Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N:23]=[N+:24]=[N-:25])=[CH:11][C:10]=1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31](=[O:54])[C:32]#[C:33][N:34]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1.CCOC(C)=O.O>CN(C=O)C>[CH3:29][O:30][C:31]([C:32]1[N:25]=[N:24][N:23]([C:12]2[CH:11]=[C:10]([CH:26]([CH3:28])[CH3:27])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][C:13]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:33]=1[N:34]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)=[CH:39][CH:40]=1)=[O:54]
Reactant: COC(=O)C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (373 mg, 1 mmol) and [t-butoxycarbonyl-(4-morpholin-4-yl-phenyl)-amino]-propynoic acid methyl ester (328 mg, 0.91 mmol) in DMF (2.5 ml) was degassed at RT by means of three vacuum-nitrogen cycles before adding [Cp*RuCl]4 (49 mg, 0.045 mmol) and repeating the three degassing cycles with nitrogen. The reaction mixture was stirred at RT until completion (i.e., monitored by TLC). AcOEt and H2O were then added. The organic phase was extracted four times with AcOEt, washed with water (three times) and brine (once) and dried over Na2SO4. The solvent was removed under reduced pressure and the reaction mixture was purified by column chromatography (PE/AcOEt:60/40). The title compound was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:15]([O:17]CC)=[O:16])[OH:14].O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:15]([OH:17])=[O:16])[OH:14]
Reactant: CCOC(=O)C1(O)CCSc2c(OC)cc(Cl)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)cc2c1SCCC2(O)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice/water-cooled solution of 6-chloro-4-hydroxy-8-methoxythiochromane-4-yl-carboxylic acid, ethyl ester (2.26 g, 7.46 mmol; see step (iv) above) in THF (20 mL) was added a solution of lithium hydroxide monohydrate (0.68 g, 16 mmol) in water (10 mL). The temperature was allowed to slowly rise to ambient overnight. THF was removed in vacuo, the residue was washed with diethyl ether, acidified with 2 M aq. HCl and then extracted with ethyl acetate. Drying (MgSO4) and removal of the solvent in vacuo afforded the sub-title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][CH:15]=[C:14]([CH:17]=[CH:18][C:19]([OH:21])=O)[C:13]=3[CH:22]=2)[S:3]1.CCN(C(C)C)C(C)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1>[O:21]=[C:19]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH:18]=[CH:17][C:14]1[C:13]2[CH:22]=[C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH:10]=[CH:11][C:12]=2[O:16][CH:15]=1
Reactant: C1CCNCC1
Reactant: O=C(O)C=Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)C(=Cc2ccc3occ(C=CC(=O)N4CCCCC4)c3c2)S1
Reaction time: 1 h

Procedure:
180 mg (0.57 mmol) of 3-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzofuran-3-yl]-acrylic acid (example 72) was suspended in THF (25 ml). To this suspension was added DIEA (2 eq.) and piperidine (3 eq.). Under stirring was added PyBOP (1.5 eq.). After 30 min the reaction mixture became clear, after an additional 1 h a precipitate was formed. The reaction was stirred overnight. The precipitate was filtered off and washed with THF and 1N HCl affording the title compound in high purity.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:32])([CH3:31])[C:15]([NH:17][CH:18]1[CH:25]2[CH2:26][C:21]3([C:28]([NH2:30])=[O:29])[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2)=[O:16])(=[O:12])=[O:11])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:32])([CH3:31])[C:15]([NH:17][CH:18]1[CH:25]2[CH2:26][C:21]3([C:28]([NH2:30])=[O:29])[CH2:22][CH:23]([CH2:27][CH:19]1[CH2:20]3)[CH2:24]2)=[O:16])(=[O:11])=[O:12]
Reactant: CC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)NC1C2CC3CC1CC(C(N)=O)(C3)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(NS(=O)(=O)c1ccccc1N)C(=O)NC1C2CC3CC1CC(C(N)=O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
