Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([OH:21])=O)=[CH:14][C:13]=2[F:23])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl:55][C:56]1[CH:57]=[C:58]([N:62]2[C:66]([CH2:67][NH2:68])=[CH:65][C:64]([C:69]([F:72])([F:71])[F:70])=[N:63]2)[CH:59]=[CH:60][CH:61]=1>C(Cl)Cl>[Si:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:22])[C:19]([NH:68][CH2:67][C:66]3[N:62]([C:58]4[CH:59]=[CH:60][CH:61]=[C:56]([Cl:55])[CH:57]=4)[N:63]=[C:64]([C:69]([F:72])([F:71])[F:70])[CH:65]=3)=[O:21])=[CH:14][C:13]=2[F:23])[CH2:10][CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(C(=O)O)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Reaction time: 3 h
Yield: 30.9 %

Procedure:
To a stirred solution of 2-(4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-3-fluorophenyl)propanoic acid (190 mg, 0.56 mmol, 1 eq) in DCM (10 mL) was added DIPEA (0.29 mL, 1.68 mmol, 3 eq) followed by EDC.HCl (128 mg, 0.67 mmol, 1.2 eq) and HOBt (103 mg, 0.67 mmol, 1.2 eq) at RT and stirred for 10 min when (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (175 mg, 0.56 mmol) was added and the mixture stirred for 3 h. After completion of the reaction the reaction mixture was washed with H2O (15 mL), brine (10 mL), dried (Na2SO4) and the solvents evaporated. The crude product was purified by CC using EtOAc/PE (3:7) to get 2-(4-(1-(tert-butyldimethylsilyloxy)-cyclopropyl)-3-fluorophenyl)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide (103 mg; 31%) as off white solid (TLC system: EtOAc/PE (3:7) Rf: 0.5).
Reaction SMILES: [Na:1].N1(C(C[C@H](CO)OCP(O)(O)=O)=O)C=C(C)C(=O)NC1=O.[N:23]1([C:31]([CH2:33][C@H:34]([CH2:47][OH:48])[O:35][CH2:36][P:37]([O:43]C(C)C)([O:39]C(C)C)=[O:38])=[O:32])[CH:30]=[CH:29][C:27]([NH2:28])=[N:26][C:24]1=[O:25].I[Si](C)(C)C>>[Na:1].[N:23]1([C:31]([CH2:33][C@H:34]([CH2:47][OH:48])[O:35][CH2:36][P:37]([OH:39])([OH:43])=[O:38])=[O:32])[CH:30]=[CH:29][C:27]([NH2:28])=[N:26][C:24]1=[O:25]
Reactant: CC(C)OP(=O)(CO[C@@H](CO)CC(=O)n1ccc(N)nc1=O)OC(C)C
Agent: C[Si](C)(C)I
Agent: Cc1cn(C(=O)C[C@H](CO)OCP(=O)(O)O)c(=O)[nH]c1=O
Agent: [Na]
Product: Nc1ccn(C(=O)C[C@H](CO)OCP(=O)(O)O)c(=O)n1
Yield: 73 %

Procedure:
This compound was prepared as described for 3f, using 22 (200 mg, 0.53 mmol) as a starting material and iodotrimethysilane (0.6 mL, 4.2 mmol). Compound 3h (130 mg, 0.38 mmol) was obtained as a colorless solid, in 73% yield, which was characterized as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCO)cc1
Reactant: BrCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(CCOCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methoxybenzeneethanol (7.0 g), 1,5-dibromopentane (20 ml), 50% aqueous sodium hydroxide (30 ml) and tetrabutylammonium bisulphate (1 g) was stirred at room temperature overnight, water (100 ml) wa added and the mixture was extracted with ER (2×100 ml). The organic extracts were washed with water and brine, dried and concentrated in vacuo to give an oil which was purified by FCC eluting with hexane→hexane-ER (9:1) to give the title compound as a colourless liquid (10.5 g). T.l.c. hexane-ER (9:1) Rf 0.28.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C:24]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][C:25]=1[C:26]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:47]([NH:50][C:51]1[CH:60]=[CH:59][C:54]([O:55][CH2:56][CH2:57]O)=[CH:53][CH:52]=1)(=[O:49])[CH3:48]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:16]([O:23][C:24]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:35][C:25]=1[C:26]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:57][CH2:56][O:55][C:54]1[CH:59]=[CH:60][C:51]([NH:50][C:47](=[O:49])[CH3:48])=[CH:52][CH:53]=1)=[O:33])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)CCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: CC(=O)Nc1ccc(OCCO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(OCCOC(=O)CCCNC(=O)c2cc(OCc3ccccc3)ccc2OCc2ccccc2)cc1
Yield: 55 %

