Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.Cl.[NH2:34][CH2:35][C:36]1[C:37]([NH2:43])=[N:38][C:39]([CH3:42])=[N:40][CH:41]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.CN(C=O)C>[NH2:43][C:37]1[C:36]([CH2:35][NH:34][C:3](=[O:4])[CH:2]([OH:1])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]=4[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=3)=[CH:8][CH:7]=2)=[CH:41][N:40]=[C:39]([CH3:42])[N:38]=1
Reactant: Cc1ncc(CN)c(N)n1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ncc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)c(N)n1
Reaction time: 1 h
Yield: 67.2 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 50 mg, 0.116 mmol), 5-(aminomethyl)-2-methylpyrimidin-4-amine-2 HCl (36.7 mg, 0.174 mmol), 4-methylmorpholine (46.9 mg, 0.464 mmol), and HATU (57.3 mg, 0.151 mmol) were added to DMF (2 mL). The mixture was stirred for 1 h. Methanol was added and the mixture was filtered for prep HPLC. It was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.2 min) to provide single enantiomer N-((4-amino-2-methylpyrimidin-5-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (45 mg, 0.078 mmol, 67.6% yield): LCMS=552.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.25 (2 H, m), 7.91 (1 H, s), 7.53-7.75 (7 H, m), 5.21 (1 H, s), 4.20-4.39 (2 H, m), 2.51 (3 H, s); HPLC peak RT=8.3 min (Method A).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C:76](=[O:77])[NH:75][C@@:6]2([O:11][C@@H:10]([CH2:12][C@H:13]([OH:71])[C@H:14]([CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[C@H:23]3[O:51][C:49](=[O:50])[C@H:47]4[NH:48][N:43]([CH2:44][CH2:45][CH2:46]4)[C:41](=[O:42])[C@H:40]([CH2:52][C:53]4[CH:54]=[CH:55][CH:56]=[C:57]([OH:59])[CH:58]=4)[NH:39][C:37](=[O:38])[C@H:36]([CH:60]([CH3:62])[CH3:61])[NH:35][C:33](=[O:34])[C@H:32]([CH2:63][CH2:64][C:65]([CH3:67])=[O:66])[C@H:31]([OH:68])[C@@H:30]([CH3:69])[C@@H:29]([OH:70])[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]3)\[CH3:22])[CH3:15])[C@H:9]([CH3:72])[C@H:8]([OH:73])[C@@H:7]2[CH3:74])[C@@H:5]([CH3:78])[CH2:4]1.[CH3:79]O>>[CH3:1][CH2:2][C@@H:3]1[C:76](=[O:77])[NH:75][C@@:6]2([O:11][C@@H:10]([CH2:12][C@H:13]([OH:71])[C@H:14]([CH2:16][CH2:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](/[C@H:23]3[O:51][C:49](=[O:50])[C@@H:47]4[NH:48][N:43]([CH2:44][CH2:45][CH2:46]4)[C:41](=[O:42])[C@H:40]([CH2:52][C:53]4[CH:54]=[CH:55][CH:56]=[C:57]([OH:59])[CH:58]=4)[NH:39][C:37](=[O:38])[C@H:36]([CH:60]([CH3:61])[CH3:62])[NH:35][C:33](=[O:34])[C@@H:32]4[CH2:63][CH2:64][C@:65]([O:66][CH3:79])([CH3:67])[O:68][C@@H:31]4[C@@H:30]([CH3:69])[C@@H:29]([OH:70])[CH:28]=[CH:27][CH:26]=[CH:25][CH2:24]3)\[CH3:22])[CH3:15])[C@H:9]([CH3:72])[C@H:8]([OH:73])[C@@H:7]2[CH3:74])[C@@H:5]([CH3:78])[CH2:4]1
Reactant: CO
Reactant: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1CC=CC=C[C@H](O)[C@H](C)[C@@H](O)[C@@H](CCC(C)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Agent: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1C/C=C/C=C/[C@H](O)[C@H](C)[C@@H](O)[C@@H](CCC(C)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Agent: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1C/C=C\C=C/[C@H](O)[C@H](C)[C@H]3O[C@](C)(OC)CC[C@H]3C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Product: CC[C@H]1C[C@H](C)[C@@]2(NC1=O)O[C@@H](C[C@H](O)[C@@H](C)CC/C=C/C=C(\C)[C@@H]1CC=CC=C[C@H](O)[C@H](C)[C@H]3O[C@](C)(OC)CC[C@H]3C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cccc(O)c3)C(=O)N3CCC[C@@H](N3)C(=O)O1)[C@H](C)[C@H](O)[C@@H]2C
Reaction time: 1 h

