Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH2:26]([Mg]Br)[CH2:27][CH3:28].[Cl-].[NH4+]>C1COCC1>[C:11]([C:10]1[S:9][C:8]([NH:17][C:18]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:19])=[N:7][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:16])[CH2:26][CH2:27][CH3:28]
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Compound 98 (200 mg, 0.559 mmol) was suspended in THF (5 mL), and a 1.01 mol/L solution of propylmagnesium bromide (2.00 mL, 2.02 mmol) in THF was added thereto under ice-cooling, followed by stirring for 1 hour at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:4) to afford the entitled Compound 382 (76.3 mg, 40%) as a yellowish green solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][CH2:24][C@@H:25]([OH:27])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:23][CH2:24][C@@H:25]([OH:27])[CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: C[C@H](O)CN
Solvent: C1CCOC1
Product: C[C@H](O)CNc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1
Temperature: 140 °C
Yield: 17.5 %

Procedure:
Following the procedure described above in Example 51, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.10 g, 0.32 mmol) was reacted with (S)-1-amino-2-propanol (0.47 g, 6.32 mmol) in 2 mL of THF. The reaction mixture was heated up in a sealed vial in a microwave reactor at 140° C. for 40 min. The crude product was purified by preparative HPLC and lyophilized to give a yellow solid (20.8 mg, 17.7% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 0.93 (d, J=6.32 Hz, 3 H) 2.96-3.03 (m, 2 H) 3.68 (s, 1 H) 4.58 (s, 1 H) 6.46 (m, 1 H) 6.80 (s, 1 H) 7.06-7.17 (m, 1 H) 7.21-7.33 (m, 1 H) 7.33-7.47 (m, 1 H) 8.05 (s, 1 H) 8.62 (s, 1 H) 9.44 (s, 1 H); HRMS (ESI+) calcd for C18H15ClFN5O 372.10219, found (MH+) 372.1019.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.O=[C:30]([CH2:48][CH3:49])[CH2:31][NH:32][C:33]([CH2:35][CH2:36][NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:34]>ClCCl>[CH2:48]([C:30]1[O:34][C:33]([CH2:35][CH2:36][NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:32][CH:31]=1)[CH3:49]
Reactant: CCC(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cnc(CCNC(=O)OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
23.07 g (49.60 mmol) PS-triphenylphosphine are suspended in 200 ml dichloromethane, 12.65 g (49.82 mmol) iodine are added. The mixture is stirred for 0.1 hours at ambient temperature, then 13.80 ml (99.28 mmol) triethylamine are added dropwise. 5.80 g (19.84 mmol) benzyl [2-(2-oxo-butylcarbamoyl)-ethyl]-carbamate dissolved in 150 ml dichloromethane are added. The reaction mixture is stirred for 72 hours at ambient temperature, then the precipitate is filtered off. The filtrate is extracted with water, the organic phase is dried and evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[O:9]2)=[CH:4][C:3]=1[S:18]([Cl:21])(=[O:20])=[O:19].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>ClC1C=CC=CC=1>[Cl:23][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:18]([Cl:21])(=[O:20])=[O:19])[CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:11])[O:9]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1OC(c2ccc(Cl)c(S(=O)(=O)Cl)c2)c2ccccc21
Solvent: Clc1ccccc1
Product: O=C1OC(Cl)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)c2ccccc21

Procedure:
In a preferred procedure, 3-(4'-chloro-3'-chlorosulfonylphenyl)phthalide (17.15 g) and phosphorous pentachloride (104 g.) is heated under reflux for 2.5 hours in 300 ml of chlorobenzene. The cooled solution is extracted three times with 100 ml portions of water, dried (Na2SO4), filtered, and concentrated under a reduced pressure to give a yellow oil from which the title compound can be fractionally crystallized.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([F:20])=[CH:22][C:23]=3[CH3:28])=[C:3]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)OC)cnc12
Yield: 100.4 %

Procedure:
In the same manner as in Example 1, step 4 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.80 g, 9.87 mmol) obtained in Example 21, step 2 and 4-fluoro-2-methylaniline (1.85 g, 14.8 mmol), the title compound (3.69 g, 100%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:13]([O-])(O)=O.[Na+]>CO.OS(O)(=O)=O>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 181.5 %

