Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.[F:30][CH:31]([CH3:35])[C:32](Cl)=[O:33].Cl>C1C=CC=CC=1>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:32](=[O:33])[CH:31]([F:30])[CH3:35])=[CH:21][CH:22]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CC(F)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCCc1cnc(-c2ccc(OC(=O)C(C)F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 5 %

Procedure:
5.4 g (173 mmol) of p-(5-decyl-2-pyrimidyl)-phenol and 1.4 g (177 mmol) of pyridine were dissolved in 30 ml of benzene, and a benzene solution of the above 2-fluoropropanoic acid chloride was added dropswise thereto at 5° C. in 15 minutes. Then, the mixture was stirred overnight at room temperature, and after the completion of the reaction, the reaction solution was poured into ice water. Then, the system was acidified with the addition of 6N-HCl and subjected to extraction with benzene. The extract benzene solution was washed with water and saline water, dried with anhydrous magnesium sulfate, and the solvent was distilled to leave 3.2 g of a crude product. The product was purified by column chromatography (eluent: hexane/acetone=10/1) to obtain 330 mg of 2-fluoropropanoic acid-p-(5-decyl-2-pyrimidyl)phenyl-ester. Yield: 5.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19](OC)=[O:20])[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[O:20])[N:14]([CH3:18])[S:15](=[O:16])(=[O:17])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Nc1ccccn1
Reactant: COC(=O)C1=C(O)c2c(c3cc(Cl)ccc3n2C)S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2c(c3cc(Cl)ccc3n2C)S1(=O)=O
Yield: 72 %

Procedure:
8-Chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(2-pyridyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 18 from methyl 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 2-amino-pyridine with a yield of 72% of theory; M.p.: 245° C. (decomposition).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl.O>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:17]
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCl)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a solution of phenethylamine (2.42 g, 20 mmol) and NaOH (0.88 g, 22 mmol) in DCM/H2O (20 mL/20 mL) was added 4-chloro-butyryl chloride (2.82 g, 20 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 20 min. The mixture was partitioned between DCM (20 mL) and H2O (10 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a white solid. This residue was purified with silica gel column (Hexane/EtOAc=3/1 to 1/1) to obtain HJC-1-48 (4.2 g, 93%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 7.32 (t, 2H, J=7.8 Hz), 7.23-7.26 (m, 1H), 7.20 (d, 2H, J=7.8 Hz), 5.46-5.47 (m, 1H), 3.52-3.58 (m, 4H), 2.82 (t, 2H, J=7.2 Hz), 2.31 (t, 2H, J=7.2 Hz), 2.07-2.11 (m, 2H).
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[S:13][CH:14]=1)(OCC)=O)C.[H-].[Na+].[CH3:27][O:28][CH2:29][O:30][C:31]1[C:35]([CH:36]=O)=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.O>O1CCCC1>[CH3:27][O:28][CH2:29][O:30][C:31]1[C:35](/[CH:36]=[CH:9]/[C:10]2[N:11]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[S:13][CH:14]=2)=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1
Reactant: CCOP(=O)(Cc1csc(-c2ccccc2C(=O)OC)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(-c2ccccc2C(=O)OC)n1
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
To a solution of methyl {4-[(diethoxyphosphoryl)methyl]-1,3-thiazol-2-yl}benzoate (4.7 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 1.1 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.8 g) was added to the reaction mixture, and the mixture was heated under reflux for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (30:70-60:40, v/v) to give methyl (4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazol-2-yl)benzoate as pale-yellow crystals (1.1 g, yield 20%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 134-135° C.
Reaction SMILES: O[CH:2]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])[CH3:3].P(Br)(Br)[Br:27]>O1CCCC1>[Br:27][CH:2]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])[CH3:3]
Reactant: BrP(Br)Br
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(C)O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(C)Br
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 5-(1-hydroxyethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.8 g) in tetrahydrofuran (10 ml) was dropped to a solution of phosphorus tribromide (0.34 ml) in tetrahydrofuran (20 ml) under ice cooling. The reaction mixture was stirred for 5 hours at the same condition and poured into ice water and extracted with ethyl acetate. The organic layer was evaporated in vacuo. The residue was chromatographed on silicagel eluting with chloroform. The fractions containing the desired product were combined and evaporated in vacuo. The residue was crystallized from diisopropyl ether to afford 5-(1-bromoethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (0.3 g).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][CH:9]([CH2:13][CH2:14][C:15]([OH:17])=O)[C:10](O)=[O:11].[NH4+:18].[OH-]>>[CH3:8][CH:9]1[CH2:13][CH2:14][C:15](=[O:17])[NH:18][C:10]1=[O:11]
Reactant: [NH4+]
Reactant: CC(CCC(=O)O)C(=O)O
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: CC1CCC(=O)NC1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Acetic anhydride was added to commercially available 2-methylglutaric acid (1 g, 6.8 mmol) at room temperature, and the mixture was stirred at 60° C. for 8 hours under reflux. After completion of the reaction was confirmed by TLC, the remaining acetic anhydride was removed under reduced pressure. The concentrated compound was dissolved in tetrahydrofuran and an ammonia aqueous solution (1.7 mL, 14.6 mmol) was slowly added thereto at 0° C., followed by stirring for 8 hours at room temperature. After the reaction was complete, the remaining ammonia aqueous solution was removed under reduced pressure and an acetic anhydride was added, followed by reflux at 60° C. for 8 hours. The residual acetic anhydride was removed under reduced pressure. The concentrate was purified by column chromatography (ethyl acetate:hexane=1:1) to afford 682 mg (yield: 78%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Oc2sc3c(c21)CCCC3
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Oc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29]Cl)[CH:26]=[CH:25][C:24]=1[O:31][CH:32]([CH2:35][F:36])[CH2:33][F:34]>>[Cl:22][C:23]1[CH:28]=[C:27]([CH:26]=[CH:25][C:24]=1[O:31][CH:32]([CH2:35][F:36])[CH2:33][F:34])[CH2:29][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([OH:17])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: FCC(CF)Oc1ccc(CCl)cc1Cl
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Product: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(OC(CF)CF)c(Cl)c3)ccc12

