Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:30][C:31](=[NH:48])[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH:34]=[CH:35][N:36]2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:14][N:48]=[C:31]([C:32]3[CH:40]=[CH:39][CH:38]=[C:37]4[C:33]=3[CH:34]=[CH:35][N:36]4[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:30]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1ccc2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (D61) (1.504 g, 6.97 mmol) in dry DMF (30 ml) was added EDC (1.604 g, 8.37 mmol) and HOBT (1.282 g, 8.37 mmol). Stirred solution at RT for 10 minutes then added ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (N4111-31-A4) (D57) (1.92 g, 6.97 mmol). The mixture was stirred for 30 minutes. LC/MS showed one product (intermediate). The solution was heated at 80° C. for 2 hours. Left standing overnight at RT then heated 80° C. for further 2 hours to give complete reaction. Cooled and added EtOAc (250 ml). The EtOAc was washed with sat. NaHCO3 (150 ml) followed by water (2×200 ml). Dried over MgSO4 and evaporated off the solvent. The residue was subjected to chromatography on the biotage (EtOAc/hexane 1:2). On evaporation of most of the solvent from clean fractions and addition of hexane a white precipitate was formed. The solid was filtered off to obtain 1.1 g of the title product. MS (ES) C23H2335ClN4O4 requires 454; found 455 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:23][OH:24])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+].O[C:49]1[CH:50]=[C:51]([C:55]2([O:61][CH3:62])[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)[CH:52]=[CH:53][CH:54]=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:23][O:24][C:53]3[CH:54]=[CH:49][CH:50]=[C:51]([C:55]4([O:61][CH3:62])[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[CH:52]=3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2oc(CO)nc2-c2ccc(F)cc2)cc1
Reactant: COC1(c2cccc(O)c2)CCOCC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(c2cccc(OCc3nc(-c4ccc(F)cc4)c(-c4ccc(S(C)(=O)=O)cc4)o3)c2)CCOCC1
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
A solution containing 4-(4-fluorophenyl)-2-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]oxazole from Step 3 (169 mg, 0.487 mmol) in 20 mL of dichloromethane was stirred at 25° C. as triethylamine (136 μL, 0.974 mmol) was added dropwise, followed by the addition of methanesulfonyl chloride (56 μL, 0.730 mmol). The reaction was stirred for 5 minutes, after which the organic solution was washed with 1N HCl, dried over sodium sulfate and concentrated in vacuo to give a yellow oil which was characterized as the expected mesylate by its NMR spectrum: 1H-NMR (CDCl3, 400 MHz) δ 3.08 (s, 3H), 3.17 (s, 3H), 5.37 (s, 2H), 7.12 (t, 2H, J=8.8 Hz), 7.58 (m, 2H), 7.78 (d, 2H, J=8.8 Hz) and 7.94 (d, 2H, J=8.8 Hz). This material was used without further purification. The mesylate was dissolved in 20 mL of DMF and potassium carbonate (81 mg, 0.584 mmol) was added, followed by the addition of 4-(3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (122 mg, 0.584 mmol). The reaction was stirred at 25 ° C. for 3 days and poured into 100 mL of water. The aqueous solution was extracted with ethyl acetate and the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a beige solid. This material was purified by flash chromatography on a silica gel column using 50% ethyl acetate/hexane as the eluent to give 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-[[3-(3,4,5,6-tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl]oxazole (185 mg, 71%) as a white crystalline solid: 1H-NMR (CDCl3, 300 MHz) δ 1.90-2.05 (m, 4H), 2.97 (s, 3H), 3.08 (s, 3H), 3.81 (m, 4H), 5.25 (s, 2H), 6.98-7.17 (m, 5H), 7.33 (t, 1H, J=7.7 Hz), 7.60 (m, 2H), 7.78 (d, 2H, J=8.5 Hz) and 7.93 (d, 2H, J=8.5 Hz). 19F-NMR (CDCl3, 280 MHz) δ -111.6. LRMS m/z 544 (M+Li)+. HRMS Calc'd. for C29H28NO6FS: 544. 1781 (M+Li)+. Found: 544. 1831 (M+Li)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:20](=[O:22])[CH3:21])[CH:10]=2)=[O:8])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)c2cn(C(C)=O)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g of compound 1 was added to the mixture of 50 ml each of acetic anhydride and pyridine, and then the solution was stirred overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure. The resulting crude crystals were recrystallized from chloroform to obtain 3-(p-methoxybenzoyl)-N-acetylindole (compound 5) in the form of white crystals. (Yield: 90%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C:16]2C=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8](C(O)=O)=[CH:9][CH:10]=[CH:11][CH:12]=1>ClCCl.CN(C)C=O>[C:16]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1-c1ccccc1

