Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([O:6][C:7]([NH:9][CH:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][C:12](=[CH2:23])[CH2:13][CH:14]([NH:20]C=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)(C)(C)C>CCOCC.C(Cl)Cl>[NH2:20][CH:14]([CH2:13][C:12](=[CH2:23])[CH2:11][CH:10]([NH:9][CH:7]=[O:6])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C=C(CC(NC=O)C(=O)OCC)CC(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(CC(N)C(=O)OCC)CC(NC=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 ml of a solution of 2.6N hydrochloric acid in anhydrous ether were added to a solution of 6.4 g of the product of Step F in 200 ml of methylene chloride and after stirring at room temperature for one hour, nitrogen was bubbled therethrough The mixture was evaporated to dryness under reduced pressure at 30° C. and the residue was taken up in methylene chloride. The mixture was neutralized and evaporated to dryness to obtain 4.6 g of raw product. The latter was chromatographed over silica and eluted with a 9-1 ethyl acetate-ethanol mixture to obtain the desired product with an Rf=0.06.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH2:12]([O:14][C:15](=[O:25])[CH2:16][C:17](=O)[CH2:18][C:19](OCC)=[O:20])[CH3:13]>>[CH2:12]([O:14][C:15]([CH2:16][C:17]1[CH2:18][C:19](=[O:20])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=1)=[O:25])[CH3:13]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Product: CCOC(=O)CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1

Procedure:
From the reaction of p-hydrazinobenzoic acid and diethyl-3-oxoglutarate, 4-(3-ethoxycarbonylmethyl-4,5-dihydro-5-oxo-1H-pyrazol-1-yl)-benzoic acid is obtained. Subsequent reaction with 2-ethylaniline yields 4-(4-(2-thylanilinomethylene)-3-ethoxycarbonylmethyl-4,5-dihydro-5-oxo-1H-pyrazol-1-yl)-benzoic acid, Mp 246° C.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:16]2[C:11]3[C:10]4[CH2:27][CH2:28][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:38]5[CH2:39][CH2:40][N:35]([C:30]6[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=6)[CH2:36][CH2:37]5)[CH2:8][C:9]=4[S:26][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Solvent: CN(C)C=O
Product: O=C(/C=C/CN1CCN(c2ccccn2)CC1)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
To a suspension of Example 59A (80 mg, 0.16 mmol) in DMF (1 mL) was added 1-pyridin-2-ylpiperazine (52 mg, 0.32 mmol), and the mixture was stirred at rt for 3 h and then heated to 50° C. for 4 h. After purification by preparative HPLC, the product crystallized upon trituration with dichloromethane to yield 74 mg (79%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6](C)=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[CH:35]=[CH:34][NH:33][C:30]3=[N:31][CH:32]=2)O1>>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:27]3[CH:28]=[C:29]4[CH:35]=[CH:34][NH:33][C:30]4=[N:31][CH:32]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[CH:6]=[N:7]1)([CH3:12])[CH3:13]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Product: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1cnn2C(C)C
Temperature: 100 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in the same manner as described for example 35 (step a) from methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate (1 g, 3.36 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.98 g, 4.04 mmol) wherein the reaction mixture was stirred at 100° C. for 5 h. The product was collected as an off white solid (600 mg, 53%). LCMS (ES−) m/z: 333.08.
Reaction SMILES: C(O[C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH2:26])[CH:20]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[O:18]=[C:4]([NH:26][CH2:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1
Reactant: NCc1cccnc1
Reactant: CCOC(=O)COc1ccc(C(=O)OCC)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1ccc(OCC(=O)NCc2cccnc2)cc1
Reaction time: 24 h
Yield: 95.4 %

Procedure:
2.9 g (11 mmole) of ethyl 4-(2-ethoxy-2-oxoethoxy)benzoate, 1.4 g (12 mmole) of 3-picolylamine and 2.1 g (1.3 mmole) of DBU were dissolved in ethanol (12 ml), and reaction was then carried out for 24 hours. After the reaction mixture had been concentrated, partition was carried out between ethyl acetate and water. The organic layer was then treated in an ordinary manner to obtain 3.3 g (yield: 90%) of ethyl 4-{2-oxo-2-[(pyridin-3-ylmethyl)amino]ethoxy}benzoate.
Reaction SMILES: [C:1]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:13][C:1](=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:17][CH2:18][CH2:19][Cl:20])=[C:5]([O:6][CH3:7])[CH:4]=1)[CH3:15]
Reactant: ClCCCBr
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(OCCCCl)c(OC)c1
Yield: 65.1 %