Procedure:
0.57 g (2.75 mmol) of dicyclohexylcarbodiimide was portionwise added to a solution of 1.05 g (2.5 mmol) of 4-{N-[2,5-di(benzyloxy)benzoyl]amino}butyric acid (compound of Example 1) in 16 ml of anhydrous methylene chloride at room temperature under stirring. After stirring the solution at the same temperature for 10 minutes 0.54 g (2.75 mmol) of 2-[4-(acetylamino)phenoxy]ethanol and 0.03 g (0.25 mmol) of 4-(N,N-dimethyl-amino)pyridine were added. The reaction mixture was stirred at room temperature for 4 hours, then diluted with methylene chloride and the solid product was filtered. The filtrate was successively washed with 5% acetic acid, 5% sodium hydrogen carbonate solution and water, then dried and evaporated under reduced pressure. The residue was separated by chromatography on a silica gel column by eluating with a 95:5 mixture of chloroform and methanol to obtain 0.82 g (55%) of the aimed product, m.p.: 141°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[F:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 37 %

Procedure:
Using the method described in Example 17, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 32) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as a white solid (0.11 g, 37%); ES+-HRMS m/e calcd for C25H29N5O5F2 [M+H+] 518.2210 found 518.2210. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H) 1.07 (s, 3H) 1.12-1.62 (m, 5H) 1.81-1.96 (m, 1H) 2.13-2.28 (m, 1H) 3.08-3.28 (m, 2H) 3.70-3.86 (m, 2H) 3.90 (s, 2H) 4.67 (s, 1H) 5.55 (dd, J=11.1, 4.3 Hz, 1H) 6.04 (d, J=3.0 Hz, 1H) 6.40 (d, J=2.3 Hz, 1H) 7.34-7.43 (m, 2H) 7.43-7.52 (m, 1H) 7.53 (d, J=2.3 Hz, 1H) 8.30 (d, J=3.0 Hz, 1H) 10.86 (s, 1H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15][OH:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1.C(N(CC)CC)C>[C:24](=[O:25])([O:16][CH2:15][CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccccc1
Reactant: OCC1c2ccccc2Oc2ccccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)OCC1c2ccccc2Oc2ccccc21
Temperature: 80 °C
Yield: 95.2 %

Procedure:
To a mixture of 1.0 g of 9-xanthenemethanol and 0.51 mL of phenyl isocyanate in 5.0 mL of dry benzene was added two drops of triethylamine. The mixture was heated in an oil bath at 80° C. for 20 hours and cooled in an ice bath for 2 hours. The precipitated crystals were filtered and rinsed with Skelly B to give 1.48 g (95.2%) of the crude urethane as white crystals. Recrystallization from EtOAc--Skelly B (5:1) gave 1.37 g (88.1%) of the pure Xmoc-aniline as white needles, m.p. 180°-181° C.; IR (KBr): 3350 (NH), 1705 (C=O) cm-1 ; 1H NMR (CDCl3): δ 4.30 (m, 3H, CHCH2O), 6.55 (b, 1H, NH , 6.90-7.40 (m, 13H, aryl).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:7]=1.[C:25]([OH:35])(=[O:34])[C:26]1[C:27](=[CH:29][CH:30]=[C:31]([CH:33]=1)[OH:32])[OH:28]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:12]([CH3:14])[CH3:13])[CH:15]([CH3:16])[CH3:17])[CH:7]=1.[C:25]([O-:35])(=[O:34])[C:26]1[C:27](=[CH:29][CH:30]=[C:31]([CH:33]=1)[OH:32])[OH:28]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Solvent: CC(C)=O
Product: O=C([O-])c1cc(O)ccc1O

