Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C:12](OC)=[O:13].[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH2:12][OH:13]
Reactant: COC(=O)c1c(Cl)ccc2nn(C)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cn1cc2c(CO)c(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of methyl 5-chloro-2-methyl-2H-indazole-4-carboxylate (3.00 g, 13.4 mmol) in tetrahydrofuran (129 mL) was slowly added a solution (1 M, 40.1 mL, 40.1 mmol) of diisobutylaluminum hydride in hexane at −78° C., and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (2.63 g, yield 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:20]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH2:18][CH3:19])[C@H:16]([C@@H:8]3[CH2:7][CH:6]([CH3:23])[C:5]=2[CH:4]=1)[CH2:15][CH2:14][C@@H:13]4[OH:17].N.[Li].C(O)C>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH:6]([CH3:23])[CH2:7][C@H:8]3[C@H:16]4[C@@:12]([CH2:18][CH3:19])([C@@H:13]([OH:17])[CH2:14][CH2:15]4)[CH2:11][CH2:10][C@@H:9]3[C:20]=2[CH2:21][CH:22]=1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Yield: 95 %

Procedure:
Add dl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-1,3,5(10)-triene (6.80 g) in tetrahydrofuran (200 cc) to liquid ammonia (800 cc) containing tetrahydrofuran (250 cc). Add lithium metal (3.5 g) portionwise and stir the solution for 1.75 hours. Discharge the blue color by dropwise addition of absolute ethanol over 0.25 hours followed by water (2,000 cc). Filter, wash and dry to obtain the dl-3-methoxy-17β-hydroxy-6-methyl-13-ethylgona-2,5(10)-diene (6.5 g), m.p. 176°-182°, λ max. KBr 3.05 μ, 5.90 μ, 6.0 μ, no absorption in the ultraviolet above 220 mμ.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][C:17]#[N:18])=[CH:13][CH:12]=1.N[CH2:22][CH2:23][NH:24][S:25]([C:28]1[C:29]2[CH:30]=[CH:31][N:32]=[CH:33][C:34]=2[CH:35]=[CH:36][CH:37]=1)(=[O:27])=[O:26]>>[ClH:10].[ClH:10].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([O:15][CH2:16][CH2:17][NH:18][CH2:22][CH2:23][NH:24][S:25]([C:28]2[C:29]3[CH:30]=[CH:31][N:32]=[CH:33][C:34]=3[CH:35]=[CH:36][CH:37]=2)(=[O:26])=[O:27])=[CH:13][CH:12]=1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: Cl
Product: O=S(=O)(NCCNCCOc1ccc(Cl)cc1)c1cccc2cnccc12

Procedure:
By following similar procedure as described in Example 31, DIBAL-H reduction of (4-chloro-phenoxy)-acetonitrile and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine product as oil. The free amine is converted to the di-hydrochloride salt of the title compound as a hygroscopic white powder. ESIMS: m/z 406 [(M+H)+, 35Cl], 408 [(M+H)+, 37Cl].
Reaction SMILES: [C:1]([C@:3]1([OH:34])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C@H:12]([CH2:24]N(C1C=CC=CC=1)CC)[CH2:11]3)#[CH:2].Cl.O>C1COCC1>[C:1]([C@:3]1([OH:34])[C:8](=[CH2:9])[CH2:7][C@H:6]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:4]12[CH3:5])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[C:12](=[CH2:24])[CH2:11]3)#[CH:2]
Reactant: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3C[C@@H](CN(CC)c4ccccc4)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3CC(=C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 8 h