Procedure:
A mixture of 50 g (0.238 mole of ethyl homovanillate (98% Aldrich), 75 g (0.476 mole) of 1-bromo-3-chloropropane and 98.7 g (0.71 mole) of anhydrous potassium carbonate in 1 L of acetone was heated at reflux for 24 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give an oil which gradually crystallized to a semi-solid. The solid was recrystallized from ethyl ether-petroleum ether (30°-60°) to yield 44.4 g (65%) of title compound a white solid, mp 36°-38° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([Cl:40])[C:27]=1[N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:30][CH2:29]1)[NH2:24]>>[Cl:40][C:26]1[CH:25]=[C:23]([NH:24][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]=2[CH3:1])=[O:18])[CH:22]=[C:21]([Cl:20])[C:27]=1[N:28]1[CH2:29][CH2:30][CH:31]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[CH2:32][CH2:33]1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Cl)c(N2CCC(N3CCOCC3)CC2)c(Cl)c1
Product: Cc1c(C(=O)Nc2cc(Cl)c(N3CCC(N4CCOCC4)CC3)c(Cl)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 68.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic chloride (0.87 g) and 3,5-dichloro-4-(4-morpholinopiperidin-1-yl)aniline (1.0 g), the title compound (1.2 g) was obtained, melting point: 252–254° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21][OH:22])=[N:6][CH:7]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O:25][CH3:26])=[O:24]>>[CH3:26][O:25][C:23](=[O:24])[C:27]1[CH:32]=[CH:31][C:30]([O:22][CH2:21][C:10]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:13][C:9]=2[S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:29][CH:28]=1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OCc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1

Procedure:
Prepared from {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (INTERMEDIATE B1.1) and 4-carbomethoxyphenol using a similar procedure as described in the preparation of example B2.1. MS: M+H=471.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:29])[CH:16]([CH:21](O)[CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH2:17][C:18]=3[O:19]C)[CH:9]=2)=[CH:4][CH:3]=1.Cl>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([CH:14]3[C:15](=[O:29])/[C:16](=[CH:21]/[CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)/[CH2:17][C:18]3=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)C(C(O)C2CCOCC2)C1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Temperature: 120 °C
Yield: 33.8 %