Procedure:
To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid (20 g, 117.5 mmol) in MeOH (150 mL), was H2SO4 (3 drops) added. The reaction mixture was heated to reflux and maintained for 2 hours. The reaction was cooled to room temperature and 5 g of NaHCO3 was added portionwise. The reaction was concentrated under vacuum and dissolved in ether (200 mL). The ether layer was washed with sat. NaHCO3. The ether layer was dried over MgSO4, and concentrated under vacuum to afford the desired compound (19.9 g, 92%) as an oil. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 9.92 (s, 1H), 7.01-7.20 (m, 2H), 3.62 (s, 2H), 3.61 (s, 3H). LCMS 185.1 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:28])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:21])[CH:15]=1.[CH3:29]N(C)P(N(C)C)(N(C)C)=O>>[CH3:29][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:28])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:21])[CH:15]=1
Reactant: COC(=O)CNC(=O)c1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CNC(=O)c1cccc(C=CC(=O)c2c(OC)cc(C)n(C)c2=O)c1

Procedure:
According to the same manner as that of Example a-25 except that 0.25 g of 4-hydroxy-3-[3-[3-[(methoxycarbonylmethyl)aminocarbonyl]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone was used in place of 4-hydroxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone, and 6 ml of hexamethylphosphoramide was used in place of dimethylformamide, 0.13 g of 4-methoxy-3-[3-[3-[(methoxycarbonylmethyl)aminocarbonyl]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (83a)] was obtained as a pale yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH2:33])[S:25][C:26]=2[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([C:10](=[O:12])[NH:33][C:24]1[S:25][C:26]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:23]=1)([CH3:14])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1nc(-c2ccc(F)cc2)c(N2CCOCC2)s1

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-2-methyl-propionic acid (1.5 eq) and 4-(4-Fluoro-phenyl)-5-morpholin-4-yl-thiazol-2-ylamine (1 eq)) in DMF (50 mL) were added HATU (1.5 eq) and TEA (2 eq). Reaction was stirred at 60 C over night. Aqueous work up followed by silica gel chromatography afforded the title compound. LCMS Method A Rt=1.51 (M+1=465.1, M−1=463.1). 1H NMR (400 MHz, DMSO-D6) 1.21 (s, 1H) 1.28-1.40 (m, 14H) 2.80-2.87 (m, 4H) 3.70-3.77 (m, 4H) 7.21-7.27 (m, 2H) 8.10-8.16 (m, 2H) 11.59 (s, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH2:15][C:16]([OH:18])=[O:17].[CH3:19][CH2:20]O>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCO
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1cc([N+](=O)[O-])ccc1Cl
Yield: 99 %

Procedure:
Thionyl chloride (16.7 g, 0.14 mol) was added drop-wise to a 0° C. solution of (2-chloro-5-nitro-phenyl)acetic acid (15 g, 0.07 mol) in EtOH (300 mL) and the resultant mixture was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue poured into ice water, and extracted with EtOAc (2×). The combined organics were washed with brine, then satd. NaHCO3, dried over Na2SO4 and concentrated in vacuo to give ethyl 2-(2-chloro-5-nitrophenyl)acetate (17 g, 99% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.35 (d, J=2.8 Hz, 1H), 8.12 (dd, J=8.4, 2.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.96 (s, 2H), 1.15 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[C:18]4[CH3:24])[CH:9]=2)=[C:4]([CH3:25])[CH:3]=1.[CH:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH3:25][C:4]1[CH:3]=[C:2]([NH:1][CH2:26][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30][CH2:29]2)[CH:7]=[CH:6][C:5]=1[C:8]1[NH:13][C:12](=[O:14])[N:11]=[C:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[CH3:24])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cc1cc(N)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1cc(-c2ccc3[nH]nc(C)c3c2)nc(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(4-amino-2-methylphenyl)-4-(3-methyl-1H-indazol-5-yl)pyrimidin-2(1H)-one (25 mg, 0.06 mmol) in 6 mL dichloroethane were added tert-butyl 4-formylpiperidine-1-carboxylate (76.6 g, 0.36 mmol), NaBH(OAc)3 (76 mg, 0.36 mmol), and 500 μL acetic acid. The reaction mixture was stirred at room temperature for 2 hours and diluted with saturated aqueous NaHCO3 (15 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford tert-butyl 4-((3-methyl-4-(6-(3-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydropyrimidin-4-yl)phenylamino)methyl)piperidine-1-carboxylate, which was submitted to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]O>OS(O)(=O)=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(F)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)cc1C
Reaction time: 1 h
Yield: 78 %

