Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([N:18]([CH3:37])[C@H:19]([C:32]([NH:34][O:35][CH3:36])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH:11]([CH3:1])[C@H:12]([C:16]([N:18]([CH3:37])[C@H:19]([C:32]([NH:34][O:35][CH3:36])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:30])[CH3:31])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CONC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NOC)C(C)C
Yield: 99.2 %

Procedure:
To a solution of Z-N-Me-Val-N-Me-Tyr(3-tBu)-NHOMe (1.23 g, 2.33 mmol) in MeOH (20 ml), palladium hydroxide/carbon (350 mg) was added and stirred in a hydrogen atmosphere for 1 hour. Insoluble matters were removed by filtration with Celite and the filtrate was concentrated under reduced pressure to give crude N-Me-Val-N-Me-Tyr(3-tBu)-NHOMe (0.91 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH2:15])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:29][C:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=2)[NH:32][CH:31]=1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH:15][C:39]([C:35]2[CH:34]=[C:33]3[C:38]([C:30]([Br:29])=[CH:31][NH:32]3)=[CH:37][CH:36]=2)=[O:40])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc2c(Br)c[nH]c2c1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc3c(Br)c[nH]c3c2)cc1
Yield: 78.9 %

Procedure:
Using the procedure described in Example 9, Part C, 4-t-butyldimethylsilyloxy-N2-(4-t-butylbenzoyl)-1,2-benzenediamine (750 mg, 1.9 mmol) and 3-bromoindole-6-carboxylic acid (456 mg, 1.9 mmol) yielded 930 mg (79%) of the title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCNC1=O.OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:115][C:116]([CH3:136])=[CH:117][CH2:118][CH2:119]/[C:120](/[CH3:135])=[CH:121]/[CH2:122][CH2:123]/[C:124](/[CH3:134])=[CH:125]/[CH2:126][S:127][CH2:128][C@H:129]([NH2:133])[C:130]([OH:132])=[O:131]>C(Cl)Cl>[OH:11][C@H:10]([C@@H:9]([C:13](=[O:15])[NH:133][C@H:129]([C:130]([OH:132])=[O:131])[CH2:128][S:127][CH2:126]/[CH:125]=[C:124](\[CH3:134])/[CH2:123][CH2:122]/[CH:121]=[C:120](\[CH3:135])/[CH2:119][CH2:118][CH:117]=[C:116]([CH3:136])[CH3:115])[NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH3:12]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-L-threonine (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture and stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (145 mg, 28%) to yield Compound N-56. 1H-NMR (500 MHz, CD3OD): δ 1.21 (d, J=6 Hz, 3H), 1.48 (s, 9H), 1.62 (bs, 6H), 1.69 (s, 3H), 1.71 (s, 3H), 1.99 (t, J=7.5 Hz, 2H), 2.05-2.22 (m, 6H), 2.82 (dd, J=7.5, 14 Hz), 3.01 (dd, J=5, 13.5 Hz, 1H), 3.17 (dd, J=7, 13.5 Hz, 1H), 3.29 (dd, J=8.5, 13.5 Hz, 1H), 3.33 (bs, 2H), 4.09-4.16 (m, 2H), 4.65 (dd, J=5, 7 Hz, 1H), 5.11 (m, 2H), 5.23 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.2, 16.3, 17.8, 19.9, 26.0, 27.4, 27.8, 28.6, 30.4, 33.5, 40.8, 40.9, 53.4, 61.3, 63.0, 68.7, 80.8, 121.6, 125.15, 125.5, 132.12, 136.26, 140.6, 157.9, 173.2, 173.6; ES-MS: mass calcd for Chemical Formula: C27H46N2O6S 526.7. Found (M+Na) m/z 549.4.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])[C:5](=O)[NH:6][N:7]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:5]1[N:6]=[N:7][C:2]([CH3:1])=[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]=1[C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
1.67 g of 6-methyl-5-phenyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.74 g of 3-chloro-6-methyl-5-phenyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xxi) of the present invention).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:15]([O:14]/[C:8](=[CH:7]\[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)/[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)/C(=C/c1ccccc1)OC(C)=O

