Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([CH3:14])[CH:7]=1.BrCCC[Cl:19].CC1C=C(O)C=CC=1C=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:19][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([CH3:14])[CH:7]=1
Reactant: Cc1cc(OCCCI)ccc1C=O
Reactant: ClCCCBr
Agent: Cc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCCCCl)ccc1C=O
Temperature: 65 °C
Yield: 82 %

Procedure:
4-(3-Iodo-propoxy)-2-methyl-benzaldehyde. 1-Bromo-3-chloropropane (5.03 g, 32.0 mmol, 1.0 equiv) was added to a solution of 2-methyl-4-hydroxybenzaldehyde (4.35 g, 32.0 mmol, 1.0 equiv) and K2CO3 (8.8 g, 64.0 mmol, 2.0 equiv) in acetonitrile (75 mL). The mixture was heated at 65° C. for 16 h, then cooled to rt and filtered through diatomaceous earth. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, 10% ethyl acetate in hexanes) to afford 5.58 g (82%) of 4-(3-chloro-propoxy)-2-methyl-benzaldehyde. To a refluxing solution of 4-(3-chloro-propoxy)-2-methyl-benzaldehyde in acetone (100 mL), KI (58 g) was added portion wise over 3 d. The mixture was cooled to rt and water was added. The aqueous mixture was extracted three times with ethyl acetate and the combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, 5% ethyl acetate in hexanes) to afford 6.13 g (77%) of the title compound. 1H NMR (400 MHz, CD3OD): 10.1 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.84 (dd, J=8.6, 2.5 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 4.11 (t, J=5.8 Hz, 2H), 3.36 (t, J=6.7 Hz, 2H), 2.65 (s, 3H), 2.29 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CN=C1>O.C(#N)C.CC(C)=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1

Procedure:
To a solution composed of 108 mg (90.2 weight %, 0.3 mmol) of the (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 62.4 mg (0.6 mmol) of 2,2-dimethoxypropane, and 5 mL of acetone were added 5.7 mg (0.03 mmol) of p-toluenesulfonic acid.1H2O and 10.2 mg (0.15 mmol) of imidazole, and the mixture was stirred at 40° C. for 16 hours. This reaction mixture was analyzed by high-performance liquid chromatography (column: Develosil ODS-HG-3 4.6×250 mm, product of Nomura Chemical, eluent: water/acetonitrile=50/50, flow rate: 1.0 mL/min, detector: UV 220 nm, column temperature: 40° C.). The compositional yield values were as follows.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=O)[N:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[C:16]1[NH:20][C:21]([C:23]1[C:31]2[NH:30][C:29]([NH2:32])=[N:28][C:27]=2[CH:26]=[CH:25][CH:24]=1)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:17]1[CH:18]=[CH:19][N:15]=[C:16]1[NH:20][C:21]([C:23]1[C:31]2[N:30]=[C:29]([NH:32][C:12]([C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[C:6]([CH:5]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:14])[NH:28][C:27]=2[CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: Cc1nc(C(=O)O)cc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2nc3c(C(=O)Nc4ncc[nH]4)cccc3[nH]2)cc2ccccc12
Yield: 14.8 %

Procedure:
17.6 mg (15%) of 1-methyl-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was synthesized according to General Procedure A using 55 mg (0.29 mmol) of 1-methyl-isoquinoline-3-carboxylic acid, 70 mg (0.29 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 144 mg (0.38 mmol) of HBTU, 0.264 mL (1.5 mmol) of DIEA in 0.8 mL of DMF stirring at 85° C. for 2 h. 1H-NMR (400 MHz, DMSO): 8.66 (s, 1H), 8.38 (d, 1H), 8.28 (d, 1H), 7.89 (m 4H), 7.34 (m, 1H), 6.85 (b, 2H), 3.07 (s, 3H) ppm. LCMS: 412 (M+1)+.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.C(C1C=CC(C([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[O:29][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])O)=CC=1)C.O>CS(C)=O.O1CCCC1>[CH3:35][Si:34]([CH3:37])([CH3:36])[CH2:33][CH2:32][O:31][CH2:30][O:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:23]=1
Reactant: CCc1ccc(C(O)c2ccncc2OCOCC[Si](C)(C)C)cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCOc1cccnc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 180.9 %

