Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11]C)=[O:9])=[CH:3][CH:2]=1.[H-].[Na+].[CH:15](OCC)=[O:16].Cl>C1(C)C=CC=CC=1.CCOC(C)=O.CCOCC>[OH:16][CH:15]=[C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)C(=CO)c1ccncc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
9 g of ethyl 2-(4-pyridinyl)acetate and 1.35 g of 95% NaH are mixed in 90 ml of toluene. The mixture is heated at 100° C. for 30 minutes and is then cooled, and 8.8 ml of ethyl formate are added. The mixture is left stirring at AT for 1 hour and at 100° C. for 45 minutes. The reaction medium is cooled and then 25.5 ml of 2N HCl are added. Filtration is carried out and then the precipitate formed is taken up in AcOEt and then in ether to produce 5.65 g of the expected compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].C(OC1C=C(C2ON=C(C3C=CC=C4C=3C=CN4)N=2)C=CC=1OCC)C>>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Br
Agent: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Product: CCCOc1ccc(-c2nc(-c3ccc4c(c3)CCN4)no2)cc1Br
Yield: 95 %

Procedure:
When the product of Step C was substituted for 5-(3,4-diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 34, Step C, the identical process afforded the title compound in 95% yield. 1H-NMR (CDCl3) 1.10 (tr, 3H, J=7.38 Hz); 1.85-1.94 (m, 2H); 3.54 (tr, 2H, J=7.92 Hz); 3.75 (tr, 2H, J=8.28 Hz); 4.08 (tr, 2H, J=6.42 Hz); 6.98 (d, 1H, J=8.73 Hz); 7.03 (d, 1H, J=7.77 Hz); 7.26 (tr, 1H, J=7.83 Hz); 7.75 (d, 1H, J=7.17 Hz); 8.09 (dd, 1H, J=2.1, 8.61 Hz); 8.39 (d, 1H, J=2.1 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14].C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:18][CH2:17][CH2:16][CH:12]2[C:13]([OH:15])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C1CCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 20.1 %

Procedure:
A mixture of 1-chloro-4-nitrobenzene (3 g, 19 mmol), L-proline (2.19 g, 19.0 mmol) and triethylamine (10.6 ml, 76 mmol) were dissolved in DMSO (15 ml) then heated at 90° C. for 24 hr. The reaction mixture was concentrated under reduced pressure, the residue treated with water and extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated to a residue. Purification by column chromatography using dichloromethane/methanol (97:3) gave 1-(4-nitro-phenyl)-pyrrolidine-2-carboxylic acid (0.9 g, 20%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][CH2:36]Br)[C:25]=1[CH2:38][CH2:39][CH3:40].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:15][O:16][C:17](=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:32])[CH3:31])=[C:26]([O:33][CH2:34][CH2:35][CH2:36][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:25]=1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1OCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCCCCC(=O)OC)c2CCC)ccc(C(C)=O)c1O
Yield: 67.9 %

Procedure:
A mixture of 2.62 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.00 g of 6-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]hexanoic acid methyl ester and 3.70 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. The reaction mixture was concentrated in vacuo and the residue was purified by liquid chromatography using 30% ethyl acetate-hexane to give 5.10 g (68% yield) of 6-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]hexanoic acid methyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:22][N:23]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:42].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:4]2[CH:3]=[C:2]([C:31]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24](=[O:42])[N:23]([CH3:22])[CH:32]=3)[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=2)=[CH:15][CH:16]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: COc1ccc(COc2cc(Br)cc(S(C)(=O)=O)c2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(COc2cc(-c3cn(C)c(=O)c4ccccc34)cc(S(C)(=O)=O)c2)cc1
Temperature: 75 °C
Yield: 79.5 %

