Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[CH3:21])[C:10](=[O:22])[CH2:9]2)=[O:7])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[O:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][N:8]([C:6]([C:5]2[CH:23]=[CH:24][C:2]([N:31]3[CH2:32][CH2:33][O:29][C:30]3=[O:34])=[CH:3][C:4]=2[S:25]([CH3:28])(=[O:27])=[O:26])=[O:7])[CH2:9][C:10]1=[O:22]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2=O)c(C)c1
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3S(C)(=O)=O)CC2=O)c(C)c1
Yield: 63.9 %

Procedure:
To a mixture of 4-(4-bromo-2-methanesulfonylbenzoyl)-1-(2,4-dimethylphenyl)piperazin-2-one (931 mg), oxazolidin-2-one (209 mg), potassium carbonate (849 mg) and copper (I) iodide (76 mg) were added toluene (2 mL) and N,N′-dimethylethylenediamine (90 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) and recrystallized from a mixed solution of hexane and ethyl acetate to give the title compound (603 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]([NH2:16])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
(5-Fluoro-2-nitrophenyl)-(4-fluorophenyl)amine (2.94 g, 11.76 mmol) was dissolved in EtOAc (120 mL) and the flask evacuated and flushed with nitrogen gas. 10% Pd/C (0.29 g) was added and the reaction mixture stirred at RT, under an atmosphere of hydrogen overnight. The resultant mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford the title compound as an orange oil (2.67 g, 91%). 1H NMR (CDCl3, 400 MHz): δ 7.01-6.92 (2H, m), 6.87-6.68 (4H, m), 6.61 (1H, td, J=8.35, 2.79 Hz), 5.24 (1H, s), 3.46 (2H, s)
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]1([C:2]2[C:7]3[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOc2cccc(Br)c2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2cccc(-c3ccccc3)c2C1
Yield: 60.5 %

Procedure:
A mixture of tert-butyl 6-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (150 mg, 0.457 mmol), a solution of phenylboronic acid (83.4 mg, 0.684 mmol) in ethanol (0.525 ml), 2N aqueous sodium carbonate solution (2 ml), and tetrakis(triphenylphosphine)palladium(0) (63.2 mg, 0.0547 mmol) in toluene (4 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (90.0 mg, 58.0%) as an oil.
Reaction SMILES: C(OC(=O)[N:7]([C:15]1[S:16][C:17]([CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[C:18]([Cl:20])[N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:20][C:18]1[N:19]=[C:15]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:16][C:17]=1[CH2:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccncc1)c1nc(Cl)c(Cc2c[nH]c3ncccc23)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1nc(NCc2ccncc2)sc1Cc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a solution of [4-chloro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (520, 126 mg, 0.000276 mol) in dichloromethane (2 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into cold sodium bicarbonate solution, extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After removal of solvents, the residue was washed with ethyl acetate to provide the desired compound as a light yellow solid (P-0168, 68.4 mg, 70%). MS (ESI) [M+H+]+=356.2.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])(=[O:18])=[O:17])=[CH:10][N:9]=1>N1C=CC=CC=1>[CH3:6][O:7][C:8]1[C:13]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][C:11]([CH2:15][S:16](/[CH:19]=[CH:20]/[C:21]2[C:26]([O:27][CH3:28])=[CH:25][C:24]([O:29][CH3:30])=[CH:23][C:22]=2[O:31][CH3:32])(=[O:18])=[O:17])=[CH:10][N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(N)c2)c(OC)c1
Solvent: c1ccncc1
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2cnc(OC)c(NS(C)(=O)=O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Methanesulfonyl chloride (0.048 mL, 0.31 mmol) was added dropwise into the solution of (E)-2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-amine (111 mg, 0.28 mmol) in dry pyridine (7 mL) on an ice bath. After warming up to room temperature the mixture was stirred overnight. After evaporated to dryness, the residue was purified by silica gel chromatography, eluting with PE/EtOAc (1:2 v/v) to afford pure product as a white solid (42 mg, 32%) 1H-NMR (Acetone-do): δ 2.98 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 3.93 (s, 6H, 2×OCH3), 3.97 (s, 3H, OCH3), 4.38 (s, 2H, CH2), 6.31 (s, 2H, Ph-H), 7.19 (d, 1H, J=15.6 Hz, CH), 7.71 (d, 1H, J=15.6 Hz, CH), 7.85 (d, 1H, J=2.0 Hz, Py-H), 7.97 (d, 1H, J=2.0 Hz, Py-H); 13C-NMR (Acetone-d6): δ 38.78, 53.30, 55.08, 55.53, 57.36, 90.67, 103.24, 119.44, 121.70, 123.17, 130.21, 134.70, 143.67, 154.11, 161.54, 164.28; HR-MS (ESI+) m/z 473.1115 [M+H]+ C19H24N2O832 requires 472.0974.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:15]4[C:14](=[O:25])[NH:13][C:12](=[O:26])[C:11]=4[C:10]=3[C:6]=2[CH:5]=[C:4]([OH:27])[CH:3]=1.[CH2:28](C([Sn])=C(CCCC)CCCC)[CH2:29]CC>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[C:15]2[C:14](=[O:25])[NH:13][C:12](=[O:26])[C:11]=2[C:10]2[C:6]3[CH:5]=[C:4]([OH:27])[CH:3]=[C:2]([CH:28]=[CH2:29])[C:7]=3[O:8][C:9]=2[CH:17]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1oc3c(Br)cc(O)cc3c21
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Product: C=Cc1cc(O)cc2c1oc1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 79 %

