Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[NH:12][C:11]([C:13](=[O:24])[NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[N:10][C:9]=12)=[O:4].Br[CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][N:31]=1)=[O:28].B(Br)(Br)Br>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([CH2:26][N:12]2[C:8]3=[CH:7][S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]3[N:10]=[C:11]2[C:13](=[O:24])[NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[O:28])=[N:31][CH:32]=1.[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27]([CH2:26][N:10]2[C:9]3=[C:5]([C:3]([OH:2])=[O:4])[S:6][CH:7]=[C:8]3[N:12]=[C:11]2[C:13](=[O:24])[NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:22])[CH3:23])[CH2:17][CH2:16]2)=[O:28])=[N:31][CH:32]=1
Reactant: COC(=O)c1scc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: BrB(Br)Br
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)scc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3csc(C(=O)O)c3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 3-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid were prepared by a procedure according to example 81 starting from 500 mg (1.40 mmol) 2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid methyl ester and 356.0 mg (1.40 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide. Hydrolysis of the resulting esters by treatment with BBr3 according to example 16 and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compounds as their formiates in form of white amorphous solids. Structural assignment of both isomers was achieved by NOE-spectroscopy.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:3][C@H:4]([C:6]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:14]([C:15]#[N:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[C:30]=1[C:31]#[N:32]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 56.3 %

Procedure:
To a solution of 2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile dihydrochloride (110 mg, 0.29 mmol) in IPA (3 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (45 mg, 0.29 mmol) and DIPEA (148 μL, 0.87 mmol) and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 330 as a white solid (65 mg, 56%). 1H NMR 400 MHz δ (d6-DMSO): 8.08 (1H, dd, J=8.9, 4.9 Hz), 7.78 (1H, s), 7.70 (1H, d, J=7.2 Hz), 7.62-7.56 (1H, m), 7.55-7.43 (4H, m), 7.33 (1H, dd, J=10.4, 9.0 Hz), 7.15 (2H, br s), 5.28 (1H, quin, J=6.9 Hz), 1.48 (3H, d, J=6.9 Hz), LCMS (Method K): RT=3.73 min, [M+H]+=399
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([OH:16])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(Cl)(=O)C(Cl)=O.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].[Mg+2].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:14]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]([O:31][CH2:32][CH3:33])=[O:30])=[O:16])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1(c2ccccc2F)CCOCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccccc2F)CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(2-fluorophenyl)-tetrahydro-2H-pyran-4-carboxylic acid (1.9 g, 8.5 mmol) in DCM (50 mL) and DMF (5 mL) was carefully added oxalyl chloride (0.79 mL, 8.9 mmol). Gas evolution was observed. The reaction was stirred at room temperature for 3 hours. In a separate flask was combined IPAc (1.0 mL, 8.7 mmol), diethyl malonate (1.6 mL, 11 mmol). and anhydrous MgCl2 (1.0 g, 11 mmol). The resulting white slurry was stirred for 30 minutes, and then TEA (4.0 mL, 29 mmol) was added and the reaction was stirred for 2.5 hours. The reaction was chilled in an ice water bath for 10 minutes, and then the concentrated acid chloride oil was added via syringe over 10 minutes. The ice bath was removed, and the reaction was stirred for 16 hours at 50° C. After cooling to room temperature, the reaction was acidified with 5N HCl solution (100 mL). The aqueous layer was removed, and the organic layer was washed with saturated NaHCO3 solution (150 mL). The aqueous layer was removed, and the organic extract was washed with water. The organic layer was dried (Na2SO4), filtered and concentrated to afford a dark colored oil. The crude reaction mixture was used in the next step.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8].[C:29]([OH:32])(=[O:31])[CH3:30].[H][H]>[Pt].CCCCCC>[C:29]([OH:32])(=[O:31])[CH3:30].[F:28][C:2]([F:1])([F:27])[CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][C:6]=1[C:7]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1)=[O:8]
Reactant: [H][H]
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 6.5 h
Yield: 71 %

Procedure:
A mixture of 0.33 mole (134.7 g.) 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide, 1.347 liter of glacial acetic acid and 13.5 g. of 5 percent platinum on carbon is reduced in a Parr apparatus at a pressure of about 10 pounds of hydrogen at room temperature. The reaction is complete in 6-7 hours. The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and washings are evaporated to provide a residue. Hexane is added to the residue and the resulting white solid is collected and recrystallized from a mixture of acetone and hexane. A 71 percent yield of 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate, m.p. 150° to 152° C., is obtained. By concentrating the residual liquid an additional 18 percent of product is obtained as a second crop with a melting point of 148°-150° C.
Reaction SMILES: Cl.[C:2]([N:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)N)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]1[C:23](=O)[CH2:22][CH2:21][C:20]([C:28]([OH:30])=[O:29])([C:25]([OH:27])=[O:26])[CH2:19]1.C(O)(=O)C>O>[C:2]([N:10]1[C:23]2[CH2:22][CH2:21][C:20]([C:28]([OH:30])=[O:29])([C:25]([OH:27])=[O:26])[CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCC(C(=O)O)(C(=O)O)CC1
Reactant: NN(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)n1c2c(c3ccccc31)CC(C(=O)O)(C(=O)O)CC2

