Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:9]=[CH:8][CH:7]=1)O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:66]([CH:4]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:9]=[CH:8][CH:7]=1)[CH:3]([CH2:19][CH3:20])[CH2:1][CH3:2])=[N+:67]=[N-:68]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCC(CC)C(O)c1ccnn1-c1ccc(OC)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)C(N=[N+]=[N-])c1ccnn1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To 2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butan-1-ol (1.0 g, 3.7 mmol) in THF (35 mL) at 0° C. was added triphenylphosphine (1.5 g, 5.6 mmol), diethyl azodicarboxylate (0.88 mL, 5.6 mmol) and diphenylphosphorylazide (1.2 mL, 5.6 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with EtOAc and washed twice with 1N HCl. The organic layer was dried (MgSO4), filtered, concentrated in vacuo and the resulting oil was purified by column chromatograhy (SiO2, EtOAc/ hexane, 1:9) to give a clear oil in 80% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, 1H, J=1.9 Hz), 7.32 (m, 2H), 7.07 (m, 2H), 6.55 (m, 1H), 4.42 (d, 1H, J=8.4 Hz), 3.80 (s, 3H), 1.60 (m, 1H), 1.41 (m, 1H), 1.25 (m, 1H), 1.14 (m, 2H), 0.69 (t, 3H, J=7.4 Hz), 0.60 (t, 3H, J=7.4 Hz).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C.CCOCC>[Si:17]([O:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCC(O)CC(=O)OCC
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Yield: 81.6 %

Procedure:
A solution of ethyl 3-hydroxyhexanoate 1 (2.0 g, 12.5 mmol), imidazole (1.09 g, 18.7 mmol), and tert-butyldimethylsilyl chloride (2.26 g, 15.0 mmol) in DMF (25 mL) was stirred at 23° C. After 16 h the reaction was diluted with Et2O and then washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 100% hex followed by 19:1 hex/EtOAc) afforded 2.8 g (82%) of silyl ether 2 (see Scheme 1).
Reaction SMILES: CON(C)[C:4](=[O:13])[CH2:5][CH2:6][C:7]1([CH3:12])[O:11][CH2:10][CH2:9][O:8]1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].CCOCC>C1COCC1>[CH3:12][C:7]1([CH2:6][CH2:5][CH:4]=[O:13])[O:11][CH2:10][CH2:9][O:8]1
Reactant: CON(C)C(=O)CCC1(C)OCCO1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(CCC=O)OCCO1
Reaction time: 1 h

Procedure:
To a solution of 2-2 (44.74 g, 0.22 mol) in 400 mL THF at -78° C. was added DIBAL (264 mL 1 M in hexanes, 0.264 mol) over 10 minutes. After stirring for 1 h, 350 ml of 1.0 M Rochelle's salt and 300 ml ether were added followed by the removal of the cooling bath. After stirring for 1 h, the organic portion was separated and dried over Na2SO4. Evaporative removal of the solvent gave 2-3 as a colorless oil. TLC Rf =0.80 (silica, ethyl acetate). 1H NMR (300 MHz, CDCl3) δ 9.73 (s, 1H), 3.50 (d, 1H, J=16 Hz), 2.61 (d, 1H, J=21 Hz), 2.48 (m, 1H), 2.07 (t, 1H, J=7H), 1.33 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.[CH3:13][C:14]1([CH3:20])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:16]2[CH2:17][CH2:18][CH2:19][C:14]([CH3:20])([CH3:13])[CH2:15]2)=[CH:7][CH:8]=1
Reactant: ClCCCOc1ccc(I)cc1
Reactant: CC1(C)CCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CCCN(CCCOc2ccc(I)cc2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-[(3-chloropropyl)oxy]-4-iodobenzene (for example, as prepared for Intermediate 1) (6.5 g, 20 mmol), 3,3-dimethyl piperidine (commercially available, for example from Alfa) (3.39 g, 30 mmol), sodium iodide (2.99 g, 20 mmol) and potassium carbonate (3.3 g, 20 mmol) in anhydrous acetonitrile (100 ml) was heated at reflux overnight. The mixture was allowed to cool to room temperature, evaporated to dryness and quenched with water and extracted with dichloromethane, dried, filtered and concentrated to afford the title compound (8 g). LCMS RT=2.37 min, ES+ve m/z 374 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1NCCc1ccccc1
Reaction time: 18 h