Procedure:
Reaction of (862) prepared as described in example 443 with tributylvinyltin using the procedure described in example 309 gave (863) (79%). 1H NMR δ [(CD3)2SO] 9.80 (s, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.91 (s, 1H), 7.56 (d, J=8 Hz, 1H), 7.45 (m, 3H), 7.2 (d, J=2.5 Hz, 1H), 6.96 (dd, J=18,1 Hz, 1H), 6.25 (d, J=18 Hz, 1H), 5.52 (d, J=11 Hz, 1H). MH−:390,388.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:45][C:40]1[CH:39]=[C:38]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:35])[CH3:36])[CH:28]=3)[CH2:21]2)[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: CC(C)Oc1cccc(CC(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(=O)N2CC[C@@](CCN3CCC(N4CCCCC4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3 N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH:7]([NH2:13])[CH2:6][CH2:5][CH2:4]1.[CH3:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][NH:15][C:16]([NH:13][CH:7]1[C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:3](=[O:2])[CH2:4][CH2:5][CH2:6]1)=[O:17]
Reactant: NC1CCCC(=O)c2sccc21
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NC1CCCC(=O)c2sccc21

Procedure:
Stoichiometric quantities of 5,6,7,8-tetrahydro-8-oxo-4H-cyclohepta[b]thiophen-4-amine hydrochloride, methyl isocyanate, and triethylamine are allowed to react in dry methylene chloride to afford the title compound.
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].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[C:34](=[N:36]O)[NH2:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[C:34]1[N:36]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:35]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1cc(Cl)ccc1Cl
Product: CCc1ccc(C2CC(c3nc(-c4cc(Cl)ccc4Cl)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 45 mg (0.22 mmol, 1.1 eq.) of 2,5-dichloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 28 mg (27% of theory)
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([O:31][Si](C(C)(C)C)(C)C)[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH3:39])[CH:19]=2)([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH3:40].C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[OH-].[Na+]>O>[CH2:14]([C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][O:5][CH2:4][C:3]([OH:41])=[O:2])=[C:8]([CH3:40])[CH:9]=1)([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[C:20]([CH3:39])[CH:19]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)(c1ccc(COCC(=O)OC)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)(c1ccc(COCC(=O)O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Yield: 60.4 %