Procedure:
To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-cyclopent-2-enone (280 mg, 0.65 mmol) in acetone (2 ml) was added 2N hydrochloric acid (2 ml) and the reaction heated to 120° C. for 60 minutes by microwave irradiation. The crude reaction was diluted with ethyl acetate (25 ml) and washed with saturated aqueous ammonium chloride solution (25 ml), brine (25 ml) and the organic layer dry loaded onto silica and purified by flash chromatography to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (88 mg).
Reaction SMILES: [C:1]([O:12]CC)(=[O:11])[C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[OH-].[Na+].Cl.C(OCC)(=O)C>C1COCC1>[C:5]1([NH:4][C:2](=[O:3])[C:1]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(=O)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
Ethyl oxanilate 83 (Aldrich, 1.0 g, 1.0 eq) in 12 mL of THF was treated dropwise with a 1N NaOH solution (5.70 mL, 1.1 eq) resulting in a white precipitate. After stirring for 3 hours at RT, 0.5N HCl and ethyl acetate were added, the organic layer separated, washed with 0.5N HCl and brine and then dried over sodium sulfate, filtered, and concentrated to give 712 mg (68%) of N-phenyl oxalamic acid 84 as a white solid with consistent analytical data. FIA M+H=166.0, M−H=163.9; 1H NMR (DMSO-d6) δ 10.70 (s, 1H), 7.75 (m, 2H), 7.35 (m, 2H), 7.15 (m, 1H) ppm.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33]C)=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([Br:28])[C:25]([OH:29])=[C:24]([Br:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1>C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([Br:28])[C:25]([OH:29])=[C:24]([Br:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.51 g (21.3 mmol) LiOH was added to a solution of (R)-2-(3,5-dibromo-4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (crude product from Example 128g) in 80 mL THF and the reaction mixture was stirred for 3 h at RT. The THF was eliminated i. vac., the aqueous phase was washed with EtOAc, acidified with 10% HCl and the aqueous phase was extracted exhaustively with EtOAc. The combined organic phases were evaporated down i.vac., suspended in diethyl ether, filtered, the residue was dried and then purified by chromatography (silica gel, DCM/MeOH/AcOH 90:10:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10](O)[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[Cl:25][C:10]1[C:9](=[O:21])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12](=[O:13])[C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C(O)=C(c2ccccc2)C(=O)N1c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
After dissolving compound 6c (2.00 g, 6.67 mmol) in DCM (10 ml) and anhydrous DMF (10 ml), oxalyl chloride (1.69 g, 13.3 mmoL) was added thereto and the agitation for 30 minutes was carried out. After the identification of the reaction progress with TLC, the reaction was terminated. Then, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the column chromatography was carried out with EA/HX ( 1/9). The suspension was carried out with EA/HX (⅓) to obtain compound 7c.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([O-:23])(=[O:22])=[O:21])[CH:8]=2)[N+:3]=1[CH2:24][CH2:25][CH2:26][CH2:27][S:28]([O-:31])(=[O:30])=[O:29].[Na+].[Na+].Cl>C(O)(=O)C>[NH:3](/[CH:2]=[CH:10]/[CH:11]=[CH:1]/[C:2]1[C:10]([CH3:19])([CH2:11][CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:20]([O-:23])(=[O:22])=[O:21])[CH:8]=2)[N+:3]=1[CH2:24][CH2:25][CH2:26][CH2:27][S:28]([OH:31])(=[O:29])=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(CCCCS(=O)(=O)O)C(/C=C/C=C/Nc2ccccc2)=[N+](CCCCS(=O)(=O)O)c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Disodium 2,3-dimethyl-1,3-bis(4-sulphonatobutyl)-3H-indolium-5-sulphonate, crude (1.0 g) and malonaldehyde bis(phenyl)mine) HCl (1.0 g) and acetic acid (10 ml) were heated under nitrogen at 130° C. for 10 hrs to give a dark orange-red solution. The solvent was then evaporated under vacuum; the residue was partitioned in a water/dichloromethane/methanol mixture. UV/Vis analysis (ethanol) confirmed the presence of the product in the upper, aqueous layer (λmax=524 nm) while the malonaldehyde starting material was present mainly in the lower, organic layer (λmax=384 nm). The aqueous layer was evaporated under vacuum and purified by HPLC (water/0.1% TFA and acetonitrile/0.1% TFA eluants). Fractions containing the product were pooled and evaporated, freeze-dried from aqueous solution, with final drying under high vacuum over phosphorus pentoxide to give the title product. Yield 240 mg as a red foam.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[N:10]([CH:17]3[CH2:19][CH2:18]3)[C:9]2=[O:20])[CH2:4][CH2:3]1.Cl[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[N:23]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[N:23]1[C:24]2[C:29](=[N:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[N:10]([CH:17]3[CH2:19][CH2:18]3)[C:9]2=[O:20])[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](n2c(=O)n(C3CC3)c3nccnc32)CC1
Reactant: Clc1ccc2ncccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1CC[C@H](Nc2ccc3ncccc3n2)CC1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-4-aminocyclohexyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.1050 g, 0.339 mmol), 2-chloro-1,5-naphthyridine (0.067 g, 0.407 mmol, 00358), and diisopropylethylamine (0.177 ml, 1.017 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (0.484 ml) and heated to 120° C. for 2 days. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 15 min. Fractions containing product were collected and concentrated. The product was taken up in DCM and loaded onto a Silicycle Si-carbonate cartridge and washed with DCM and MeOH to remove any salts to give the title compound (6.4 mg, 0.016 mmol, 4.7% yield). LCMS showed product peak at 1.434 min (m+1=402.0). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09-1.24 (m, 4 H) 1.37-1.53 (m, 2 H) 1.94 (d, J=11.93 Hz, 2 H) 2.39 (d, J=12.13 Hz, 2 H) 2.68 (qd, J=12.91, 3.13 Hz, 2 H) 2.97-3.09 (m, 1 H) 4.08-4.24 (m, 1 H) 4.47 (tt, J=12.32, 3.91 Hz, 1 H) 6.85 (d, J=9.19 Hz, 1 H) 7.45 (dd, J=8.41, 4.30 Hz, 1 H) 7.91-7.96 (m, 2 H) 7.97 (d, J=8.61 Hz, 1 H) 8.03 (d, J=9.19 Hz, 1 H) 8.60 (d, J=3.33 Hz, 1 H)
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][N:12]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][C:23]=4[C:24]([F:27])([F:26])[F:25])[C:13]3=[O:17])=[CH:8][C:7]=2[CH:6]=[N:5]1)(=O)C.Cl>C(Cl)(Cl)Cl>[F:26][C:24]([F:25])([F:27])[C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][C:16]3[NH:4][N:5]=[CH:6][C:7]=3[CH:8]=2)[C:13]1=[O:17]
Reactant: CC(=O)n1ncc2cc3c(cc21)C(=O)N(c1cnccc1C(F)(F)F)CC3
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C1c2cc3[nH]ncc3cc2CCN1c1cnccc1C(F)(F)F
Yield: 37.6 %