Procedure:
To a stirred, cooled (0° C.) solution of 20 mg (18.3 μmol) of Sanglifehrin A in 0.5 mL of methanol is added one crystal of paratoluenesulfonic acid monohydrate. The resulting yellow solution is stirred for one hour and the reaction is quenched with saturated aqueous sodium bicarbonate solution. The resulting mixture is extracted twice with ethyl acetate. The organic solution is washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (95:5 methyl-tert.-butyl ether:methanol) to yield Sanglifehrin C as a white amorphous powder. The latter consisted of a 4:1 mixture of Sanglifehrin C and its C53 epimer, Sanglifehrin C having the (S) configuration as depicted below (R=Me). ##STR53##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH:12]1[CH2:16][CH2:15][C:14](=O)[CH2:13]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][CH:14]1[CH2:15][CH2:16][CH:12]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH3:11])[CH:6]=2)[CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1cc(C2CCC(=O)C2)c2cc(F)ccc21
Reactant: NCc1ccccc1
Product: Cn1cc(C2CCC(NCc3ccccc3)C2)c2cc(F)ccc21
Yield: 101.6 %

Procedure:
This compound was prepared in the same manner as for Intermediate 6, using 3-(5-fluoro-1-methyl-1H-indol-3-yl)-cyclopentanone (1.25 g, 5.19 mmol) and benzylamine (0.66 g, 6.2 mmol) to afford 1.7 g of the desired product as a mixture of cis and trans isomers. Flash chromatography on silica gel (3% 2 M NH3 in methanol/ethyl acetate) afforded 0.4 g (23%) of the cis isomer (first eluting) and 0.45 g (27%) of the trans isomer.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15](Br)[CH:16]=[CH2:17].O>CN(C=O)C>[CH2:17]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:12]=1)[CH:16]=[CH2:15]
Reactant: Cc1ccccc1-c1ccc(O)cc1
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(-c2ccccc2C)cc1

Procedure:
The phenol from step A (1.72 g, 9.35 mmol), CS2CO3 (3.6 g, 10.5 mmol) and allylbromide (0.9 mL, 10.3 mmol) in DMF (47 nmL) were stirred at room temperature for 48 h. The mixture was poured into water and extracted with EtOAc, washed with water (3×), brine, dried and evaporated to give the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([Cl:9])[NH:4][C:3]1=[O:10].Br[CH2:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Cl:9][C:5]1[N:4]([CH2:12][C:13]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=2[C:15]#[N:16])[C:3](=[O:10])[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: N#Cc1ccc(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(=O)cc(Cl)n(Cc2cc(F)ccc2C#N)c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc'd for C13H9ClFN3O2, 293.68; found 293.68.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].O>C(O)C>[CH2:1]([O:3][C:4](=[O:29])[C:5]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CCCc1ccccc1)(CC(=O)N1CCOCC1)C(=O)OCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCc1ccccc1)(CC(=O)N1CCOCC1)C(=O)O
Temperature: 40 °C

