Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[CH2:11][CH2:10][CH:5]([CH2:6][C:7]1=NO)[CH:4]([CH3:12])[O:3]2.N([O-])=[O:14].[Na+].O.S(=O)(=O)(O)O>C(OCC)C>[CH3:1][C:2]12[CH2:11][CH2:10][CH:5]([CH2:6][C:7]1=[O:14])[CH:4]([CH3:12])[O:3]2
Reactant: O=N[O-]
Reactant: CC1OC2(C)CCC1CC2=NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1OC2(C)CCC1CC2=O
Reaction time: 3 h

Procedure:
To a mixture of 20.5 g. 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-6-one-oxime, 16 g. sodium nitrite, 350 ml. water and 100 ml. diethylether at 25° C. there is added dropwise 100 ml. of 2 N sulfuric acid and the mixture is allowed to stand with occasional stirring for 3 hours. The organic layer is washed with 10% aqueous sodium bicarbonate and evaporated. To the resulting residue at 0° C. there is added 70 ml. concentrated ammonium hydroxide. This mixture is then extracted several times with diethyl ether and the combined ether extracts are dried over magnesium sulfate and evaporated to give 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-6-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH2:19][OH:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH2:19][O:20][C:29]3[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1COc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-hydroxymethyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.6 mmol), 4-methanesulfonyl-phenol (0.1 g, 0.6 mmol) and PPh3 (0.19 g, 0.72 mmol) in THF (5 mL) was added diethylazodicarboxylate (DEAD) (0.22 g, 0.72 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed and the residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.9 (2H, d, J=9 Hz), 7.09 (2H, d, J=9 Hz), 5.2 (2H, s), 4.28-4.10 (2H, m), 3.14-3.04 (1H, m), 3.04 (3H, s), 2.9-2.8 (2H, m), 2.44 (3H, s), 2.1-2 (2H, m), 1.76-1.64 (2H, m), 1.47 (9H, s).
Reaction SMILES: [CH2:1]1[C@:7]([OH:10])([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[C:2]1=O.[NH2:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17].Cl>CN(C=O)C.CO>[CH2:1]1[C@:7]([OH:10])([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[C@H:2]1[NH:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17]
Reactant: NC(CO)CO
Reactant: O=C1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5 mmol of valiolone and 5 mmol of 2-amino-1,3-propanediol in 25 mL DMF or methanol is added a catalytic amount of HCl. After 1 hour at room temperature, 2.5 mmol of solid Na(CN)BH3 is added and the reaction mixture is stirred over night at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in water and applied to a Dowex 50 (H+) column. The column is washed with water and the product is eluted with 0.5 N NH4OH. After concentrating the eluate, the residue is dissolved in water and applied successively first to a Amberlite CG-50 (NH4+) or Diaion WK-100 (NH4+) and then a Dowex 1 (OH-) column and each time the product is eluted with water to give voglibose.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27](O)=[O:28])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:32]1[C:36]2C=CC=C[C:35]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O1CCCC1.C(N)C>CN(C)C=O.CCCCCC.C(OCC)(=O)C.CO.O>[CH2:36]([NH:32][C:27](=[O:28])[CH2:26][CH:23]1[S:22][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([O:11][C:8]2[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:20][CH:19]=3)=[N:25][CH2:24]1)[CH3:35]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)ccc3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.8 %

Procedure:
To a solution of [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (80 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg), and 2M ethylamine tetrahydrofuran solution (0.35 mL), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio) and crystallized from acetonitrile to give the title compound (89 mg, yield 56%) as white crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29].Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH:29][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccccc1Cl)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (5 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-chlorobenzylamine (54.7 μl, 95%, 0.43 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60.6 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum and the resulting residue was redissolved in CH2Cl2 (100 ml). The organic layer was washed with aqueous NaHCO3, dried over anhydrous MgSO4, and concentrated to give the crude mixture. Chromatography of the crude (Hex:EtOAc=1:1 to pure EtOAc) afforded desired product as white solid (83 mg, 97%): m.p. 120-121° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].O1CCCC1.CCOC(C)=O>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][NH2:13]
Reactant: N#CCc1ccc2ccccc2c1
Agent: Cl[Ni]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NCCc1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
Combine naphth-2-ylacetonitrile (1.0 g, 6.0 mmol) and nickel(II) chloride hexahydrate (0.7 g, 3.0 mmol) and tetrahydrofuran (30 ml). Add dropwise borane-tetrahydrofuran complex, 1M solution in tetrahydrofuran (24.0 ml, 24.0 mmol). After 1 hour, evaporate to give a residue. Chromatograph on silica gel eluting with 8:2 EtOAc:MeOH+2% NH4OH) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9]([I:10])=[C:4]2[CH:3]=1.I[CH2:14][CH3:15]>>[Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH:11][CH2:14][CH3:15])[N:7]=[CH:8][C:9]([I:10])=[C:4]2[CH:3]=1
Reactant: Nc1ncc(I)c2cc(Cl)oc12
Reactant: CCI
Product: CCNc1ncc(I)c2cc(Cl)oc12
Yield: 45 %

