Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.[CH2:18]([O:20][C:21](Cl)=[O:22])[CH3:19]>ClCCl>[CH2:18]([O:20][C:21](=[O:22])[NH:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)[CH3:19]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 35.2 %

Procedure:
To a stirred solution of 1H-indol-5-amine (11 g, 83.2 mmol) and triethyl amine (25.22 g, 250 mmol) in dichloromethane (110 mL) at −10° C., ethyl-chloro-formate (13.5 g 124.8 mmol) was added dropwise and stirred at 0° C. for 2-3 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the resultant residue was purified by flash column chromatography to give ethyl-1H-indol-5-ylcarbamate (5.980 g, 35.2%); MS: 205 (M+1).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]([NH:24][N:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]([NH:24][N:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN1CC(=O)NC1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN1CC(=O)NC1=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 30.8 %

Procedure:
A solution of 0.298 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-N-(2,4-dioxo-1-imidazolidinyl)valeramide in 3 ml of methanol was treated with 0.030 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 3.5 hours at room temperature and then diluted with ethyl acetate and washed in sequence with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether to give 0.076 g of (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methyl-N-(2,4-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [C:1]([F:4])([F:3])=O.[F:5][C:6]([F:11])([F:10])[C:7]([F:9])=O>>[F:5][C:6]([F:11])([F:10])[C:7]([F:9])=[C:1]([F:4])[F:3]
Reactant: O=C(F)F
Reactant: O=C(F)C(F)(F)F
Product: FC(F)=C(F)C(F)(F)F

Procedure:
The procedure described in Example 9 is employed in which 10.2 grams hexafluoropropylene is condensed in at high pressure and 12 grams liquid carbon dioxide is added. The temperature is raised to 60° C., and the cell is charged with molecular oxygen to approximately 2,500 psi. Oxygen is supplied continuously to the reactor. 0.5 grams of a clear fluid is collected in the cold trap corresponding to a 5% yield of perfluoropolyether (based on hexafluoropropylene). Analysis using 19F NMR spectroscopy is consistent with a perfluoropolyether structure. Analysis of portions of the gaseous products shows evidence of carbonyl fluoride and trifluoroacetyl fluoride in addition to other low molar mass fluorooxy compounds.
Reaction SMILES: [I:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=O.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:7]1[C:8]2[C:3](=[C:2]([I:1])[C:11]([CH3:12])=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(=O)[nH]ccc2c1I
Product: Cc1ccc2c(Cl)nccc2c1I
Temperature: 100 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
5-Iodo-6-methylisoquinolin-1(2H)-one (2.00 g, 7.02 mmol) was treated with phosphorous oxychloride (6.54 ml, 70.2 mmol) and the mixture stirred at 100° C. for 4 hours. The mixture was cooled and the volatiles removed in vacuo. The residue was taken up in DCM and washed twice with cold water and then twice with saturated aqueous sodium bicarbonate. The organic was dried with sodium sulfate, loaded unto silica and purified by column chromatography on silica gel using 20 to 60% EA in hexanes to give 1-chloro-5-iodo-6-methylisoquinoline (2.00 g, 93.9% yield) as a tan solid. MS (M+H)+ 303.7.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22](OC)=[O:23])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:18][CH:19]=3)=[CH:7][C:6]=2[C:5]2[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:4]=2[N:3]=1
Reactant: COC(=O)CCc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CCCO)cc3)cc12

Procedure:
3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)propan-1-ol was prepared from methyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)propanoate (from Example 61) following the procedures described for Example 42/Step 3. 1H NMR of the TFA salt: (DMSO-d6): δ 9.56 (s, 1H), 9.24 (s, 1H), 8.92 (d, 1H), 8.81 (d, 1H), 8.43 (d, 1H), 7.44 (d, 1H), 7.35 (d, 1H), 7.13 (dd, 2H), 7.05 (dd, 2H), 3.32 (t, 2H), 3.18-3.12 (dd, 2H), 3.02-2.95 (dd, 2H), 2.50 (t, 2H), 2.44 (s, 3H), 1.65-1.57 (m, 2H). LRMS [M+H]=372.2
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:11])[CH2:9][O:10][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H](O)c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(Cl)nc2)cc1
Reaction time: 0.33 h