Ina 25-mL flask, 4-[2-(2-nitro-benzenesulfonylamino)-2-methyl-propionylamino]-adamantane-1-carboxylic acid amide (30 mg, 0.0645 mmol) and methanol (5 mL) were charged and dissolved, and 5% Pd/c (10 mg) was added thereto. The reaction vessel was degassed under reduced pressure, and filled with hydrogen. At room temperature, through stirring for 3 hours, the reaction was completed. Then, through celite filtering, Pd was removed. At 35° C., through vacuum evaporation, 4-[2-(2-amino-benzenesulfonylamino)-2-methyl-propionylamino]-adamantane-1-carboxylic acid amide (21 mg, 75.0%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]12[CH2:16][CH:15]1[CH2:14][NH:13][CH2:12]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:11]12[CH2:16][CH:15]1[CH2:14][N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:12]2
Reactant: C1NCC2CC12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CC3CC3C2)nc1
Yield: 85.1 %

Procedure:
A suspension of 0.2 g (1.26 mmol) of 2-chloro-5-nitropyridine, of 0.166 g (1.39 mmol) of 3-azabicyclo[3.1.0]hexane (Bioorg. &Med. Chem. Lett. 2005, 15(8) 2093) and of 0.52 g (3.78 mmol) of potassium carbonate in 5 ml of dimethylformamide is stirred at ambient temperature for 36 hours. The mixture is subsequently poured into 5 ml of water and then extracted 3 times with 20 ml of ethyl acetate. The organic phases are subsequently combined, dried over magnesium sulfate, and then concentrated under reduced pressure. 0.22 g of the expected product is thus obtained, which product is used as it is in the rest of the synthesis.
Reaction SMILES: C(OC([N:8]([C:24]1[N:25]([CH2:38][CH2:39][CH3:40])[N:26]=[C:27]2[C:36]=1[C:35]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:29]=[C:28]2[Cl:37])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=O)(C)(C)C.[ClH:41].[NH3:42]>CO.C(O)C>[ClH:37].[ClH:41].[NH:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][NH:8][C:24]2[N:25]([CH2:38][CH2:39][CH3:40])[N:26]=[C:27]3[C:36]=2[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:29]=[C:28]3[NH2:42])[CH2:16][CH2:15]1
Reactant: CCCn1nc2c(Cl)nc3ccccc3c2c1N(CCC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C
Reactant: N
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCNCC1
Temperature: 150 °C

Procedure:
A solution of tert-butyl 4-{2-[(tert-butoxycarbonyl)(4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}piperidine-1-carboxylate (1.41 g) in 7N ammonia in methanol (25 mL) was placed in a stainless steel pressure vessel and heated at 150° C. for 18 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure to provide a brown residue. The residue was suspended in anhydrous ethanol (20 mL). Hydrochloric acid (4 mL of 3M) was added and the reaction mixture was heated at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was isolated by filtration to provide 0.7 g of N1-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine dihydrochloride as a brown solid. MS (APCI) m/z 353.30 (M+H)+. The experiment was repeated using 5.75 g of tert-butyl 4-{2-[(tert-butoxycarbonyl)(4-chloro-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}piperidine-1-carboxylate in 70 mL of 7N ammonia in methanol followed by treatment with 16.75 mL of 3M hydrochloric acid to provide 4.1 g of product as a brown solid. MS (APCI) m/z 353.26 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]([CH3:19])([CH2:17]O)[C:13]([O:15][CH3:16])=[O:14].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH3:11][C:12]([CH3:19])([CH2:17][O:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C)(C)CO
Reactant: O=[N+]([O-])c1ncccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)COc1cccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
