Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.Cl.[CH3:42][C:43]1[N:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:49]([C:46]2[CH:47]=[N:48][C:43]([CH3:42])=[CH:44][CH:45]=2)(=[O:51])=[O:50])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 31 mg) in tetrahydrofuran (3 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg), 15-crown-5 (170 mg), 6-methylpyridine-3-sulfonyl chloride hydrochloride (91 mg) at room temperature, and the mixture was stirred for 1.5 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=17:3→1:1) to give the title compound as a pale-yellow oil (yield 123 mg, 83%).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[C:33]([OH:40])[C:32]=2[CH2:41][CH2:42][CH3:43])[C:10]=1[CH2:44][CH2:45][CH3:46])C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH-].[Na+].CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])=[C:10]([CH2:44][CH2:45][CH3:46])[C:11]=1[O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[C:33]([OH:40])[C:32]=1[CH2:41][CH2:42][CH3:43])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 78.1 %

Procedure:
A solution of 2.30 g of 4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester in 17 ml of 1.0N sodium hydroxide and 50 ml of methanol was stirred at reflux for 7 hours. The methanol was removed in vacuo and the residue was acidified. The product was extracted with ether and the dried (magnesium sulfate) extract was concentrated in vacuo to an oil (2.40 g). Chromatography on 150 g of silica gel and elution with a solvent mixture of 5% acetic acid: 70% toluene: 25% ethyl acetate gave 1.72 g (78% yield) of 4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[N:17]1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:30]#[C:29][CH:31]3[CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[N:17]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 56.8 %

Procedure:
To a solution of N-(4-chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-95, 0.100 g, 0.196 mmol) in DMSO (3.0 mL), ethynylcyclopropane (0.035 g, 0.530 mmol), TBAF (0.150 g, 0.574) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were added and the reaction mass was stirred at 80° C. for 5-6 h. After completion of the reaction, the reaction mass was quenched with water and extracted with DCM and concentrated to afford 0.050 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 0.76-0.91 (m, 2H), 0.91-0.92 (m, 2H), 1.11 (s, 9H), 1.57 (m, 1H), 4.28 (br d, 2H), 7.31-7.34 (br d, 1H), 7.42 (br s, 1H), 7.47-7.50 (br m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 8.18 (s, 1H), 12.58 (s, 1H); MS (m/z): 449.52 (M+H)+.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:33]=[C:32]([O:34]CC2C=CC=CC=2)[CH:31]=[CH:30][C:11]=1[C:12]([NH:14][C@H:15]([C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13])C1C=CC=CC=1>[H][H].[C].[Pd]>[ClH:1].[OH:9][C:10]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:11]=1[C:12]([NH:14][C@H:15]([C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])=[O:13]
Reactant: [H][H]
Reactant: CN1CCN(C(=O)[C@H](CCC(N)=O)NC(=O)c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Product: CN1CCN(C(=O)[C@H](CCC(N)=O)NC(=O)c2ccc(O)cc2O)CC1
Yield: 85.9 %

Procedure:
10% Palladium-carbon (200 mg) was added to an ethanolic solution (50 ml) of 1-(2,4-dibenzyloxybenzoyl-L-glutaminyl)-4-methylpiperazine.hydrochloride (270 mg) obtained above and catalytic reduction was carried out at room temperature and under atmospheric pressure in hydrogen stream. Thereafter, treatments were conducted in the same manner as in Example 5 (ii) to obtain colorless crystalline powder 1-(2,4-dihydroxybenzoyl-L-glutaminyl)-4-methylpiperazine.hydrochloride (160 mg). Melting point: 144°-145° C.
Reaction SMILES: [C:1]1(=[CH:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[N+:15]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=C2CCCC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC2CCCC2)c(N)c1
Yield: 64.4 %