Procedure:
A solution containing 22 g. of ethyl phenylpyruvate, 65 g. of acetic anhydride and 20 mg. of p-toluenesulfonic acid monohydrate was refluxed for 2.5 hours. Excess acetic anhydride was stripped from the reaction mass and the product, crude (Z)-ethyl 2-acetyloxy-3-phenyl-2-propenoate, was distilled at about 1.6 mm. Hg. (b.p. 120°-135° C.). The recovered product crystallized on standing in refrigeration and was recovered by filtration and recrystallized from ethanol; recovered 12.1 g., m.p. 41°-47° C.; second recrystallization, 10.5 g., m.p. 47°-49° C.; third recrystallization, 9.2 g., m.p., 47°-49° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2ccccc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 200-205° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]C(N)CN)=[CH:3][CH:2]=1.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:15][CH2:14][CH2:13][NH2:16])=[CH:5][CH:6]=1
Reactant: NCC(N)CCc1ccncc1
Reactant: NCCN
Product: NCCNCCc1ccncc1
Yield: 35 %

Procedure:
This was an adaptation of the procedure reported by R. G. Lacoste and A. E. Martel in Inorganic Chemistry 1964, 3(6), 881, for the preparation of N-[2-(4-pyridyl-ethyl]ethylene diamine. To a 250 ml three neck round bottom flask, fitted with a dropping funnel, a reflux condenser, and magnetic stirring, was added 12.02 g (0.2 mol) ethylene diamine, 24 g distilled water, and 31.50 g (0.3 mol) freshly distilled 4-vinylpyridine. The temperature was maintained at 20°-30° C. while 12.0 g glacial acetic was added through the dropping funnel. After all the acetic acid was added, the reaction mixture was heated on the steam bath for two hours. The product was fractionally distilled to give 11.48 g (35% yield). The product was characterized by IR and NMR.
Reaction SMILES: [CH3:1]N(C=O)C.[CH3:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]([OH:28])=[O:27])[S:25][C:18]=13)=[CH:11][CH:10]=2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CO>[CH3:1][O:27][C:26]([C:24]1[S:25][C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:17]=2[O:16][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([CH3:6])=[CH:15]3)[CH:23]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: Cc1cc2cc(Oc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2nccc(Oc3ccc4[nH]c(C)cc4c3)c2s1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of DMF was added 7-(2-Methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid (0.6 g, 1.85 mmol), DIEA (0.62 mL, 3.70 mmol), HATU (0.77 g, 2.03) and MeOH (0.5 mL). The solution was stirred for 3 h then 50 mL of EtOAc added and partitioned between 50/50 NaHCO3 (2×50 mL). The organic layer was dried over Na2SO4 then concentrated. Purification was through silica (50 mL) eluting with EtOAc/Hex (2:1). The purified fraction combined and concentrated to give 7-(2-Methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid methyl ester as white foam (0.6 g, 96%). HPLC: Rt 4.01 min. (100% area). 1H NMR (CDCl3-d3, 400 MHz) δ: 8.42 (1H, d, J=5.6 Hz), 8.29 (1H, bs), 7.26-7.23 (2H, m), 6.85 (1H, dd, J=7.5, 1.6 Hz), 6.51 (1H, d, J=5.3 Hz), 6.17 (1H, s), 3.91 (3H, s), 2.40 (3H, s). LCMS (ACPI) M+H+ m/z: 339.1.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1.[CH2:23]([NH2:25])[CH3:24]>C(O)C.C1COCC1>[CH2:23]([NH:25][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1)[CH3:24]
Reactant: N#Cc1ccc2c(c1)COC2(CCCI)c1ccc(F)cc1
Reactant: CCN
Solvent: C1CCOC1
Solvent: CCO
Product: CCNCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Yield: 56.7 %

Procedure:
To a stirred solution of 1-(3-iodopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (12.9 g, 30 mmol, 8% pure) in ethanol (150 mL) was added a solution of ethylamine (20.3 g, 450 mmol) in THF (50 mL) portionwise, and the mixture was stirred over night. The solution was evaporated, and was dissolved/suspended in water. The pH was adjusted to 12 using aqueous sodium hydroxide solution (2M) and was extracted with ether. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. This oil was purified by silica chromatography using 50% v/v ethyl acetate/heptane as eluent, followed by 10% v/v triethylamine/40% v/v ethyl acetate/heptane followed by 20% v/v triethylamine/ethyl acetate to give the title compound (5.52 g, 57%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.05 (t, 3H), 1.2-1.6 (m, 2H), 2.15 (ddd, 1H), 2.24 (ddd, 1H), 2.57 (q, 2H) 2.58 (t, 2H), 5.12 (dt, 1H), 5.20 (dt, 1H), 7.00 (t, 2H), 7.38 (d, 1H), 7.42 (dd, 2H), 7.49 (s, 1H), 7.58 (ddt, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[C:22]4[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][O:27][C:23]4=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[Cl:1][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]3[O:27][CH2:28][CH2:29][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][C:22]3=2)[N:18]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c2C1
Temperature: 130 °C
Yield: 66.8 %