Procedure:
1.54 ml (0.018 mol) of oxalyl chloride are added dropwise to a suspension of 3 g (0.015 mol)) of biphenyl-2-carboxylic acid in 100 ml of dichloromethane and 0.3 ml dimethylformamide at 0° C. After the reaction has ended the reaction mixture is concentrated by distillation and the biphenyl-2-carboxylic acid chloride is further reacted as a crude product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=O)[CH2:7]Br)[CH3:2].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>C(#N)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]2[CH:7]=1)[CH3:2]
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)CC(=O)CBr
Solvent: CC#N
Product: CCOC(=O)Cc1cn2cc(Br)ccc2n1
Yield: 70.3 %

Procedure:
Add 4-bromo-3-oxo-butyric acid ethyl ester (12.08 g, 57.8 mmol) to a solution of 2-amino-5-bromo pyridine (5.0 g, 28.9 mmol) in acetonitrile (80 mL). Reflux for 4 days and concentrate to dryness. Purify by flash chromatography using appropriate ethyl acetate/methanol mixtures to give the subtitled compound (5.75 g, 70%) as a brown oil. TOF MS ES+ exact mass calculated for C, HI BrN2O2 (p+1): m/z=283.0082 Found: 283.0084. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (m, 1H), 7.82 (s, 1H), 7.45 (d, J=10 Hz, 1H), 7.30 (dd, J=10, 2.0 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.77 (s, 2H), 1.18 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][N:6]([C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=3[O:34][CH3:35])=[CH:22][CH:21]=2)[CH:13]=1)[C:7]([CH3:10])([CH3:9])[CH3:8])C.[Li+].[OH-]>C1COCC1.O>[C:7]([N:6]([CH2:5][C:4]([OH:37])=[O:3])[C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=3[O:34][CH3:35])=[CH:22][CH:21]=2)[CH:13]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)CN(C(=O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(C(=O)N(CC(=O)O)C(C)(C)C)c2)cc1

Procedure:
A solution of {[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoyl]-tert-butyl-amino}-acetic acid ethyl ester (11.6 g, 23.3 mmol) in THF (500 mL) was treated with a solution LiOH (2.8 g, 116.7 mmol) in water (500 mL) at room temperature for 12 h. THF was then removed by evaporation. The mixture was then poured into ice and carefully acidified with dilute HCl to pH-1. The precipitate was collected by filtration, washed with water, and dried in vacuum to afford {tert-butyl-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzoyl]-amino}-acetic acid as a white solid, 10.6 g (94%). LC-MS (ES) calculated for C27H27F2NO5, 483; found m/z 484 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 3-nitroaniline(13.8 g, 99.9 mmol) in pyridine (200 mL) were added 3-(trifluoromethyl)benzoylchloride (21.4 g, 103 mmol) and N,N-dimethylaminopyridine (69.1 mg, 566 μmol), and the mixture was stirred at room temperature for 1.5 hr. The reaction was quenched with methanol (50 mL), and the solvent was evaporated under reduced pressure. The residue was suspended in ethyl acetate (300 mL), washed with water (200 mL×2), diluted hydrochloric acid (200 mL×2), saturated aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (31.0 g, 100%) as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:35]O)[NH2:34]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:35]=[C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])[N:34]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1ccccc1F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4F)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 34 mg (0.22 mmol, 1.1 eq.) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 39 mg (42% of theory)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.CC([O-])(C)C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Cl.O1CCOCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc(NC3CCNCC3)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 100 °C