Procedure:
From tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate and 2-chloro-4-(chloromethyl)-1-(1,3-difluoropropan-2-yloxy)benzene, the title compound was prepared using a similar method to the one described in Example 1.48, Step B. LCMS m/z=450.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.27-2.36 (m, 1H), 2.67 (dd, J=16.4, 8.4 Hz, 1H), 2.87-2.97 (m, 2H), 3.75 (quintet, J=7.4 Hz, 1H), 3.98-4.05 (m, 1H), 4.15 (ddd, J=9.9, 8.6, 4.1 Hz, 1H), 4.56-4.69 (m, 3H), 4.75-4.78 (m, 2H), 5.00 (s, 2H), 6.12 (s, 1H), 6.86 (dd, J=8.7, 2.4 Hz, 1H), 7.06-7.09 (m, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.31 (dd, J=8.4, 2.1 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11](Cl)[C:10]=1[C:24]#[N:25].[C:26]([O-:29])(O)=O.[Na+]>CO.N1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11]([N:12]2[CH2:13][CH2:26][O:29][CH2:10][CH2:11]2)[C:10]=1[C:24]#[N:25]
Reactant: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(Cl)nc2n(C)c1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CO
Product: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(N3CCOCC3)nc2n(C)c1=O
Temperature: 80 °C

Procedure:
An amount of 50 mg (0.117 mmole) of 47a was dissolved in 500 μL, of MeOH, 1 ml of morpholine and 512 mg (6.203 mmole) of NaHCO3. The mixture was heated to 80° C. for 1 hr to give 5-(2-Bromo-5-fluoro-phenyl)-1,3-dimethyl-7-morpholin-4-yl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (47b).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[ClH:21].CCO[CH2:25][CH3:26]>>[ClH:21].[C:8]([C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)#[C:9][CH2:10][CH2:5][CH2:25][CH3:26]
Reactant: Brc1cnc2ccc(NCCCN3CCOCC3)nn12
Reactant: CCOCC
Agent: Cl
Product: CCCCC#Cc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 18 %