Procedure:
The title compound was prepared in 45% yield from 2-chloro-4-iodo-furo[2,3-c]pyridin-7-ylamine and iodoethane by a procedure analogous to Intermediate 7. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1 H), 6.47 (s, 1 H), 4.71 (br. s., 1 H), 3.59 (qd, J=5.6, 7.2 Hz, 2 H), 1.31 (t, J=7.2 Hz, 3 H); MS (ESI): 322.96, 324.96 [M+H]+; HPLC tR=3.75 min (ZQ3: polar—4 min).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH:20]=[CH2:21])(=[O:19])=[O:18])=[C:12]([CH:22]=[CH2:23])[CH:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:20]([S:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([NH2:7])[CH3:9])=[CH:11][C:12]=1[CH:22]=[CH2:23])(=[O:18])=[O:19])=[CH2:21]
Reactant: C=Cc1cc(C(C)NC(=O)OC(C)(C)C)ccc1NS(=O)(=O)C=C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cc(C(C)N)ccc1NS(=O)(=O)C=C
Reaction time: 12 h
Yield: 154.6 %

Procedure:
[1-(4-Ethenesulfonylamino-3-vinyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (20.0 mg, 0.04 mmol) and CF3COOH (5 eq, 0.22 mmol, 17.04 μl) were dissolved in methylene chloride. The reaction mixture was stirred for 12 hrs. A reaction mixture was concentrate to yield [1-(4-Ethenesulfonylamino-3-vinyl-phenyl)-ethylamine (15.6 mg, 76%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:30][CH3:31])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([O:28]C)=[O:27])[CH2:25][CH2:24]3)=[O:22])[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].O.[OH-].[Li+]>O1CCCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:30][CH3:31])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)OC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Reaction time: 0.33 h

Procedure:
To methyl 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylate (12.25 g, 28.5 mmol) in a 500 mL round-bottom flask under nitrogen in tetrahydrofuran (THF) (170 mL) and water (55 mL) was added lithium hydroxide (1.025 g, 42.8 mmol). After 30 min the THF was evaporated off and the aqueous residue cooled in ice and taken to pH 6 using 2M hydrochloric acid causing, with scratching, a brown precipitate to form. This was stirred for about 20 min before filtering under vacuum (damp weight=7.1 g) then being dried at 40° C. under vacuum over a weekend. This gave a sandy-brown solid, 5.91 g (50%). HPLC 1.72 min (ret time), 99.1%; LC-MS m/z 416 (M+H)+, 0.68 min (ret time). HPLC showed much of the desired product still in solution (pH still 6). The pH of the aqueous solution was adjusted to pH 10 and evaporated in order to re-acidify it to precipitate more product. The mixture was left to stand over a weekend and the solid then collected. This gave a brown crystalline solid, 2.76 g (23%). HPLC 1.72 min (ret time), 99.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:4]=1[CH3:10].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]=[C:12]=[O:14])[C:4]=1[CH3:10]
Reactant: COc1cccc(N)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cccc(N=C=O)c1C
Yield: 95.3 %

Procedure:
A mixture of 1-methoxy-2-methyl-3-aminobenzene 15.0 g, triphosgene 48.7 g and toluene 350 mL was stirred with heating under reflux for three hours. The reaction mixtures after standing to cool were concentrated under reduced pressure to give 1-methoxy-3-isocyanato-2-methylbenzene 17.0 g.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([OH:22])([CH3:21])[CH3:20]>>[CH:19]([O:22][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:21])[CH3:20]
Reactant: CC(C)O
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Product: CC(C)OC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 122-124° C. and MS: m/e=297 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl isocyanate and isopropyl alcohol.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][CH2:10][CH:11]1[N:24]([CH3:25])[C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[C:14](=[O:26])[N:13]([CH3:27])[CH2:12]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:31][CH:30]=1>C(N(CC)CC)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH:35]([C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)[CH:36]2[CH2:41][CH2:40][N:39]([CH2:9][CH2:10][CH:11]3[N:24]([CH3:25])[C:16]4=[N:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:15]4[C:14](=[O:26])[N:13]([CH3:27])[CH2:12]3)[CH2:38][CH2:37]2)=[CH:43][CH:44]=1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CC(CCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)N(C)c2nc3ccccc3n2C1=O
Reaction time: 24 h