Procedure:
3.25 g of tolterodine dissolved in 50 mL of acetone was mixed at room temperature (25° C.) with 4.80 g of gentisic acid, which was suspended in 50 mL of acetone, and then stirred. Acetone in the above mixture was removed by nitrogen reflux apparatus, and when about 10 20 mL of acetone was removed there started to appear a solid precipitate. After stirring the mixture at room temperature (25° C.) for 1 hour, the solid precipitate was filtered and then washed with hexane. The resultant was dried at room temperature (25° C.) for 24 hours and 2.04 g (theoretical yield: 42.5%) of the final product in white solid was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:4]=1[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]2[O:28]C(C)(C)[O:26][CH2:25][C:24]=2[CH:31]=1)[OH:19].C(=O)(O)[O-].[Na+].ClCCl>C(O)C>[Cl:2][C:3]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:4]=1[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]([C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH2:25][OH:26])[CH:31]=1)[OH:19]
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3c(Cl)cccc3Cl)ccc2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: OCc1cc([C@@H](O)CNCCCCCCOCCOCc2c(Cl)cccc2Cl)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
1N HCl (295 mL) was added to a solution of (R)-2-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexylamino}-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-ethanol (52 g, 0.099 mol) in ethanol (312 mL), and the reaction stirred at ambient temperature for 1.5 h. Saturated sodium bicarbonate solution (500 mL) was added followed by dichloromethane (500 mL). The aqueous layer was separated and extracted with further dichloromethane (500 mL). The combined organic solutions were washed with water/brine mixture (500 mL/100 mL), then evaporated. The residue (50 g) was chromatographed on silica (800 g, Biotage) eluting with a dichloromethane/ethanol/ammonia mixture (50/8/1), to afford the title compound as an oil (35.2 g)—LC RT=4.1 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[C:14]([Cl:21])[C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH3:20])=[C:14]([Cl:21])[C:10]=1[C:11]([O:13][CH3:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(Cl)cc(NC(=O)OC(C)(C)C)c(C(=O)O)c1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(NC(=O)OC(C)(C)C)cc(Cl)c(OC)c1Cl
Yield: 96 %

Procedure:
To a cold (ice bath) stirred solution of 2-(tert-butoxycarbonylamino)-4,6-dichloro-5-methoxybenzoic acid (2.0 g, 5.9 mM) in 20 mL of dry dimethylformamide under a nitrogen atmosphere was added sodium hydride (0.24 g, 5.9 mM); a precipitate formed which slowly redissolved on stirring. To the resulting stirred solution was added iodomethane (8.4 g, 59 mM). After stirring at room temperature for 1.5 hr, the reaction mixture was poured into water and the resulting mixture extracted with ether. The combined ether extracts were washed with brine, dried (MgSO4), filtered and concentrated to leave the title compound as a yellow oil (2.0 g, 96%); MS(CI): 350 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:35][CH2:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCc3ccc(OC)cc3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and (4-methoxyphenyl)methanamine as a yellow solid (100%). MS 466 (MH+).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[CH3:18].[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[NH:25][CH2:24][C:23]=12>>[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([C:2]4[CH:1]5[CH2:8][CH:5]([CH2:4][CH:3]=4)[CH2:6][CH2:7]5)=[C:10]([CH3:18])[CH:11]=3)=[O:14])[CH2:24][C:23]=12
Reactant: Cc1cc(C(=O)O)ccc1C1=CCC2CCC1C2
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCC2CCC1C2
Yield: 68.3 %

