N=C=O
Reactant: COc1ccc2c(c1)C(=CCN)C(C)(C)CC2
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)/C(=C\CNC(=O)NC(C)(C)C)C(C)(C)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-aminoethylidene)-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene (1.5 g, 6.48 mmol) in THF (30 ml) was gradually added dropwise, under ice-cooling, Tert-butyl isocyanate (0.84 g, 8.43 mmol). The mixture was stirred for 2 hours at room temperature. The reaction mixture was then poured into water. The organic layer was subjected to ethyl acetate. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=8:2),-followed by recrystallization to give the above-titled compound (yield 780 mg, 36%), m.p.175-176° C. (recrystallized from ethyl acetate/diethyl ether).
Reaction SMILES: C(O)=O.[CH3:4][C:5](=[CH2:8])[CH:6]=O.[NH2:9][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)(C)C>[CH3:8][C:5]1[CH:4]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:9][CH:6]=1
Reactant: C=C(C)C=O
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Solvent: O=CO
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C)cnc1C(=O)OCC
Temperature: 70 °C
Yield: 50 %

Procedure:
Isopropyl alcohol 675 ml and 90% formic acid 61.5 g (1.20 mol) were placed in 1 liter four-neck flask equipped with a reflux condenser. After heating the content to 70° C., 2-methyl-2-propenal 84.3 g (1.20 mol) and ethyl β-amino-β-ethoxycarbonylacrylate 150 g (0.801 mol) were simultaneously added dropwise thereto over a period of 1 hour with air-bubbling and refluxed for 10 hours. After removing isopropyl alcohol, 400 ml of water was added thereto and neutralized with sodium bicarbonate. After standing at 65°-67° C., separated oil layer was concentrated under reduced pressure to obtain 200 g of oily substance, which was distilled under reduced pressure to give 95 g of 5-methyl-2,3-diethoxycarbonylpyridine.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:39]1([CH2:45][CH2:46][CH:47]([OH:50])[CH2:48][OH:49])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:42]3[CH2:41][CH2:40][N:39]([CH2:45][CH2:46][CH:47]([OH:50])[CH2:48][OH:49])[CH2:44][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OCC(O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC(O)CO)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-piperazin-1-yl-butane-1,2-diol hydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C37H48Cl2N5O4 [(M+H)+] 696.3078, observed 696.3074.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)O)=[CH:30][CH:29]=1>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:34]([C:31]1[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)=[O:11])[CH2:3]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: O=C(OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (150 mg, 0.78 mmol), EDC (225 mg, 1.17 mmol) and HOBT (180 mg, 1.17 mmol) were dissolved in dry THF (7.5 ml). Bis(4-chlorophenyl)methanol (218 mg, 0.86 mmol) was added followed by TEA (382 μl, 2.74 mmol). The resulting reaction was stirred at room temperature overnight. THF was removed under vacuum, and the crude was partitioned between EtOAc and water. The organic phase was washed with sat. NaHCO3, dried over sodium sulphate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to 7:3+1% of NH4OH) to obtain bis(4-chlorophenyl)methyl quinuclidine-3-carboxylate (85.0 mg, racemic mixture).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](O)=[O:10])[CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[F:12][C:2]([F:1])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccn1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(C(F)(F)F)ccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
To a solution of 4-trifluoromethyl-pyridine-2-carboxylic acid (500 mg, 2.62 mmol) in THF (20 mL) at 0° C. was added triethylamine (0.40 mL, 2.88 mmol) followed by ethyl chloroformate (0.28 mL, 2.88 mmol). A thick white precipitate formed. The reaction mixture was stirred at 0° C. for 15 min then a solution of sodium borohydride (297 mg, 7.85 mmol) in water (5 mL) was slowly added via pipet. Vigorous gas evolution was observed and all solids dissolved. The reaction was stirred at 0° C. for 10 min then warmed to room temperature and stirred for 1 h. The reaction was diluted with water and extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by chromatography with 20% to 50% EtOAc/hexanes to afford 296 mg (64%) of (4-trifluoromethyl-pyridin-2-yl)-methanol as a colorless oil that freezes just below room temperature. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.76 (d, J=4.9 Hz, 1H), 7.55 (s, 1H), 7.45 (d, J=4.9 Hz, 1H), 4.87 (s, 2H).
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][O:17][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:18]C(OC(Cl)C)=O>ClC(Cl)C.C(Cl)Cl.CO>[ClH:18].[O:17]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[CH:15]=[CH:16]1
Reactant: c1ccc(CN2CCc3ccoc3CC2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CC(Cl)Cl
Product: Cl
Product: c1cc2c(o1)CCNCC2
Temperature: 22 °C
Yield: 87 %