Procedure:
A solution of 1-(cyclopentylidenemethyl)-4-methoxy-2-nitrobenzene (1.8 g; 0.09 M, 7.72 mmol; 1 eq) in MeOH (80 mL) is pumped through the H-Cube™ flow hydrogenator fitted with a 10 mol % Pd/C catalyst cartridge (30×4 mm) heated to 25° C. at 1 bar with the full hydrogen option enabled. The flow rate is set at 1 mL/min. The catalyst is pre-saturated with hydrogen gas for 2 min before passing the substrate through. The solvent is evaporated under reduced pressure and the residue is taken up in HCl 1N and EtOAc. The organic phase is washed with brine then dried over MgSO4, and the solvent is evaporated under reduced pressure to afford 1.02 g (64%) of the title compound as a brown oil. 1H NMR (CDCl3) δ 6.94 (d, J=8.3 Hz, 1H), 6.45-6.35 (m, 2H), 4.45-3.90 (m, 2H), 3.75 (s, 3H), 2.45 (d, J=7.0 Hz, 2H), 2.12 (q, J=7.0 Hz, 1H), 1.78-1.45 (m, 6H), 1.35-1.05 (m, 2H). HPLC (max plot) 89%; Rt 2.86 min. LC/MS: (ES+): 206.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH2:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn].C([O-])(O)=O.[Na+].CCOCC>CO.Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH2:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1CS(=O)(=O)c1ccccc1
Temperature: 45 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A mixture of 1-benzyl-4-{4-nitro-3-[(phenylsulfonyl)methyl]phenyl}piperazine (6.77 g, 15.0 mmol) and granular tin (7.48 g, 63.0 mmol) in methanol and conc. hydrochloric acid is heated at 45° C. for 4 h, stirred at ambient temperature for 18 h, carefully poured into saturated aqueous NaHCO3, treated with ether and stirred for 0.5 h. The phases are separated and the aqueous phase is extracted sequentially with ether and CH2Cl2. The extracts and organic phase are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is dissolved in CH2Cl2 and filtered through Celite®. The filtrate is concentrated in vacuo to afford the title compound as a pale yellow solid, 6.11 g (97% yield), mp 141–143° C., characterized by NMR and mass spectral analyses
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].Cl[C:9]1[C:10]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[N:12]=[CH:13][N:14]=1.[CH2:26]([O:28][CH:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)[CH3:30])[CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)CC>[CH2:26]([O:28][CH:29]([N:31]1[CH:35]=[C:34]([C:9]2[C:10]3[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:33]=[N:32]1)[CH3:30])[CH3:27]
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Product: CCOC(C)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 90 °C