Procedure:
To a solution of o-iodoxybenzoic acid (IBX) in dimethyl sulfoxide (15 mL), a solution of (4-ethylphenyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridin-4-yl]-methanol (synthesized in Reference Example 6; 3.0 g, 8.34 mmol) in tetrahydrofuran (20 mL) was added and the reaction mixture was stirred at room temperature for 17.5 hours. Water was added to the reaction mixture and the resulting precipitate was filtered and washed with ethyl acetate. The filtrate was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 4-(4-ethylbenzoyl)-[3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].ClC1C=C(Cl)C=CC=1C([C:33]1[C:41]2[C:36](=[C:37]([CH2:43][S:44][CH3:45])[CH:38]=[C:39](F)[CH:40]=2)[NH:35][CH:34]=1)CCO.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:33]2[C:41]3[C:36](=[C:37]([CH2:43][S:44][CH3:45])[CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: OC(c1ccc(F)cc1)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2.94 g (12.41 mmol) of the compound from Example 81A and 2.50 g (11.28 mmol) of indium(III) chloride were added to 2.00 g (11.28 mmol) of the compound from Example 8 in 100 ml of toluene. The reaction mixture was stirred at 80° C. for 3 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate and the solid was filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 0.83 g (19% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[N:7]2.[F:19][C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][C:21]=1[C:35]1[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[F:18])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:22][C:21]=1[C:35]1[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Fc1ccccc1-c1ccc2c(Cl)ccnc2n1
Product: N#Cc1ccccc1-c1cc(-c2ccnc3nc(-c4ccccc4F)ccc23)ccc1F
Yield: 62 %

Procedure:
This was prepared in 62% yield from 5-chloro-2-(2-fluorophenyl)-[1,8]naphthyridine (from step a) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (from Example 2, step e) using a similar procedure to that described in step a. δH (400 MHz, CDCl3) 7.20 (1H, ddd, J 11.7, 8.2 and 1.2), 7.34 (1H, td, J 7.4, 1.2), 7.42-7.48 (2H, m), 7.50 (1H, d, J 4.3), 7.54 (1H, td, J 7.4, 1.2), 7.60-7.65 (3H, m), 7.71 (1H, td, J 7.4, 1.2), 7.84 (1H, dd, J 7.8, 0.8), 8.09 (1H, dd, J 8.6 and 2.3), 8.42 (1H, td, J 7.8, 2.0), 8.49 (1H, d, J 8.6), 9.18 (1H, d, J 4.7). m/z (ES+) 420 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[CH:5][C:3]=1[OH:4].Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1.[H-].[Na+]>>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([O:10][C:12]2[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=2)=[C:8]([CH3:9])[C:2]=1[CH3:1]
Reactant: Cc1c(O)ccc(O)c1C
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: Cc1c(O)ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c1C
Yield: 49.5 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2,3-dimethylhydroquinone (1.38 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.87 g) and anhydrous N-N-dimethylformamide (20 ml) and the reaction mixture was purified to give the title compound (1.92 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26](Cl)=[O:27])=[C:19]2[N:18]=1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([NH:13][C:12]3[C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH3:15])=[N:9][N:10]([CH3:14])[CH:11]=3)=[O:27])=[C:19]2[N:18]=1
Reactant: Cc1ccc(Cl)cc1-c1nn(C)cc1N
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1cnn2ccc(Cl)nc12
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a solution of 3-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrazol-4-amine (182.9 mg, 0.4826 mmol, 1.2 equiv) in dichloromethane (5 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (91.2 mg, 0.411 mmol, 1.0 equiv) and triethylamine (0.30 mL, 2.2 mmol, 5.2 equiv) at room temperature. After 16 hours, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 143.1 mg (87%) of 5-chloro-N-(3-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide which was carried forward without purification. LCMS (ESI) m+H=401.0.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCc2ccco2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(CCc2ccco2)cc1