Procedure:
1-Acetyl-7-(4-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-g]isoquinolin-8(5H)-one (I-72c: 45 mg, 12 mmmol) in chloroform was deacylated with 6N HCl for 16 hours. Purification by column chromatography on silica gel (4% methanol in DCM) afforded 15 mg of the product (37.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[C:19](C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.IC>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH3:19])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Reactant: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CI
Solvent: ClCCl
Product: COCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 52.8 %

Procedure:
4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (861 mg, 3.32 mmol) was dissolved in DCM (6.6 mL) then 2,6-di-tert-butyl-4-methylpyridine (1.023 g, 4.98 mmol) and AgOTf (938 mg, 3.65 mmol) were added. The reaction mixture was cooled to 0° C. and iodomethane (0.25 mL, 3.98 mmol) was added. After 4 min, the reaction mixture was diluted with DCM and it was filtered over elite. The filtrate was concentrated to a residue which was dissolved in diethyl ether. The organic solution was washed with 10% HCl and brine, then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (20% to 80% EtOAc/Hex) to afford the title compound (479 mg, 53%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][C:9]1[CH:14]=CC=CN=1.SCC[OH:18]>N1C=CC=CC=1.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH:9]([OH:18])[CH3:14]
Reactant: c1ccc(SSc2ccccn2)nc1
Reactant: OCCS
Solvent: c1ccncc1
Solvent: CO
Product: CC(O)SSc1ccccn1
Reaction time: 8 h

Procedure:
2.25 g of bis(2-pyridyl)disulfide are dissolved in 100 ml of pyridine:methanol (1:99). β-mercaptoethanol (700 μl, 1 eq.) is added dropwise to the solution. An immediate yellow color is observed. The medium is stirred overnight. The following day, starting product is no longer observed, and the solution is evaporated. The residue is passed over two silica columns, so as to obtain 770 mg of the expected product (column prepared with dichloromethane with a slight ethyl acetate gradient). Only the cleanest fractions are evaporated.
Reaction SMILES: [O:1]=[C:2]([CH2:8][N:9]1[CH:12](SC)[CH2:11][C:10]1=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:16]Cl>C(Cl)(Cl)(Cl)Cl>[O:1]=[C:2]([CH2:8][N:9]1[CH:12]([Cl:16])[CH2:11][C:10]1=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: ClCl
Reactant: COC(=O)CC(=O)CN1C(=O)CC1SC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CC(=O)CN1C(=O)CC1Cl
Temperature: 25 °C

Procedure:
Methyl 3-oxo-4-(2-oxo-4-methylthioazetidin-1-yl)butyrate (300 mg) was dissolved in dry carbon tetrachloride (10 ml) and the solution was stirred and ice-cooled with exclusion of moisture while chlorine (90 mg) in dry carbon tetrachloride (1.5 ml) was added in one portion. After addition, the mixture was warmed to room temperature and stirred for 3 minutes. The solvent was then evaporated under reduced pressure. The residue was dissolved in fresh carbon tetrachloride (5 ml) and again the solvent was removed under reduced pressure. The title compound was thus obtained as a yellow gum (300 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:43][C:44](=[O:45])[NH:46][C:47]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 60 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide (Compound IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][C:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:15])[CH3:14].[OH-].[Na+]>CO>[CH3:15][C:13]([C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[CH:1][C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)=[O:3])=[CH:22][CH:23]=1)([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2ccc(C(C)(C)C)cc2)cc1
Temperature: 30 °C
Yield: 89.9 %

Procedure:
97.6 g (0.65 mol) of 4-methoxyacetophenone and 105.4 g (0.65 mol) of 4-(1,1-dimethylethyl)benzaldehyde were dissolved in 600 ml of methanol in a 1 1 round-bottom flask fitted with internal thermometer, reflux condenser and paddle stirrer. 20 g (0.05 mol) of 10% NaOH were then added at room temperature. The mixture was then stirred at 30° C. The crystals which formed were filtered off, washed with 50 ml of cold methanol and then dried under reduced pressure (150 mbar) at 75° C. Yield: 172 g (90% yield) of pale yellow crystals; m.p.: 114-116° C.; purity: >99%.