Procedure:
1-Benzoyl-1-phenylhydrazine hydrochloride (5 g.) and 4 g. of cyclohexanone-4,4-dicarboxylic acid in 10 ml. of glacial acetic acid were heated at 60°-70°C. for thirty minutes. The mixture was diluted with water and the resulting solid was collected by filtration and washed with water to give 7.1 g. of the title compound; m.p. 160°C. (acetone and hexane).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH3:18].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>CS(O)(=O)=O.C(Cl)Cl>[CH:1]1([N:6]2[C:10]3=[N:11][C:22]([C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[O:19][CH2:17][CH3:18])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOc1ccccc1C=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOc1ccccc1-c1nc2n(C3CCCC3)[nH]c(CC)c-2c(=O)n1
Yield: 44.5 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9 mmol), o-ethoxybenzaldehyde (2.7 g, 18 mmol), methanesulfonic acid (5 drops), and xylenes (50 ml) was refluxed for 48 hours. The reaction mixture was stripped to dryness, and treated with 10% K2CO3 and CHCl3 (100 ml). The layers were separated and the aqueous layer was extracted with chloroform (2×100 ml). The organic layers were combined, and concentrated in vacuo. The dark oil thus obtained was dissolved in CH2Cl2 (30 ml) and combined with silica gel (30 g). The preloaded silica gel was placed on a silica gel column and eluted with Et2O/hexanes (20/80) to Et2O (100%) to afford 1.41 g (45%) of 1-cyclopentyl-3-ethyl-6-(2-ethoxyphenyl)-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 146-147° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:15]3[CH:16]=[C:17]([CH3:20])[CH2:18][CH2:19][C@H:14]3[C:13]([CH3:22])([CH3:21])[O:12][C:10]=2[CH:11]=1.[N+](C1C=CC=CC=1S[NH:34][CH2:35][CH2:36][C:37]([O-:39])=[O:38])([O-])=O>ClCCl.C1(S)C=CC=CC=1.C(O)(C(F)(F)F)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:15]3[CH:16]=[C:17]([CH3:20])[CH2:18][CH2:19][C@H:14]3[C:13]([CH3:22])([CH3:21])[O:12][C:10]=2[CH:11]=1.[NH2:34][CH2:35][CH2:36][C:37]([O-:39])=[O:38]
Reactant: O=C([O-])CCNSc1ccccc1[N+](=O)[O-]
Agent: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Agent: Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)[O-]

Procedure:
THC N-(2-nitrophenylsulfenyl)-β-alaninate (35.8 mg, 0.0665 mmol) was dissolved at ambient temperature in dry dichloromethane containing 10% (v/v) of thiophenol and 1.5% (v/v) of TFA (150 μL). After 10 min the mixture was quenched by addition of 180 μL 3% triethylamine in DCM (at 0° C.). The solution of crude product was chromatographed directly on silica gel with dichloromethane-methanol (gradient 1:0, 30:1, 20:1, 10:1, 7:1). The combined fractions containing the product were diluted with chloroform, concentrated at 25° C. to ˜3 mL, diluted with chloroform and concentrated again to ˜0.5 mL. The solution of product was diluted with chloroform again (˜5 mL) and concentrated to dryness. The remaining oil was immediately dissolved in chloroform, concentrated to dryness (11.47 mg, 45%), and immediately dissolved in chloroform to afford a stock solution of THC β-alaninate (ALL00133) stored at −20° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[N:13][CH:14]=1.[N:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO.C(O)(=O)C.CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)[CH2:28][CH2:27]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=Cc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)C1CCN(Cc2ccncc2)CC1
Reaction time: 15 h

