Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=O)[O:18][CH:17]3[CH3:22])[N:4]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:32]2)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[S:32])[O:18][CH:17]3[CH3:22])[N:4]=1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3C)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: COc1cc(OC)nc(Oc2cccc3c2C(=S)OC3C)n1

Procedure:
A mixture of 6.35 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-methyl-phthalide (see Example 1) and 8.92 g of 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithia-diphosphetan (Lawesson reagent) is maintained at reflux temperature for approximately 16 hours in 40 ml of xylene. The reaction material is then filtered over silica gel (eluant: 30% diethyl ether/n-hexane) and recrystallised from ethyl acetate/n-hexane to yield 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-methyl-isobenzofuran-1(3H)-thione in the form of yellow crystals, m.p. 163°-164° C.; IR spectrum (CHCl3): 1602, 1570, 1358, 1304, 1195 cm-1 ; 1H-NMR (CDCl3): 5.80 ppm (q, 1H), 1.71 ppm (d, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:35])(=[O:34])[N:22]([CH:30]3[CH2:33][CH2:32][CH2:31]3)[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:30]1([N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[S:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:16][CH:17]=2)(=[O:35])=[O:34])[CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(S(=O)(=O)N(c3cccc(F)c3)C3CCC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(OC2CCNCC2)cc1)N(c1cccc(F)c1)C1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
To a solution of 4-{4-[cyclobutyl-(3-fluoro-phenyl)-sulfamoyl]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (330 mg, 655 μmol) in DCM (9 mL) was added TFA (1 mL) and then the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and then purified by SCX eluting with 2 M NH3 in MeOH to give N-cyclobutyl-N-(3-fluoro-phenyl)-4-(piperidin-4-yloxy)-benzenesulfonamide (195 mg, 483 μmol). To a solution of N-cyclobutyl-N-(3-fluoro-phenyl)-4-(piperidin-4-yloxy)-benzenesulfonamide in DCM (10 mL) was added DIPEA (168 μL, 965 μmol) and methanesulfonyl chloride (41 μL, 531 μmol) and the reaction was stirred at room temperature for 30 minutes. Water was added and then extracted with DCM, filtered through a phase separator and concentrated. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) followed by preparative reverse a phase HPLC gave the title compound (169 mg). 1H NMR δ (DMSO): 7.46 (2H, d, J=8.8 Hz), 7.38-7.39 (1H, m), 7.16-7.17 (3H, m), 6.77-6.78 (2H, m), 4.69-4.71 (1H, m), 4.20-4.22 (1H, m), 3.33-3.38 (4H, m), 3.13 (2H, ddd, J=12.1, 8.09, 3.4 Hz), 2.91 (3H, s), 2.03-2.06 (4H, m), 1.77-1.81 (4H, m), 1.53-1.56 (2H, m). LCMS (m/z, Method B) ES+ 482.9 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([N:18]3[CH2:27][C:26]4[CH:25]=[N:24][C:23]5[N:28](CC6C=CC(OC)=CC=6)[N:29]=[CH:30][C:22]=5[C:21]=4[CH2:20][CH2:19]3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[N:2]1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([N:18]3[CH2:27][C:26]4[CH:25]=[N:24][C:23]5[NH:28][N:29]=[CH:30][C:22]=5[C:21]=4[CH2:20][CH2:19]3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[N:2]1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)Nc3ccon3)c2)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccon1)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
Step 2 To the crude N-(3-(isoxazol-3-ylcarbamoyl)phenyl)-3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide obtained above was added trifluoroacetic acid (1 mL). The reaction mixture was shaken at 65° C. for 16 hours. On completion of the reaction, toluene (1 mL) was added and solvent removed under reduced pressure. The crude product was purified reverse phase HPLC to give the desired product, N-(3-(isoxazol-3-ylcarbamoyl)phenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide. LCMS [M+H]: 404.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].C1CCC(N=C=NC2CCCCC2)CC1.[C:42]([O:46][C:47]([NH:49][CH2:50][C:51]([NH:53][CH2:54][CH2:55][C:56](O)=[O:57])=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]>CN(C1C=CN=CC=1)C.ClCCl>[C:42]([O:46][C:47]([NH:49][CH2:50][C:51]([NH:53][CH2:54][CH2:55][C:56]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[C:13]3[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=3[CH2:7][CH2:6][C@H:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=2[CH:16]=1)=[O:57])=[O:52])=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: CC(C)(C)OC(=O)NCC(=O)NCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)CNC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Reaction time: 5 h
Yield: 61 %