Procedure:
4-(Bicyclo[3.2.1]oct-2-en-2-yl)-3-methyl-benzoic acid of Step B (0.132 g, 0.545 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.111 g, 0.6 mmol) were reacted by in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from 1:1 ethyl acetate/petroleum ether afforded the title compound (0.152 g) as white crystals, m.p. 168–169° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])(O)=O>C(O)(=O)C>[NH2:17][C:4]1[CH:5]=[CH:6][C:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:2][CH:3]=1
Reactant: c1ccc(-c2cccc3ccccc23)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Nc1ccc(-c2cccc3ccccc23)cc1
Yield: 39 %

Procedure:
204 g of 1-phenylnaphthalene was nitrated in 1 l of acetic acid using nitric acid. The product was reduced using a reduced iron to obtain 1-(4-aminophenyl)naphthalene (yield: 39%).
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([NH:19][C:20]3[C:25]([C:26]4[N:34]=[CH:33][N:32]=[C:31]5[C:27]=4[N:28]=[CH:29][N:30]5C4CCCCO4)=[CH:24][CH:23]=[CH:22][N:21]=3)[C:13]=2[F:41])(=[O:10])=[O:9])=[CH:5][CH:4]=1>>[N:34]1[C:26]([C:25]2[C:20]([NH:19][C:14]3[C:13]([F:41])=[C:12]([NH:11][S:8]([C:6]4[S:7][C:3]([Cl:2])=[CH:4][CH:5]=4)(=[O:10])=[O:9])[CH:17]=[CH:16][C:15]=3[F:18])=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:27]2[C:31]([NH:30][CH:29]=[N:28]2)=[N:32][CH:33]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(Cl)s1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccc(Cl)s1
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the 5-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)thiophene-2-sulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[CH:30]1([C:33]2[N:34]=[C:35]([NH2:38])[S:36][CH:37]=2)[CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[CH3:27][C:25]([CH3:28])([CH3:26])[CH2:24][O:23][C:5]1[C:4]([O:3][CH:2]([F:29])[F:1])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:10]=[CH:11]/[C:12]1[N:13]=[C:14]2[N:18]([C:19]=1[C:20]([NH:38][C:35]1[S:36][CH:37]=[C:33]([CH:30]3[CH2:32][CH2:31]3)[N:34]=1)=[O:21])[CH:17]=[CH:16][S:15]2
Reactant: Nc1nc(C2CC2)cs1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C3CC3)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 4-(cyclopropyl)-1,3-thiazol-2-amine (36 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (26 mg, 0.236 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 40 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ0.80-0.86 (m, 2H), 1.06 (s, 9H), 1.13-1.23 (m, 2H), 1.94-2.00 (m, 1H), 3.57 (s, 2H), 6.60-6.66 (m, 1H), 7.18 (t, J=74.7 Hz, 1H), 7.22-7.30 (m, 2H), 7.40-7.48 (m, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.82 (d, J=15.6 Hz, 1H), 8.08-8.16 (m, 1H), 8.52-8.60 (m, 1H), 12.99 (br s, 1H); APCI-MS (m/z) 545.18 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH:26]3[CH2:30][O:29]C(C)(C)[O:27]3)[CH:21]=[CH:20][C:19]=2[CH3:33])=[O:17])=[C:12]([N+:34]([O-:36])=[O:35])[CH:11]=1>C(O)(C(F)(F)F)=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH:26]([OH:27])[CH2:30][OH:29])[CH:21]=[CH:20][C:19]=2[CH3:33])=[O:17])=[C:12]([N+:34]([O-:36])=[O:35])[CH:11]=1
Reactant: Cc1ccc(OCC2COC(C)(C)O2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1[N+](=O)[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(OCC(O)CO)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 311 (48 mg, 0.01 mmol) was dissolved in TFA:H2O (3:1, 8 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:1) as the eluent, affording the title compound as a yellow oil. 13C NMR (DMSO-d6) δ 193.5, 156.3, 150.1, 148.8, 137.5, 132.5, 132.3, 129.3, 126.6 (dd), 123.9 (dd), 122.9, 117.3, 116.1, 115.6, 112.1 (dd), 108.6, 105.1 (dd), 69.8, 62.5, 19.0
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:38]=[CH:39][C:32]=23)[CH:28]=[N:27]1.C(#N)C.N12CCCN=C1CCCCC2>>[Si:1]([O:18][CH:19]1[CH2:22][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]4[N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:38]=[CH:39][C:32]=34)[CH:28]=[N:27]2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutylidene)acetonitrile (4.0 g, 8.7 mmol, from Step 4 of Intermediate Example A1) and 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.50 g, 4.77 mmol, US 20090181959) in acetonitrile (10 mL, 200 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.68 mL, 4.6 mmol). The reaction was stirred overnight. A further portion of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.7 mL, 5 mmol) was added and the reaction was allowed to continue for an additional 72 hours. Acetonitrile was removed in vacuo. Flash chromatography on silica gel, eluting with 0%-30% EtOAc/Hexanes, was used to purify product, which was obtained as a mixture of diastereomers (2 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.33 (d, J=5.0 Hz, 1H major), 8.29 (d, J=5.0 Hz, 1H minor), 8.06 (s, 1H major), 8.03 (s, 1H major), 8.00 (s, 1H minor), 7.93 (s, 1H minor), 7.70-7.31 (m, 10H major and 10H minor), 7.19 (d, J=5.0 Hz, 1H major), 7.11 (d, J=5.0 Hz, 1H minor), 6.74 (d, J=3.6 Hz, 1H major), 6.63 (d, J=3.7 Hz, 1H minor), 5.71 (s, 2H major), 5.69 (s, 2H minor), 4.49-4.39 (m, 1H minor), 4.33 (tt, J=7.0, 7.0 Hz, 1H major), 3.67-3.45 (m, 2H major and 2H minor), 3.22 (s, 2H minor), 3.11-2.95 (m, 2H minor), 2.92-2.77 (m, 6H major), 2.65-2.50 (m, 2H minor), 1.08 (s, 9H minor), 1.03 (s, 9H major), 0.98-0.80 (m, 2H major and 2H minor), −0.06 (s, 9H major), −0.08 (s, 9H minor); LCMS (M+H)+: 662.1.
Reaction SMILES: C[O:2][P:3]([CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])[O:4]C>Cl>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][P:3](=[O:2])([OH:6])[OH:4]
Reactant: COP(=O)(Cc1ccc2ccccc2c1)OC
Agent: Cl
Product: O=P(O)(O)Cc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 44.6 %