3-Hydroxynitropyridine (10.0 g, 64 mmol), methyl 2,2-dimethyl-3-hydroxypropionate (9.29 g, 70.4.0 mmol) and PPH3 (15.15 g, 76.8 mmol) were dissolved in dioxane (500 mL). DIAD (14.5 mL, 76.8 mmol) was added at 0° C. over 5 min and the mixture was stirred at rt for 4 h then refluxed overnight. The mixture was evaporated, dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo to afford the title compound (9.1 g, 61%). 1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=1.4 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.70 (m, 1H), 4.43 (s, 2H), 3.59 (s, 3H), 1.17 (s, 6H)
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[ClH:24]>Br>[ClH:24].[ClH:24].[N:18]1([CH2:17][CH2:16][N:11]2[C@@H:12]3[C@@H:8]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([OH:2])[C:15]=4[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCN1CCCCC1
Agent: Br
Agent: Cl
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCN1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
3.8 g (0.0121 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-(2-piperidinoethyl)-1H-benzo[e]indole were dissolved in 0.351 of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was concentrated and the residue was taken up in CH2Cl2 and extracted with a mixture of 100 ml of saturated NaHCO3 solution and 20 ml of 2N NaOH solution. The extracts were dried with MgSO4, filtered and concentrated. The foam (3.8 g) remaining as the residue was dissolved in 50 ml of ethanol. The mixture was filtered, 4.8 ml (27.84 mmol) of 5.8N ethanolic HCl solution were added dropwise thereto and the mixture was stirred at room temperature for 1 hour and at 0° for 1 hour. The separated crystals were filtered off under suction and washed with ethyl acetate. There were obtained 4.3 g (95%) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(2 -piperidinoethyl)-1H-benzo[e]indol-6-ol dihydrochloride as white crystals with m.p. 265°-267°.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[N:13]=[C:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[C:35]5[C:30](=[CH:31][C:32]([O:36]CC6C=CC=CC=6)=[CH:33][CH:34]=5)[C:29]([C:44]#[N:45])=[CH:28]4)=[CH:22][C:20]=3[CH:21]=2)[S:15][CH:16]=1)([CH3:11])([CH3:10])[CH3:9].C1C(O)=CC=CC=1C.C1(SC)C=CC=CC=1.C(S)(S)C.C(=O)([O-])O.[Na+]>O>[C:8]([C:12]1[N:13]=[C:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[C:35]5[C:30](=[CH:31][C:32]([OH:36])=[CH:33][CH:34]=5)[C:29]([C:44]#[N:45])=[CH:28]4)=[CH:22][C:20]=3[CH:21]=2)[S:15][CH:16]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(OCc6ccccc6)ccc54)ccc3o2)n1
Agent: CC(S)S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSc1ccccc1
Solvent: O
Solvent: Cc1cccc(O)c1
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(C#N)c5cc(O)ccc54)ccc3o2)n1
Reaction time: 4 h
Yield: 68.4 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a mixture of 4-tert-butyl-2-{5-[(3-cyano-5-benzyloxyindol-1-yl)methyl]benzofuran-2-yl}thiazole (0.54 g), m-cresol (0.28 ml), thioanisole (0.28 ml) and ethanedithiol (0.56 ml) under ice-cooling. After being stirred for 4 hours, the mixture was poured into water (100 ml) and the resulting mixture was neutralized with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine successively, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-[(3-cyano-5-hydroxyindol-1-yl)methyl]benzofuran-2-yl}thiazole (305 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[N:8]=1)C.O.[NH2:25][NH2:26].C(O)C>O>[Cl:13][C:11]1[CH:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])[N:8]=[C:7]([S:6][CH2:5][C:4]([NH:25][NH2:26])=[O:3])[N:12]=1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Nc2cccc(C)c2C)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)NN)n2)c1C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g of [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid ethyl ester and 5.0 g of hydrazine hydrate (98%) in 40 ml. of ethanol was allowed to stand overnight at room temperature. Water was added to the mixture until a precipitate appeared. This material was recrystallized from ethanol affording 4.8 g of product, mp. 185°-189°C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2([OH:24])[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH3:23].[CH3:25][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[S:35](Cl)(=[O:37])=[O:36].S(Cl)(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:35]([C:28]1[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=1[O:26][CH3:25])(=[O:37])=[O:36])[C:12](=[O:17])[C:11]2([OH:24])[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: Cc1ccsc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2C(=O)C(O)(c3sccc3C)c3cc(Cl)ccc32)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