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamide trifluoroacetate (25 mg, 0.053 mmol) in methanol (0.5 mL) was added 4-pyridinecarboxaldehyde (17.1 mg, 0.16 mmol) followed by a solution of sodium cyanoborohydride (7 mg, 0.106 mmol) in 7.5% acetic acid/methanol (1 mL). After shaking for 15 h, the solution was loaded onto an SCX column, which was pretreated with a solution of 5% acetic acid in methanol. The column was washed once with methanol and eluted with 2 N ammonia in methanol. The product containing fractions were combined and concentrated in vacuo. The residue was dissolved in a small amount of methanol and a few drops of acetic anhydride were added. After shaking for 0.5 h, the SCX purification procedure was repeated to give 9.8 mg (41%, 91% pure by HPLC analysis) of the title compound. IS-MS, m/e 450.1 (m+1) HPLC, Analytical method, RT=18.56 min.
Reaction SMILES: [C:1]([C:5]1[C:6]([Cl:41])=[C:7]([C:11]2[NH:40][C:14]3[C:15]([O:29][CH2:30][CH2:31][O:32][Si](C(C)(C)C)(C)C)=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[C:1]([C:5]1[C:6]([Cl:41])=[C:7]([C:11]2[NH:40][C:14]3[C:15]([O:29][CH2:30][CH2:31][OH:32])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCCO[Si](C)(C)C(C)(C)C)c2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCCO)c2[nH]1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine (390 mg, 0.641 mmol, prepared as described in the previous step) and tetrabutylammonium fluoride hydrate (914 mg, 3.21 mmol) in THF (10 mL) was stirred at 50° C. for 18 h. After cooling to room temperature, the resulting mixture was treated with EtOAc (50 mL) and washed with H2O (2×20 mL), brine (20 mL). The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (40:60-60:40 EtOAc/heptane) to yield 2-[2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy]-ethanol as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 7.67 (dd, J=7.3, 2.0 Hz, 1H), 7.48-7.56 (m, 2H), 7.39 (td, J=6.7, 1.8 Hz, 2H), 4.64-4.68 (m, 2H), 4.05 (s, 3H), 3.97-4.02 (m, 2H), 1.42-1.49 (m, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C23H23ClF3N5O2: 492.2 (M+H), Measured: 492.4.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.CCN(CC)CC.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:25][CH2:26][C:27]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 75.6 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (4.43 g, 20 mmol) and Et3N (3 mL, 22 mmol) in THF (100 mL), chloroacetyl chloride (1.6 mL, 20 mmol) was added dropwise with stirring. The solvent was evaporated in vacuo. The residue was slurred with water, filtered, and dried. The solid was dissolved in hot toluene (300 mL), treated with silica gel, filtered and left to recrystallize to afford 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (4.5 g, 76% yield). LCMS calculated for C16H12ClN3O (M+H): 298.75. found 298.06. 1H-NMR (400 MHz, DMSO-d6) δH: 10.6 (1H, br. s), 9.52 (1H, s), 8.54 (1H, m), 8.20-8.05 (3H, m), 7.90-7.70 (3H, m), 7.62-7.51 (1H, m), 4.31 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=O.BrC1C=C(Cl)C=CC=1[O:27][CH2:28][O:29][CH2:30][CH2:31]OC.C(=O)[C:35]1[C:36]([O:41]C)=CC=CC=1>>[CH2:30]([O:29][C:28]([C:35]1[C:36](=[O:41])[O:18][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=2[C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=[O:27])[CH3:31]
Reactant: COc1ccccc1C(=O)c1cc(Cl)ccc1O
Reactant: COCCOCOc1ccc(Cl)cc1Br
Reactant: COc1ccccc1C=O
Product: CCOC(=O)c1c(-c2ccccc2OC)c2cc(Cl)ccc2oc1=O
Temperature: 180 °C

Procedure:
A mixture of 5-chloro-2-hydroxy-2'-methoxybenzophenone [prepared from 2-bromo-4-chloro-(2-methoxyethoxy)methoxybenzene and orthoanisaldehyde as the starting materials: melting point, 94°-98° C. (recrystallized from isopropyl ether)](11.8 g), diethyl malonate (13.6 g) and potassium fluoride (2.61 g) was heated at 180° C. for 8.5 hours. After cooling, ethyl acetate was added to the mixture, washed with water, dried and evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane: 1:10) to yield 6-chloro-4-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid ethyl ester as colorless crystals (7.78 g).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[NH:34]1[C:38](B(O)O)=[CH:37][CH:36]=[N:35]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:36]2[NH:35][N:34]=[CH:38][CH:37]=2)[CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: OB(O)c1ccn[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1ccn[nH]1)c(OCc1ccccc1)c2=O
Yield: 62.5 %

