Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:30]=[CH:31]/[C:32]([O:34]C)=[O:33])[CH:7]=[CH:8][C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:24])([CH3:23])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3.C1COCC1>CO>[F:3][C:4]1[CH:5]=[C:6](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH:7]=[CH:8][C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:24])([CH3:23])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](CF)CN1C(c2ccc(/C=C/C(=O)O)cc2F)c2[nH]c3ccccc3c2CC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2M Sodium hydroxide (3.31 ml, 6.63 mmol) was added to a solution of (E)-methyl 3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (600 mg, 1.33 mmol) (mixture of diastereoisomers) in methanol (5 ml), and THF (20 ml) and the mixture stirred at ambient temperature for 4 hours. The mixture was concentrated to a volume such that all of the organic solvent had been removed, diluted with water (50 ml), acidified with dilute HCl to pH 6 and extracted with ethyl acetate (2×50 ml). The extracts were combined and evaporated under reduced pressure. The residue was purified by preparative HPLC (Chiralpak IA column, 20 ml silica, 20 mm diameter, 250 mm length), Heptane:IPA 90:10, 0.2% acetic acid at 80 ml/min. Fractions containing the desired compounds were combined and analysed to yield (E)-3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (isomer 1, first eluted, 130 mg, 22.36%) and (E)-3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahyrdo-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (isomer 2, second eluted, 30.0 mg, 5.16%). 1H NMR (500 MHz, DMSO, 30° C.) δ 0.49 (3H, d), 1.03 (3H, s), 1.14-1.21 (1H, m), 1.28 (3H, s), 2.17 (1H, dd), 2.59-2.71 (1H, m), 2.8-2.99 (2H, m), 4.09-4.34 (2H, m), 4.99 (1H, s), 6.59 (1H d), 6.86-7.07 (2H, m), 7.1-7.19 (1H, m), 7.18-7.29 (1H, m), 7.36-7.49 (2H, m), 7.49-7.66 (2H, n), 10.31 (1H, s), CO2H not observed. m/z: ES+ [M+H]+ 439. *Stereochemistry inferred to be (R) at the undefined centre by analogy with other examples.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:30][CH2:31][O:32][CH3:33])=[CH:4][C:5]([O:26][CH2:27][O:28][CH3:29])=[C:6]([C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[S:13])[NH:11][N:12]=2)[CH:7]=1.[C:34](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[Br:1][C:2]1[C:3]([O:30][CH2:31][O:32][CH3:33])=[CH:4][C:5]([O:26][CH2:27][O:28][CH3:29])=[C:6]([C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10]([S:13][CH3:34])=[N:11][N:12]=2)[CH:7]=1
Reactant: COCOc1cc(OCOC)c(-c2n[nH]c(=S)n2-c2ccc(N3CCOCC3)cc2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COCOc1cc(OCOC)c(-c2nnc(SC)n2-c2ccc(N3CCOCC3)cc2)cc1Br

Procedure:
5-(5-bromo-2,4-bis-methoxymethoxy-phenyl)-4-[4-(morpholin-4-yl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-thione (Example 1-5, IM6-S-d01: 54 mg, 0.1 mmol), potassium carbonate (13.8 mg, 0.17 mmol) and ethanol (5 mL) were placed in a test tube, and then methyl iodide (14.2 mg, 0.1 mmol) was added, and the mixture was heated for 2 hours under reflux. After completing the reaction, potassium carbonate was removed by filtration, and the mother liquor was concentrated. The crude product (IM6-SMe-d01) thus obtained was subjected to the next reaction without further purification in particular.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C([O-])(O)=O.[Na+].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>O1CCOCC1.O>[C:16]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
4-piperidone monohydrate hydrochloride (250 g, 1.62 mole) was dissolved in dioxane (1.5 L) and water (0.5 L). 217 g of NaHCO3 was added at 0° C. followed by slow addition of (BOC)2O (459 g, 2.1 mole). Reaction mixture was stirred for overnight. Solution was concentrated; residue was taken in water and extracted with ethyl acetate, washed with water and dried over anhydrous Na2SO4. Solvent was evaporated and product obtained was washed with hexane to get N-boc 4-piperidone (280 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[C:19]([OH:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[CH:16][C:15]=1[CH3:25])=O.Cl(O)(=O)(=O)=O.[C:31](O)(=[O:33])[CH3:32]>[Pd]>[C:31]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:14]1[C:19]([OH:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[CH:16][C:15]=1[CH3:25])(=[O:33])[CH3:32]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCCCO)c(O)c1OC
Reactant: CC(=O)O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1cc(C)c(CCCCCCCCCCCOC(C)=O)c(O)c1OC