Procedure:
To a reactor equipped with overhead stirring, condenser, thermowell, and nitrogen inlet was charged water (H2O, 1.5 L), potassium carbonate (K2CO3, 1047 g, 7.58 mol, 2.45 equiv), 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 755 g, 2.66 mol), crude 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14, 822 g based on 100% conversion, 3.09 mol, 1.16 equiv) made as described above, and 1-propanol (6 L) at room temperature. The resulting reaction mixture was degassed three timed backfilling with nitrogen each time before being treated with tetrakis(triphenylphosphine)palladium(0) (9.2 g, 0.008 mol, 0.0026 equiv) at room temperature. The resulting reaction mixture was heated to gentle reflux (about 90° C.) for 1-4 hours. When the reaction was deemed complete by HPLC, the reaction mixture was concentrated under reduced pressure to remove solvents. The residue was then cooled to room temperature, diluted with ethyl acetate (9 L) and water (4 L). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×2.5 L). The combined organic layers were washed with water (2×2 L) and concentrated under reduced pressure to afford the crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (15), which was directly used in the subsequent acid-promoted de-protection reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1/[CH:15]=[C:16](\[CH3:22])/[C:17]([O:19]CC)=[O:18].[OH-].[K+]>CCO>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1/[CH:15]=[C:16](\[CH3:22])/[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
Emmons ester 28a (0.231 g, 0.769 mmol) was dissolved in EtOH (10.0 mL) and then KOH (0.400 g, 7.13 mmol) was added to the reaction. The reaction was heated to boiling and stirred at this temperature for 30 minutes. The reaction was then cooled, acidified, and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and condensed. The resulting acid was then used as crude, or can be purified via flash chromatography (1:3 EtOAc:hexanes 0.5% AcOH) or recrystallization from Et2O/hexanes to provide 29a (0.175 g, 0.643 mmol, 83%) as a white solid.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21](=[O:78])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([Cl:40])[CH:38]=3)[N:33]([CH:41]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:32]=2[CH2:54][CH2:55][O:56][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:24][C:23]=1[O:74][CH:75]([CH3:77])[CH3:76]>C1COCC1>[CH3:19][O:20][C:21](=[O:78])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([Cl:40])[CH:38]=3)[N:33]([CH:41]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:32]=2[CH2:54][CH2:55][OH:56])=[CH:24][C:23]=1[O:74][CH:75]([CH3:76])[CH3:77]
Reactant: COC(=O)c1ccc(OCCc2c(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
TBAF (1M in THF) (0.29 mL, 0.29 mmol) was added to a solution of the silyl ether from step 3 (0.20 g, 0.24 mmol) in THF (4 mL). Reaction was stirred at room temperature for 30 minutes. Reaction solution was concentrated by rotary evaporation and the resulting residue was purified with silica gel prep plates and 1:9 EtOAc/dichloromethane as eluent. Obtained 0.10 g of 4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoic acid methyl ester (brown solid) in 70% yield.
Reaction SMILES: [ClH:1].C([O:4][C:5](=[O:44])[C@@H:6]([NH:14][C:15](=[O:43])[C@@H:16]([NH:23][C:24](=[O:42])[CH:25]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[NH:35])[NH2:34])=[CH:29][CH:28]=1)[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH2:13])=[NH:12])C.O>Cl>[ClH:1].[C:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH:25]([CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)[C:24]([NH:23][C@@H:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:15]([NH:14][C@@H:6]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH2:13])=[NH:12])[C:5]([OH:44])=[O:4])=[O:43])=[O:42])=[CH:32][CH:31]=1)(=[NH:34])[NH2:35]
Reactant: CCOC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C1CCCCC1)C1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(S)-{2(S)-[3-(4-Carbamimidoyl-phenyl)-2-cyclohexyl-propionylamino]-2-cyclohexyl-acetylamino}-5-guanidino-pentanoic acid ethyl ester hydrochloric acid salt (6 mg, 8.07 μmol, less polar diastereomer, example 5) was solved in 4 N hydrochloric acid (1 ml) and stirred for 4 hours at room temperature. Water was added and the reaction mixture lyophilized to give 5 mg (quantitative yield) of the desired product. MS m/z: 570.5 ((M+H)+, 1%), 285.9 ((M+2H)2+, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.O.O.[Sn](Cl)Cl.Cl>CC(O)=O>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1noc2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1noc2ccc(N)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a stirred solution of 3-methyl-5-nitrobenzo[d]isoxazole (Step 33.2) (1.8 g, 10.10 mmol) in AcOH (40 mL) was added a solution of tin(II) chloride dihydrate (6.84 g, 30.3 mmol) in HCl (15 mL, 494 mmol). The reaction mixture was stirred for 1 hr at 100° C., quenched with a saturated aq. NaHCO3 solution, diluted with water, and extracted with CH2Cl2. The combined organic layers were washed once with a saturated aq. NH4Cl solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50) to afford the title product (458 mg, 3.09 mmol, 31% yield) as a pink solid. tR: 0.50 min (LC-MS 2); ESI-MS: 149 [M+H]+ (LC-MS 2); Rf=0.45 (hexane/EtOAc 1:1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.I.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](SC)=[NH:23].ClCCl>C(O)C.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)=[NH:23])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCn1ccc2cc(N)ccc21
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CN(C)CCn1ccc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 3 h
Yield: 21.9 %