Procedure:
In a cylindrical quartz tube was placed 4-fluoro-2-methyl-benzoic acid (1.5 g, 9.7 mmol) in MeOH (15 ml) and 2 drops of H2SO4 conc. were added. The tube was introduced into a Smith Creator® Personal chemistry microwave reactor. Microwave irradiation was carried out at 130° C. for 1 h until HPLC revealed the disappearance of the starting-material. The mixture was allowed to cool down and the solvent was removed under reduced pressure. The crude was diluted with DCM and washed with NaHCO3 sat. The organic phase was dried over anhydrous Na2SO4 and concentration of the solution gave the final compound (1.3 g, 78%) as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][C:23]([F:31])([F:30])[CH:24]([F:29])[C:25]([F:28])([F:27])[F:26])=[N:4][N:5]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[C:6]=1[NH2:7].ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)(Cl)Cl>[NH2:7][C:6]1[N:5]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:40])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:4]=[C:3]([O:22][C:23]([F:30])([F:31])[CH:24]([F:29])[C:25]([F:26])([F:27])[F:28])[C:2]=1[Cl:1]
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)c(Cl)c2N)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 77.5 %

Procedure:
0.3 g of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)-5-aminopyrazole was dissolved in 10 mL of chloroform, and 140 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.24 g of 5-amino-4-chloro 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Reactant: OB(O)c1ccccc1O
Product: Cc1ccc(-c2cccc(-c3cccc(-c4ccccc4O)n3)n2)c(O)c1
Yield: 68 %

Procedure:
6-(2-Hydroxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 2-hydroxyphenylboronic acid in 68% yield using method F; δH [2 H6]-DMSO 13.55,(1H, b), 13.39,(1H, b), 8.38-8.32,(4H, m), 8.30-8.20,(4H, m), 8.13,(3H, d,), 8.03,(1H, d), 7.37,(1H, t), 7.00,(2H, m), 6.81,(2H, m), 2.30,(3H, s); MS 355 (MH)+; HPLC retention time (system 1) 4.34 minutes.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH2:33][CH3:34].Cl>C(O)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH2:33][CH3:34])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CCOc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 43.8 %

Procedure:
A mixture of 1.0 g (3.159 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.740 g (3.79 mmole) of 4-amino-3-ethoxybenzoic acid, 10 mL of ethanol and 40 mL of 1M hydrochloric acid was heated at reflux for 18 hours. The mixture was cooled and the white precipitate was collected by filtratration, washed with cold water and dried in vacuum to give 0.6391 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:38](Cl)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:38](=[O:40])[CH3:39])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN1CCC(NCCOc2cccc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Reactant: CC(=O)Cl
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCN(C)CC1
Yield: 41 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(1-methylpiperidin-4-yl)amino]ethoxy}quinazolin-4-amine and acetyl chloride to give the title compound in 41% yield; NMR spectrum (DMSO-d6) 1.62-1.90 (m, 4H), 2.09 (s, 3H), 2.15-2.43 (m, 4H), 2.79-3.13 (m, 3H), 3.76-3.83 (m, 2H), 3.86-3.92 (m, 1H), 4.30-4.47 (m, 2H), 5.31 (s, 2H), 7.21 (d, 1H), 7.26 (d, 1H), 7.32-7.40 (m, 2H), 7.57-7.61 (m, 2H), 7.69-7.75 (m, 1H), 7.86-7.92 (m, 1H), 7.98-8.00 (m, 1H), 8.46 (s, 1H), 8.61 (d, 1H), 9.95 (s, 1H); Mass spectrum MH+ 561.
Reaction SMILES: [CH2:1](OC(=O)C1C=CC(C#CC2C=CC3C(NC4CC4)CCC(C)(C)C=3C=2)=CC=1)C.[Br:30][C:31]1[CH:32]=[C:33]2[C:38](=[C:39]([CH:41]=O)[CH:40]=1)[O:37][C:36]([CH3:44])([CH3:43])[CH2:35][C:34]2([CH3:46])[CH3:45]>CCCCCC>[Br:30][C:31]1[CH:32]=[C:33]2[C:38](=[C:39]([CH:41]=[CH2:1])[CH:40]=1)[O:37][C:36]([CH3:44])([CH3:43])[CH2:35][C:34]2([CH3:46])[CH3:45]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3NC2CC2)cc1
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Solvent: CCCCCC
Product: C=Cc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Yield: 71.6 %