Procedure:
Acetic anhydride (0.28 ml) was added dropwise to a solution of 2-[2-(4-aminophenyl)ethyl]furan (0.50 g) in pyridine (5 ml) at ambient temperature with stirring. After being stirred for 1 hour, the mixture was poured into water (50 ml) and the resulting precipitate was collected by filtration to give 2-[2-(4-acetamidophenyl)ethyl]furan (0.58 g).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[OH:15].[CH3:16]O>>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([Br:5])=[C:7]([OH:15])[CH:8]=1
Reactant: O=C(O)c1ccc(Br)c(O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(O)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
1.5 ml of thionyl chloride was added to 40 ml of MeOH at 0° C. The solution was stirred for 10 min and 5 g of 4-Bromo-3-hydroxy-benzoic acid was added. The reaction was stirred for 16 h at RT then heated to 50° C. for 3 h. The solvents were removed under reduced pressure. The residue was used directly in the next step. Yield 5.92 g
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[H-].[Na+].[CH2:18](Br)[C:19]#[CH:20]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH2:20][C:19]#[CH:18])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccccc2cc1O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOc1cc2ccccc2cc1C(=O)OC
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Methyl-3-hydroxy-2-naphthoate (2.63 g, 0.013 mol) was dissolved in dry THF (80 ml) and treated with sodium hydride (80%) ((0.398 g, 0.013 mol), with stirring under N2. After 0.5 h, propargyl bromide (80% in toluene) (2.57 ml 0.017 mol) was added and the mixture heated to reflux. After 20 h, the reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was then evaporated under reduced pressure. The residue was then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (1×), and the combined organic layers were dried (Na2SO4) and evaporated to given an orange oil. Crystallisation of the oil from petrol (60/80) diethyl ether provided the title compound as a pale yellow solid (1.0 gg, 35%).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:20][CH:21]1[CH2:24][N:23]([C:25]([C:27]2[O:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[N:30][N:31]=2)=[O:26])[CH2:22]1)(=O)=O>CN(C=O)C>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[O:28][C:27]([C:25]([N:23]3[CH2:24][CH:21]([O:20][C:2]4[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=4)[CH2:22]3)=[O:26])=[N:31][N:30]=2)=[CH:33][CH:34]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
4-Hydroxybenzaldehyde (1.10 g, 9.17 mmol), cesium carbonate (3.49 g, 10.70 mmol) and 4B (2.70 g, 7.64 mmol) were mixed with DMF (80 mL). The mixture was stirred at 110° C. for 18 h then cooled to RT. The solids were filtered off and the filtrate was evaporated. The residue was treated with methanol and the solid formed was collected by filtration. Drying under vacuum gave 1.8 g (62%) of 9A as a beige solid. 1H NMR (500 MHz, DMSO-d6): δ 3.85 (s, 3H), 4.13 (dd, 1H), 4.57 (dd, 1H), 4.65 (dd, 1H), 5.12 (dd, 1H), 5.29 (m, 1H), 7.10 (d, 2H), 7.16 (d, 2H), 7.90 (d, 2H), 8.00 (d, 2H), 9.90 (s, 1H), MS (APCI+) m/z 380 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:21]([C:17]2[C:18]3[C:19](=[CH:20][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:5]=4[CH:4]=[CH:3][N:2]=[CH:1]5)=[CH:12][CH:13]=3)[CH:14]=[CH:15][CH:16]=2)=[O:22])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1cccc2cc(-c3cccc4cnccc34)ccc12
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)c1cccc2cc(-c3cccc4cnccc34)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(isoquinolin-5-yl)-1-naphthoyl chloride (0.85 g, 0.27 mmol) was suspended in CH2Cl2 (1 mL) and triethylamine (0.057 mL, 0.4 mmol) was added followed by 4-chloroaniline (33 mg, 0.26 mol). The mixture was stirred at room temperature for 2 h, 0.1 mL of DMF was added and the mixture was stirred for an additional 72 h. A solution of aqueous NaHCO3 was added and mixture was extracted with CH2Cl2. Organic phase was dried, filtered and evaporated. Residue was purified by prep plate (ethyl acetate) to give a white solid. MS (ESI pos. ion) m/z: 409 (M+H). Calc'd Exact Mass for C26H17ClN2O: 408.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][NH:5][C:6](=O)[CH2:7][CH2:8][CH3:9].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][NH:5][C:6](=[S:21])[CH2:7][CH2:8][CH3:9]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCC(=O)NCC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=S)NCC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the product of Example 5A (0.774 g, 4.862 mmol) in anhydrous THF (50 mL) was treated with Lawesson reagent (1.338 g, 3.209 mmol), then heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction was cooled to 0° and a saturated aqueous sodium bicarbonate solution (40 mL) was slowly added dropwise. The mixture was stirred at room temperature for 15 minutes, and then extracted with ethyl acetate (100 mL), and the organic extract washed with saturated aqueous sodium bicarbonate (50 mL), water (2×25 mL), and brine. Dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated under vacuum giving the title compound. Purification by silica gel flash chromatography with 1% ethyl acetate/methylene chloride afforded the title compound as a colorless oil (0.790 g, 4.508 mmol, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH3:20][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(C)O
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C(C)O)N(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Compound 9A (5.5 g, 19 mmol) dissolved in DMF (15 ml) was added with K2CO3 (1.1 equiv., 2.75 g) and methyl iodide (1.1 equiv., 1.94 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 5 g of 10A as a semisolid. Yield=86%. 1HNMR (DMSO, 200 MHz) δ 1.10 (3H, d, J=6.2 Hz), 2.94 (3H, s), 3.46 (3H, s), 4.22 (1H, q, J=6.4 Hz), 4.39 (1H, d, J=5.2 Hz), 5.16 (1H, d, J=3.2 Hz), 7.40 (2H, m), 7.82 (2H, m)
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.Cl.[CH3:32][O:33][C:34](=[O:47])[C@H:35]([CH2:37][NH:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:36].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:39]([NH:38][CH2:37][C@@H:35]([C:34]([O:33][CH3:32])=[O:47])[NH:36][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])=[CH:19][C:11]=1[Cl:10])(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
Diisopropylethylamine (27 mL, 147.2 mmol) was added dropwise to a cooled (˜0° C.) solution of 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 26; 9.00 g, 29.4 mmol), 3-benzoylamino-L-alanine methyl ester hydrochloride (Example 300; 11.4 g, 44.2 mmol), HTBU (13.4 g, 35.3 mmol) and HOBT (4.8 g, 35.3 mmol) in N,N-dimethylformamide (125 mL). The reaction was allowed to warm to room temperature and to stir for 18 h. The solvent was concentrated under vacuum to remove most of the N,N-dimethylformamide. Ethyl acetate was added and the solution was washed with water (2×150 mL). 1 M HCl (3×100 mL) and brine. The solution was dried (MgSO4), filtered, evaporated, and chromatographed (0-50% acetone/dichloromethane) to give 3-benzoylamino-N-[2-chloro-4-[[[(3-hydroxyphenyl) methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (10.7 g, 71%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=O)[CH:17](Br)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]([NH2:35])=[S:34]>C(O)C.O>[NH2:35][C:33]1[S:34][C:17]([CH2:18][N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])=[C:16]([C:10]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:32]=1
Reactant: NC(N)=S
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1C(=O)C(Br)CN1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccc(Cl)cc2C(=O)c2ccccc2)c(CN2C(=O)c3ccccc3C2=O)s1