Procedure:
A solution of the product from step f) (2.56 mg, 11.3 mmol) in anhydrous dichloroethane (56 ml) was cooled to 0° C., treated with 1-chloroethyl chloroformate (6.11 ml, 56.4 mmol) and the reaction was warmed to 22° C. for 1 hour. The reaction was diluted with CH2Cl2 (100 ml) and washed with sat. NaHCO3 (50 ml). The sat NaHCO3 was back extracted with CH2Cl2 and the combined organic layers were washed with brine (50 ml), dried (MgSO4) and concentrated providing an oily residue, which was taken up in anhydrous MeOH (150 ml) and refluxed for 1 hour. The MeOH was evaporated and the crude was triturated with ether and filtered providing 1.71 g (87%) of the subtitle compound. 1H NMR (300 MHz, DMSO) δ 9.56 (br s, 2H); 7.43 (d, J=2 Hz, 1H); 6.34 (d, J=2 Hz, 1H); 3.18-3.30 (br m, 4H); 3.03-3.10 (br m, 2H); 2.74-2.82 (br m, 2H); MS: ESI (positive): 138 (M+H).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15].[NH2:27][C@H:28]([C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31]>C1COCC1>[NH:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:14]([C:17]([NH:27][C@H:28]([C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:19])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 63.1 %

Procedure:
3.76 g (19.6 mmol) of EDCl was added to 40 ml of THF solution of 1.99 g (9.79 mmol) of Boc-Aib-OH (manufactured by Sigma-Aldrich Corporation), and 2.03 g (9.79 mmol) of H-Leu-NHPh obtained in Synthesis Example 2-2, followed by stirring for 17 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 2.42 g of the product with a yield of 63.1%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:10][O:11]/[N:12]=[C:13](/[C:17]2[N:18]=[C:19]([NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH:21]=2)\[C:14]([OH:16])=O)[CH2:9][CH2:8]1.[NH2:42][C@@H:43]1[C:71](=[O:72])[N:45]2[C:46]([C:55]([O:57][CH:58]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])=[C:47]([CH2:50][O:51][C:52](=[O:54])[NH2:53])[CH2:48][S:49][C@H:44]12.CN(C)C1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[C:52]([O:51][CH2:50][C:47]1[CH2:48][S:49][C@@H:44]2[C@H:43]([NH:42][C:14](=[O:16])/[C:13](=[N:12]\[O:11][CH2:10][CH:7]3[CH2:8][CH2:9]3)/[C:17]3[N:18]=[C:19]([NH:22][C:23]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[S:20][CH:21]=3)[C:71](=[O:72])[N:45]2[C:46]=1[C:55]([O:57][CH:58]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:56])(=[O:54])[NH2:53]
Reactant: NC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)/C(=N\OCC1CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Product: NC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Reaction time: 0.08 h
Yield: 83.6 %