Procedure:
A mixture of N-acetyl-colchicinol (0.357 g; 1 mmol), DCCI (0.248 g; 1.2 mmol), DMAP (0.025 g; 0.2 mmol) and (7) (0.246 g; 1 mmol) in dichloromethane (7 ml) was stirred under argon atmosphere for 5 hours. After removal of the insoluble material by filtration the residue was purified by flash chromatography eluting with dichloromethane/ethanol (92/8) to give (4) as a foam.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][P:16](Cl)(Cl)=[O:17]>>[CH3:15][P:16]1(=[O:17])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CP(=O)(Cl)Cl
Reactant: c1ccc(CNc2ccccc2)cc1
Product: CP1(=O)c2ccccc2CN1c1ccccc1
Yield: 1.75 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and methyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation yielded without additional purification 1-methyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.4 g, 1.75% yield) as a brown glass.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12]([CH:19]4[CH2:21][CH2:20]4)(O)[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[CH:12]([CH:19]4[CH2:20][CH2:21]4)[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(C1CC1)CC3
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C1CC1)CC3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from step (a) was dissolved in DCM (20 ml) and cooled to 0° C. To the stirred solution triethylsilane (943 μL, 5.85 mmol) was added, followed by borontrifluoride etherate (456 μL, 3.66 mmol). After 1 hour, additional borontrifluoride etherate (456 μL, 3.66 mmol) was added and the reaction mixture was stirred for an additional hour at 0° C. The reaction was quenched with saturated aqueous NaHCO3 (50 ml) and the aqueous layer was extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo. The residue was purified by silica gel chromatography (gradient elution: 0 to 20% EtOAc in hexane) to give the sub-title compound as a colorless oil (103 mg). 1H NMR (CDCl3) δ 7.01-6.93 (m, 2H); 4.16 (q, J=7.2 Hz, 2H); 3.75-3.68 (m, 2H); 3.52-3.43 (m, 2H); 3.11-2.99 (m, 4H); 2.80-2.72 (m, 2H); 2.25-2.14 (m, 1H); 2.06-1.99 (m, 1H); 1.29 (t, J=6.9 Hz, 3H); 0.88-0.77 (m, 1H); 0.55-0.41 (m, 2H); 0.34-0.26 (m, 1H); 0.20-0.13 (m, 1H); MS: ESI (positive): 300, (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]([NH:31][C:32](=[O:44])[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH3:45][O-:46].[Na+]>CO>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([NH:31][C@@:9]([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][O:46][CH3:45])=[CH:8][CH:7]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:44])=[CH:34][C:35]=1[C:40]([F:43])([F:41])[F:42]
Reactant: O=C(N[C@](Cc1ccccc1)(c1ccc(CBr)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1
Reaction time: 0.67 h
Yield: 67 %

