Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH2:18]O)([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.N1C(C)=CC(C)=CC=1C.[F:42]C(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH2:18][F:42])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CO)C3)n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CF)C3)n1
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (227) (62 mg, 0.140 mmol) and 2,4,6-collidine (0.0359 mL, 0.271 mmol) in dry CH2Cl2 was added trifluoromethanesulfonic acid anhydride (0.0365 mL, 0.217 mmol) at 0° C. The mixture was stirred at 0° C. to room temperature for 1 hr. TLC indicated that the reaction was complete. The reaction was quenched with 0.5 N aqueous HCl, extracted with 3×CHCl3, dried over Na2SO4, and concentrated. The residue was dissolved in anhydrous CH2Cl2(3 mL), and TBAF (1 mL, 1 M in THF) was added. The resulting mixture was stirred at room temperature for 1.5 hr, quenched with H2O, and extracted with 3×CHCl3. The combined organic layer was dried over Na2SO4, concentrated, and purified by column chromatography eluting with 50-65% EtOAc in hexanes to give a white solid (18 mg, 28% yield). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1 H) 7.84-7.96 (m, 2 H) 7.25-7.31 (m, 2 H) 7.02-7.15 (m, 3 H) 6.72-6.83 (m, 1 H) 4.26-4.54 (m, 2 H) 3.79 (s, 3H) 3.20 (d, J=16.67 Hz, 1H) 3.08 (s, 3 H) 2.89 (dd, J=16.67, 1.77 Hz, 1 H) 1.52 (s, 3 H); LCMS for C22H22FN3O5S m/z 460.00 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([CH2:35][O:36]C(=O)C)=[O:34]>>[OH:36][CH2:35][C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(CO)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[CH2:21][NH:20][CH2:19]5)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([OH:28])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:29]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[CH2:21][N:20]([CH3:29])[CH2:19]5)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([OH:28])=[O:27])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=O
Reactant: COc1c(-c2ccc3c(c2)CNC3)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: O=CO
Product: COc1c(-c2ccc3c(c2)CN(C)C3)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 73.3 %

Procedure:
To 100 mg of 1-cyclopropyl-7-(isoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were added 1 ml of formic acid and 65 mg of formalin, and the resulting mixture was heated under reflux for 1 hour, after which the solvent was distilled under reduced pressure to remove the solvent. To the resulting residue was added 5 ml of water, and the resulting mixture was adjusted to pH 7 with a saturated aqueous sodium hydrogencarbonate solution and extracted with five 5-ml portions of chloroform. The chloroform layer obtained was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent. To the resulting residue were added ethanol and diethyl ether, and the crystals were collected by filtration. To the crystals collected were added 1 ml of ethanol, 1 ml of a 1N aqueous sodium hydroxide solution and 1 ml of water to dissolve the crystals, after which carbon dioxide was bubbled into the resulting solution and the crystals were collected by filtration to obtain 76 mg of light-yellow 1-cyclopropyl-8-methoxy-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[C@H:21]1([NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC1CCc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 20 h
Yield: 59.7 %