Procedure:
A solution of (2-naphthalenylmethyl)phosphonic acid dimethyl ester (Compound 4, 520 mg, 2.08 mM) in concentrated hydrochloric acid (15 mL) is heated at reflux temperature for ten hours. The reaction mixture is then cooled and allowed to stand at room temperature until a white precipitate is formed. The reaction is cooled to room temperature and the aqueous HCl is removed at a reduced pressure. The white solid residue is recrystallized from water to give 0.206 g of the title compound as white crystals, mp 234°-236° C. with softening at 225° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]([O:28]C)=[O:27])[N:3]=1>CO.[OH-].[Na+]>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:26]([OH:28])=[O:27])[N:3]=1
Reactant: COC(=O)[C@@H](CC(C)C)Nc1nc(Cl)c2c(c1F)CN(Cc1ccc(OC)cc1OC)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(=O)O)nc(Cl)c3C2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-methyl 2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanoate (2.9 g, 6.04 mmol) in MeOH (10 mL) and 1N NaOH (40.0 mL) was stirred at 50° C. for 2 h. UPLC showed 30% starting material remained. Additional saturated NaOH solution (5 mL) was added and the reaction mixture was stirred for 3 h at 50° C. The solvent was removed and the resulting residue was dispersed in H2O (100 mL) and acidified to pH 3 using HCl. After stirring at RT for 2 h, the solid was filtered to give the title compound. [M+H] calc'd for C22H25ClFN3O5, 466; found, 466.