Procedure:
Prepared from the product of step A (example 16) according to general procedure 6. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (27 mg, 18%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.67 (d, J=9.7 Hz, 1H), 7.60 (s, 1H), 6.83 (d, J=9.7 Hz, 1H), 3.95 (m, 4H), 3.54 (t, J=6.4 Hz, 2H), 3.34-3.24 (m, 6H), 2.56 (t, J=6.4 Hz, 2H), 2.21-2.15 (m, 2H), 1.67-1.54 (m, 4H), 0.99 (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 156.1, 136.6, 132.2, 124.9, 116.5, 115.1, 100.7, 68.1, 65.1, 56.8, 53.4, 39.5, 31.8, 24.3, 23.0, 20.1, 14.0; HPLC tR=12.7 min (Luna), 97.5%; ES-MS: (M+H)=342 m/z.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([F:29])=[CH:24][N:23]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:18][C:24]3[C:25]([F:29])=[CH:26][N:27]=[C:22]([Cl:21])[N:23]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Product: Fc1cnc(Cl)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 4-(N-benzylpiperazino)aniline and 2,4-dichloro-5-fluoropyrimidine gave N4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 2.81 (m, 4H), 3.37 (m, 6H), 6.85 (br, 1H), 6.93 (d, J=9.0 Hz, 2H), 7.40 (m, 5H), 7.50 (d, J=9.3 Hz, 2H), 8.02 (d, J=2.7 Hz, 1H); LCMS: ret. time: 20.56 min, purity: 97.75%; MS (m/e): 398.00 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH2:11].[CH2:12]([O:14][CH2:15][C:16](Cl)=[O:17])[CH3:13]>N1C=CC=CC=1>[CH2:12]([O:14][CH2:15][C:16]([NH:11][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:10][C:16](=[O:17])[CH2:15][O:14][CH2:12][CH3:13])[C:2]=1[Cl:1])[C:6]#[N:7])=[O:17])[CH3:13]
Reactant: CCOCC(=O)Cl
Reactant: N#Cc1cc(N)c(Cl)c(N)c1
Solvent: c1ccncc1
Product: CCOCC(=O)Nc1cc(C#N)cc(NC(=O)COCC)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-3,5-diaminobenzonitrile (3.3 g) in pyridine (80 ml) is added dropwise ethoxyacetyl chloride (4.8 ml) at room temperature. The mixture is stirred at room temperature for 3 hours, and thereafter, pyridine is distilled off under reduced pressure. To the residue is added water, and the resulting solid substance is separated by filtration and washed with water. The resulting crude crystals are recrystallized from ethanol to give the title compound (4.0 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[CH3:21][C:22]([Mg]Br)=[CH:23][CH3:24].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:23]([CH3:24])=[C:22]([CH3:21])[NH:18][C:5]2=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[N:7]=1
Reactant: CC=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1ccc(Cl)nc1N1CCc2ccccc2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(Cl)cc2c1C
Temperature: -20 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
2-(6-Chloro-3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (16 g, 56.6 mmol) prepared in Preparation 7 was dissolved in anhydrous tetrahydrofuran (300 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 283 ml, 141.5 mmol) was slowly added at −78° C. to the solution. The reaction mixture was stirred for 2 hours at −20° C. and then 20% (w/v) ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give 7.8 g of the titled compound as yellow oil. (Yield: 45%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)CCCCN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)CCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a cold (ca -30° ), stirred solution of 26.5 g (0.1 mole) of t-butoxycarbonylphenylalanine (BOC-Phe) and 11.2 g (0.1 mole) of N-methylmorpholine in 150 ml of dimethylformamide (DMF) was added dropwise 13.2 ml (0.1 mole) of isobutylchloroformate. After warming and then holding the temperature at ca. -15° for about ten minutes, the solution was recooled to ca. -39°. To the cold mixture was added additional N-methylmorpholine (12.3 ml, ca. 0.11 mole), followed by 18.5 g (0.11 mole) of methyl 5-aminopentanoate hydrochloride. The mixture was allowed to warm to room temperature and to stand overnight. Solvent and other volatiles were removed by concentration in vacuo. The residue was triturated with ethyl acetate, which was then washed successively with water, 0.5M potassium bisulfate, water, and again with 0.5M potassium bisulfate, and then dried over magnesium sulfate, filtered, and concentrated to a white solid. After collection, the white solid was washed thoroughly with Skellysolve B to give 36.4 g of the title compound, m.p. 98°-100°. Recrystallization from ethyl acetate/Skellysolve B afforded analytically pure crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCCO[C@H]1COCc1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@H]1CCCO[C@H]1COCc1ccccc1