Potassium tert-butoxide (1.21 g, 10.8 mmol) was added to an ice-cold solution of the intermediate from step A (3.00 g, 10.8 mmol) in DMF (30 ml), and the mixture was stirred at 0° C. for 30 min. After addition of 2,4-dimethoxy-benzenesulfonyl chloride (2.5 g, 10.8 mmol), the reaction mixture was left to stir at 0° C. for 1 hour. Further addition of 0.2 equivalent each of potassium tert-butoxide and sulfonyl chloride led to no further advance in the reaction according to thin-layer chromatography. The reaction mixture was stirred into dilute potassium carbonate solution, and the resulting precipitate was filtered off. The precipitate was taken up in ethyl acetate, and the extract was washed with saturated brine and dried over magnesium sulfate. Purification by chromatography (silica gel, gradient 30% to 50% ethyl acetate in heptane) and recrystallization from diethyl ether resulted in 0.96 g of the desired product.
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>C(OCC)(=O)C.[Pd]>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Yield: 98 %

Procedure:
The resulting Boc-Gly-Phe-Gly-OBzl (1.78 g) was dissolved in ethyl acetate (60 ml) and subjected to catalytic reduction for 24 hours in the presence of 5%-Pd—C (1.8 g). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain Boc-Gly-Phe-Gly-OH (1.41 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH2:24][C@H:25](O)[CH3:26])[CH:23]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[O:28]1CCC(N2C=C(N)C=N2)[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH:24]5[CH2:25][CH2:26][O:28][CH2:29][CH2:30]5)[CH:23]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccn3nc(Nc4cnn(C[C@@H](C)O)c4)nc23)cc1
Reactant: Nc1cnn(C2CCOCC2)c1
Product: COc1ccc(-c2cccn3nc(Nc4cnn(C5CCOCC5)c4)nc23)cc1

Procedure:
Made by following the procedure described for the preparation of (R)-1-(4-(8-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1H-pyrazol-1-yl)propan-2-ol with 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine and making non-critical variations. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.64 (dd, J=6.6, 0.9 Hz, 1H), 8.14 (d, J=8.9 Hz, 2H), 7.87 (s, 1H), 7.73 (m, 1H), 7.50 (s, 1H), 7.08 (d, J=8.9 Hz, 3H), 4.35 (m, 1H), 3.98 (dd, J=13.4, 10.9 Hz, 2H), 3.83 (s, 3H), 3.47 (m, 2H), 1.93 (m, 4H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[S:31][C:30]3[N:32]4[C:23](=[CH:24][N:25]=[C:26]4[CH:27]=[CH:28][CH:29]=3)[CH:22]=2)=[O:20])[C:11](=[O:33])[CH2:10]1)=O)(C)(C)C>>[ClH:1].[ClH:1].[O:33]=[C:11]1[CH2:10][NH:9][CH2:14][CH2:13][N:12]1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[S:31][C:30]2[N:32]3[C:23](=[CH:24][N:25]=[C:26]3[CH:27]=[CH:28][CH:29]=2)[CH:22]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCNC(=O)C2=Cc3cnc4cccc(n34)S2)C(=O)C1
Agent: Cl
Product: O=C(NCCCN1CCNCC1=O)C1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid (4.0 ml) was added to N-[3-(4-tert-butoxycarbonyl-2-oxopiperazin-1-yl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.53 g, 3.34 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo to give N-[3-(2-oxopiperazin-1-yl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride as an orange amorphous powder(1.53 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([S:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccccc1S
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccccc1Sc1ccc(C=O)c(Cl)c1Cl