Procedure:
A mixture of 1-bromo-3[(4-methoxyphenyl)methoxy]-5-methylsulfonylbenzene (103 mg, 0.28 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (79 mg, 0.28 mmol), Pd(dppf)Cl2 (20 mg) and K3PO4 (153 mg, 0.7 mmol) in dioxane (1.9 mL) and water (100 uL) was purged with nitrogen for 10 min, capped, and heated to 75° C. for 15 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of EtOAc (5 to 100%) in DCM to afford the title compound (100 mg, 80%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.30 (s, 3H) 3.58 (s, 3H) 3.77 (s, 3H) 5.14-5.28 (m, 2H) 6.88-7.04 (m, 2H) 7.32-7.80 (m, 9H) 8.29-8.43 (m, 1H). LCMS (M+H)+=450.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[O:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: O=C(Cl)c1ccoc1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccoc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.061 mMol) 3-furoyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 413(M+1)
Reaction SMILES: [CH2:1]([C@@H:4]1[C@@H:8](/[CH:9]=[CH:10]/[C@@H:11]([O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C@H:7]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:6][C@@H:5]1[OH:40])[CH:2]=[CH2:3].[C:41](O)(=[O:47])[CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:41]([O:40][C@H:5]1[CH2:6][C@@H:7]([O:32][Si:33]([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:35])[CH3:34])[C@H:8](/[CH:9]=[CH:10]/[C@@H:11]([O:24][Si:25]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:30][CH3:31])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C@H:4]1[CH2:1][CH:2]=[CH2:3])(=[O:47])[CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46]
Reactant: C=CCCCC(=O)O
Reactant: C=CC[C@@H]1[C@@H](/C=C/[C@H](COc2cccc(C(F)(F)F)c2)O[Si](CC)(CC)CC)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: C=CCCCC(=O)O[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](/C=C/[C@H](COc2cccc(C(F)(F)F)c2)O[Si](CC)(CC)CC)[C@H]1CC=C
Temperature: 40 °C
Yield: 90.7 %

Procedure:
A 50 ml two-necked round-bottom flask was flame dried and allowed to be cooled under nitrogen. (1S,2R,3R,4R)-2-allyl-4-(tert-butyldimethylsilyloxy)-3-((R,E)-3-(triethylsilyloxy)-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)cyclopentanol (1 g, 1.66 mmol) in 10 ml of DMF, 0.05 g (0.33 mmol) of DMAP, 0.21 g (1.83 mmol) of 5-hexenoic acid, and 0.41 g (2.00 mmol) of N,N′-dicyclohexylcarbodiimide were added to the reaction flask. The reaction mixture was heated at 40° C. for 24 hours. The reaction was quenched with 10 ml saturated aqueous sodium bicarbonate. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off and organic solvent was evaporated off under vacuum. The crude product was purified by chromatography and then concentrated under reduced pressure to provide 1.05 g of the title compound (90.52% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]([N+:12]([O-])=O)C)[CH:4]=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(c2ccccc2)C(C)[N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cccc(C(CN)c2ccccc2)c1
Yield: 78.3 %

Procedure:
A mixture of 1-methoxy-3-(1-phenyl-2-nitro-propyl)-benzene (7.8 g, 30.33 mmoles), obtained as described in example 41, ammonium formate (9.56 g, 151.6 mmoles), methanol (80 ml), 10% Pd/C (1.8 g) and 3A molecular sieves (15 g) was kept under reflux for 2 hours, then filtered over celite by washing with methanol and brought to dryness. The residue was taken up with ethyl ether and extracted with 10% HCl. The aqueous phase was basified with K2CO3 and re-extracted with ethyl ether. The organic phase was anhydrified and brought to dryness to give 5.4 g of the title compound (yield: 78.4%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22](=[O:31])[C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[Cl:30])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[Cl:30])=[O:31])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3cc(Cl)ccc3Cl)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3cc(Cl)ccc3Cl)CC2)CC1