Procedure:
To a solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid diethyl ester (934 mg, 2.3 mmol) in a 2:1 mixture of ethanol and water (12 ml) LiOH.H2O (193.3 mg, 4.61 mmol) was added and heated at 40° C. for 19 hrs. Ethanol was evaporated under reduced pressure, the residual aqueous mixture was acidified to pH 1 and extracted with methylene chloride (2×40 ml). The organic extract was dried with MgSO4 and evaporated under reduced pressure to give 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid monoethyl ester as a thick, yellow oil (831 mg); 1H NMR (CDCl3) 7.4–7.1 (m, 6H), 4.25 (q, J=7.1 Hz, 2H), 3.8–3.4 (m, 8H), 3.20 (d, J=16.4 Hz, 1H), 2.9 (d, J=16.4 Hz, 1H), 2.6 (m, 2H), 2.1–1.8 (m, 4H), 1.25 (t, J=7.1 Hz, 3H). MS: 378 (MH+).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:22]=[CH:23][C:24]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:25]=2[N:26]=1)C.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:35]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:22]=[CH:23][C:24]2[N:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][C:25]=2[N:26]=1)(=[O:39])=[O:37])[CH3:3]
Reactant: CCSc1ccccc1-c1ncc2ncc(C(F)(F)F)cc2n1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1ccccc1-c1ncc2ncc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
60 mg of 3-chloroperbenzoic acid (purity of 65% or more) was added to a mixture of 40 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidine and 3 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 44 mg of 2-(2-ethylsulfonylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidine (Compound of Present Invention 19).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.F[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[C:25](=O)([O-])[O-:26].[K+].[K+]>CN(C=O)C>[CH3:25][O:26][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(F)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), 3-fluorophenol (63 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1.5 mL), and stirred for 20 minutes at 180° C. in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to provide 77 (52 mg, 91% yield) as a tan solid. LC-MS (M+H=307, obsd.=307). 1H NMR (400 MHz, d6-DMSO): δ 12.00 (s, 1H), 8.77 (dd, 1H), 8.51 (dd, 1H), 8.36 (d, 1H), 8.21 (d, 1H), 7.50 (t, 1H), 7.30 (m, 2H), 7.09 (m, 2H), 7.02 (dd, 1H).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][C:6](=[CH2:11])[CH2:7][C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[N+](=[CH2:14])=[N-].C(O)(=O)C>C(OCC)C>[CH3:1][Si:2]([CH2:5][C:6](=[CH2:11])[CH2:7][C:8]([O:10][CH3:14])=[O:9])([CH3:4])[CH3:3]
Reactant: C=C(CC(=O)O)C[Si](C)(C)C
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: C=C(CC(=O)OC)C[Si](C)(C)C

Procedure:
To a solution of 3-(trimethylsilylmethyl)but-3-enoic acid (36.5 g) in diethyl ether (200 ml) at 10°-15° C. was added a solution of diazomethane in diethyl ether (ca 0.6 M solution, 400 ml). The excess of diazomethane was decomposed by addition of acetic acid. The resultant solution was concentrated in vacuo to 200 ml and the concentrate was washed with an aqueous sodium bicarbonate and brine. Drying over magnesium sulfate and evaporation of the solvent left a yellow oil, which was distilled in vacuo to give methyl 3-(trimethylsilylmethyl)but-3-enoate (34.74 g) as a colorless oil, bp 74°-75° C. (10 Torr).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=2)[CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:22])=[C:11]2[CH3:23])[CH2:5][CH2:4]1)#[N:2].[CH:27]1([C:30]2[CH:31]=[C:32]([C@@H:36]([NH2:38])[CH3:37])[CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28]1>>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=2)[CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([NH:38][C@H:36]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([CH:27]5[CH2:29][CH2:28]5)[CH:31]=4)[CH3:37])=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:22])=[C:11]2[CH3:23])[CH2:5][CH2:4]1)#[N:2]
Reactant: C[C@H](N)c1cccc(C2CC2)c1
Reactant: Cc1c(C)n(Cc2cccc(C3(C#N)CC3)c2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2cccc(C3(C#N)CC3)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C4CC4)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 5, Example 35, using 1-(3-(1-cyanocyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and (S)-1-(3-cyclopropylphenyl)ethanamine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1>>[BrH:7].[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[CH2:8][N:6]1[CH:5]=[CH:4][S:3][C:2]1=[NH:1]
Reactant: Nc1nccs1
Reactant: BrCC1CCCCO1
Product: Br
Product: N=c1sccn1CC1CCCCO1