Procedure:
N-(2-Phenylethyl)-2-nitroaniline (3.0 g, 12.4 mmol) was dissolved in MeOH (60 mL), and 10% Pd/C (300mg) was added. The mixture was hydrogenated at 1 atm for 18 hrs at room temperature, filtered over a celite pad and concentrated to an oil. The resulting oil was applied to a column prepacked with silica. The title compound was eluted from the column with EtOAc/Hexanes (1:3, v:v).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:18])=O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([Cl:18])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
Typically, the 3,4-dinitrobenzoic acid starting material is dissolved in an aprotic solvent such as benzene or toluene and refluxed with thionylchloride for a period of about 2-6 hours to form the desired 3,4-dinitrobenzoyl chloride.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([C:20]#[N:21])[CH:13]=2)[CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=O)[CH2:3][CH2:2]1.[CH2:22]([NH2:24])[CH3:23]>>[CH:1]1([CH2:4][N:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([C:20]#[N:21])[CH:13]=2)[CH:6]([CH2:10][CH3:11])[C:7]([NH:24][CH2:22][CH3:23])=[O:9])[CH2:2][CH2:3]1
Reactant: CCC(C(=O)O)N(CC1CC1)c1ccc(C#N)c(C#N)c1
Reactant: CCN
Product: CCNC(=O)C(CC)N(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 3 using 2-[(cyclopropylmethyl)(3,4-dicyanophenyl)amino]butanoic acid and ethylamine: MS (ES) m/z 311 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[C:12]([CH:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:13]
Reactant: CCOC(=O)CCCBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCC(C#N)c1ccc(Cl)c(Cl)c1
Yield: 42.1 %

Procedure:
5.9 g of sodium hydride as a 55% dispersion in oil are suspended in 50 ml of THF; the suspension is cooled in an ice bath and 25 g of 3,4-dichlorophenylacetonitrile in 25 ml of THF are added dropwise; the mixture is cooled again in an ice bath and a solution of 26.21 g of ethyl 4-bromobutanoate in 25 ml of THF is added dropwise. After one night at RT, the mixture is evaporated to dryness and the residue is then taken up with 2N hydrochloric acid solution and extracted with ether. The extract is washed with 2N hydrochloric acid solution and then with saturated sodium chloride solution. The organic phase is dried over MgSO4 and then concentrated under vacuum and the residue is chromatographed on silica using pure toluene up to a toluene/AcOEt mixture (100/3; v/v) as the eluent to give 17 g of the expected product.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:13]=1[F:26]>C1COCC1>[F:26][C:13]1[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[CH2:11][NH:10][C:3]1[C:2]([F:1])=[C:7]([OH:8])[CH:6]=[CH:5][C:4]=1[F:9]
Reactant: O=C(Nc1c(F)ccc(O)c1F)c1c(F)ccc(-c2cccc(F)c2)c1F
Solvent: C1CCOC1
Product: Oc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2F)c1F
Yield: 83 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-2,6-difluoro-3-(3-fluorophenyl)benzamide (500 mg, 1.32 mmol, 1.0 eq) in THF (10 mL) under N2 was added dropwise a solution of BH3 (1M in THF, 7 mL, 7.0 mmol, 5.3 eq) at room temperature. The reaction mixture was heated at reflux for 4 h then cooled and the reaction was quenched by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound (400 mg, 83%) as an oil which was used in the next step without purification.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9])[CH:3]=[CH2:4].[Na].[N:16](=[C:18]([C:24]#[N:25])[C:19](OCC)=[O:20])[OH:17].O>CO.C(O)(=O)C>[CH2:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]1[NH:10][C:19](=[O:20])[C:18]([N:16]=[O:17])=[C:24]([NH2:25])[N:9]=1)[CH:3]=[CH2:4]
Reactant: C=CCOc1ccccc1C(=N)N
Reactant: CCOC(=O)C(C#N)=NO
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: C=CCOc1ccccc1-c1nc(N)c(N=O)c(=O)[nH]1
Yield: 55.9 %

Procedure:
2-Allyloxybenzamidine hydrochloride (10.2 g.) was added to a solution of sodium (4.6 g.) in anhydrous methanol (200 ml.) with stirring, followed by ethyl α-oximinocyanoacetate (7.6 g.), and the mixture was stirred under reflux for 6 hours. The hot mixture was poured into water (500 ml.) and acidified with glacial acetic acid. The blue solid was filtered off, washed with water and recrystallised from 50% aqueous acetic acid to give 2-(2-allyloxyphenyl)-4-amino-5-nitrosopyrimid-6-one (7.3 g.), m.p. 217°-220° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:29][NH:30][CH3:31]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([N:30]([CH3:31])[CH3:29])=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CNC
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: Cl
Product: CN(C)C(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to N,N-dimethylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 19.7 mg of 263. MS (Q1) 408.8 (M)+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]([CH:13]=[CH:14][CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[C:11]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:36].O>CCO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:27])[CH2:16][CH:17]([OH:26])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:36]
Reactant: CC(C)n1c(C=CC(O)CC(O)CC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Reaction time: 2.5 h
Yield: 77.1 %