Procedure:
17α-Ethynyl-17β-hydroxy-6β-(N-phenyl-N-ethylaminomethyl)-16-methyleneandrosta-4-en-3-one (Example 5) in THF (20 ml) are mixed. Degassed hydrochloric acid (6N, 55 ml plus 20 ml THF) are added. The mixture is stirred overnight at 20°-25° under nitrogen, at which time TLC shows the reaction to be complete. Water (110 ml) is added, the mixture filtered, the solids washed with 10% hydrochloric acid, twice with water, once with 5% sodium bicarbonate, and three times with water to neutrality. Solids were then dried under nitrogen overnight to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[O:21])=[C:9]2[CH3:34])=[O:7])=[CH:4][CH:3]=1.[CH3:37][I:38]>CC(C)=O>[I-:38].[CH3:37][N+:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:26](=[O:27])[NH:25][CH2:24][CH2:23][O:22][C:20](=[O:21])[CH2:19][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:36][CH:35]=3)[C:9]=2[CH3:34])[CH:29]=1
Reactant: CI
Reactant: COc1ccc2c(c1)c(CC(=O)OCCNC(=O)c1cccnc1)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: CC(C)=O
Product: COc1ccc2c(c1)c(CC(=O)OCCNC(=O)c1ccc[n+](C)c1)c(C)n2C(=O)c1ccc(Cl)cc1
Product: [I-]
Yield: 66 %

Procedure:
The quaternization of the indomethacin ester prepared in Example 93 (0.50 g, 1.0 mmol) was carried out in acetone, using methyl iodide (1.7 g, 12 mmol). The reaction was refluxed overnight. The solvent was removed under reduced pressure and a yellow solid was obtained. The product was recrystallized using ethanol and a very small amount of ether. Small mold-like crystals were obtained which were light yellow in color. The reaction gave 0.43 g or a 66% yield of the purified material; mp 178°-179° C. UV, NMR and elemental analyses confirmed that the product had the structural formula: ##STR124##
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:25]3[CH2:31][CH2:30][CH:28]([CH:29]=2)[CH2:27][CH2:26]3)=[O:23])=[CH:17][C:16]=1[C:32]([F:35])([F:34])[F:33])([O-:14])=[O:13]>C(Cl)Cl>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]23[O:9][CH:29]2[CH:28]2[CH2:27][CH2:26][CH:25]3[CH2:31][CH2:30]2)=[O:23])=[CH:17][C:16]=1[C:32]([F:33])([F:34])[F:35])([O-:14])=[O:13]
Reactant: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C1=CC2CCC1CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1)C12OC1C1CCC2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
mCPBA (60% mixture, 518 mg, 3.00 mmol, 3 eq) was added to a solution of 11D (340 mg, 1.0 mmol, 1.0 eq) in CH2Cl2 (20 mL). The reaction mixture was stirred at rt overnight and then diluted with CH2Cl2 (40 mL). The organic solution was washed with sat. NaHCO3 (1×50 mL), brine (1×50 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 80% CH2Cl2/hexane gave 205 mg (0.58 mmol, 57.6%) of compound 11E. HPLC conditions: 95% at 3.70 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2% H3PO4, detecting at 220 nm). F. 3-Oxa-tricyclo[3.2.2.02,4]nonane-2-carboxylic acid N-(4-nitro-3-trifluoromethyl-phenyl)-hydrazide (11F)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:25][C:24](=[O:26])[CH2:23][N:22]=3)[C:9]=2[CH2:27][CH3:28])=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]([CH3:29])[C:24](=[O:26])[CH2:23][N:22]=3)[C:9]=2[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCc1c(C2=NCC(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC#N
Product: CCc1c(C2=NCC(=O)N2C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 68 %