Procedure:
Oxalyl chloride (0.37 ml) was added to a solution of N,N-dimethylformamide (0.38 ml) in methylene chloride (10 ml) at -20° with stirring. After five minutes at 0°, the mixture was recooled to -20° and (Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (1.94 g) was added. The solution was stirred at 0° for ten minutes before recooling to -20°. A slurry of diphenylmethyl (6R,7R)-7-amino-3-carbamoyloxymethylceph-3-em-4-carboxylate (1.76 g) in methylene chloride (10 ml) containing N,N-dimethylaniline (1.26 ml) was added. The solution was allowed to warm to 21° and was stirred for 1.5 hours. After dilution with methylene chloride, the solution was washed with dilute hydrochloric acid and water, each time back-extracting with methylene chloride. The combined organic layers were dried (magnesium sulphate) and concentrated. The solution was loaded into a column of Sorbsil U30 (70 g) which was eluted with a gradient of ethyl acetate (10 to 100%) in petroleum ether (b.p. 40°-60°). Evaporation of the appropriate eluate gave the title compound (3.03 g) as a foam, [α]D21 +10.7° (c 1.03, CHCl3); νinfl 238.5 nm (E1 cm1% 2.78), 258.5 (E1 cm1% 227), 264.5 (E1 cm1% 212), 271.5 (E1 cm1% 186) and 296.5 (E1 cm1% 88)
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[CH:10]([CH2:20][Cl:21])[CH2:9]1)=[O:7])(C)(C)C.Cl.CN(C)CCCN=C=NCC.C([C:37]1[NH:38][C:39]2[C:44]([CH:45]=1)=[CH:43][CH:42]=[C:41]([C:46]([NH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1)=[O:47])[CH:40]=2)(O)=O>Cl.CN(C=O)C>[Cl:21][CH2:20][CH:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:8]([C:6]([C:37]2[NH:38][C:39]3[C:44]([CH:45]=2)=[CH:43][CH:42]=[C:41]([C:46]([NH:48][CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:47])[CH:40]=3)=[O:7])[CH2:9]1
Reactant: O=C(NCCc1ccccn1)c1ccc2cc(C(=O)O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2ccc([N+](=O)[O-])cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccn1)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Temperature: 20 °C
Yield: 67.1 %

Procedure:
1-(t-Butoxycarbonyl)-3-(chloromethyl)-6-nitroindoline (248 mg, 0.79 mmol) was stirred in HCl-saturated dioxane (8 mL) at 20° C. for 40 min (until tlc indicated complete reaction) and the mixture evaporated. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.30 g, 1.58 mmol) and 2-carboxy-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide (245 mg, 0.79 mmol) in DMF (20 mL) were added and the orange solution stirred at 20° C. After 24 h the DMF was evaporated, and the residue triturated with EtOAc and aqueous NaHCO3. The solid was filtered off and recrystallised from MeOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl]-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide as a yellow solid (267 mg, 67%), mp 204-207° C. 1H NMR [(CD3)2SO] δ12.15 (s, 1H, indole NH), 8.99 (d, J=2.1 Hz, 1H, H-7), 8.61 (t, J=5.5 Hz, 1H, amide NH), 8.55-8.52 (m, 1H, H-6"), 8.04 (dd, J=8.3, 2.3 Hz, 1H, H-5), 8.02 (s, 1H, H-3' or H-7'), 7.75 (d, J=8.6 Hz, 1H, H-4 or H-4'), 7.74 (d, J=8.3 Hz, 1H, H-4 or H-4'), 7.71 (dd, J=7.6, 1.9 Hz, 1H, H-4"), 7.56 (dd, J=8.5, 1.3 Hz, 1H, H-5'), 7.31 (d, J=7.7 Hz, 1H, H-3"), 7.28 (d, J=1.4 Hz, 1H, H-3' or H-7'), 7.23 (ddd, J=7.2, 4.9, 0.8 Hz, 1H, H-5"), 4.86 (t, J=10.1 Hz, 1H, H-2), 4.51 (dd, J=10.7, 5.1 Hz, 1H, H-2), 4.19-4.06 (m, 3H, H-3 and CH2Cl), 3.66 (q, J=6.7 Hz, 2H, NHCH2CH2 py), 3.04 (t, J=7.4 Hz, 2H, NHCH2CH2 py); 13C NMR δ166.7 (CONH), 160.4 (CON), 159.2 (C-2"), 147.6, 144.6, 139.9, 135.7, 131.8, 130.8, 128.9 (C-6,8,9,2',6',8',9'), 149.0, 136.4, 123.1, 121.4 (C-3",4",5",6"), 125.5, 121.6, 119.4, 118.8, 112.0, 111.2, 106.1 (C-4,5,7,3',4',5',7'), 54.0 (C-2), 47.0 (CH2Cl), 42.0 (C-3), 39.3, 37.3 (NHCH2CH2 py). A sample was converted to the hydrochloride salt and triturated with hot EtOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl) carbonyl]-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide hydrochloride as a pale yellow powder, mp 250-255° C. (dec.). Anal. (C26H22ClN5O4.0.25HCl) C,H,N.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.C(O)(C)C>[Fe].O>[NH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: [Fe]
Solvent: O
Solvent: CC(C)O
Product: Nc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
2,3-Dichloro-5-nitropyridine (3.9 g) and iron powder (3.0 g) were added to isopropyl alcohol (40 ml) and water (8 ml) and the mixture refluxed for 4 hours. The mixture was then cooled to room temperature and filtered (celite). The filtrate was evaporated under reduced pressure and chromatographed [SiO2 ; hexane:ethyl acetate (80:20) to (50:50)] to give 5-amino-2,3-dichloropyridine (1.71 g).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:29])[C@@H:16]2[CH2:20][C@@H:19](O)[CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([N:57]1[C:62](=[O:63])[C:61]([CH3:64])=[CH:60][NH:59][C:58]1=[O:65])(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]1([CH:7]([O:14][C:15](=[O:29])[C@@H:16]2[CH2:20][C@H:19]([N:59]3[CH:60]=[C:61]([CH3:64])[C:62](=[O:63])[N:57]([C:49](=[O:56])[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:58]3=[O:65])[CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1c[nH]c(=O)n(C(=O)c2ccccc2)c1=O
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)OC(C)(C)C)C2)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: -15 °C