Procedure:
N-chlorosuccinimide (0.23 g, 0.54 mmol) was added to a solution of tert-butyl 8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 17, 0.23 g, 0.54 mmol) in chloroform (4 mL) and heated at 130° C. for 40 minutes in a microwave heater. The mixture was evaporated and purified by flash chromatography on silica gel using MeOH and DCM (1:99) as the eluent to give 167 mg of tert-butyl 10-chloro-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate. This intermediate (167 mg, 0.360 mmol) was dissolved in EtOH (20 mL) and a solution of 10 M KOH (0.2 mL, 2 mmol) was added. The mixture was heated at 65° C. for 20 minutes and the reaction mixture was evaporated and purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give an off-white solid (40 mg) in the form of the trifluoroacetate salt. MS m/z 223 [M+H−Boc]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:23]2([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[C:31]3[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=3)[NH:25][C:24]2=[O:33])[CH2:15][C:16](=[O:22])[NH:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:32][C:28]1[CH:27]=[C:26]2[C:31]([C:23]([N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][C:16]([NH:17][CH:18]3[CH2:19][CH2:20][CH2:21]3)=[O:22])([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[C:24](=[O:33])[NH:25]2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CC(=O)NC2CCC2)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN(C1CCNCC1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCC1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
At room temperature, 4-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-cyclobutylcarbamoylmethyl-amino}-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 1.17 mmol) was dissolved a mixture solution of CF3COOH and CH2Cl2. After stirred 0.5 h, the solution was concentrated and the organic layer was washed with NaOH aqueous solution. The organic layer was dried, concentrated to obtain crude product. The crude product was purified by chromatography to obtain 200 mg rac-2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidin-4-yl-amino}-N-cyclobutyl-acetamide.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=[O:19].C(N(CC)CC)C.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:28][SH:29]>N1C=CC=CC=1>[CH2:32]([O:31][C:27]([CH2:28][S:29][C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=[O:19])=[O:30])[CH3:33]
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(C=O)=C2Cl
Reactant: CCOC(=O)CS
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC1=C(C=O)CCc2c(C(=O)OCC)sc(SC)c21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a mixture of ethyl 4-chloro-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (3.00 g), triethylamine (1.44 g) and pyridine (25 ml), ethyl thioglycolate (1.37 g) was added at 0° C., followed by stirring at 0° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure; the residue was poured over water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and water in that order and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:7 to 1:5, v/v) to yield ethyl 4-ethoxycarbonylmethylthio-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (3.07 g, 81.0%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 102-103° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][SH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].II>C(Cl)Cl.C(N(CC)CC)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:9][S:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CSSCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
1.0 g of p-nitrobenzylmercaptan was dissolved in 30 of methylene chloride and 0.83 ml of triethylamine and 750 mg of iodine were added while maintaining the temperature at 25° C. and stirring for 10 minutes. After washing with N hydrochloric acid, the organic phase was dried and the solvent was evaporated. 20 ml of ether were added to the residue, and after stirring for 10 minutes, separating and drying, 839 mg of p-nitrobenzyl disulfide melting at 126° C. were obtained.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[C:6]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CN=C1.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[C:6]([C:11]([CH3:12])([O:14][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH3:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(O)c1cccc2c(I)n[nH]c12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(O[Si](C)(C)C)c1cccc2c(I)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
In a round-bottomed flask, 2-(3-iodo-1H-indazol-7-yl)-propan-2-ol (crude from Step 2, 479 mg, 1.11 mmol) was dissolved in DMF (3.2 ml) and imidazole (189 mg, 2.77 mmol) and trimethylsilyl chloride (0.17 ml, 1.33 mmol) were added. The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to give 383 mg (88%) of 3-iodo-7-(1-methyl-1-trimethylsilanyloxy-ethyl)-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 10.86 (br. s., 1H), 7.40 (dd, J=6.8, 2.3 Hz, 1H), 7.12-7.21 (m, 2H), 1.73 (s, 6H), 0.11 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][C:3]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].[Cl:34][CH:35](Br)[CH2:36][CH3:37]>CC(C)=O>[NH2:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][C:3]=1[O:27][CH2:37][CH2:36][CH2:35][Cl:34]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(N)c(O)c2)c2ccccc21
Reactant: CCC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(N)c(OCCCCl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 4-[3-(4-amino-3-hydroxybenzoyl)indol-1-yl]butanoate (30 g) was suspended in acetone (390 ml), potassium carbonate (23.8 g) and chlorobromopropane (24 ml) were added to the suspension. The mixture was stirred at room temperature for four hours. The reaction mixture was cooled and filtrated. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 22.8 g of ethyl 4-{3-[4-amino-3-(3-chloropropoxy)benzoyl]indol-1-yl}butanoate as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[S:7][CH3:8].ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[S:7]([CH3:8])=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccsc1Br
Solvent: ClCCl
Product: CS(=O)c1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of compound 25 (3.64 g, 17.4 mmol) in CH2Cl2 (100 mL) at −40° C., was added 3-chloroperbenzoic acid (3 g, 17.4 mmol) in CH2Cl2 (50 mL) dropwise and the resulting solution was allowed to stir at room temperature overnight. The reaction mixture was washed with aqueous Na2CO3, dried with anhydrous sodium sulfate and evaporated in vacuum. Column chromatography (silica gel, hexane/EtOAc (1/2) yields the pure compound 26 (2.74 g, 70%). 1H NMR (CDCl3): δ 2.82 (3H, s), 7.35 (1H, d), 7.43 (1H, d). MS (EI): calcd, 225.1. found M+, 210.1=product-16).
Reaction SMILES: [OH-:1].[K+].OO.[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[C:11]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>O.C(O)C>[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:1])[C:11]([CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[N:10]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: [OH-]
Reactant: CC(C)(C)n1nc(CC2CCCCC2)c(C#N)c1N
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)n1nc(CC2CCCCC2)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 12.2 %