Procedure:
To a solution of enantiomer 1 of [4-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-benzyloxy]-acetic acid methyl ester (0.96 g, 1.64 mmol) and THF (10 mL) is added 1M TBAF (3.3 mL, 3.28 mmol). The solution is heated at a reflux overnight and concentrated. The residue is dissolved in MeOH (5 mL) and water (1 mL), NaOH (0.33 g, 8.21 mmol) is added and the solution is heated at reflux for 3 hours. The solution is concentration, dissolved in EtOAc (20 mL), washed with 1M HCl (15 mL), water (15 mL), brine (15 mL), dried over MgSO4, and concentrated. The residue is chromatographed to furnish the title compound (0.45 g, 0.99 mmol, 60%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C=O)C>[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:2]=2)[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:6])[CH2:27][CH2:26]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: COC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.379 g, 1.00 mmol) was added to 3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (0.200 g, 0.71 mmol), 4-methoxypiperidine (0.090 g, 0.78 mmol) and triethylamine (0.249 mL, 1.78 mmol) in DMF (3 mL). The resulting solution was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.211 g, 78% yield); 1H NMR (400.132 MHz, DMSO) δ 1.24-1.49 (2H, m), 1.63-1.93 (2H, m), 2.94-3.14 (2H, m), 3.30 (3H, s), 3.34-3.44 (2H, m), 3.88 (1H, s), 4.35 (2H, s), 7.21 (1H, m), 7.30-7.43 (3H, m), 7.80-7.90 (2H, m), 7.96 (1H, d), 8.27 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.57 min (M+H=378.20).
Reaction SMILES: [P:1]([OH:35])([OH:34])([O:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([NH:14][C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]4[CH:28]=[C:27]([CH3:29])[C:26]([F:30])=[C:25]([O:31][CH3:32])[CH:24]=4)[N:16]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:33])=[O:2].[OH-].[Na+:37]>O>[P:1]([O-:35])([O-:34])([O:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([NH:14][C:15]3[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]4[CH:28]=[C:27]([CH3:29])[C:26]([F:30])=[C:25]([O:31][CH3:32])[CH:24]=4)[N:16]=3)[CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:33])=[O:2].[Na+:37].[Na+:37]
Reactant: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)n(COP(=O)(O)O)c4c3)n2)cc(C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)n(COP(=O)([O-])[O-])c4c3)n2)cc(C)c1F
Reaction time: 1 h
Yield: 89 %

Procedure:
With stirring, to a H2O (500 mL) suspension of crude (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl dihydrogen phosphate, 1N NaOH (aq., 163 mL, 163 mmol) was added dropwise over 15 min, with ice-bath cooling. Remove ice-bath, add additional H2O until final volume reaching ˜1 L. Solid was removed by filtration through a filter paper, washing with H2O Solid (˜3 g) appeared as a 1:1 mixture of prodrug and parent compound (I-105) which was formed during previous hydrolysis reaction.). Filtrate was collected, and most H2O was removed by lyophilization (˜20 mL of H2O left as solid ice). With stirring, i-PrOH (800 mL) was added to the solid, stirring was continued for 1 h until solid was evenly dispersed in the solution. Solid was collected by filtration, washed with i-PrOH (˜100 mL×3), and was further dried under high vac. Compound disodium (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate was obtained as a light beige color solid: 38.87 g (89% yield over 3 steps, starting from the TFA salt described above); 1H NMR (300 MHz, D2O) δ 7.63 (s, 1H), 7.39-7.33 (m, 2H), 7.13-7.09 (m, 1H), 6.77-6.71 (m, 2H), 5.41 (d, J=6.1 Hz, 2H), 3.62 (s, 3H), 2.01 (br s, 3H), 1.99 (br s, 3H); LRMS (M−) m/z 504.12.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21])([CH3:3])[CH3:2].[H-].[Na+].[C:26](=O)([O:30]CC)[O:27][CH2:28][CH3:29].Cl>C1COCC1>[CH2:28]([O:27][C:26](=[O:30])[CH2:18][C:17]([C:14]1[CH:15]=[CH:16][C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[C:12]([C:20]([F:23])([F:21])[F:22])[CH:13]=1)=[O:19])[CH3:29]
Reactant: CC(=O)c1ccc(Sc2ccccc2C(C)C)c(C(F)(F)F)c1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(Sc2ccccc2C(C)C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
Then, 3-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-3-oxo-propionic acid ethyl ester 45 was prepared as follows. To a solution of compound 44 (11.5 g, 34.0 mmol) in THF (150 mL) was added 60% sodium hydride in mineral oil (1.84 g, 40.8 mmol). The mixture was stirred at room temperature for 10 minutes. Diethyl carbonate (46.5 mL, 340 mmol) was added and the mixture was heated under reflux for 2 hours. 10% HCl aq. (100 mL) was added and the solution was extracted with ethyl acetate (200 mL). The organic layer was separated, washed with brine (5×250 mL), dried over MgSO4 and filtered. The filtrate was concentrated on a rotor-vapor to give a brown oil 45 (10.6 g, 76%); MS (DCI) m/z 411 (M+H)+; 428 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[C@H:22]4[CH2:23][CH2:24][C@@H:18]3[CH2:19][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]4)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:32]([O:35][CH2:36][C:37]1[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][CH:40]=[CH:39][C:38]=1[N:52]1[N:61]=[CH:60][C:59]2[C:54](=[C:55]([F:66])[CH:56]=[C:57]([C:62]([CH3:65])([CH3:64])[CH3:63])[CH:58]=2)[C:53]1=[O:67])(=[O:34])[CH3:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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.[Pd]>[C:32]([O:35][CH2:36][C:37]1[C:38]([N:52]2[N:61]=[CH:60][C:59]3[C:54](=[C:55]([F:66])[CH:56]=[C:57]([C:62]([CH3:64])([CH3:63])[CH3:65])[CH:58]=3)[C:53]2=[O:67])=[CH:39][CH:40]=[CH:41][C:42]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][N:20]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:21]4)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(N3[C@@H]4CC[C@H]3CN(C(=O)OC(C)(C)C)C4)cn2)c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C5CCC4CN(C(=O)OC(C)(C)C)C5)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 60.2 %