Procedure:
A 250 ml round bottom flask was loaded with fluvastatin tert-butyl ester (4.0 g, 8.56 mmole), NaOH (0.35 g), water (48 ml) and EtOH (120 ml) which were added gradually till clear solution was obtained. The mixture was stirred for 2.5 h then the EtOH was evaporated. The volume of the water was completed to 8 vol. and the mixture was extracted with EtOAc (2×30 ml). The aqueous solution was evaporated to obtain 6.07 g and ACN (60 ml) was added. The solution was stirred at room temperature over night. The product was isolated by filtration under nitrogen, washed with ACN (20 ml) and dried at 40° C. in a vacuum oven for 24 h to obtain 2.86 g (77.1%) of fluvastatin sodium crystal form LXXX.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42](O)=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[C:18]([O:20][CH3:21])=[O:19])=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)c(C(=O)OC)c1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 115 %

Procedure:
To a stirred solution of dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate (616 mg, 2.10 mmol) in DMF (13 mL) was added pentafluoro ester of 3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.00 g, 2.08 mmol) and Et3 N (425 μl, 3.12 mmol), and the resulting mixture was stirred for 3.5 hr at room temp. The resulting mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over Na2SO4. After removal of the solvent, the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 1.41 g(q.y.) dimethyl (S)-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalate as a yellow oil. 1H-NMR (CDCl3) δ 1.86–2.29 (m, 4 H), 2.30 (s, 3 H), 3.47–3.57 (m, 2 H), 3.58 (s, 3 H), 3.59 (s, 2 H), 3.83 (s, 3 H), 3.91 (s, 3 H), 4.22–4.37 (m, 2 H), 4.42–4.47 (m, 1 H), 6.44–8.46 (series of m, 12 H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][C:27]([CH2:30][OH:31])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>ClCCl>[CH2:12]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][C:27]([CH:30]=[O:31])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCc1ccc(-c2ccc(CO)cc2-c2ccccc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCc1ccc(-c2ccc(C=O)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a vigorously stirred solution of pyridinium chlorochromate (1.29 g, 5.97 mmol) and celite (2.6 g) in dichloromethane (30 mL) was added a solution of (4-hexyl-1,1′:2′,1″-terphenyl-4′-yl)methanol (1.37 g, 3.98 mmol) in dichloromethane. After stirring at RT for 3 h, the reaction mixture was filtered through a plug of silica gel and eluted well with dichloromethane. Concentration yielded 1.21 g of the aldehyde as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[C:22]#[N:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[ClH:36]>O1CCOCC1>[ClH:36].[CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[C:22]#[N:23])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N

Procedure:
A solution of (S)-3-tert-Butoxycarbonylamino-2-{[3-cyano-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.033 g, 0.066 mmol)) and 4.0M Hydrogen Chloride in Dioxane (5 mL) was stirred at room temperature 1 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: [C:1]([CH:6]([CH:9]=O)[CH:7]=O)([O:3][CH2:4][CH3:5])=[O:2].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1>C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:9]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=[N:20]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C=O)C=O
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2)c1
Yield: 48.9 %

Procedure:
A solution of carbethoxymalonaldehyde (0.8 g, 5.55 mmol; obtained according to Panizzi, L. Gazz.Chim.Ital., 1946, 76, 56) in ethanol (25 mL) was treated with 4-chlorophenylhydrazine hydrochloride (1.0 g, 5.55 mmol) at reflux for 5 h. The resulting reddish mixture was concentrated to an oil that was purified by flash chromatography to give ethyl 1-(4-chlorophenyl)-1H-pyrazole-4-carboxylate (0.68 g, 49%) as a white solid: mp 127°-128° C.; 1H NMR (80 MHz, CDCl3) δ (TMS) 8.37 (s, 1H, pyrazole), 8.09 (s, 1H, pyrazole), 7.67 (dt, Jt =2, Jd =9, 2H, arom), 7.44 (dt,Jt =2, Jd =9, 2H, arom), 4.35 (q, J=7, 2H, OCH2), 1.38 (t, J=7, 3H, OCH2CH3). Analysis calculated for C12H11ClN2O2 : C 57.50; H 4.42; N 11.17. Found: C 57.49; H 4.46; N 11.16.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH2:21][C:22]#[N:23])[C:13]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:14])[C:8](=[O:24])[C:7]3=[CH:25][N:26]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:5]([C:6]=23)=[N:4][CH:3]=1.[OH-:37].[Na+]>CO>[Cl:1][C:2]1[C:11]([CH2:10][NH:9][C@H:12]([CH2:21][C:22]#[N:23])[C:13]([NH:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])=[C:6]2[C:7]([C:8]([OH:24])=[O:37])=[CH:25][N:26]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@H](CC#N)C(=O)NC2CCCC2)C3=O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@H](CC#N)C(=O)NC4CCCC4)c(Cl)cnc32)cc1
Reaction time: 0.33 h
Yield: 2.1 %