Procedure:
To a solution (200 ml) of 6-(11-hydroxy-1-oxoundecyl)-2,3-dimethoxy-5-methylphenol (14 g) in acetic acid is added 5% palladium-on-carbon (50% hydrate; 3 g) and 70% perchloric acid (0.1 ml), and catalytic reduction is carried out at ambient temperature and atmospheric pressure. After completion of the absorption of hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane, and the dichloromethane layer is washed with 5% aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Removal of the solvent by distillation gives a colorless oil of 6-(11-acetoxyundecyl)-2,3-dimethoxy-5-methylphenol (15 g).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:7](=[O:26])[C@H:8]([CH2:20][C:21]1[N:25]=[CH:24][NH:23][CH:22]=1)[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])C.COC(=O)CN(C(=O)[C@H](CC1N=CNC=1)NC(OCC1C=CC=CC=1)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1>>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:6]([C:7](=[O:26])[C@H:8]([CH2:20][C:21]2[N:25]=[CH:24][NH:23][CH:22]=2)[NH:9][C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:5][C:4]([OH:36])=[O:3])=[CH:29][CH:30]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: COC(=O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Product: COc1ccc(CN(CC(=O)O)C(=O)[C@H](Cc2c[nH]cn2)NC(=O)OCc2ccccc2)cc1

Procedure:
According to Example 1, Step 3, but substituting the compound from Step 2 above for N-[N-[(phenylmethoxy)carbonyl]-L-histidyl]-N-[[4-(phenylmethoxy)phenyl]methyl]glycine methyl ester, the title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH3:4].[H][H]>CO.[Pd]>[CH3:1][CH:2]([CH3:15])[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=1)[CH3:4]
Reactant: COC(=O)c1ccc(C(C)=C(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C(C)C(C)C)cc1
Yield: 97 %

Procedure:
To a solution methyl 4-(3-methylbut-2-en-2-yl)benzoate (0.2 g, 1.0 mmol) in methanol (30 mL) was added Pd/C (0.50 g). The reaction mixture was stirred at room temperature for 3 hour at 4 atm of hydrogen, after the reaction, it was filtered, and the filtrate was removed in vacuo to give pure product methyl 4-(3-methylbutan-2-yl)benzoate (0.20 g, 100%) as the colorless oil.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].Cl>C1COCC1>[CH:18]([O:17][C:15]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)Cl
Reactant: NC(C(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)OC(=O)NC(C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Amino-phenyl-acetic acid (0.505 g, 2.44 mmol) was dissolved in THF (7 mL) and cooled to 0° C. in an external ice/brine bath. Aqueous sodium hydroxide (12.5M, 0.47 mL, 5.856 mmol) and isopropyl chloroformate (0.23 mL, 2.948 mmol) were added at 0° C. Upon completion of the addition, the solution was removed from the ice bath and allowed to warm to room temperature, and stirred. After 18 hours, the crude reaction mixture was adjusted to pH 1 with 1N HCl and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated to give Isopropoxycarbonylamino-phenyl-acetic acid as an off-white solid. LCMS-ESI+: calc'd for C12H15NO4: 237.10 (M+); Found: 238.05 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[N:22]=[N:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:10]=1[N:20]1[C:24]([CH3:25])=[C:23]([C:26]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:27])[N:22]=[N:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C)c(OCc2ccccc2)c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{2-(benzyloxy)-4-[(ethylamino)carbonyl]phenyl}-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (3.95 g) obtained in Example 140a) in DMF (30 ml) were successively added cyclopropylamine (0.86 ml), triethylamine (1.73 ml), HOBt (1.91 g) and WSC (2.40 g), and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a pale-yellow amorphous substance (3.30 g, 76%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([O:34][CH3:35])[CH:26]=3)=[O:24])=[N:21][CH:22]=2)[CH:19]=1.C(=O)(O)[O-].[Na+]>ClCCCl.O>[CH3:35][O:34][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[N+:31]([O-:33])=[O:32])[C:23]([C:20]1[N:18]2[CH:19]=[C:14]([NH:13][C:8](=[O:10])[CH3:9])[CH:15]=[CH:16][C:17]2=[CH:22][N:21]=1)=[O:24]
Reactant: COc1cc(C(=O)c2ncc3ccc(N)cn23)ccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: COc1cc(C(=O)c2ncc3ccc(NC(C)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
1.29 ml (9.29 mmol) of triethylamine and then 0.51 ml (7.15 mmol) of acetyl chloride are added to 0.50 g (1.43 mmol) of (6-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone hydrochloride in 25 ml of 1,2-dichloroethane cooled to 5° C. and then the mixture is allowed to return to ambient temperature and is stirred for 18 hours. The medium is taken up in water, basified with a sodium bicarbonate solution and extracted with dichloromethane. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The product is purified by column chromatography on silica gel, elution being carried out with a mixture of dichloromethane and acetone (90/10). 316 mg of a yellow solid are obtained. Melting point: 257° C.; 1H NMR (d6-DMSO): 2.15 (3H, s), 4.01 (3H, s), 7.45 (1H, d), 7.92 (1H, s), 8.00-8.06 (3H, m), 8.13 (1H, s), 10.62 (1H, s)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:51]1[CH:52]=[C:53]([NH:57][C:58](=[O:62])[N:59]([CH3:61])[CH3:60])[CH:54]=[N:55][CH:56]=1>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].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.O.CN(C=O)C>[CH:17]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:51]3[CH:52]=[C:53]([NH:57][C:58](=[O:62])[N:59]([CH3:60])[CH3:61])[CH:54]=[N:55][CH:56]=3)[CH:3]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=1)=[O:18]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Reactant: CN(C)C(=O)Nc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C=O)nn3C2CCCCO2)c1
Temperature: 90 °C
Yield: 18 %