Procedure:
To a solution of 50 mL of toluene containing 4.0 g (0.04 mol) of triethylamine was added 3.0 g (0.01 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one and 4.0 g (0.014 mol) of 4-[bis(4-fluorophenyl)methyl]piperidine. The mixture was heated to reflux for 3 days after which time 1.0 g (0.003 mL) of 4-[bis(4-fluorophenyl)methyl]piperidine and 1.0 g (0.01 mol) of triethylamine was added. Heating under reflux was continued for 24 hr. The solvent was removed by rotary evaporation and the residue dissolved in 100 mL of CH2Cl2. The organic phase was washed with 2×100 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was subjected to preparative HPLC using silica gel as the stationary phase and eluting with ethanol. Combination of like fractions afforded 3.1 g (57%) of analytically pure material as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([C:32]([O:34]CC)=[O:33])=[N:26][CH:27]=2.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[C:32]([C:25]1[N:24]=[C:23]2[C:28]([NH:29][C:30](=[O:31])[N:22]2[C:3]2[CH:4]=[C:5]([O:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[F:21])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Cl:1])=[CH:27][N:26]=1)([OH:34])=[O:33]
Reactant: CCOC(=O)c1ncc2[nH]c(=O)n(-c3cc(OCc4c(OC)ccc(F)c4F)c(OC)cc3Cl)c2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3cnc(C(=O)O)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-cyano-7,9-dihydro-8H-purin-8-one (0.12 g) was added hydrochloric acid (20% ethanol solution, 3 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the precipitated crystals were collected by filtration. The crystals were washed with water and diethyl ether, and dried under reduced pressure. The obtained crystals were purified by column chromatography on silica gel (eluent: ethyl acetate) to give 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-ethoxycarbonyl-7,9-dihydro-8H-purin-8-one (93 mg). To the obtained 9-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenyl]-2-ethoxycarbonyl-7,9-dihydro-8H-purin-8-one (50 mg) were added tetrahydrofuran (4 mL), methanol (2 mL), water (2 mL) and lithium hydroxide monohydrate (40 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and the solvent was removed under reduced pressure. The residual solids were suspended in diethyl ether, and collected by filtration. The collected solids were washed with water and diethyl ether, and dried under reduced pressure to give the title compound (22 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([C:27](=O)[CH2:28][CH3:29])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25](/[C:27](=[N:16]/[NH:15][C:13](=[O:14])[C:12]2[CH:17]=[CH:18][CH:19]=[C:10]([S:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)(=[O:9])=[O:8])[CH:11]=2)/[CH2:28][CH3:29])[CH:26]=1
Reactant: CCC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CO
Solvent: CC(=O)O
Product: CC/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.6 %

Procedure:
3-(Morpholinosulfonyl)benzohydrazide (40 mg, 0.140 mmol) and 1-(5-chloro-2-hydroxyphenyl)propan-1-one (25.9 mg, 0.140 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (20 mg). 1H NMR (400 MHz, acetone-d6): δ 8.26 (m, 2H), 8.00 (d, 1H, J=7.6 Hz), 7.84 (t, 1H, J=8.0 Hz), 7.64 (d, 1H, J=2.4 Hz), 7.33 (m, 1H), 6.98 (d, 1H, J=9.2 Hz), 3.69 (m, 4H), 3.10 (q, 2H, J=7.6 Hz), 2.99 (m, 4H), 1.26 (t, 3H, J=7.6 Hz). ESI-MS: 452.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]12[NH:11][C:10](=[O:12])[O:9][CH:8]1[CH2:7][CH2:6][N:5]([C:13](OCC1C=CC=CC=1)=O)[CH2:4][CH2:3]2.CC1CC=CCC=1.Cl[C:31]1[N:35](C)[N:34]=[CH:33][C:32]=1[N+:37]([O-:39])=[O:38].[F-].[K+]>CCO.[Pd].CS(C)=O>[CH3:1][C:2]12[NH:11][C:10](=[O:12])[O:9][CH:8]1[CH2:7][CH2:6][N:5]([C:13]1[N:34]([CH3:33])[N:35]=[CH:31][C:32]=1[N+:37]([O-:39])=[O:38])[CH2:4][CH2:3]2
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC12CCN(C(=O)OCc3ccccc3)CCC1OC(=O)N2
Agent: [Pd]
Agent: CC1=CCC=CC1
Agent: [F-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cn1ncc([N+](=O)[O-])c1N1CCC2OC(=O)NC2(C)CC1
Temperature: 60 °C