Procedure:
To a cooled 5° C., stirred solution of (R)-1-(6-chloro-pyridin-3-yl)-ethane-1,2-diol (17.8 grams) in anhydrous pyridine (100 mL) was added p-toluenesulfonyl chloride (19.5 grams) in one portion. After 20 minutes, the cooling bath was removed and stirring was continued an additional 12 hours. The reaction solution was concentrated in vacuo, azeotroped with toluene (2 times), diluted ethyl acetate, washed with half-saturated aqueous brine, saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo. The resulting solids were recrystallized from ethyl acetate/hexanes to afford the title compound as colorless crystals, 23.3 grams 1H NMR (400 MHz, CDCl3)=8.29 (s, 1H); 7.72 (d, 2H); 7.64 (d, 1H); 7.32 (d, 2H); 7.28 (d, 1H); 5.00 (dd, 1H); 4.09 (AB pattern, 2H); 2.44 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([NH:50][CH3:51])=[O:49])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([NH:50][CH3:51])=[O:49])[CH:42]=[CH:43][N:44]=5)=[O:61])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(=O)NC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(=O)NC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 83.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-[4-(methylamino)-4-oxobutyl]-1H-imidazol-2-yl]methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (400 mg) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.2 g) in dichloromethane (15 ml) at −78° C. The mixture was stirred for 1.5 hours at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, washed with an aqueous solution of sodium bicarbonate and saturated brine, and dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetatel:19), and was further recrystallized from ethyl acetate-diisopropyl ether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-[4-(methylamino)-4-oxobutyl]-1H-imidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 424) (342.8 mg) as yellow crystals.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][N:16]=1.Cl>O.CO>[C:17]1([C:14]2[O:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:23])=[O:4])=[N:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCCCCCc1ncc(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCc1ncc(-c2ccccc2)o1
Reaction time: 4 h
Yield: 85.3 %

Procedure:
Add a solution of sodium hydroxide (1.80 g, 45.0 mmol) in water (30 mL) to a solution of 7-(5-phenyloxazol-2-yl)heptanoic acid methyl ester (9.0 g, 31.3 mmol) in methanol (30 mL) at room temperature and stir the mixture for 4 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (500 mL). Wash the combined organic layers with water (3×100 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Crystallize the residue from ethyl acetate/hexanes to afford 7-(5-phenyloxazol-2-yl)heptanoic acid (7.3 g, 85%): APCI mass spectrum m/z 272 [C16H19NO3—H]−.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]>C(OCC)C>[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([Cl:3])=[O:18])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CC(=O)N1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into thionyl chloride (300 ml) was added 3-(1-acetyl-4-piperidinyl)propionic acid (88.2 g, 0.443 mol) in small portions under ice cooling. After the resulting mixture was stirred at room temperature for 10 minutes, the thionyl chloride was evaporated under reduced pressure at 25° C. The resulting residue was mixed with diethyl ether and was evaporated under reduced pressure to leave a yellow solid residue. An additional diethyl ether was added to the residue and the solid substance was subjected to pulverization by the use of a spatula, followed by evaporation under reduced pressure to obtain a crude product of 3-(1-acetyl-4-piperidinyl)propionyl chloride as a yellow powder. To a suspension of this yellow powder and 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one (64.0 g, 0.369 mol) in 1,2-dichloroethane (200 ml) was added aluminum chloride (162 g, 1.21 mol) in small portions at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvents, thereby obtaining an oily pale yellow substance. This oily substance was purified by column chromatography on silica gel (eluent: ethyl acetate-methanol=9:1) and crystallization from ethanol and diethyl ether to obtain 123 g of 8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo-[3,2,1-ij]quinolin-4-one, as colorless crystals having the melting point of 157-159° C.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)=O>C(O)C.C1(C)C=CC=CC=1.Cl[Pd]Cl>[CH3:12][C@@H:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=12
Reactant: C[C@@H](NC/C=C/c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl[Pd]Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=CO
Product: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Yield: 66.3 %

Procedure:
A mixture of compound (VI) (3.0 g), PdCl2 (0.01 g) in ethanol (10 mL) was heated up to reflux temperature and added in 5 hrs with formic acid (0.3 g). The mixture was then cooled down, diluted with toluene and washed with 30% w/w aqueous sodium hydroxide until neutrality. The organic layer was dried and concentrated to give Cinacalcet free base, compound (I) (2.0 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].N1CCCCC1.CC(O)=O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:14]2[S:10][C:11](=[O:16])[NH:12][C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Yield: 85 %