Procedure:
A solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) (1.780 g, 5.0 mmol), bis(pinacolato)diboron (1.523 g, 6.0 mmol), KOAc (1.471 g, 15 mmol) and dry DMF (20 mL) was purged with argon. PdCl2(dppf)2 (0.245 g, 0.3 mmol) was added to the reaction and purged again with argon. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (CXIV), the solution was cooled to room temperature. To this solution was added K3PO4 (1.592 g, 7.5 mmol), 3-(5-bromopyridin-3-yl)-1,1-dimethylurea (XXII) (1.220 g, 5.0 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and water (2 mL). The solution was purged with argon and heated at 90° C. for 3 h. The solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in DCM and washed with water, dried over MgSO4, filtered and then evaporated under vacuum. The residue was purified on a silica gel column (100% DCM→2:98 MeOH:DCM) to give 3-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-1,1-dimethylurea (CXXIII) as a brown viscous oil which solidified under vacuum at room temperature (354 mg, 0.90 mmol, 18% yield for 2 steps). 1H NMR (DMSO-d6) δ ppm 10.22 (s, 1H), 8.76 (d, J=1.6 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.36 (s, 1H), 8.24 (m, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.91 (dd, J=7.2, 1.4 Hz, 1H), 6.13 (dd, J=7.6, 2.0 Hz, 1H), 3.93 (m, 1H), 3.85 (m, 1H), 2.98 (s, 6H), 2.47-2.42 (m, 1H), 2.11-2.06 (m, 2H), 1.82-1.79 (m, 1H) 1.64 (m, 2H); ESIMS found for C21H23N5O3 m/z 394.0 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([CH3:15])[CH:7]=2)[CH2:3][CH2:2]1.Cl[C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][N:20]=[C:19]([O:26][CH2:27][C@@H:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])[CH:18]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]3[O:12][C:17]4[CH:18]=[C:19]([O:26][CH2:27][C@@H:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])[N:20]=[CH:21][C:22]=4[N:23]=3)=[C:8]([CH3:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c([N+](=O)[O-])cn1
Reactant: Cc1cc(OCC2CC2)ccc1C(=O)O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4CC4)cc3C)nc2cn1

Procedure:
Using 4-(cyclopropylmethoxy)-2-methylbenzoic acid and N-((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)acetamide, and in the same manner as in Step B and Step C of Example 31, the title compound was obtained.
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:42]=[CH:41][CH:40]=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[O:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)[N:10]=1.O.[OH-].[Li+]>C1COCC1.O>[C:35]([O:34][C:32]([N:28]1[CH2:29][CH2:30][O:31][CH:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:39]=[CH:40][CH:41]=[CH:42][C:5]=4[CH2:4][C:3]([OH:43])=[O:2])[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][N:12]=3)=[CH:21][CH:22]=2)[CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)CCO3)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cc2)C1
Yield: 85 %