Procedure:
A degassed mixture of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (80. mg, 0.26 mmol, from Example 228, Step 7), tert-butyl 4-aminopiperidine-1-carboxylate (210 mg, 1.0 mmol, Combi-Blocks), NaOtBu (49 mg, 0.51 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (30. mg, 0.051 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol, Aldrich) in toluene (4.0 mL) was heated at 100° C. overnight. After cooling, the reaction mixture was diluted with EtOAc and washed sequentially with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in DCM (5.0 mL) and was treated with 4.0 M HCl in dioxane (2.0 mL, 8.0 mmol) for 1 hour. The reaction mixture was concentrated in vacuo. The product was purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (40 mg, 38%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]#[C:12][Si](C)(C)C)[OH:10])=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]#[CH:12])[OH:10])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(O)C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
Place a mixture of 4-dimethylamino-α-[(trimethylsilyl)-ethynyl]-benzenemethanol (2.26 g, 9.13 mmol) and tetrahydrofuran (11 mL) under argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1 M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between ethyl ether and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter, and concentrate in vacuo to yield 1.37 g, (85.6%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:36])[C:25]([O:29][CH2:30][CH:31](OC)OC)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:37]4[N:38]=[C:39]([NH:42][CH:43]([CH3:45])[CH3:44])[S:40][CH:41]=4)[CH:20]=3)[CH2:15][N:14]2[C:46](=[O:62])[CH:47]([NH:52][C:53]([O:55][CH:56]2[CH2:61][CH:60]3[CH:58]([CH2:59]3)[CH2:57]2)=[O:54])[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].Cl.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:36])[C:25]([O:29][CH2:30][CH2:31][N:64]5[CH2:69][CH2:68][O:67][CH2:66][CH2:65]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:37]4[N:38]=[C:39]([NH:42][CH:43]([CH3:44])[CH3:45])[S:40][CH:41]=4)[CH:20]=3)[CH2:15][N:14]2[C:46](=[O:62])[CH:47]([NH:52][C:53]([O:55][CH:56]2[CH2:57][CH:58]3[CH:60]([CH2:59]3)[CH2:61]2)=[O:54])[C:48]([CH3:50])([CH3:51])[CH3:49])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4]
Reactant: C1COCCN1
Reactant: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCC(OC)OC)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-yloxy]pyrrolidine-2-carbonyl}amino)-2-ethylcyclopropanecarboxylic acid methyl ester (23.6 g, 26 mmol) was dissolved in glacial acetic acid (200 ml) and 1.4N HCl in H2O (75 ml) was added to the solution. The mixture was stirred at 60° C. for 1 h. The mixture was concentrated to remove the solvents, followed by co-evaporation with toluene (×2) to remove residual acetic acid. The residue was then dissolved in EtOAc (500 ml) and sat. NaHCO3 aqueous solution while monitoring CO2 evolution. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was further dried under high vacuum for 1 h and used without further purification in the next step. The crude material was dissolved in CH2Cl2 (360 ml) and morpholine (3.4 g, 39 mmol) and sodium triacetoxyborohydride (7.2 g, 34 mmol) were added to the mixture at 0° C. Then glacial acetic acid (0.47 g, 7.8 mmol) was added dropwise to the mixture. The reaction was complete in 10 min at 0° C. Saturated aqueous NaHCO3 solution was added to quench the reaction. After stirring for another 20 min, the organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester as a yellow solid (12 g, 50% yield). LCMS found 924.63 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[C:25]=2[O:34][CH3:35])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:36].[Li+]>C(COC)OC.O.[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[C:25]=1[O:34][CH3:35])[C:20]([OH:36])=[O:22])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](CC3CCCCC3)NC(=O)OC(C)(C)C)OC2=O)c(OC)c1OC
Reactant: [OH-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Reaction time: 2 h