Procedure:
A solution of methylidene triphenyl phosphorane [generated from methyl triphenylphosphonium bromide (7 g, 20 mmol) and (11.8 mL, 19 mmol) of a 1 .6M solution of n-butyl lithium in hexanes] was added 6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Intermediate 30, 0.52 g, 1.75 mmol). After 1 h the reaction mixture was diluted with hexane, washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a clear oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the title compound as a clear oil (0.37 g, 72%).
Reaction SMILES: [C:1]([C:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:5][CH2:6][CH3:7])[CH3:4])#[N:2].CC(O)(C)C>CO.[Ni]>[NH2:2][CH2:1][C:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(C)(C#N)NC(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Solvent: CC(C)(C)O
Product: CCCC(C)(CN)NC(=O)OC(C)(C)C

Procedure:
61.0 g (212.98 mmol) of rac-tert-butyl (2-cyanopentan-2-yl)carbamate-2-methylpropan-2-ol from Example 151A were dissolved in 618 ml of 7 N ammoniacal methanol and admixed under argon with 66 g of Raney nickel (50% aqueous slurry). Subsequently, the reaction mixture was hydrogenated in an autoclave at 20-30 bar overnight. The reaction mixture was filtered through Celite, rinsed well with methanol and concentrated. 43.70 g (95% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].B(F)(F)F.[CH3:16]COCC>CO>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[CH3:11]
Reactant: CCOCC
Reactant: Cc1c(F)cccc1C(=O)O
Agent: FB(F)F
Solvent: CO
Product: COC(=O)c1cccc(F)c1C
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of 3-fluoro-2-methyl-benzoic acid (Aldrich, 10.2 g, 66.17 mmol) in methanol (135 mL) at room temperature was treated with boron trifluoride etherate (15 mL) and was allowed to stir at room temperature. The reaction mixture was then concentrated in vacuo to remove the methanol and then diethyl ether (−300 mL) was added. The solution was transferred to a separatory funnel and washed with water (200 mL) and a 5% aqueous sodium bicarbonate solution to pH>7.5. The organic layer was then dried over magnesium sulfate and concentrated in vacuo to afford 3-fluoro-2-methyl-benzoic acid methyl ester (9.74 g, 87%) as a light orange colored oil which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1([CH2:21]O)[CH2:20][CH2:19]1>>[CH3:17][C:18]1([CH2:21][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: CC1(CO)CC1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCC1(C)CC1

Procedure:
Following General Procedure C above, and using N-(3-chloroph,enylacetyl alanine (from Example D above) and (1-methylcyclopropyl)methanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows:
Reaction SMILES: [C:1]1(=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CCO>[C:1]1(=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Temperature: 87.5 °C
Yield: 52 %

Procedure:
To a solution of methyl 4-[cyclohexylidene(4-hydroxyphenyl)methyl]benzoate (156) (0.175 g, 0.54 mmoL) in THF (3 mL) and EtOH (3 mL) was added 1 N NaOH (6 mL) at RT. The reaction mixture was heated between 85-90° C. under a nitrogen atmosphere for 2 h. The oil bath was removed and the reaction mixture was allowed to cool to RT. The reaction mixture was partially concentrated in vacuo to remove the THF and EtOH. The basic aqueous mixture was diluted with H2O and the pH was adjusted to ˜1 (as judged by litmus paper) with 1 N HCl. The acidic aqueous mixture was extracted with CH2Cl2 (2×). The organic extracts were combined, dried (MgSO4), filtered, and the filtrate was concentrated to give the 0.087 g (52%) of compound 157 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (m, 6H), 2.11 (m, 2H), 2.17 (m, 2H), 6.67 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 9.35 (s, 1H), 12.81 (br s, 1). LRMS (ESI): m/z 307 (M−H)−.