Procedure:
(R)—N-(1-(4-(bromomethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (prepared as described in Procedure 3, 4, 5, 6, 7, 56, 57, 100 and 32, 24 mg, 0.035 mmol) was dissolved in 0.5 mL of methanol. To this solution was added sodium methoxide (25% by wt, 0.5 mL) and the reaction mixture was stirred for 40 min. The reaction was quenched with 1.0 M HCl and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The resulting oil was purified by flash chromatography (4 g silica gel column, 0-100% EtOAc/hexane gradient over 11 min., flow rate 18 mL/min) to provide (R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-(methoxymethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 321) as a white solid (15 mg, 67% yield). LC/MS: RT=1.62 min [M+H] 642 (Chromolith Performance 18e 4.6×100 mm column, 50-90% acetonitrile, water with 0.1% trifluoroacetic acid gradient over 2 min, 5 mL/min); 1H NMR (400 MHz, CDCl3) ppm 7.91 (1H, d, J=7.15 Hz), 7.77-7.87 (1H, m), 7.08-7.44 (7H, m), 6.97-7.05 (2H, m), 6.92 (1H, d, J=8.79 Hz), 6.66-6.75 (3H, m), 5.87 (1H, tt, JHH=2.75 Hz, JHF=53 Hz), 4.47 (2H, s), 4.09 (1H, d, J=13.2 Hz), 3.81 (1H, d, J=13.2 Hz), 3.42 (3H, s).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1.C[N:17](C=O)C>>[F:15][C:4]([F:3])([F:14])[C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[NH2:17])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Nn1ccc2ccc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A suspension of NaH (6.5 g, 162 mmol, 60% in mineral oil) in DMF (54 mL) at 0° C. is treated with 6-trifluoromethylindole (2.0 g, 10.8 mmol) and stirred at 0° C. for 0.5 h. The mixture is treated with HOSA (6.1 g, 54 mmol) portion wise and warmed to rt over 2 h. The mixture is then poured over ice and filtered through a pad of Celite. The filtrate is extracted with Et2O (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-30% EtOAc in heptane to afford 6-trifluoromethyl-indol-1-ylamine (1.79 g, 83%). MS: 201 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.74 (s, 1H), 7.67 (d, 1H), 7.35 (d, 1H), 7.30 (m, 1H), 6.45 (d, 1H), 4.83 (s, NH2, 2H).
Reaction SMILES: Cl[C:2]([CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3].[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[N:18]=[CH:17][N:16]=[C:15]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:35][C:30]1[CH:29]=[C:28]([NH:27][C:15]2[C:14]3[C:19](=[CH:20][C:21]([O:22][CH2:23][CH:24]4[CH2:25][CH2:26]4)=[C:12]([NH:11][C:2](=[O:3])[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:13]=3)[N:18]=[CH:17][N:16]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: CCOC(=O)C=CC(=O)Cl
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1

Procedure:
A solution of 3.00 g of ethyl 3-chlorocarbonyl-acrylate in 50 ml of tetrahydrofuran is added dropwise to 5.00 g of 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-7-cyclopropylmethoxy-quinazoline and 3.5 ml of diisopropylethylamine in 150 ml of tetrahydrofuran while cooling with an ice bath. The reaction mixture is stirred for a further hour while cooling with an ice bath and then stirred overnight at ambient temperature. Next, the solvent is largely distilled off in the rotary evaporator and the residue is partitioned between water and ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The brown, oily crude product is stirred with diethylether, the precipitate formed is suction filtered and washed with a little diethylether. Yield: 3.20 g (47% of theory), Rf value: 0.80 (silica gel, ethyl acetate) Mass spectrum (ESI*): m/z=485, 487 [M+]*
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8](=[O:13])[C:7]=2[CH:14]=1.[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[N:11]([CH3:19])[C:10](=[O:12])[O:9][C:8](=[O:13])[C:7]=2[CH:14]=1
Reactant: CI
Reactant: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Reaction time: 0.17 h

Procedure:
To a solution of 500 mg (3.06 mmol) of 6,7-dimethoxy-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (XV), in 6 ml of anhydrous DMF, add under an inert atmosphere 134 mg (3.37 mmol) of 60% NaH in oil. After 10 minutes at room temperature, add dropwise 219 μl (3.52 mmol) of MeI. Allow to stand at room temperature for 3 hours.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[CH2:8]2)([O-])=O>C(O)C.[Pd]>[NH:17]1[CH:18]=[C:14]([CH:9]2[CH2:8][C:7]3[C:11](=[CH:12][CH:13]=[C:5]([NH2:2])[CH:6]=3)[CH2:10]2)[N:15]=[CH:16]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(c1c[nH]cn1)C2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)CC(c1c[nH]cn1)C2

Procedure:
The hydrochloride of the product obtained in Step 3 is stirred under a hydrogen atmosphere in the presence of 10% palladium-on-carbon in ethanol. After filtration and concentration of the solvent, the product is used as it is in the following Step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:23]([O:30][C:31](=[O:41])[N:32]([CH2:34][C:35](N(OC)C)=[O:36])[CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:23]([O:30][C:31](=[O:41])[N:32]([CH2:34][C:35]([C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])[CH3:9])=[CH:11][CH:12]=1)=[O:36])[CH3:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CON(C)C(=O)CN(C)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)CN(C)C(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 12.8 %