Procedure:
A solution of compound 92 (0.104 g, 0.512 mmol) in absolute ethanol (3 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.290 g, 1.02 mmol) at room temperature and the resulting mixture was stirred for 3 hours. The reaction was diluted with saturated aqueous sodium bicarbonate (5 mL) followed by dichloromethane (30 mL) and transferred to a separatory funnel. The aqueous was extracted twice more with dichloromethane (2×30 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 5:95). Product was dried under high vacuum. HPLC revealed a 10% impurity. A second purification by column chromatography using less polar solvent conditions (2M ammonia in methanol:dichloromethane, 0:100-2.5:97.5) afforded pure product 93 (35 mg, 22%) as a yellow oil. 1H NMR (CDCl3) δ 7.43 (d, J=4.5 Hz, 2H), 7.33 (d, J=8.7 Hz, 1H), 7.21 (d, J=1.2 Hz, 1H), 7.13 (d, J=3.0 Hz, 1H), 7.08 (t, J=4.2 Hz, 1H), 6.67 (dd, J=1.8, 8.7 Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 4.22 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.31 (s, 6H); ES-MS (m/z, %): 313 (M+1); ESI-HRMS calculated for C17H21N4S (MH+): 313.1481, Observed: 313.1467.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[H-].[Na+].[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][NH:25][C:26](=[O:29])[CH2:27]Cl)[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24][NH:25][C:26](=[O:29])[CH2:27][S:3][C:1](=[O:4])[CH3:2])[CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(O)=S
Reactant: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 0.47 ml of thioacetic acid in 20 ml of tetrahydrofuran was added dropwise, whilst ice-cooling and in an atmosphere of nitrogen, to a suspension of 0.29 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 20 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 2.00 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-chloroacetamide [prepared as described in step (a) above] in 20 ml of tetrahydrofuran was added dropwise to the mixture, whilst ice-cooling, after which it was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, the residue was mixed with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 1.72 g (yield 77%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[NH4+:23].[OH-]>O1CCOCC1>[NH2:23][C:2]1[C:19](=[O:20])[CH:18]=[CH:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: C[C@]12C=CC(=O)C(Cl)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)C(N)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 75 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A mixture of 4-chloroandrosta-1,4-diene-3,17-dione (957 mg, 3 mmole), dioxane (30 ml) and 30% NH4OH aqueous solution (60 ml) is stirred at 75° C. in a pressure vessel during 18 hours. After cooling to room temperature, the reaction mixture is worked up as described in the Example 1. There are obtained 242 mg (0.81 mmole, 27% yield) of the title compound as a yellow solid.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[S:24])[NH2:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].N1(C(OC(C)(C)C)=O)CCNCC1.C(N1C=CN=C1)(N1C=CN=C1)=S.N>>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22](=[S:24])[N:23]=[CH:3][N:4]([CH3:6])[CH3:5])[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: COC(OC)N(C)C
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: N
Agent: S=C(n1ccnc1)n1ccnc1
Product: CN(C)C=NC(=S)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 95 %

Procedure:
A mixture of 122 mmol N,N-dimethylformamide dimethyl acetal and 6.11 mmol 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl 1-piperazinecarboxylate, 1,1′-thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037–5054) was heated at 110° C. for 3 h. The reaction mixture was then concentrated in vacuo and the residue was resuspended in ethyl acetate/tetrahydrofuran (1:1) and washed with brine. The organic phase was dried over sodium sulphate and concentrated in vacuo to afford the title compound as a light yellow crystalline solid (yield 95%). MS (m/e): 301.4 (M+H+, 100%).
Reaction SMILES: [K].[CH2:2]([O:4][C:5](=[O:11])[C:6]([C:9]#[N:10])=[CH:7]O)[CH3:3].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>ClCCl>[CH2:2]([O:4][C:5](=[O:11])[C:6](=[CH:7][Cl:13])[C:9]#[N:10])[CH3:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C#N)=CO
Agent: [K]
Solvent: ClCCl
Product: CCOC(=O)C(C#N)=CCl
Reaction time: 2 h

Procedure:
Potassium salt of 2-cyano-3-hydroxy-acrylic acid ethyl ester described in Preparation Example C-1 (18 g, 0.1 mol) was dissolved in dichloromethane (80 mL), phosphorus pentachloride (20.9 g, 0.1 mol) was added, and the solution was stirred for 2 hours under reflux. After the reaction was completed, the residue obtained by evaporating dichloromethane was subjected to distillation in vacuo, and ethyl(chloromethylene)cyanoacetate (9.5 g, 56 mmol) was obtained.