Procedure:
To potassium hydroxide (4.95 g, 0.09 mol) in 50% water/ethanol (83 ml) was added 30% hydrogen peroxide (6.7 ml, 0.06 mol) followed by 1-tert-butyl-3-(cyclohexylmethyl)-5-amino-1H-pyrazole-4-carbonitrile (2.8 g, 0.01 mol). The reaction mixture was stirred at room temperature for 24 hours, then was heated on a steam bath for 4 hours. More 30% hydrogen peroxide was added (6.5 ml, 0.057 mol) and the reaction mixture was heated for an additional 2 hours. The solvent was removed in vacuo, water was added and the residue was extracted with ethyl acetate (2×). The organic layer was washed with brine, dried over anhydrous MgSO4 and the solvent was removed in vacuo. The residue was purified by preparative thin layer chromatography on silica eluting with ethyl acetate (100%) to afford 0.34 g (11%) of 1-tert-butyl-3-(cyclohexylmethyl)-5-amino-1H-pyrazole-4-carboxamide as an amber oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][C@H:8]1/[CH:32]=[CH:33]\[C:34]([NH2:36])=[O:35])=[O:6])[CH:2]=[CH2:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([SH:12])[CH2:9][C@H:8]1/[CH:32]=[CH:33]\[C:34]([NH2:36])=[O:35])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C\C(N)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1/C=C\C(N)=O
Reaction time: 0.5 h

Procedure:
To a solution of (Z)-3-[(2S,4S)-N-allyloxycarbonyl-4-tritylthiopyrrolidin-2-yl]acrylamide (1.02 g, 2.06 mmol) in methylene chloride (1 ml) were added trifluoroacetic acid (1 ml) and triethylsilane (0.33 ml, 2.07 mmol) under ice-cooling under nitrogen. The reaction mixture was stirred for 30 minutes at the same temperature, concentrated under reduced pressure, and diluted with methylene chloride (5 ml). The mixture was concentrated again, and extracted with ethyl acetate (50 ml). The organic layer was washed with 0.1M phosphate buffer (pH 5.7×2) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to give (Z)-3 [(2S,4S)-N-allyloxycarbonyl-4-mercaptopyrrolidin-2-yl]acrylamide, which was used for the next reaction without purification. ##STR328##