Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:45]C(=O)OC(C)(C)C)([CH2:36][O:37][Si](C)(C)C(C)(C)C)[C:3](=[O:35])[NH:4][C@@H:5]([C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C:19]2([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH:20]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18]1)=[O:16])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.CCOCC.O>>[NH2:45][C@:2]([CH3:1])([CH2:36][OH:37])[C:3]([NH:4][C@H:5]([CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C:19]2([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH:20]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18]1)=[O:16])=[O:35]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)C2)C1=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)[C@](C)(N)CO)C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising tert-butyl (4R)-7,10,10,11,11-pentamethyl-4-(2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decane-7-carbonyl)-6-oxo-1-phenyl-2,9-dioxa-5-aza-10-siladodecan-7-ylcarbamate (Intermediate from step 4) (140 mg, 0.190 mmol) and 2M HCl in Et2O (2.9 mL, 5.70 mmol) was treated with water (300 mg, 16.65 mmol) dropwise and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The resulting crude was dried in a vacuum oven for 24 hours at 50° C. to afford the title compound. No purification was performed on the title compound.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]4)=[N:21][CH:22]=2)=[N:13][C:12]([C:37]2[CH:42]=[C:41]([F:43])[C:40]([OH:44])=[C:39]([Cl:45])[CH:38]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.FC(F)(F)C([O-])=O>>[NH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:37]5[CH:42]=[C:41]([F:43])[C:40]([OH:44])=[C:39]([Cl:45])[CH:38]=5)[N:13]=4)[N:8]=[CH:7][C:6]=3[C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 68 %

Procedure:
Following general procedure IV-2, (R)-tert-butyl [1-(5-{[3-(cyclopropanecarbonyl)-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (0.98 g, 0.16 mmol) was reacted with TFA (2 mL). The resulting trifluoroacetate salt of the product was converted to the free base to afford the desired product (58 mg, 71%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.18 (s, 1H), 8.09 (d, J=9.0 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.37 (dd, J=9.0, 2.0 Hz, 1H), 6.97 (d, J=13.0 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H), 4.18-4.15 (m, 1H), 3.83-3.81 (m, 1H), 3.31-3.22 (m, 1H), 3.15-3.05 (m, 2H), 2.91-2.85 (m, 1H), 2.12-2.08 (m, 1H), 1.91-1.83 (m, 1H), 1.71-1.58 (m, 2H), 1.25-1.08 (m, 4H); ESI MS m/z 533 [M+H]+; HPLC 99.0% (AUC), tR=9.18 min.
Reaction SMILES: C([Li])CCC.[C:6]([CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])#[N:7].[C:19]1([N:25]=[N+:26]=[N-:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:19]1([N:25]2[C:6]3=[N:7][C:11](=[O:12])[C:10]4[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=4[C:8]3=[N:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: COC(=O)c1ccccc1CC#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1nc2n(-c3ccccc3)[nH]nc-2c2ccccc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
n-Butyllithium (1.6 M, 7.5 ml, 12 mmol) was added dropwise at −78° C. over 5 min to a stirred solution of methyl 2-cyanomethylbenzoate (Tetrahedron Lett., 1991, 32, 4133-4134) (2.10 g, 12 mmol) in dry THF (50 ml) under nitrogen. The deep red solution was stirred at −78° C. for 10 min, followed by the addition of a solution of phenyl azide (1.47 g, 12.3 mmol) in dry THF (10 ml). The green solution was stirred at −78° C. for 1.5 h then warmed to r.t. over 30 min, becoming bright blue. Saturated aqueous ammonium chloride (50 ml) was added and the mixture was acidified to pH 5 with 1M citric acid. The white precipitate was collected and washed with water and diethyl ether, then dried to give 3-phenyl-1,2,3-triazolo[4,5-c]isoquinolin-5-one (2.00 g, 64%). δH (360 MHz; DMSO) 7.58-7.68 (4H, m), 7.80-7.84 (2H, m), 7.93 (1H, ddd, J=8, 8 and 1), 8.30 (2H, d, J=8) and 12.80 (1H, s); m/z (ES+) 263 (M+H+).
Reaction SMILES: [O:1]=[C:2]([C:6]1[C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)C(O)=O.C1C=CC2N(O)N=[N:27]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[N:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:14][C:10]3[C:11](=[C:6]([C:2]([NH2:27])=[O:1])[CH:7]=[CH:8][CH:9]=3)[N:12]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)C(=O)c1cccc2oc(-c3ccncc3)nc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2oc(-c3ccncc3)nc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 14.2 %