Procedure:
A solution of 600 mg (1.22 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-3(R)-[(2,3,4-trimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 20 ml of dimethoxyethane and 9.9 ml of water is treated, at RT, with 4.9 ml of a 1M solution of lithium hydroxide in water, and this reaction mixture is stirred for 2 h. It is then transferred to a separating funnel and diluted with 60 ml of sat. ammonium chloride solution and 5 ml of a 10% citric acid solution (both being cold); this mixture is then extracted with ethyl acetate and a little THF. The title compound, which is dried under HV and subjected to further processing without being purified, is obtained after washing the organic phase with (cold) saline and drying it over sodium sulfate. IR(CH2Cl2) inter alia: 3431, 1710, 1602, 1495, 1165 and 1100 cm-1. FAB-MS (M+H)+ =510. HPLC tRet =16.13 min (gradient II).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH3:14]>C(O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: CCO
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
131 g of product of Example 3 are added portionwise to 1 l of ethanol saturated with ammonia. The reaction mixture is stirred at ambient temperature for 24 h, then concentrated and water is added thereto. The solid obtained is filtered, then washed with isopropanol and pentane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=1)=[O:7]
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: COc1cc(OC)cc(C(=O)Nc2ccc(C(=O)CCC(=O)O)cc2)c1
Yield: 3.4 %

Procedure:
In a manner similar to that described in Example 3, 3,5-dimethoxy-benzoyl chloride (0.068 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.003 g of 4-[4-(3,5-dimethoxy-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+358.
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C1O[C:21]2([CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[O:20]C1>C(OCC)C.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][C:24]1([OH:27])[CH2:25][CH2:26][C:21](=[O:20])[CH2:22][CH2:23]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CCOCC
Product: O=C1CCC(O)(CC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
To a suspension of zinc dust (2.06 g, 31.5 mmol) in diethyl ether (50 mL) under argon was added trimethylsilyl chloride (3.0 mL, 23.6 mmol) and the reaction stirred for 15 min at RT. The reaction was then heated at reflux for 25 min. Benzyl bromoacetate (3.9 mL, 24.6 mmol) and 1,4-cyclohexanedione monoethylene acetal (3.05 g, 19.6 mmol) were added and the reaction was kept at reflux for 1.3 hr. The reaction was then cooled to RT, quenched with 1N HCl (125 mL) and stirred overnight. The aqueous layer was extracted with Et2O (3×). The combined organic layers were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc:Hexane) to provide 2.79 g (54%) of pure product. ESI-MS m/z 285 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]([N:12]([CH3:14])[CH3:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[CH:18]([CH3:33])[CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].C(N(CC)CC)C>CC(C)=O>[CH3:14][N:12]([CH3:13])[C:5]1[C:4]([O:15][CH3:16])=[CH:3][C:2]([NH:1][CH:18]([CH3:33])[CH2:19][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2ncccc2c1N(C)C
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2ncccc2c1N(C)C
Reaction time: 2 h

Procedure:
A stirred mixture of 17.2 g (0.033 mole) of 8-amino-5-dimethylamino-6-methoxyquinoline and 9.8 g (0.033 mole) of 4-bromo-1-phthalimidopentane was maintained at 145° while 5 ml of triethylamine was added dropwise. Addition of 9.8 g of 4-bromo-1-phthalimidopentane and 5 ml of triethylamine was repeated three more times, at the same temperature (145°) at 2 hr intervals. The mixture was allowed to cool, diluted with acetone and filtered. The filtrate was concentrated to a brown oil which was diluted with ether, washed with 30% KOH and extracted with chloroform. The extract was passed through a silica column and the eluate was concentrated, dissolved in ether, treated with Darco and slowly evaporated to give yellow crystals which, after washing with petroleum ether (bp 20°-40°) weighed 9.5 g and melted at 103°-105°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[C:5](I)=[CH:4][N:3]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[C:5]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[CH:4][N:3]=1
Reactant: CC(=O)NCCNc1nc(Cl)ncc1I
Reactant: OB(O)c1cccs1
Product: CC(=O)NCCNc1nc(Cl)ncc1-c1cccs1
Yield: 79 %

Procedure:
In the reaction of N-[2-(2-chloro-5-iodopyrimidine-4-ylamino)ethyl]-acetamide (870 mg, 2.6 mmol) with thiophen-2-boronic acid (359 mg, 2.8 mmol) according to procedure 3, the desired product is obtained in 79% yield (602 mg) after chromatographic purification (silica gel, ethyl acetate/hexane (0%-90% ethyl acetate)).