Procedure:
Jones oxidation was carried out by the same procedure as described in Preparation 3, but using 2.22 g of dl-trans-2-benzyloxymethyl-3-hydroxytetrahydropyran (prepared as described in Preparation 6). The crude substance, 2.08 g, obtained in this way was dissolved in 10 ml of tetrahydrofuran, and 12 ml of a 1M tetrahydrofuran solution containing L-selectride were added dropwise to this solution at 0°-5° C. Using the same procedure and purification as described in Preparation 4, 1.135 g of the title compound was obtained as a colorless liquid, boiling at 130°-140° C. (bath temperature)/1 mmHg (133 Pa).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:10]2[C:11]([O:13][CH3:14])=[O:12])=[O:8])=[CH:3][CH:2]=1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:17][C@H:16]([O:18][Si:29]([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30])[CH2:15][C@H:10]2[C:11]([O:13][CH3:14])=[O:12])=[O:8])=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)c1ccc(-c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 24 h

Procedure:
Methyl (4R)-1-(1,1′-biphenyl-4-ylcarbonyl)-4-hydroxy-L-prolinate (intermediate 2a, 2.07 g, 6.35 mmol) was dissolved in DCM (30 ml) and treated with 4-DMAP (776 mg, 6.35 mmol), TEA (2.21 ml, 15.88 mmol) and TBDMS-Cl (1.91 g, 12.7 mmol). The reaction was monitored by LC/MS. After 24 h, as the reaction was not completed, TBDMS-CL (300 mg, 2 mmol) and TEA (1 ml) were added. After 48 h, the reaction was completed. The mixture was washed with sat. NH4Cl and brine (twice), dried over magnesium sulfate, filtered and concentrated. The crude (2.85 g) was purified by flash chromatography using EtOAc/cHex 50:50 as eluant.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH:24]C(=O)C(F)(F)F)[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)=[N:10][N:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(NC(=O)C(F)(F)F)c3)nn2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(-c3ccnc(Cl)n3)c(-c3cccc(N)c3)nn2c1

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.70 g, 3.94 mmol) and LiOH (0.50 g, 11.8 mmol) were combined in THF (30 mL) and water (5 mL) and stirred at 40° C. for 3 h. The mixture was cooled, concentrated to remove the THF, and extracted with DCM. The organic phase was concentrated to afford {3-[3-(2-chloro-4-pyrimidinyl)-6-methylpyrazolo[1,5-a]pyridin-2-yl]phenyl}amine which was carried on crude to Step C. ES-LC/MS m/z=336 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:9]=1.[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 140 °C

Procedure:
In a 2-5 mL microwave vial was charged ethyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4k, 300 mg, 0.45 mmol), phenylboronic acid (108 mg, 0.89 mmol), K3PO4 (189 mg, 0.89 mmol), and Pd(PPh3)4 (52 mg, 0.045 mmol). To this was added 3:1 1,4-dioxane:H2O (4 mL). The vial was flushed with argon and sealed. The reaction was heated to 140° C. for 20 minutes in a microwave synthesizer. The reaction was then diluted with DCM (30 mL) and washed with H2O. The organic phase was dried over Na2SO4 and the residue was purified via silica gel chromatography to yield the title compound. Yield=265 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[C:23]1([CH3:40])[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([NH:32][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:40])=[CH:24][CH:25]=3)(=[O:31])=[O:30])=[CH:39][CH:38]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(N)cc2)cc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(NC(=O)c3ccc(-c4cc(-c5nnc(C)o5)ccc4C)cc3)cc2)cc1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(p-toluenesulphonamido)phenyl]-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-(p-toluenesulphonamido)aniline using method I. NMR; δH [2H6]—DMSO 10.26,(1H, s), 10.08,(1H, b), 8.01,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.63,(4H, m), 7.56,(3H, m), 7.33,(2H, d), 7.06,(2H, d), 2.56,(3H, s), 2.33-2.32,(6H, m). LCMS; retention time 3.52 min, MH+ 539.