Procedure:
To a solution of benzyl 3a-methyl-2-oxo-3,4,5,7,8,8a-hexahydrooxazolo[4,5-d]azepine-6-carboxylate (305 mg, 1.0 mmol) and 1-methyl-1,4-cyclohexadiene (1.1 mL, 10.00 mmol) in EtOH (10 mL) was added 10% palladium on carbon (53 mg, 0.50 mmol) under nitrogen and the mixture was heated at 60° C. for 2 hr. The mixture was cooled to room temperature, filtered through Celite® and concentrated under reduced pressure. To a solution of the residue (170 mg, 1.00 mmol) in DMSO (5 mL) was added 5-chloro-1-methyl-4-nitro-pyrazole (178 mg, 1.10 mmol) and potassium fluoride (232 mg, 4.00 mmol) and the mixture was heated in the microwave at 110° C. for 4 hr. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% MeOH/DCM) gave a yellow solid (220 mg, 74% over two steps). The material was combined with another batch to give 350 mg for separation of the diastereoisomers by reverse-phase preparative HPLC. The major diastereomer was isolated as a yellow solid (196 mg, 67% over two steps) 1H NMR (400 MHz, d6-DMSO) δ 8.11 (s, 1H), 7.72 (s, 1H), 4.48 (dd, J=6.6, 2.7 Hz, 1H), 3.74 (s, 3H), 3.10-3.01 (m, 2H), 2.20-1.96 (m, 3H), 1.85 (dd, J=15.2, 7.8 Hz, 1H), 1.32 (s, 3H). Two protons under water peak. LCMS (ES+) m/z 296 (M+1).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][NH:16][CH2:15]2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[C:50](O)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(Cl)Cl>[C:50]([N:16]1[CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]([CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:25])[CH2:8][CH2:9]2)[CH2:15]1)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccccc1C1CCN(CC2CNCC2c2ccccc2)CC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C1CCN(CC2CN(C(=O)c3ccccc3)CC2c2ccccc2)CC1

Procedure:
The title compound was prepared from 3-(SR)-(4-(2-tolyl)-piperidin-1-ylmethyl)-4-(SR)-phenylpyrrolidine (Step A), 0.014 mL of DIEA, 12.5 mg of BOP-Cl and 5 mg of benzoic acid in 0.5 mL of CH2Cl2 using a procedure analogous to that described in Example 63 to provide the title compound. RF : 0.45 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 1.4-4.5 (m, 20H), 7.05-7.6 (m, 14H). Mass Spectrum (CI): 439.4 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22])[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH3:1][N:2]([CH2:19][CH:20]1[O:23][CH2:24][CH2:22][O:21]1)[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([C:12]([F:14])([F:15])[F:13])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(CN(C)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CN(CC1OCCO1)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 1 h

Procedure:
N-Methyl-N-(2,2-dimethoxyethyl)-2,6-dinitro-4-trifluoromethylaniline (3.2 grams; 0.0915 mole), ethylene glycol 0.57 grams; 0.0915 mole), para-toluenesulfonic acid (200 mg) and ethyl acetate were charged into a glass reaction vessel equipped with a stirrer, heating mantle, reflux condenser and thermometer. The reaction mixture was heated at 120° C. with stirring for one hour. After this time the mixture was cooled to room temperature and washed with aqueous sodium bicarbonate. The washed solution was dried over anhydrous sodium sulfate, filtered and stripped of solvent leaving a solid residue. The residue was recrystallized from hexane to yield the desired N-methyl-N-1,3-dioxolan-2-ylmethyl-2,6-dinitro-4-trifluoromethylaniline as a yellow crystalline solid melting at 83° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([NH:7][CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[C:9]1[C:14]([Cl:15])=[N:13][CH:12]=[CH:11][N:10]=1)=O)[CH3:2]>O=P(Cl)(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:14]([Cl:15])[C:9]2=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)[N:7]=1)=[O:30])[CH3:2]
Reactant: CCOC(=O)C(=O)NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Temperature: 75 °C

Procedure:
A solution of N-[(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-oxalamic acid ethyl ester (50 mg, 0.12 mmol) in POCl3 (2 mL) was heated to 55° C. for 17.5 h. Very little reaction occurred therefore DMF (3 drops) was added to reaction mixture and heated to 75° C. overnight. The brown reaction mixture was allowed to cool to rt, concentrated in vacuo and then quenched with 2M NH3 in i-PrOH at 0° C. until the pH was basic. The reaction mixture was concentrated in vacuo and the crude material was purified by chromatography on silica gel [eluting with 2% EtOAc in DCM], resulting in the title compound as an off-white solid; 1H NMR (CDCl3, 400 MHz) δ 1.48 (t, J=7.2 Hz, 3H), 4.56 (q, J=7.2 Hz, 2H), 5.13 (s, 2H), 7.05-7.09 (m, 1H), 7.22-7.29 (m, 2H), 7.29-7.47 (m, 6H), 7.67 (d, J=5.2 Hz, 1H), 9.15 (d, J=5.2 Hz, 1H); MS (ES+): m/z=408.07 (100) [MH+], HPLC: tR=3.88 min (MicromassZQ, polar—5 min).