Procedure:
To a solution of 26 (100 mg, 0.23 mmol) in acetonitrile (8 mL) at room temperature was sequentially added potassium carbonate (150 mg, 1.09 mole) and methyl iodide (2 g, 14.08 mmol) slowly. The mixture was stirred at 60° C. for 6 h. Water was added and the resulting mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the crude residue by flash chromatography on silica gel eluting with hexanes/ethyl acetate (1:1) gave the compound 29 (70 mg, 68%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.30 (d, 2H), 7.25 (dd, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 4.88 (s, 0.82H), 4.51 (s, 1.18H), 3.42 (s, 1.77H), 3.24 (s, 1.23H), 2.65 (q, 2H), 1.15 (t, 3H); ESMS m/: 447.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6].[N:14]([O-])=O.[Na+].[Sn](Cl)Cl>O1CCOCC1.O.Cl>[NH:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([NH:7][O:8][CH3:9])=[O:6])[NH2:14]
Reactant: CONC(=O)c1ccc(C)c(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CONC(=O)c1ccc(C)c(NN)c1
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
To a stirred solution of 3-amino-4-methylbenzoic acid 1 (5.64 g, 31.2 mmol, 1.0 eq) in 100 mL of dioxane and 100 mL of water at 0° C. was added 100 mL of conc. HCl followed by the portionwise addition of sodium nitrite (2.82 g, 40.9 mmol, 1.1 eq) as a solid at a rate to control gas evolution and foaming over 45 minutes. A clear brown solution resulted. Anhydrous tin(II)chloride (15.62 g, 83.7 mmol, 2.25 eq) was dissolved in conc. HCl (25 mL) and added dropwise over 25 mL at 0° C. After 1 hour, the precipitate was filtertered and washed with dioxanes then dried under vacuum to provide 3-hydrazino-4-methyl-benzoic acid hydrochloride 2 as a tan solid (4.98 g, 66%): HPLC (4 minute gradient) tR 0.97 min; MS m/z 167 [M+H]+; 1H (300 MHz, DMSO-d6) δ 10.03 (s, 1 H, COOH), 7.89 (s, 1 H), 7.51 (s, 1 H), 7.27 (d, J=8.0, 1 H), 3.38 (s, 3 H, NHNH2), 2.23 (s, 3 H) ppm.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Br:22])[CH:18]=2)[CH:13]=1>C1C=CC=CC=1>[Br:22][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([NH:11][S:2](=[O:4])(=[O:3])[NH2:5])[CH:13]=2)[CH:18]=1
Reactant: Nc1ccc2cc(Br)ccc2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O=CO
Solvent: c1ccccc1
Product: NS(=O)(=O)Nc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
A solution of chlorosulfonyl isocyanate (870 μl, WAKO) in benzene (10 ml) was added dropwise with formic acid (377 μl, WAKO) under ice cooling, warmed to room temperature, stirred for 19.5 hours, then heated to 40° C. and further stirred for 4 hours. The reaction mixture was added dropwise with a solution (5 ml) of 2-amino-6-bromonaphthalene (443 mg) in benzene under ice cooling, warmed to room temperature and stirred for 21.5 hours. The reaction mixture was filtered, and the obtained solid was added with ethyl acetate and mixed. The mixture was filtered again, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=2:1) to obtain the title compound (Intermediate 28, 158 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH2:22]([NH:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH3:24]>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:25]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:23][CH3:24])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: CCCNC(C)C
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Product: CCCN(c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1)C(C)C

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)amide (Intermediate 17) and propyl-isopropylamine (Matrix), the title compound was obtained as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[N-:10]=[N+:11]=[N-:12].[Na+].O>CO>[N:10]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[N+:11]=[N-:12]
Reactant: COC(=O)CCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CCCCN=[N+]=[N-]
Yield: 99.7 %

Procedure:
A solution of methyl 5-bromovalerate (5.00 g, 25.6 mmol), NaN3 (3.33 g, 51.2 mmol) and 15 ml of water in 40 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water. After drying and removal of solvent, methyl 5-azidovalerate (4.01 g, 99.7%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12]C)=[O:11])[CH:7]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: COC(=O)/C=C/c1cc(Cl)c(F)cc1-n1cnnn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cc(Cl)c(F)cc1-n1cnnn1
Reaction time: 2 h
Yield: 42.1 %