Procedure:
tert-Butyl 2-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)morpholine-4-carboxylate (I89) (46 mg, 0.077 mmol) was dissolved in THF (2 mL), and lithium hydroxide hydrate (6.0 mg, 0.15 mmol) in water (0.5 mL) was added. After 18 hours the mixture was concentrated, diluted with water (5 mL) and the pH adjusted to 3 with 6 M HCl. The mixture was extracted with ethyl acetate (3×10 mL), and the combined organic extracts washed with brine (20 mL), dried over sodium sulfate and evaporated to give the title compound (I90) (39 mg, 85% yield) as a pale yellow syrup; 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.35-7.27 (m, 4H), 4.38 (d, J=10.1 Hz, 1H), 4.07-3.80 (m, 5H), 3.67 (td, J=11.7, 2.7 Hz, 1H), 3.06 (s, 4H), 2.84 (s, 2H), 1.47 (s, 9H). LCMS Method C: rt 6.49 min; m/z 587.1 [M+H]+, 531.0 [M-tBu+2H]+, 487.1 [M-Boc+2H]+; m/z 585.2 [M−H]−.
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:15]([NH2:17])=[O:16])=[N:13][NH:14][C:5]=3[C:4]=2[N:3]=1.Br[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:15]([C:12]1[C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[N:11][C:2]([I:1])=[N:3][C:4]=3[C:5]=2[N:14]([CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]2)[N:13]=1)(=[O:16])[NH2:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: NC(=O)c1n[nH]c2c1CCc1cnc(I)nc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2nc(C(N)=O)c3c2-c2nc(I)ncc2CC3)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of 8-iodo-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (prepared following the method reported in WO2008074788A1) 50 mg, (0.146 mmol) in DMF (3 ml), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate 61 mg, (0.219 mmol) and Cs2CO3 95 mg, (0.293 mmol), were added. The mixture was heated at 70° C. and stirred for 4 hours. The cooled mixture was treated with water (10 ml) and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography eluting with DCM/EtOH 9/1 to afford the desired title product 63 mg (80%) as a white solid. LC/MS (254 nm) HPLC method 2 Rt 6.51 min. 1H NMR (401 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.47 (s, 1H), 7.32 (s, 1H), 4.50-4.55 (m, 2H), 3.84-3.96 (m, 2H), 2.99-3.07 (m, 2H), 2.84-2.95 (m, 2H), 2.59-2.75 (m, 2H), 2.07 (s, 1H), 1.56 (br. s., 2H), 1.39 (s, 9H), 1.08-1.22 (m, 2H). HRMS (ESI) calcd for C21H27IN6O3 [M+H]+ 539.1262 found 539.1274.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>CN(C)C=O>[C:13]([O:16][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: BrCc1cccc2cccnc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cccc2cccnc12
Yield: 85.5 %

Procedure:
8-Bromomethylquinoline (1.11 g) and sodium acetate (0.82 g) were suspended and dissolved in dimethyl formamide, and heated for 2 hours at 80° to 90° C. After completion of the reaction, dimethyl formamide was distilled off, and the residue was extracted with a mixed solvent of ethyl acetate-toluene (3:1). The solvent was distilled off to give 8-acetoxymethylquinoline (0.86 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])O1>>[CH3:12][C:4]1[C:5]([NH2:11])=[C:6]([NH2:8])[CH:7]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH:3]=1
Reactant: CC1(C)OB(c2ccccc2C(F)(F)F)OC1(C)C
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Product: Cc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N

Procedure:
The title compound was prepared from 4-bromo-2-methyl-6-nitro-phenylamine and 4,4,5,5-tetramethyl-2-(2-trifluoromethyl-phenyl)-[1,3,2]dioxaborolane according to the procedures described in Example 1, steps D and E. 1H-NMR (400 MHz, CDCl3) δ: 7.68 (d, J=7.8 Hz, 1H), 7.47 (t, J=7.3 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 6.59 (s, 1H), 6.61 (s, 1H), 3.41 (br. s., 4H), 2.19 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:15][C:14]=2[F:30])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:43][O:44][CH2:45][CH2:46][OH:47]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:15][C:14]=2[F:30])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:43][O:44][CH2:45][CH2:46][OH:47])=[O:6]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(C#CCCOC2CCCCO2)cc1F
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCCOC2CCCCO2)cc1F

Procedure:
The title compound was prepared by reaction of 3,4-difluoro-2-{2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]anilino} benzoic acid with CDI and 2-(aminooxy)ethanol by the general procedure of Example 1, Step E, then purified by column chromatography on silica gel (50% EtOAc/PE as eluant) to give 3,4-difluoro-2-{2-fluoro-4-[4-(tetrahydro-2H-pyran-2-yloxy)-1-butynyl]anilino}-N-(2-hydroxyethoxy)benzamide as a viscous transparent oil which was immediately dissolved in EtOH and treated with 1 M HCl according to the general procedure of Example 10, Step D. Purification of the resulting oil was carried out by filtration through a plug of silica gel (EtOAc as eluant) to give 3,4-difluoro-2-[2-fluoro-4-(4-hydroxy-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide as a pale yellow crystalline solid (51%); m.p. (EtOAc/Et2O) 126-129° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.82 (br s, 1 H), 8.85 (br s, 1 H), 7.45-7.39 (m, 1 H), 7.25-7.17 (m, 2 H), 7.07 (dd, J=8.3, 1.4 Hz, 1 H), 6.78 (dd, J=8.8, 8.8,4.7 Hz, 1 H), 4.88 (t, J=5.6 Hz, 1 H), 4.73 (br s, 1 H), 3.85 (t, J=4.8 Hz, 2 H), 3.59-3.53 (m, 4 H), 2.53 (t, J=6.9 Hz, 1 H). Anal. calcd. for C19H17F3N2O4.0.25Et2O: C, 58.2; H, 4.8; N, 6.8. Found C, 58.1; H, 4.8; N, 7.1.