Procedure:
The title compound was prepared as described on example 1 from Trans (4-{2-[4-(2,5-Dichloro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester and trifluoroacetic acid (m/e): 383.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[CH:14][C:15]([OH:17])=[O:16])[CH2:7][CH2:6]2.O>C(O)(=O)C.O.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([OH:17])=[O:16])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=CC(=O)O)C2=O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC(CC(=O)O)C2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Zinc (493 g, 7536 mmol) was added to a solution of 1A (350 g, 1507 mmol) in acetic acid-water mixture (1 L+420 mL), and the mixture was stirred at 100° C. for 3 h. The reaction mixture was then filtered over celite bed, and the organic layer was removed under reduced pressure to give a residue. Water (5 L) was added to the residue. The resulting solids were filtered off and dried under vacuum to afford the title compound (280 g, 77%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 12.2 (bs, 1H), 7.8 (d, J=8.4 Hz, 1H), 6.9 (m, 2H), 3.8 (s, 3H), 3.1 (m, 1H), 3.0-2.8 (m, 2H), 2.7 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H), 1.9 (m, 1H). ESI-MS m/z: 235 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.Br[CH2:19][C:20]1C=C[CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>O.CO.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][C:13]2[CH:19]=[CH:20][CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[CH:23]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1sc(Br)cc1NCc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (500 mg, 1.51 mmol), 1-(bromomethyl)-3-nitrobenzene (490 mg, 2.27 mmol), cesium carbonate (1.23 g, 3.78 mmol) and DMF (10 mL) was stirred at 70° C. for 1 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 80:20 hexane/EtOAc) to give a yellow oil. A mixture of this oil, MeOH (5 mL), potassium carbonate (500 mg) and water (2.5 mL) was stirred at room temperature for 0.5 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the title compound (495 mg, 88%) was obtained as a yellow oil:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].C[O:19][C:20](=O)[C:21]([CH2:29][CH3:30])([CH2:24][NH:25][CH:26]([CH3:28])[CH3:27])[CH2:22][CH3:23].C(O)(=O)C>CC(C)=O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([NH:9][C:20](=[O:19])[C:21]([CH2:22][CH3:23])([CH2:29][CH3:30])[CH2:24][N:25]2[CH:26]([CH3:28])[CH3:27])=[CH:4][N:3]=1
Reactant: CCC(CC)(CNC(C)C)C(=O)OC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCC1(CC)CN(C(C)C)c2nc(Cl)ncc2NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (Aldrich; 5.1 g, 26.4 mmol) and K2CO3 (4.4 g, 31.6 mmol) in acetone (150 mL) was slowly added methyl2-ethyl-2-[(propan-2-ylamino)methyl]butanoate (Intermediate 200; 5.3 g, 26.4 mmol) in acetone (30 mL). The mixture was stirred at room temperature for 18 hours. The reaction was filtered and the solvent evaporated. The residue and iron (4.4 g, 79.2 mmol) were added to acetic acid (175 mL) and heated at 80° C. overnight. The resulting solution was filtered and the solvent evaporated and the residue quenched with 2.0 N NaOH(aq) (75 mL), to the resultant emulsion, was added 10% MeOH/DCM (100 ml) and the suspension filtered through a pad of celite. The obtained filtrate was extracted with 10% MeOH/DCM (3×150 mL, dried and the solvent removed. The resultant material was dissolved in DCM and filtered. Acetonitrile was added to the DCM and the DCM was slowly removed in vacuo to give a precipitate, which was filtered and dried to yield the title compound as a white solid. (3.1 g, 33%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[C:12]3=[N:13]C=[CH:15][C:16](OC4C=CC(N)=CC=4F)=[C:11]3[C:10]([NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH:29]([OH:33])[CH2:28]3)=[N:9]2)=[CH:5][CH:4]=1.FC1C=CC(N2C(=[O:49])C(C(O)=O)=CC=N2)=CC=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C.O.CCN(CC)CC>[CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]2[CH:15]=[CH:16][C:11]([C:12]([NH2:13])=[O:49])=[C:10]([NH:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH:29]([OH:33])[CH2:28]3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(NC3CCCC(O)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CN2C=CC(C(N)=O)=C(NC3CCCC(O)C3)N2)cc1
Yield: 97.6 %

Procedure:
A solution of 3-(1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)cyclohexanol (50 mg, 0.10 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (74 mg, 0.31 mmol, obtained from Example 19 Step C), EDCI (120 mg, 0.63 mmol), Et3N (0.1 mL) and HOBT-H2O (96 mg, 0.63 mmol) was stirred in DMF (1 mL) for 10 hours. The reaction mixture was poured into water and extracted with CH2Cl2. The organic layer washed with saturated aqueous NaHCO3, 10% aqueous LiCl, dried with Na2SO4, filtered and concentrated. The residue was purified with flash silica gel chromatography (5% MeOH in CH2Cl2) to afford the product (35 mg, 48% yield) as a brown solid. LRMS (APCI pos) m/e 694.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[C:1]([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])([OH:3])=[O:2]
Reactant: CC(Oc1ccc(Cl)cc1C(=O)O)C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(Oc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-])C(=O)O

Procedure:
To a solution of 220 g of 2-(2-carboxy-4-chlorophenoxy) propionic acid in 550 ml of concentrated sulfuric acid is added dropwise a mixed liquid of 44 ml of fuming nitric acid and concentrated sulfuric acid under stirring with keeping at a temperature below 10° C. After the addition, the reaction mixture is stirred below 10° C. for 3 hours and poured into 10 1 of ice-cold water. The precipitated crystals are collected by filtration, washed with 2 1 of water four times and them dried to give 190 g of 2-(2-carboxy-4-chloro-6-nitrophenoxy)propionic acid, melting at 190° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:15]O>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: Nc1ccccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1N
Yield: 93 %