Procedure:
N-Boc-trans-4-hydroxy-L-proline diphenylmethyl ester (2a) (0.425 g, 1.07 mmol), triphenylphosphine (0.290 g, 1.10 mmol) and N3-benzoylthymine (0.250 g, 1.09 mmol) were dissolved in dry THF (10 ml) and the solution was cooled to −15° C. DEAD (180 μL, 1.10 mmol) was then added dropwise with stirring. The reaction mixture was stirred under argon at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica gel using dichloromethane-acetone 20:1 as eluant to give N-tert-butoxycarbonyl-cis-4-(N3-benzoylthymin-1-yl)-L-proline diphenylmethyl ester (3a) (Rf 0.56), which was recrystallised from ethanol to give a white fluffy solid (0.310 g, 51%), m.p. 183-185° C., (Found C, 68.9; H, 5.5; N, 6.7%; C35H35N3O7 requires C, 69.0; H, 5.8; N, 6.9%), δH (200 MHz; CDCl3) 1.30 and 1.49 (9H, 2×br s, Boc rotamers), 1.82 (3H, br s, thymine CH3), 2.05 and 2.85 [2H, br m, CH2(3′)], 3.65 (1H), br m) and 4.02 (1H, dd, J=12.0, 8.0 Hz)[CH2(5′)], 4.54 [1H, br m, CH(2′)]5.26 [1H, br m, CH(4′)], 6.94 (1H, s, CHPh2), 7.12 and 7.18 [1H, 2×br s, CH(6) rotamers], 7.30-7.42 (10H, br m, phenyl CH), 7.50 (2H, t, J=7.9 Hz, benzoyl m-CH), 7.67 (1H, t, J=7.0 Hz, benzoyl p-CH), 7.92 (2H, d, J=7.0 Hz, benzoyl o-CH); δC (50.28 MHz; CDCl3) 12.3 (thymine CH3), 27.9 and 28.2 (Boc CH3 rotamers), 34.9 and 35.3 [CH2(3′) rotamers], 49.3 and 49.4 [CH2(5′) rotamers], 52.1 and 52.5 [CH(4′) rotamers], 57.5 [CH2(2′)], 78.1 and 78.4 (CHPh2 rotamers), 81.3 (Boc C), 111.7 [C(5)], 126.9-130.6 (aromatic CH), 131.6 (benzoyl C), 135.3 (benzoyl p-CH), 136.0 and 136.2 [CH(6) rotamers], 139.4 (phenyl C), 150.1 [C(2)], 153.6 (Boc CO), 162.6 [C(4)], 169.1 (benzoyl CO), 171.6 (ester CO); m/z (FAB+) 632 (M+Na+, 10%), 610 (M+H+, 39), 554 ([M−C4H8+H]+, 27), 506 ([M−PhCO+H]+, 18), 338 ([M−PhCO−Ph2CH]+, 20), 266 (31), 231 (BzT+H+, 52), 167 (Ph2CH+, 100), 105 (PhCO+, 24), 57 (C4H9+, 28); νmax (KBr)/cm−1 1751, 1694 and 1659 (C═O); [α]D25−17.2 (c=1.0, DMF).
Reaction SMILES: Cl.[C:2]([C:5](=[N:11][O:12][CH:13]1[CH2:15][CH2:14]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[NH:4])[NH2:3].C(N(CC)CC)C.BrBr.[S-:25][C:26]#[N:27].[K+]>CO.C(OCC)(=O)C>[NH2:27][C:26]1[S:25][N:3]=[C:2]([C:5](=[N:11][O:12][CH:13]2[CH2:14][CH2:15]2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:4]=1
Reactant: N#C[S-]
Reactant: CCOC(=O)C(=NOC1CC1)C(=N)N
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)C(=NOC1CC1)c1nsc(N)n1
Temperature: -5 °C
Reaction time: 0.03 h
Yield: 56.3 %