Procedure:
Intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.27 mmol) was reacted with 1H-pyrazol-5-ylboronic acid (0.060 g, 0.54 mmol), sodium carbonate (0.085 g, 0.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.070 g) to give 0.085 g (62% yield) of the title material as a white solid after chromatography on silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.63 (6H, s, 2×CH3), 4.03 (4H, m, 2×CH2), 4.65 (2H, d, J=6.5 Hz, NCH2), 5.25 (2H, s, OCH2), 6.54 (1H, d, J=2.5 Hz, CH), 7.03 (1H, m, aromatic), 7.25 (1H, dd, J=2.5 Hz and J=9.8 Hz, aromatic), 7.35 (3H, m, aromatics), 7.53 (2H, m, aromatics), 7.56 (1H, d, J=2.5 Hz, CH), 7.60 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic), 8.96 (1H, broad t, NH). HRMS (ESI+) calculated for C27H27FN5O4 [M+H+]: 504.2047: found: 504.2068.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C(Cl)(Cl)Cl.N1C=CC=CC=1.[F:17][C:18]1[CH:19]=[C:20]([C@H:26]2[NH:31][C@@H:30]([C:32]([OH:35])([CH3:34])[CH3:33])[CH2:29][O:28][CH2:27]2)[CH:21]=[C:22]([F:25])[C:23]=1[F:24]>O>[CH3:34][C:32]1([CH3:33])[C@H:30]2[CH2:29][O:28][CH2:27][C@@H:26]([C:20]3[CH:19]=[C:18]([F:17])[C:23]([F:24])=[C:22]([F:25])[CH:21]=3)[N:31]2[C:2](=[O:3])[C:1](=[O:5])[O:35]1
Reactant: CC(C)(O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)OC(=O)C(=O)N2[C@H](c3cc(F)c(F)c(F)c3)COC[C@@H]21
Reaction time: 1 h

Procedure:
Under ice-cooling, oxalyl chloride (205 μL) was added dropwise into a chloroform (10 mL) solution of pyridine (2 mL) and 2-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]propane-2-ol (330 mg). The reaction solution was stirred for 1 hour at the same temperature, and the resultant was stirred a further 2 hours at room temperature. Water was added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum. The residue was purified by silica gel column chromatography (heptane/ethyl acetate), and the title compound (260 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:31][C@H:32]([CH2:37][CH3:38])[C:33]([CH3:36])([OH:35])[CH3:34])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](N)C(C)(C)O
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCCCO
Product: CC[C@@H](Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1)C(C)(C)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (20 mg, 1 eq, 0.07 mmol) in n-BuOH/DMSO (1.25 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.25 mL, 20.4 eq, 1.43 mmol) followed by (R)-3-amino-2-methyl-pentan-2-ol (22 mg, 2.68 eq, 0.19 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with hexane:ether:MeOH (50:50:0→50:50:2) to afford the title compound as a white solid; Yield: 4.2 mg (16%). 1H-NMR (d-CDCl3, 250 MHz): δ 1.01 (t, 3H, J=7.50 Hz, —NHCH(CH2CH3)C(CH3)2OH), 1.23+1.30 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.68-1.89 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 3.69-3.86 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.58-4.74 (m, 1H, —CH(CH3)2), 4.75-4.94 (m, 2H, —HNCH2-Bz), 7.22-7.45 (m, 6H, 5×Bz-H+HNCH2-Bz), 7.57 (s, 1H, —N═CH—N). FABMS m/z (relative intensity): 383 ([M+H]+, 75), 323 (60), 308 (20), 246 (20), 192 (60), 176 (100), 165 (40). Accurate Mass (M+H): Actual: 383.2559, Measured: 383.2544.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:19])[NH:16][CH2:17][CH3:18])[N:11]=[CH:10][C:9]=1[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:26](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.N>CN(C=O)C.CO.C(Cl)Cl>[CH2:17]([NH:16][C:15](=[O:19])[NH:14][C:12]1[CH:13]=[C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([C:20]([NH2:26])=[O:22])=[CH:10][N:11]=1)[CH3:18]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8918.5 %

Procedure:
4-anilino-6-(ethylcarbamoylamino)pyridine-3-carboxylic acid (i) (70 mg, 0.23 mmol) was suspended in DMF (2 mL) and N,N-diisopropylethyl amine (0.16 mL, 0.93 mmol) was added, causing the solid to dissolve. The [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl-ammonium hexafluorophosphate (97 mg, 0.26 mmol) was added. After stirring at RT for 10 min, ammonia (1 mL, 25 mass %, 14.7 mmol) was added. The mixture was stirred overnight at RT. The mixture was quenched with NH4Cl and diluted with water and EtOAc. The mixture was extracted into EtOAc (3×20 mL), the organics combined and dried with brine then over MgSO4. The solvent was removed to afford a crude residue as a white solid. The solid was dissolved in MeOH/DCM and applied to a silica column, eluting with MeOH/DCM, to give Compound 6140 mg. 1H NMR (400 MHz, CD3OD) δ 8.46-8.39 (m, 1H), 7.44-7.37 (m, 2H), 7.29-7.23 (m, 2H), 7.22-7.14 (m, 1H), 6.84 (s, 1H), 3.29-3.24 (m, 2H), 1.18 (t, J=7.2 Hz, 3H).