Procedure:
A mixture of 2-aminothiazole and 2-(bromomethyl)tetrahydro-2H-pyran were processed using the method described in Example 12A to afford the title compound. MS (DCI/NH3) m/z 199 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:22][C:21]3[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[N:17]([CH3:26])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)=[O:28].N1C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH:27]=[O:28])[C:21]3[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[N:17]([CH3:26])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 17.6 %

Procedure:
4-(1,3-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylic acid tert-butyl ester (226 mg), 2-formylphenyl boronic acid (200 mg), and copper (II) acetate (200 mg) were suspended in anhydrous tetrahydrofuran (5 ml), and pyridine (0.2 ml) was added thereto. The reaction mixture was stirred at room temperature for 5 days, filtered through a short column filled with silica gel, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 51 mg of the title compound from a fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[SH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[S:11][CH2:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2
Reactant: CCOC(=O)CCS
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Br)ccc2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (0.49 g, 2.62 mmol) and ethyl 3-mercaptopropionate (0.37 ml, 2.88 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (0.90 g, 6.55 mmol), and the mixture was stirred at room temperature for 1 hour and then at 70° C. for 15 hours. The mixture was poured into ice-water, and made pH 4 with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography [hexane:ethyl acetate (5:1)] to give ethyl 6-bromo-2H-thiochromene-3-carboxylate (0.45 g, 58%) as yellow powder, a part of which was recrystallized from ethanol to give pale yellow needles.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]3SC=N[C:24]=3[CH:28]=2)[CH2:11][CH2:10]1.[Na+].[I-].ClC1C(Cl)=CC=CC=1C1C[CH2:43][NH:42][CH2:41][CH2:40]1.C([O-])([O-])=[O:46].[K+].[K+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:28]=[C:24]3[C:23]([CH2:40][CH2:41][NH:42][C:43]3=[O:46])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: Clc1cccc(C2CCN(CCCCOc3ccc4scnc4c3)CC2)c1Cl
Reactant: O=C([O-])[O-]
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=C1NCCc2ccc(OCCCCN3CCC(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A mixture of intermediate 21 (103 mg, 0.35 mmol) and NaI (105 mg, 0.7 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 47 (142 mg, 0.53 mmol) and anhydrous K2CO3 (194 mg, 1.4 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH 30:1) to give 7-(4-(4-(2,3-dichlorophenyl)piperidin-1-yl)butoxy)-3,4-dihydroisoquinolin-1(2H)-one (compound 33) (108 mg, 69%). 1H NMR (300 MHz, CDCl3): δ 7.58 (d, J=2.1 Hz, 1H), 7.23-7.11 (m, 5H), 7.02-6.99 (m, 1H), 6.05 (s, 1H), 4.05 (t, J=6.0 Hz, 2H), 3.56-3.53 (m, 2H), 3.15-3.06 (m, 3H), 2.93 (t, J=6.6 Hz, 2H), 2.51 (m, 2H), 2.18 (m, 2H), 1.82 (m, 8H). HPLC: 99%, RT 2.746 min. MS (ESI) ink 447.2 [M+H]+. mp: 113-114° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:22][O:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[C:30]([NH2:33])[CH:31]=2)[NH:26][N:25]=1.[CH2:34]([N:36]([C:42]1[C:43]([F:52])=[C:44]([C:48]([F:51])=[CH:49][CH:50]=1)[C:45](O)=[O:46])[S:37](=[O:41])(=[O:40])[NH:38][CH3:39])[CH3:35]>CN(C=O)C.CCOC(C)=O.C(Cl)Cl>[CH2:34]([N:36]([C:42]1[C:43]([F:52])=[C:44]([C:48]([F:51])=[CH:49][CH:50]=1)[C:45]([NH:33][C:30]1[CH:31]=[C:32]2[C:24]([O:23][CH3:22])=[N:25][NH:26][C:27]2=[N:28][CH:29]=1)=[O:46])[S:37](=[O:40])(=[O:41])[NH:38][CH3:39])[CH3:35]
Reactant: COc1n[nH]c2ncc(N)cc12
Reactant: CCN(c1ccc(F)c(C(=O)O)c1F)S(=O)(=O)NC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(c1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1F)S(=O)(=O)NC
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
HOBt (0.017 g, 0.13 mmol), EDCI (0.054 g, 0.28 mmol), and 3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine (0.046 g, 0.28 mmol) was added to 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluorobenzoic acid (0.075 g, 0.25 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (6 mL) and washed with brine (3×5 mL). The organic layers were dried over sodium sulfate, decanted, and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 5% MeOH:DCM to afford 3-(N-ethyl-N-methylsulfamoylamino)-2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.055 g, 0.12 mmol, 49% yield). 1H NMR (400 MHz, CD3OD) δ 8.60-8.63 (m, 1H), 8.50-8.52 (m, 1H), 7.63-7.70 (m, 1H), 7.09-7.15 (m, 1H), 4.09 (s, 3H), 3.18-3.25 (m, 2H), 2.83 (s, 3H), 1.09-1.14 (m, 3H); m/z (APCI-neg) M−1=439.0.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[C:6]([O:15][CH3:16])=[CH:5][C:4]=1[NH:17][C:18](SCC=C)=[NH:19].[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=1)[C:30](O)=O.CN1CCOCC1.C(N(CC)C(C)C)(C)C.[NH2:60][NH2:61]>>[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([C:30]1[NH:61][N:60]=[C:18]([NH:17][C:4]2[CH:5]=[C:6]([O:15][CH3:16])[C:7]([N:9]3[CH:13]=[N:12][C:11]([CH3:14])=[N:10]3)=[CH:8][C:3]=2[F:2])[N:19]=1)[C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:35][CH:34]=1
Reactant: C=CCSC(=N)Nc1cc(OC)c(-n2cnc(C)n2)cc1F
Reactant: NN
Reactant: O=C(O)C(CCCCCl)c1ccc(OC(F)(F)F)cc1
Agent: Br
Solvent: CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)(F)F)cc3)n2)c(F)cc1-n1cnc(C)n1
Yield: 29.1 %