Procedure:
To a stirred solution of 2-aminobenzoic acid (2.0 g, 14.59 mmol) in MeOH (70 mL) at 0° C. was added SOCl2 (7.4 g, 145.9 mmol) dropwise. The mixture was heated at reflux overnight and was then concentrated under reduced pressure. DCM and saturated aqueous NaHCO3 were added and the aqueous phase extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to afford methyl 2-aminobenzoate (2.05 g, 93%). LC-MS (ES-API); rt 8.46 min; m/z calculated for C8H9NO2[M+H]+ 152.0, found 152.1.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:33])[C:18]=3[C:22]([NH:24][CH2:25][CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:23])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[K+]>O>[Cl:33][C:17]1[C:18]([C:22]([NH:24][CH2:25][CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:23])=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:9]1[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH:21]=[CH:20]2
Reactant: CCOC(=O)C1CCN(c2ccc3c(C(=O)NCCC4CCCCC4)c(Cl)ccc3n2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NCCC1CCCCC1)c1c(Cl)ccc2nc(N3CCC(C(=O)O)CC3)ccc12
Temperature: 70 °C
Yield: 79.7 %

Procedure:
To a 10 mL vial was added 1-[6-chloro-5-[[(2-cyclohexylethyl)amino]carbonyl]-2-quinolinyl]-4-piperidinecarboxylic acid ethyl ester (Example 76(d)) (200 mg), methanol (2 mL) and potassium hydroxide (100 mg) in water (1 mL)). The vial was sealed and heated at 70° C. in a microwave for 10 minutes. The mixture was concentrated and the residue was acidified to pH 5 with aqueous 2 M hydrochloric acid. The resulting solid was collected by filtration. Purification (Varian NH2 cartridge using methanol:dichloromethane 1:1 (100 mL) and then 2% acetic acid in methanol:dichloromethane 1:1(100 mL) as eluant) afforded the title compound (150 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:39])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:39])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg (0.49 mmol) of the compound from Example 279 were introduced into 20 ml of dichloromethane at 0° C., 120 mg (0.49 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 134 mg (65% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1([OH:19])[CH2:11][O:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1.[ClH:24].O1CCOCC1>O1CCOCC1>[ClH:24].[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][C:5]1([OH:19])[CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(Cc2ccccc2F)C1
Agent: Cl
Solvent: C1COCCO1
Product: OC1(Cc2ccccc2F)CNCCOC1
Reaction time: 24 h
Yield: 91.7 %

Procedure:
tert-Butyl 6-(2-fluorobenzyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (Preparation 45, 38 g, 0.12 mol, 1 eq) was dissolved in dioxane (200 mL), and 4M hydrogen chloride/dioxane (60.4 mL, 0.24 mol, 2 eq) was added. The mixture was stirred for 24 h, evaporated, and coevaporated with ether. The formed precipitate was washed with ether and dried to give title compound (29.8 g, 0.11 mol, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20](O)=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[CH3:31][O:32][C:33](=[O:37])[C@@H:34]([CH3:36])[NH2:35]>C(Cl)Cl>[CH3:2][C:1]([CH3:3])([O:5][C:6]([NH:8][CH:9]([C:20]([NH:35][C@@H:34]([C:33]([O:32][CH3:31])=[O:37])[CH3:36])=[O:21])[CH2:10][C:11]1[C:12]([CH3:19])=[CH:13][C:14]([OH:18])=[CH:15][C:16]=1[CH3:17])=[O:7])[CH3:4]
Reactant: COC(=O)[C@@H](C)N
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](C)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
Racemic t-butoxycarbonyl 2,6-dimethyltyrosine (3.9 g, 10 mmol) was dissolved in 30 ml of CH2Cl2 by adding 1.12 ml (10 mmol) of NMM. After bringing this mixture to reflux it was cooled to -30° C. and 1.32 ml (10 mmol) of IBCF were added to this stirred solution. The temperature was allowed to rise to -15° C. and then lowered to -50° C. (D)alanine methyl ester hydrochloride (1.54 g, 11 mmol) was added to the solution followed by 1.3 ml (11 mmol) of NMM. The mixture was allowed to warm to room temperature and stand for 16 h. The majority of the CH2Cl2 was removed under reduced pressure. Ethyl acetate (EtOAc, 200 ml) was added and this solution was washed twice with 100 ml portions of 0.5 molar KHSO4, once with 100 ml of H2O and dried over MgSO4. Removal of all solvent gave 3.9 g of the mixture of diastereomers. Recrystallization of this material from Skelly B(hexanes)/CH2Cl2 produced 1.6 g (4.2 mmol) of diastereomer F. Removal of the solvent from the filtrate gave 1.3 g (3.3 mmol) of diastereomer S contaminated by less than 10% of diastereomer DF. The mixture of diastereomers or either of the separated diastereomers were used in subsequent examples without further purification.