Procedure:
A mixture of p-hydroxybenzaldehyde (vi; 0.5 mmol), 2,4-thiazolidinedione, (0.6 mmol), and catalytic amounts of piperidine and AcOH was refluxed in toluene (5 mL) for 24 h. The precipitated product was filtered, washed with toluene (3×10 mL), and dried in vacuo at 60° C. overnight, yielding 5-(4-hydroxybenzylidene)-thiazolidine-2,4-dione (vii) in a 85% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7](O)(=[O:11])[CH:8]([CH3:10])[CH3:9].N1C=CC=C1.C(O)(=O)CCCCCC>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(=O)O
Reactant: Cn1cccc1
Agent: CCCCCCC(=O)O
Solvent: c1cc[nH]c1
Product: CC(C)C(=O)c1cccn1C
Yield: 79.4 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 12, except that 5.27 g (0.065 mole) of 1-methylpyrrole and 4.4 g (0.05 mole) of isobutyric acid were substituent for the pyrrole and heptanoic acid, to obtain 6 g of 1-methyl-2-isobutyrylpyrrole.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:17])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[N:4][C:3]=1[CH3:18].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][CH:28]=[CH:29][N:30]=2)=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1.C([O-])(O)=O.[Na+].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[F:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[C:8]([NH:7][C:5]1[S:6][C:2]([C:21]2[CH:22]=[C:23]([C:26]3[O:27][CH:28]=[CH:29][N:30]=3)[CH:24]=[CH:25][C:20]=2[CH3:19])=[C:3]([CH3:18])[N:4]=1)=[O:17]
Reactant: Cc1ccc(-c2ncco2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: Cc1ccc(-c2ncco2)cc1-c1sc(NC(=O)c2c(F)cccc2F)nc1C
Temperature: 170 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
N-(5-bromo-4-methylthiazol-2-yl)-2,6-difluorobenzamide (60 mg), 2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (70 mg), 2 M NaHCO3 solution (0.5 mL), dichlorobis(benzonitrile)palladium (5 mg) and 1,4-Bis(diphenyl-phosphino)butane (10 mg) were mixed together in 2 mL of toluene in a sealed tube. The resulting suspension was stirred in microwave oven at 170° C. for 1 hour. After the reaction, the mixture was extracted with Et2O. The organic phases were removed under reduced pressure and the residue was chromatographed to give the title compound as a white solid. Yield 27%.
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][C@@H:48]([CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:19]([NH:47][C@@H:48]([CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[CH2:49][C@H:50]([OH:69])[C@@H:51]([NH:59][C:60]([O:62][CH2:63][C:64]1[S:68][CH:67]=[N:66][CH:65]=1)=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[S:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (4.13 g, 13.18 mmole) and hydroxybenztriazole (2.23 g, 16.48 mmoles) were dissolved in 70 mL THF and then dicyclohexyl-carbodiimide(2.71 g, 13.18 mmoles) was added in one portion to the stirred solution under nitrogen atmosphere. This mixture was stirred for 4 h at room temperature and then filtered to remove dicyclohexylurea precipitate. The product of Example 69B (5.1 g, 11.99 mmoles) was dissolved in 100 mL THF under nitrogen atmosphere. To this stirred solution was added the filtrate of HOBT-active ester and the resulting solution was stirred at room temperature for 4 h, and the solvent removed via rotary evaporation. The residue was dissolved in 150 mL ethyl acetate and washed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueous KHSO4 and the solvent was removed by rotary evaporation to afford a residue. The residue was dissolved in 175 mL 1N HCL, and the solution filtered to remove the small quantity of dicyclohexylurea. The filtrate solution was added to 175 mL ethyl acetate and the two phase mixture rapidly mixed. The pH of this rapidly stirred mixture was adjusted to pH=7 by dropwise addition of cold 3N NaOH. The organic layer was isolated, washed with 100 mL brine, dried over Na2SO4, filtered, and the solvent was removed to afford 8.6 g of a colorless foam. This material was crystallized from 42 mL EtOAc and 21 mL hexane to give 7.85 g of the desired product as a white solid. mp=122°-123° C. ClMS m/z 721 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8](=[O:32])[N:9]2[C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[F:28])[C:15]([O:29][CH3:30])=[CH:14][C:13]=2[Cl:31])=[C:5]([O:33][CH3:34])[N:4]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42].Cl>C(Cl)Cl>[C:41]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8](=[O:32])[N:9]2[C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[F:28])[C:15]([O:29][CH3:30])=[CH:14][C:13]=2[Cl:31])=[C:5]([O:33][CH3:34])[N:4]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CN)nc32)cc1OCc1c(F)cccc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CNC(C)=O)nc32)cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a mixture of 2-aminomethyl-9-[2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (94 mg) and pyridine (0.1 mL) in methylene chloride (3 mL) was added acetic anhydride (0.055 mL), and the mixture was stirred at room temperature for 5 days. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate). The obtained product was suspended in diethyl ether, and collected by filtration. The collected material was dried under reduced pressure to give the title compound (44 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1>CS(C)=O.CC(OC)(C)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Reactant: O[C@H]1CCNC1
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@H](O)C2)c(Br)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 100 mg, 0.264 mmol), (S)-pyrrolidin-3-ol (46.1 mg, 0.529 mmol) and TEA (147 μL, 1.058 mmol) in DMSO (200 μL) was stirred at 90° C. for 16 h. The RM was diluted with 30 mL of TBME/EtOAc (1:1), sequentially washed 5 times with 0.5 M HCl and brine then evaporated to dryness under reduced pressure. The crude product was purified by flash column chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 10% to 50% EtOAc-EtOH+0.1% NH4OH (9:1)) to afford the title compound as a white solid. UPLC-MS (condition 1) tR 2.83 min, m/z=444.9 [M+H]+, m/z=443.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.92 (m, 1H) 1.91-2.04 (m, 1H) 3.27 (d, J=10.76 Hz, 1H) 3.34-3.45 (m, 1H) 3.67 (dd, 1H) 3.81 (dd, J=10.39, 4.77 Hz, 1H) 4.30-4.42 (m, 1H) 4.97 (d, J=3.42 Hz, 1H) 6.93 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.81-7.90 (m, 3H) 8.13 (d, J=2.20 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH:9]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of ethyl 3-(3-fluorophenyl)-3-oxopropionate (20 g, 95 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil, 3.80 g, 95 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (22.7 g, 95 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 4 hrs. The reaction solution was poured into water (300 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) and recrystallized from ethyl acetate-hexane to give ethyl 3-(3-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (28.8 g, 82%).