Procedure:
For 20 hours, 1.83 g 6-chloropurine riboside, 0.95 g (R) (-)-1-aminoindane and 0.862 g triethylamine are refluxed in 50 ml absolute ethanol under nitrogen atmosphere. The solvent is evaporated to dryness and residue is treated with 50 ml cold water. The solid material is filtered, dissolved in excess ethanol, and volatiles are evaporated under reduced pressure to remove water. Residue upon treatment with ethanol affords solid material. It is filtered and dried. One more crop of the same material is obtained from the mother liquor yielding 1.46 g (60% of theory) of N(6) [1-(R)-indanyl]adenosine having a melting point of 185°-187° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39]>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:36][C@H:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:38][OH:39])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Reactant: N[C@@H](CO)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Intermediate 17 (0.25 g, 0.86 mmol), EDC (0.23 g, 1.2 mmol) and HOBT (0.139 g, 1.03 mmol) were suspended in DMF (5 ml) and the suspension was stirred at room temperature. After 25 min, (2R)-2-Amino-2-phenylethanol (0.13 g, 0.95 mmol, commercially available from Aldrich) was added, and the mixture was stirred at room temperature for 20 hours. Solvents were removed in vacuo and the residue was dissolved in DCM (50 ml) and washed successively with water (25 ml) and 5% sodium hydrogen carbonate solution (25 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml) and applied to a SPE cartridge (silica, 10 g), which was eluted with a gradient of ethyl acetate—petroleum ether (1:2, 1:1 and 1:0). Fractions containing the desired material were combined and concentrated in vacuo to afford Intermediate 42 as a white foam (0.318 g). LCMS showed MH+=410; TRET=2.55 min.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].O/[N:7]=[C:8](\[NH2:15])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]1[O:4][N:15]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:7]=1
Reactant: O=C(Cl)CCl
Reactant: N/C(=N\O)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1nc(-c2ccccn2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-chloroacetyl chloride (0.209 mL) in dichloromethane (3 mL) was added dropwise to a solution of (Z)—N′-hydroxypicolinamidine (0.300 g) in dichloromethane (7 mL). Triethylamine (0.366 mL) was added dropwise to the reaction solution and stirring at room temperature continued for 18 hours. The mixture was purified by column chromatography on silica gel (10-50% ethyl acetate in hexane). Desired fractions were evaporated in vacuo to a pale pink residue (0.21 g). This material was taken in toluene and refluxed for 18 hours. The solvent was evaporated in vacuo and the residue purified by column chromatography on silica gel (1-3% methanol in dichloromethane) to provide the title compound (0.085 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:22]1([CH2:28][CH2:29][CH2:30]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][CH2:30][O:20][C:19](=[O:21])[CH2:18][NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCCCc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCCCc1ccccc1

Procedure:
Following General Procedure X and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (from Example 73 below) using General Procedure O) and and 3-phenyl-1-propanol (Aldrich), the tide compound was prepared as a solid (mp=137° C.). The reaction was monitored by tdc (Rf=0.15 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 50% EtOAc/hexanes as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([OH:28])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1.N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([O:28][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@@H](O)CCc1cc(Br)c(C)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A dichloromethane (6 mL) solution of 6 (497 mg, 1.03 mmol) was treated with 2,6-lutidine (143 μL, 1.22 mmol) and TBSOTf (0.26 mL, 1.13 mmol). After 1.5 h, 50 mL saturated NaHCO3 was added and the resulting mixture was extracted with 25 mL CH2Cl2. The CH2Cl2 layer was washed with 50 mL 1 M HCl and 50 mL brine. The CH2Cl2 solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (8% ethyl acetate/hexanes→10%) gave 7 (553 mg, 0.93 mmol, 90%).
Reaction SMILES: [F:1][CH:2]([F:44])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36]O)[CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:5]=2[N:4]=1.CS(Cl)(=O)=O.[N:50]1([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21]([N:20]([C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:5]=4[N:4]=[C:3]3[CH:2]([F:44])[F:1])[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=2)[CH2:34][CH2:35][CH2:36][N:53]2[CH2:52][CH2:51][N:50]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:55][CH2:54]2)[CH2:26][CH2:25]1)=[O:28])([CH3:32])([CH3:31])[CH3:33]
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCO)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CS(=O)(=O)Cl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCN(C(=O)OC(C)(C)C)CC2)C2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
Sequential reaction of tert-butyl 4-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylate with methanesulfonyl chloride and tert-butyl 1-piperazinecarboxylate gave tert-butyl 4-(3-{[1-(tert-butoxycarbonyl)-4-piperidinyl][4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}propyl)-1-piperazinecarboxylate, as an oil; 1H NMR (DMSO-d6) (rotamers) δ 7.94 and 7.90 (2d, J=8.4, 8.3 Hz, 1H), 7.72 and 7.70 (2t, JHF=53.1 53.0 Hz, 1H), 7.42 and 7.38 (2t, J=8.2 Hz, 1H) 6.95 (d, J=8.1 Hz, 1H), 4.75-4.64 and 4.58-4.50 (2m, 1H), 4.14-4.05 (m, 2H), 3.98 and 3.96 (2s, 3H), 3.80-3.77 (m, 4H), 3.69 (br m, 4H), 3.55-3.45 (m, 2H), 2.55-2.50 (m, 4), 2.37-2.28 (m, 9H), 1.67 (br, 5H), 1.42 (s, 9H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:51][S:52][CH3:53].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH2:51][S:52][CH3:53])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC
Reactant: 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
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CSCO[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of the compound of Example 1 (5.0 g, 6.9 mmol) and methyl sulfide (4.1 mL) in acetonitrile (35 mL) at 0° C. was added benzoyl peroxide (6.7 g) in four portions over 20 minutes, and the mixture was stirred at 0° C. for 1 hour and then at room temperature for 1 hour. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient of 33-100% ethyl acetate in chloroform to give the title compound (4.56 g, 84% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]2[NH:9][NH:10][C:11](=O)[C:6]2=[CH:5][N:4]=1.P(Br)(Br)([Br:15])=O.O.[OH-].[NH4+]>CC#N>[Br:15][C:11]1[C:6]2[C:7](=[N:8][C:3]([S:2][CH3:1])=[N:4][CH:5]=2)[NH:9][N:10]=1
Reactant: CSc1ncc2c(=O)[nH][nH]c2n1
Reactant: O=P(Br)(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CSc1ncc2c(Br)n[nH]c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a suspension of 6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one (0.50 g, 2.7 mmol) in CH3CN (15 mL) was added a CH3CN solution of P(O)Br3 (1.57 g, 5.5 mmol) in a pressure vessel. The mixture was sonicated for 30 min before being heated to 100° C. for 16 h (overnight). After it was cooled to 0° C., H2O and aqueous ammonium hydroxide were added to basify the mixture. The mixture was stirred at 0° C. for 1 h. The aqueous layer was extracted with EtOAc (10×). The combined EtOAc layer was dried (Na2SO4), and concentrated to give 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.51 g, 77%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1H), 5.57 (s, 3H); MS m/z 245.00 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=[O:12])[C:6]=12)=O)(=O)C.[F:19][C:20]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][C:21]=1[OH:27].CS(O)(=O)=O>O>[NH2:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:7]2[C:6]=1[C:11](=[O:12])[O:10][C:8]12[C:25]2[CH:26]=[C:20]([F:19])[C:21]([OH:27])=[CH:22][C:23]=2[O:24][C:23]2[C:25]1=[CH:26][C:20]([F:19])=[C:21]([OH:27])[CH:22]=2
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)OC2=O
Reactant: Oc1ccc(F)c(O)c1
Agent: CS(=O)(=O)O
Solvent: O
Product: Nc1c([N+](=O)[O-])ccc2c1C(=O)OC21c2cc(F)c(O)cc2Oc2cc(O)c(F)cc21
Temperature: 80 °C
Reaction time: 60 h
Yield: 60.7 %