Procedure:
To a solution of ethyl 2-amidino-2-(cyclopropoxyimino)acetate hydrochloride (syn isomer) (1.44 g) in methanol (11 ml) was added triethylamine (3.06 ml) at -15° C. To the solution was dropwise added bromine (852 mg) at -5° C. After the solution was stirred at -5° C. for 2 minutes, to the solution was added a solution of potassium thiocyanate (518 mg) in methanol (5 ml) at -5° C. The mixture was allowed to be stirred under ice-cooling for 2 hours. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate. The solution was washed successively with 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo, and triturated with diethyl ether to give ethyl 2-(5-amino-l,2,4-thiadiazol3-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(769 mg) as a crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)O
Temperature: 68 °C
Yield: 16.6 %

Procedure:
To a stirred solution of Ethyl 2-Ethoxy-6-pentadecylbenzoate (20 g, 240 mmol) in dimethyl sulfoxide (80 mL) was added potassium tert-butoxide (20 g, 890 mmol) in portions. The solution was heated to 68° C. on a water bath for 3 h, the reaction was monitored by TLC using a hexane-ethyl acetate (9:1) solvent system. The reaction mass was cooled to 15° C., poured into ice water, and then acidified with 10% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in petroleum ether (50 mL) to yield an off-white solid of 2-Ethoxy-6-pentadecylbenzoic Acid (15 g, 80%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[CH3:32][C:33]1[CH:34]=[C:35]([NH2:42])[C:36](=[CH:40][CH:41]=1)[C:37]([OH:39])=[O:38]>ClCCl>[CH3:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([NH:42][C:17](=[O:18])[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:34]=1
Reactant: O=C(O)Cc1c(-c2ccccc2)[nH]c2ccccc12
Reactant: Cc1ccc(C(=O)O)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)c(NC(=O)Cc2c(-c3ccccc3)[nH]c3ccccc23)c1
Yield: 20.9 %

Procedure:
2-Phenyl-3-indole acetic acid (0.166 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.127 g) and 4-methylanthranilic acid (0.100 g) in dichloromethane (20 ml) were refluxed for 48 h under nitrogen. The solvent was then removed and the residue purified using mass spectroscopy directed automated HPLC to afford the title compound (0.053 g). LC/MS TR 3.58 min, MH+ 384.