Temperature: 50 °C
Yield: 84.5 %

Procedure:
2,3-Dichloro-4-trifluoromethanesufonyloxy-benzaldehyde (2.50 g) was dissolved in 6 mL acetonitile. 2-Methoxybenzenethiol (2.55 g of 70% pure material, 50% excess) was added. With cooling 2.50 g diisopropylethylamine was added slowly. The solution was removed from the ice bath, whereon a solid formed. The solution was warmed in a 50° C. waterbath for 5 minutes. More acetonitrile (5 mL) was added and the mixture was cooled in ice, and then filtered to get 2.047 g of product, m.p. 137-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([NH:29][CH3:30])[C:6]=2[CH:31]=1.C=O.[C:34]([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:26])=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([N:29]([CH3:34])[CH3:30])[C:6]=2[CH:31]=1
Reactant: CNC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)s2)c2ccc(Cl)cc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C)c3cc(Cl)ccc32)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of 7-chloro-5-methylamino-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g) in methanol (10 ml) are added 37% formaldehyde (0.8 ml) and sodium cyanoborohydride (0.1 g), and further thereto is added dropwise acetic acid (0.6 ml) at a temperature below 10° C. The mixture is stirred at room temperature for one hour, and poured into ice-water. The mixture is made basic with potassium carbonate, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-dimethylamino-1-[5-(2-methylbenzoylamino)thenoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.41 g) as colorless amorphous.
Reaction SMILES: [O:1]1[C:11]2([CH3:12])[CH:2]1[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:13]([OH:15])=[O:14])=[CH:9][C:10]=12.[K].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.N1C=CN=C1.[K]>CN(C=O)C>[OH:1][C:11]1([CH3:12])[C:10]2[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: CC12OC1CCc1ccc(C(=O)O)cc12
Agent: [K]
Solvent: CN(C)C=O
Product: CC1(O)c2cc(C(=O)O)ccc2CCC1n1ccnc1
Temperature: 130 °C

Procedure:
A solution of 1.9 g of 5,6-dihydro-7,8-epoxy-8-methyl-2-naphthalenecarboxylic acid (prepared by epoxidation of 5,6-dihydro-8-methyl-2-naphthalenecarboxylic acid, m.p. 150°-153° C.) in anhydrous DMF is added to a solution of imidazole potassium salt, prepared from prepared from 3.16 g of imidazole and 1.81 g of potassium, in anhydrous DMF (100 ml) and heated at 130° C., with vigorous stirring, for 6 hours. The solvent is evaporated under reduced pressure and the residue is taken up with water and ethyl acetate. The aqueous layer is separated and acidified to pH=5 with acetic acid. The water is evaporated under vacuum and the residue is chromatographed on silica gel (eluent CHCl3 :CH3OH, 70:30) giving 1.6 g of 5,6,7,8-tetrahydro-8-hydroxy-8-methyl-7-(1H-imidazol-1-yl)-2-naphthalenecarboxylic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]4[C:26]=3[C:25]3[C@@H:24]([CH2:27][C:28]#[N:29])[CH2:23][CH2:22][C:21]=3[S:20]4)[CH2:10][CH2:9]2)[CH2:3]1.[OH:30][Li].O.OO>CO>[O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:9][CH2:10][CH:11]([O:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]4[C:26]=3[C:25]3[C@@H:24]([CH2:27][C:28]([NH2:29])=[O:30])[CH2:23][CH2:22][C:21]=3[S:20]4)[CH2:12][CH2:13]2)[CH2:3]1
Reactant: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Reactant: [Li]O
Agent: OO
Solvent: CO
Solvent: O
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (330 mg, 0.80 mmol, 1.00 equiv) in methanol (10 mL) was added LiOH.H2O (101 mg, 2.40 mmol, 3.00 equiv) and H2O2 (30%, 0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature and quenched with Na2SO3 (aq.), extracted with DCM (80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give 50 mg (15%) of 2-[(3R)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide as a white solid. [Note: The product was found to decompose during column purification].