Procedure:
To a solution of (R)-2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-cyano-N-cyclopentylpropanamide in MeOH (2 mL) was added aqueous NaOH (1N, 0.5 mL). The reaction mixture was stirred for 20 min and the product was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (0.5 mg, 2.1% from Step A starting material). 1H NMR (400 MHz, CD3OD) δ 1.37-1.72 (m, 4 H) 1.83-1.95 (m, 4 H) 3.22-3.26 (m, 2 H) 3.69-3.76 (m, 1 H) 5.11 (s, 1 H) 5.14-5.17 (m, 1 H) 5.18 (s, 1 H) 7.88 (s, 1 H) 8.27 (s, 1 H). [M+H] calc'd for C18H18ClN5O2, 372; found, 372.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Br[C:11]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:20])[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:20])[C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: COc1ccc(Br)c(C(=O)O)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc(Br)cc2F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
To a 1 L RB was added 4-bromo-2-fluorophenol (18.85 mL, 169 mmol), 6-bromo-2-fluoro-3-methoxybenzoic acid (40 g, 161 mmol), copper (I) trifluoromethanesulfonate toluene complex (4.16 g, 8.03 mmol), ethyl acetate (1.6 mL, 16.06 mmol) and cesium carbonate (105 g, 321 mmol) in dry toluene (300 mL). The reaction mixture was stirred at rt for 15 min and heated at 110° C. for overnight. The toluene was decanted and the resulting green sticky precipitate was washed with excess hexanes and then acidified by addition of 6N aqueous HCl. The resulting solution was added water and extracted with EtOAc 3×. The light brown organic phase was then washed by brine and dried by MgSO4. The solution was filtered and concentrated in vacuo to give the crude material 6-(4-bromo-2-fluorophenoxy)-2-fluoro-3-methoxybenzoic acid (45.4 g, 126 mmol, 79% yield) as a brown solid. It was used for next step without further purification.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:9]([NH:11][C@H:12]([C:25]([O:27][CH3:28])=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:46](N)[CH2:47]N(CCN)CCN>C(OCC)(=O)C>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:25]([O:27][CH2:28][CH:46]=[CH2:47])=[O:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:16][CH:15]=1)=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: NCCN(CCN)CCN
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)COC(C)(C)C
Yield: 88 %

Procedure:
According to the general procedure for Fmoc-cleavage, 9 g Fmoc-Ser(tBu)-Tyr(tBu)-OMe, 22 ml TAEA in ethyl acetate yielded 4.7 g of crude product (yield based on HPLC: 88%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:8]([O:6][CH:3]1[CH2:4][CH2:5][CH:1]([OH:7])[CH2:2]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC1CCC(O)C1
Solvent: c1ccncc1
Product: O=C(OC1CCC(O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
To a solution of 1,3-cyclopentanediol (500 mg) in pyridine (10 mL) was added benzoyl chloride (688 mg), and the mixture was stirred for 18 hours at ambient temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with 1N-hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (3:1 to 1:1) to give 3-hydroxycyclopentyl benzoate as a colorless oil (630 mg).
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.[Br:16][CH2:17][CH:18](Br)[CH3:19]>>[Br:16][CH2:17][CH2:18][CH2:19][N:2]1[C:3](=[O:14])[C:4]2[CH:13]=[CH:12][CH:11]=[C:6]3[C:5]=2[C:10](=[CH:9][CH:8]=[CH:7]3)[C:1]1=[O:15]
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: CC(Br)CBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCBr

Procedure:
This compound was prepared according to GP-1 using benzo[de]isoquinoline-1,3-dione (1) and 1,2 dibromopropane (2a) The crude product was purified by flash column chromatography using EtOAc-hexane to provide 3a. 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J=7.0 Hz 2H), 8.23 (d, J=8.0 Hz, 2H), 7.77 (t, J=7.5 Hz, 2H), 4.34 (t, J=7.5, 2H), 3.51 (t, J=7.0 Hz, 2H), 2.37-2.32 (m, 2H). MS (ES+) m/z 340 (M+Na)+.