Procedure:
To Intermediate 5C (5 g, 17.7 mmol) in MeOH (50 mL) and THF (25 mL) was added 10% NaOH solution (25 mL). After 2 h, the reaction was concentrated and the residue was diluted with H2O. The pH was adjusted to 2 to 3 with 1.5 N HCl and the resultant solid was filtered and washed with petroleum ether to afford 2 g of Intermediate 5. MS (ESI) m/z: 269.0 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[NH:3]1.[OH-].[Na+].[CH3:20][S:21]([CH3:23])=O.CI.C(=S)=[S:27]>O>[CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[N:3]1[C:20]([S:21][CH3:23])=[S:27]
Reactant: CS(C)=O
Reactant: C[C@@H]1N[C@H](C(=O)O)Cc2c1[nH]c1ccccc21
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSC(=S)N1[C@H](C(=O)O)Cc2c([nH]c3ccccc23)[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a mixture of (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2.30 g), 10N NaOH (2 ml) and dimethylsulfoxide (6 ml) is added dropwise carbon disulfide (912 mg) and further added dropwise methyl iodide (1.7 g) at 0° C. The mixture is stirred at room temperature for one hour, and to the mixture is added water, and then extracted with ethyl acetate. The aqueous layer is acidified with 10% HCl and extracted with ethyl acetate. The extract is dried and distilled to remove the solvent. The residue is crystallized from chloroform to give the title compound (1.59 g, 50%) as colorless needles, m.p. 134°-137° C. (decomp.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:12][C:13]1[N:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1.C(N(CC)CC)C>COCCO.C(Cl)Cl>[NH2:12][C:13]1[N:18]=[C:17]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: COCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1ccnc(N)n1
Temperature: 130 °C

Procedure:
tert-Butyl 2-aminoethylcarbamate (3.27 g, 20.4 mmol) and 2-amino-6-chloropyrimidine (2.38 g, 18.4 mmol) were combined in 2-methoxyethanol with triethylamine (4.3 mL, 30.3 mmol) and heated to 130° C. overnight. The mixture was diluted with methylene chloride and washed with 1 N sodium hydroxide. The aqueous layer was extracted with methylene chloride followed by ethyl acetate. The organic layers were combined, absorbed on silica gel, and purified using silica gel chromatography, eluting with a gradient of methanol in methylene chloride (1-12%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.44 (s, 9H) 3.32 (q, J=5.31 Hz, 2H) 3.38-3.50 (m, 2H) 4.70 (s, 2H) 4.91-5.19 (m, 2H) 5.78 (d, J=5.76 Hz, 1H) 7.81 (d, J=5.76 Hz, 1H); MS (ESI+) m/z 253.9 (M+H)+.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:27][C@H:28]([C:41]([OH:43])=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C1CCC(NC2CCCCC2)CC1.OS(O)(=O)=O>CN(C=O)C.C(O)(=O)C.C(N(CC)CC)C>[CH2:20]([O:19][C:17]([NH:1][C@H:2]([C:7]([NH:27][C@H:28]([C:41]([OH:43])=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of Z-Leu-OSu (122.5 g, 0.338 mol) in DMF (1.2 L) was stirred at 0° in a 3 L, 3-necked round bottom flask fitted with a mechanical stirrer and thermometer. The H-Lys(Boc)-OH (83.26 g, 0.338 mol) was added and the solution stirred at 0° for 15 min. Triethylamine (47.6 mL, 0.338 mol) was added and the reaction mixture stirred at 0° for 30 min and 25° for 3 h. Additional triethylamine (20 mL) was added to maintain the pH at 8 and the reaction mixture stirred for an additional 20 h. At the end of this time, tlc showed some unreacted H-Lys(Boc)-OH and the reaction mixture was stirred for an additional 24 h (pH 8). The reaction mixture was cooled (0°), acidified with glacial acetic acid (160 mL) and evaporated in vacuo. The residue (oil) was dissolved in EtOAc (1.5 L) and washed with 1M citric acid (2×600 mL) and 10% NaCl (2×700 mL), dried (MgSO4), filtered and concentrated in vacuo. The oily residue was dissolved in anhydrous ether (4 L) and dicyclohexylamine (70.7 mL) added followed by the addition of 1 L of ether. After standing in the cold room for 72 h, the white salt was collected and dried to yield 210.8 g (90%); m.p. 125°-128° (recrystallization of an analytical sample increased the m.p. to 143°-146°); [α]D25 -4.17 (c 1, MeOH); Rf 0.39 (CHCl3 :MeOH:AcOH; 85:10:5). The free acid was generated from the DCHA salt in the following manner: Z-Leu-Lys(Boc)-OH.DCHA (201.9 g, 0.291 mol) was stirred in EtOAC:0.5N H2SO4 (2 L:727 mL) until all the solid dissolved. The organic layer was separated, washed with 0.5N H2SO4 (730 mL), dried (MgSO4) and evaporated in vacuo. Yield: 150.6 g (100%); [α]D25 +3.38° (c 1, CHCl3); Rf 0.64 (CHCl3 :MeOH:AcOH; 85:10:5).
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]\[C:4](O)=O.C[N:10]1[C:14]2[CH2:15][N:16]([CH3:25])[CH2:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)C=2C=[CH:11]1.C=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.N>C(O)(=O)C>[CH3:11][N:10]1[C:14]2[CH2:15][N:16]([CH3:25])[CH2:17][CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:4]=2[CH:3]=[C:2]1[CH2:1][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CN1Cc2c(ccn2C)C(c2ccccc2)C1
Reactant: C1COCCN1
Reactant: O=C(O)/C=C\C(=O)O
Agent: C=O
Agent: N
Solvent: CC(=O)O
Product: CN1Cc2c(cc(CN3CCOCC3)n2C)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.7 gm of 1,6-dimethyl-4-phenyl-4,5,6,7-tetrahydro-pyrrolo[2,3-c]pyridine maleate, 5 ml of glacial acetic acid, 2 ml of a 30% formalin solution and 1.5 ml of morpholine was stirred for 15 minutes at room temperature. Afterwards, the resulting solution was made alkaline with concentrated ammonia and extracted twice with ether. The organic phase was washed twice with water and, after drying, evaporated in vacuo. The residue crystallized from diisopropylether. 700 mg=43.3% of theory of the title compound were obtained;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](I)[CH3:20].O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])[CH3:20]
Reactant: CCI
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])c(C=O)c1
Reaction time: 48 h