Procedure:
This reaction was carried out under similar conditions to those described above in step 7 of preparation of Example 6. (1R,5S)-tert-butyl 8-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (100 mg, 224 umol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (114 mg, 224 umol), xPhos (10.7 mg, 22.4 umol) and potassium phosphate (119 mg, 559 umol) in 7 ml of Dioxane/water (9:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (6.42, 11.2 umol) was added. The reaction mixture was heated to 100° C. for 2 hr. After work up, the product was purified by preparative HPLC on silica gel, using a gradient of 5% to 70% ethylacetate/hexane. This provided the desired product as a light yellow solid (105 mg 60.3%). (M+H)+=779 m/e.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[Cl:6][C:7]1[C:8]([F:27])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([CH:24]=[O:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:6][C:7]1[C:8]([F:27])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:4][CH2:3][O:2][CH3:1])=[C:21]([CH:24]=[O:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Temperature: 90 °C

Procedure:
2-Chloroethyl methyl ether (0.967 g, 6.2 mmol) was added to a stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-hydroxyquinazoline-6-carbaldehyde (1.0 g, 3.1 mmol) and K2CO3 (1.30 g, 9.45 mmol) in dimethyl formamide (10 ml) at room temperature. The resulting suspension was heated at 90° C. for 8 hours, cooled to room temperature, concentrated and purified by preparative LCMS (standard basic system) to give 4-[(3-chloro-2-fluorophenyl)amino]-7-(2-methoxyethoxy)quinazoline-6-carbaldehyde as a pale yellow solid, (0.150 g, 15%); Mass Spectrum: (M+H)+ 376.
Reaction SMILES: C([O:5][C:6](=[O:8])[CH3:7])(C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH3:17][O:18][C:19]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH2:23][C:24]2=O.Cl.Cl.C(O)(=O)C>C1COCC1.O.CO>[CH3:17][O:18][C:19]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][CH:23]=[C:24]2[CH2:7][C:6]([OH:8])=[O:5]
Reactant: CC(=O)OC(C)(C)C
Reactant: COc1ccc2c(c1OC)CCCC2=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1OC)CCC=C2CC(=O)O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
tert-Butylacetate is added to a solution of lithium di-isopropyl amide in THF at -78° C. To this solution is added 5,6-dimethoxy-1,2,3,4-tetrahydro-1-naphthalenone and the resulting mixture is stirred at 0° C. for 20 minutes, then cooled back to -78° C. One equivalent of HCl in water is added to the solution, followed by concentration of this mixture. The residue is heated with a solution of HCl/acetic acid (1:1) in water and methanol for 20 minutes, giving 5,6-dimethoxy-3,4-dihydronaphthalene-1-acetic acid. The latter acid is refluxed in benzene with PCl3 for one hour. This solution is filtered while hot, and the filtrate is concentrated and added to at 0° C. triethylamine and 1-(2-methoxyphenyl)piperazine in chloroform to give the corresponding amide. This intermediate product is reduced to the amine by refluxing in THF with lithium aluminum hydride for 2 hours and decomposing the excess lithium aluminum hydride with H2O and NaOH. The lithium and aluminum salts are removed, the THF concentrated, and the residue treated with HCl and isopropyl alcohol to yield 1-(2[4-(2-methoxyphenyl) piperazinyl]ethyl)-5,6-dimethoxy-3,4-dihydronaphthalene HCl.