Procedure:
3-Acetamido-4-nitrophthalic anhydride (1.3 g, 5.0 mmol) and 4fluororesorcinol (1.3 g, 10 mmol) were added to methanesulfonic acid (10 ml), and the mixture was stirred at 80° C. under an argon atmosphere for 60 hours. The reaction mixture was added with water (120 ml) and refluxed for 2 hours. The reaction mixture was adjusted to pH 2, and precipitates were collected by filtration. The obtained product was dried and purified by silica gel chromatography (3% methanol/97% dichloromethane, v/v) to obtain the title compound (1.3 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnc(Cl)nc1-c1ccncc1
Temperature: 90 °C
Yield: 49.3 %

Procedure:
A mixture of 2,4-dichloro-5-methoxy-pyrimidine (3.0 g, 1.0 eq.), 4-pyridinylboronic acid (2.26 g, 1.1 eq.), Pd(PPh3)2Cl2 (0.58 g, 0.05 eq.), K3PO4—H2O (10.67 g, 3.0 eq.), H2O (3 ml) and 1,4-Dioxane (20.0 ml) was heated at 90° C. and refluxed overnight. The solvent was removed in vacuo, and the residue was extracted with EA and water. The combined organic layers was wash with brine, dried and evaporated in vacuo. The crude was purified by chromatography to give a yellow thick liquid (1.83 g, 49.26%).
Reaction SMILES: [C:1]1([C@@H:7]([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@@H](C)C(O)=O)C=CC=CC=1.[C:23]([N:26]1[N:30]=[C:29]([NH2:31])[S:28][C:27]1([CH2:38][CH2:39][NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:25])[CH3:24].N1C=CC=CC=1>S(Cl)(Cl)=O>[C:23]([N:26]1[C:27]([CH2:38][CH2:39][NH:40][S:41]([CH3:44])(=[O:42])=[O:43])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[S:28][C:29]([NH:31][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])=[N:30]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1N=C(N)SC1(CCNS(C)(=O)=O)c1ccccc1
Reactant: C[C@@H](C(=O)Cl)c1ccccc1
Agent: C[C@@H](C(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N1N=C(NC(=O)C(C)c2ccccc2)SC1(CCNS(C)(=O)=O)c1ccccc1
Yield: 12 %