Procedure:
To a suspension of 5-hydroxy-2-nitrobenzaldehyde (500 mg) and cesium carbonate (1.46 g) in N,N-dimethylformamide (10 mL) was added ethyl iodide (0.265 mL) at room temperature, and the mixture was stirred for 2 days. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (519 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].Cl.[OH-].[Na+].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21](Cl)=[O:22])=[CH:15][CH:14]=1>O>[CH2:19]([O:20][C:21](=[O:22])[NH:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9])[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc(O)cc1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a cooled solution (0° C.) of 4-amino resorcinol.HCl (1.0 g, 6.18 mmol) in H2O (10 mL) was added dropwise aq. NaOH (0.49 g, 12.3 mmol) in H2O (15 mL). To this mixture were added slowly Cbz-Cl (Carbobenzoxy chloride, 1.06 mL, 7.43 mmol) and NaOH (0.25 g) in H2O (5 mL). After stirring for 1 h at room temperature, the mixture was extracted with EtOAc (2×50 mL). The organic layer was dried over MgSO4 (10 g), filtrated and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc:hexane=1:5) to give (2,4-dihydroxyphenyl)-carbamic acid benzyl ester (KCBG02. 1.28 g, 80%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[NH:17][C:18]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:19])[C:8]1=[O:26].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[O:46]=[C:47](Cl)OC(Cl)(Cl)Cl.CCOCC>ClCCl>[Cl:25][C:22]1[S:21][C:20]([C:18]([NH:17][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[C:15](=[O:16])[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][CH:29]=[C:3]([CH2:2][N:1]=[C:47]=[O:46])[CH:4]=2)[C:8]3=[O:26])=[O:19])=[CH:24][CH:23]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCOCC
Solvent: ClCCl
Product: O=C=NCc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 430 mg (1.0 mmol) of N-{2-[3-(aminomethyl)benzyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-5-chloro-2-thiophenecarboxamide and 433 mg (2.0 mmol) of 1,8-bis-(dimethylamino)naphthalene in 222 ml of dichloromethane is added dropwise to an ice-cooled solution of 0.12 ml (0.96 mmol) of diphosgene in 7.5 ml of dichloromethane. After 5 min at 0° C., the mixture is warmed to room temperature and stirred for 35 min, and 40 ml of ether are then added. Insoluble particles are filtered off and the filtrate is concentrated and dried under high vacuum. The resulting solid is immediately reacted further, without further purification. Yield: 454 mg (99.5% of theory).