Procedure:
200 mg of the compound [1-1] was dissolved in 4 mL of tetrahydrofuran, and the mixture was cooled to −78° C. and then 626 μL of n-butyllithium (2.66 M hexane solution) was added thereto. After a 1 hour stirring at the same temperature, 0.6 mL of tetrahydrofuran solution containing 177 mg of the compound [2-1] was added thereto, and the mixture was further stirred for 2 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=6/4), to obtain 36.2 mg of benzyl[2-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-2-oxoethyl]methylcarbamate [2-2] (hereinafter, referred to as the compound [2-2]) as a colorless oily product.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][NH:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1>>[CH3:29][N:30]([CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][O:33]1)[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CNCC1CCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN(C)CC3CCCO3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N-methyl-1-(tetrahydrofuran-2-yl)methanamine via General Procedure E to give 10.7 mg of 290 following reverse phase purification. MS (Q1) 477.2 (M)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1.[NH:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:25]([O:24][C:22]([N:14]([CH2:10][C:9]1[CH:12]=[CH:13][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:7][CH:8]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: BrCc1ccc(-c2nccs2)cc1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2nccs2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
To a solution of 4-(thiazol-2-yl)benzyl bromide (1.25 g, 4.92 mmol) obtained in Reference Example 4-(b) in N,N-dimethylformamide (16 ml) were added di-tert-butyl iminodicarboxylate (1.28 g, 5.89 mmol) and potassium carbonate (1.35 g, 9.76 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (2.05 g) substantially quantitatively as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17](S(C)(=O)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:35]#[N:36].[K+]>CN(C)C=O.O>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:35]#[N:36])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of N-(2,2-diphenylethyl)-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (Preparation 22) (20.1 g, 42.1 mmol) in dry N,N-dimethylformamide (100 ml) was treated with potassium cyanide (5.5 g, 84.6 mmol) and the mixture was heated at 120° C. for 24 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water (1000 ml) and stirring was continued for a further 1 hour. The resultant solid was filtered off and washed several times with water. The solid was then dissolved in dichloromethane and the solution was washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was azeotroped with diethyl ether (twice) to afford the title compound as an oil (17 g).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([CH:42]=O)[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:42][C@H:39]1[CH2:38][CH2:37][C@H:36]([C:33]2[CH:32]=[CH:31][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1ccc([C@H]2CC[C@H](C=C(Br)Br)CC2)cc1
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
A solution of 5.0 g of tetrabromomethane in 60 ml of methylene chloride was placed a -10° C. in a sulphonation flask under argon gasification and treated within 5 minutes with a solution of 7.9 g of triphenylphosphine in 20 ml of methylene chloride. The resulting clear orange solution was stirred at -10° C. for a further 1 minute and then a solution of 1.95 g of trans-4-(p-pentylphenyl)cyclohexanecarboxaldehyde in 20 ml of methylene chloride was added dropwise within 3 minutes. The mixture was subsequently left to stand at -18° C. overnight, then poured into 600 ml of hexane and the separated precipitate was filtered off (rinsing with hexane). The concentrated filtrate was digested with 300 ml of hexane, left to stand at -18° C. for 30 minutes, filtered (rinsing with hexane) and the filtrate was concetrated. Low-pressure chromatography (0.5 bar) of the residue (1.87 g) on silica gel with hexane gave 503 mg of 1-[trans-4-(2,2-dibromovinyl)cyclohexyl)-4-pentylbenzene as colourless crystals (purity 95.8%); m.p. 35°-37.7° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([CH:29]4[CH:33]=[CH:32][C:31](=[C:34]=[O:35])[O:30]4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:37]Cl=O.[Na+].CC#N>O>[C:1]([N:9]1[CH2:10][CH2:11][N:12]([C:15](=[O:36])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:29]4[O:30][C:31]([C:34]([OH:37])=[O:35])=[CH:32][CH:33]=4)[N:23]=[CH:24][C:25]=3[O:27][CH3:28])[NH:20][CH:19]=2)=[O:17])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cnc(C2C=CC(=C=O)O2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cnc(-c2ccc(C(=O)O)o2)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.5 %

Procedure:
A mixture of the compound of Example 85 (19 mg), NaClO2 (9.2 mg) in a mixed solution of CH3CN (3 mL) and water (0.5 mL) was stirred at room temperature for 24 hours. After the reaction was quenched by 1N NaOH solution (1 ml), the mixture was extracted with diethyl ether (3×10 mL). The aqueous phase was acidified with 1N HCl to give a yellow solid precipitate (5 mg) which was the product shown. MS m/z: (M+H)+ Calc'd for C26H23N6O7: 503.16; found 503.19. HPLC retention time: 1.37 minutes (column A).