Procedure:
Allyl 2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydrobromide (1.42 g, 3.54 mmol, from preparation U) and 6-chloro-2-(4-(trifluoromethoxy)phenyl)hexanoic acid (1.375 g, 4.43 mmol, from preparation AY) were coupled [N-methylmorpholine (2.00 mL, 17.7 mmol) was substituted for N,N-diisopropylethylamine] and then reacted with hydrazine (0.556 mL, 17.7 mmol) using a procedure analogous to Step A of Example 13. After purification by silica gel column chromatography, 5-(5-chloro-1-(4-(trifluoromethoxy)phenyl)pentyl)-N-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (570 mg, 1.03 mmol, 29% yield) as a foamy solid. LC-MS (M+H)+ 554.3.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](O)[C:3]=1[CH3:9].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH3:9]
Reactant: Cc1c(O)ncnc1Cl
Reactant: Nc1ccccc1
Product: Cc1c(Cl)ncnc1Nc1ccccc1

Procedure:
Synthesized according to the method of reagent preparation 49 using 6-chloro-5-methylpyrimidin-4-ol and aniline in step 1.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([OH:14])[CH:13]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH3:19]O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([OH:14])[CH:13]=1)[C:8]([O:10][CH3:19])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)cc(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)cc(C(C)(C)C)c1

Procedure:
3-tert-Butyl-5-hydroxybenzoic acid (O7.043; 1.93 g) was dissolved in methanol (20 ml), and thionyl chloride (0.937 ml) was slowly added dropwise while stirring. After stirring at 65° C. for 1 h, the mixture was dried, the residue was taken up in DCM, and the solution was washed with saturated sodium hydrogencarbonate solution, dried over MgSO4, filtered and concentrated by rotary evaporation. 2.19 g of the title compound were obtained.