Procedure:
Next, (R)-(−)-2-phenylpropionyl chloride prepared from (R)-(−)-2-phenylpropionic acid (4.65 g, 3.10 mmol) and thionyl chloride (30 mL), and N-[2-(3-acetyl-5-amino-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)ethyl]methane-sulfonamide obtained above were treated in pyridine (5.0 mL, 61.8 mmol) in the same manner as that in Step 1 of Example 20, and the resultant was purified by silica gel column chromatography (chloroform/n-hexane/ethyl acetate/methanol=20/3/2/1) to give one diastereomer of N-[4-acetyl-5-(2-methanesulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2-phenylpropanamide (0.75 g, 12%) as a fraction eluted first, and another diastereomer of N-[4-acetyl-5-(2-methane-sulfonylaminoethyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2-phenylpropanamide (0.82 g, 13%) as a fraction eluted later.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[NH2:25][C:24]1[CH:23]=[C:22]([CH:28]=[CH:27][CH:26]=1)[O:21][C:12]1[C:11]2[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1O
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A mixture of 3-(6-(benzyloxy)-7-methoxyquinazolin-4-yloxy)aniline (3.64 g, 0.00974 mol) and Pd/C (10%) in ethanol/THF (400 mL, 3/1) was hydrogenated at 1 atm. of H2, at 50-55° C. for 3 h. The mixture was filtered through Celite and the filtrate was concentrated to about 100 mL. The crude was left in the fridge overnight. The solid was filtered and washed with small portion of cold ethanol to afford 4-(3-aminophenoxy)-7-methoxyquinazolin-6-ol (2.05 g, 74.3% yield). 1HNMR (DMSO-d6): δ 10.30 (1H, s), 8.49 (1H, s), 7.46 (1H, s), 7.34 (1H, s), 7.07 (1H, m), 6.48 (1H, m), 6.40 (2H, m), 5.29 (2H, s), 3.90 (3H, s). LC-MS (ESI) m/z 284 (M+H)+.
Reaction SMILES: [C:1]1([P:9]([C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=2)([C:11]2[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=2[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[P:21]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=2)([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=2)=O)=[O:14])=O)[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.C(N(CC)CC)C.Cl[SiH](Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:31]1([P:21]([C:23]2[CH:24]=[C:25]([CH3:30])[CH:26]=[C:27]([CH3:29])[CH:28]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([C:12]2[CH:39]=[CH:40][CH:41]=[CH:42][C:11]=2[P:9]([C:1]2[CH:2]=[C:3]([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=2)[C:43]2[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([CH3:50])[CH:44]=2)=[O:14])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[CH:32]=1
Reactant: Cc1cc(C)cc(P(=O)(c2cc(C)cc(C)c2)c2ccccc2C(=O)c2ccccc2P(=O)(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2ccccc2C(=O)c2ccccc2P(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Yield: 20 %

Procedure:
Into 10 ml of toluene was dissolved 252 mg (0.36 mmol) of 2,2′-bis{di-(3,5-xylyl)phosphinyl}benzophenone, and further 2.0 ml (14.4 mmol) of triethylamine was added thereto, and the resultant solution was cooled to 0° C. Thereto was added 360 μl (3.6 mmol) of trichlorosilane, and then the resultant solution was stirred for 30 minutes while the temperature thereof was kept at 0° C. Thereafter, the temperature thereof was slowly raised to a temperature at which the solution was allowed to be refluxed. The solution was then refluxed for 4 hours. The reaction mixture was cooled, and thereto was dropwise added 10 ml of 25% aqueous sodium hydroxide slowly. The aqueous phase was extracted with 10 ml of methylene chloride. The organic phases were combined, washed with 1N hydrochloric acid two times and then dried over magnesium sulfate. The resultant was concentrated under reduced pressure to distill off the solvent, and then purified by column chromatography on silica gel (ethyl acetate:hexane=1:6) to give 47.7 mg (yield: 20%) of the title compound in the form of a yellow solid.