Procedure:
A stirred solution of 10 g (0.02 mole) of the end product of Example 2 and 2 g (0.026 mole) of thiourea in 60 ml of ethanol, protected by a drying tube, was refluxed for 1 hr. The yellow solution was poured over ice and diluted with water. The pale yellow solid was collected by filtration, washed with water and air dried on the funnel to give the end product. Recrystallization of a sample from methanol/methylene chloride solution gave pale yellow crystals: mp 253°-255° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@@H:13]([OH:18])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1.O.CN(C1C=CC=CN=1)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@@H:13]([O:18][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])[C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)[C@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 112.1 %

Procedure:
20 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyrate was dissolved in 100 ml of pyridine and 13.3 g of p-toluenesulfonyl chloride was added thereto while maintaining the reaction temperature at 10° to 20° C. Next, 0.03 g of dimethylaminopyridine (DMAP) was added thereto as a catalyst and the mixture was stirred at 20° to 25° C. for 5 hours. Then the reaction mixture was diluted with 500 ml of water and extracted with 150 ml portions of ethyl acetate twice. The extract was washed successively with 50 ml of 2 N hydrochloric acid and 50 ml of a saturated aqueous solution of sodium chloride, dehydrated over anhydrous sodium sulfate and filtered. After distilling off the solvent, 32.5 g of methyl N-benzyloxycarbonyl-3(S)-amino-2(R)-p-toluenesulfonyloxy-4-phenylbutyrate was obtained as a pale yellow, oily substance.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([O-])([O-])=[O:9].[K+:12].[K+]>CO>[C:4]([O:9][CH3:8])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[K+:12]
Reactant: O=C([O-])[O-]
Reactant: O=C1C=CC(=O)O1
Agent: [K+]
Solvent: CO
Product: COC(=O)/C=C\C(=O)[O-]
Yield: 177.1 %

Procedure:
46.5 grams (0.46 mole) maleic anhydride is dissolved in 500 mls methanol. 36 g K2CO3 is added to a pH of 8.5-8.6, the solution is filtered and evaporated to dryness. 77.6 grams of product is obtained. Purity=96.4% by NMR analysis.