Procedure:
To a solution of 2-oxo-2-(2-(pyridin-4-yl)benzo[d]oxazol-4-yl)acetic acid (120 mg, 0.5 mmol) in DMF (15 mL) was added HOBt (148 mg, 1.1 mmol), NH4Cl (54 mg, 1.0 mmol), DIPEA (387 mg, 3.0 mmol) and EDCI (211 mg, 1.1 mmol). The mixture was stirred at 25° C. for 10 hr., water (10 mL) and 1N aqueous hydrochloric acid was added to the mixture until pH=3, then extracted with ethyl acetate (100 mL×4). The organic phase was washed with saturated sodium bicarbonate solution and brine, concentrated and dried in vacuum. The crude product was purified by preparative HPLC to obtain 2-(pyridin-4-yl)benzo[d]oxazole-4-carboxamide as a solid (17 mg, yield 14%). 1H-NMR (400 MHz, DMSO-d6) δ 7.60-7.64 (t, J=8 Hz, 1H), 8.01-8.03 (d, J=8 Hz, 1H), 8.06-8.08 (d, J=8 Hz, 2H), 8.23-8.24 (d, J=8 Hz, 2H), 8.41 (s, 1H), 8.87 (d, 2H); LC-MS (ESI) m/z 240 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[S:13](Cl)(=[O:15])=[O:14].[NH2:17][C:18]1[CH:19]=[C:20]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH:21]=[CH:22][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[S:13]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH:19]=1)(=[O:15])=[O:14]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(C(F)(F)F)cc1Cl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 54.8 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 2,6-dichloro-4-(trifluoromethyl)benzenesulfonyl chloride (17 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 12 mg (54%) of the title compound. MS (ESI+) calcd for C14H8Cl2F3N5O2S 436.972785, found 436.973025.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8]C(OCC)=O)[N+:5]([O-:14])=[C:4]([NH:15]C(OCC)=O)[CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)C.[OH-].[K+]>O>[NH2:15][C:4]1[CH:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:7]=[C:6]([NH2:8])[N+:5]=1[O-:14]
Reactant: C1COCCN1
Reactant: CCOC(=O)Nc1cc(Cl)cc(NC(=O)OCC)[n+]1[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(N2CCOCC2)cc(N)[n+]1[O-]
Reaction time: 24 h
Yield: 69 %

Procedure:
A mixture of 4-chloro-2,6-bis(ethoxycarbonylamino)pyridine 1-oxide (10.0 g., 0.03 mole) and 60 ml. of morpholine is refluxed with stirring under a nitrogen atmosphere for a period of 24 hrs. and concentrated to dryness. The residual material thus obtained is taken up in 200 ml. of absolute ethanol and 24.0 g. (0.36 mole) of 85% potassium hydroxide. After stirring at reflux temperature for a period of 16 hr., 200 ml. of absolute ethanol is added and reflux continued for an additional period of 30 hr. Concentration of the basic solution to dryness provides a residue which o stirring with water affords 4.4 g. (69% yield) of 2,6-diamino-4-(4-morpholinyl)-pyridine 1-oxide as the free base, m.p. 315°-325° C. (dec.). The free base is taken up in absolute ethanol and acidified with ethanolic hydrogen chloride. Addition of ethyl acetate to the acidified ethanolic solution and cooling affords the product which is collected and crystallized from absolute ethanol to provide 2.8 g. of analytically pure 2,6-diamino-4-(4-morpholinyl)pyridine 1-oxide hydrochloride hydrate, m.p. 203.5°-206.5° C. (dec.) (corr.).
Reaction SMILES: Cl.[Br:2][C:3]1[N:4]=[C:5]([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.C(N(CC)C(C)C)(C)C.[C:27]([O:30][CH2:31][C:32](Cl)=[O:33])(=[O:29])[CH3:28]>ClCCl>[C:27]([O:30][CH2:31][C:32]([N:15]1[CH2:16][CH2:17][C@@H:13]([C:5]2[N:6]3[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]3=[C:3]([Br:2])[N:4]=2)[CH2:14]1)=[O:33])(=[O:29])[CH3:28]
Reactant: Cc1nccn2c([C@@H]3CCNC3)nc(Br)c12
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1CC[C@@H](c2nc(Br)c3c(C)nccn23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To (R)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride (0.15 mmol, 50 mg) in dichloromethane (4 ml) and N,N-diisopropylethylamine (0.889 mmol, 0.155 ml) at 0° C. was added dropwise a solution of acetoxyacetyl chloride (0.187 mmol, 0.020 ml) in dichloromethane (0.5 ml). After stirring at room temperature for one hour the reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution, water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give (R)-2-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-2-oxoethyl acetate (45 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:21]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([CH3:43])([O:38][Si](C)(C)C)[CH3:37])=[CH:32][CH:31]=2)=[C:26]([CH3:44])[CH:25]=1)[CH2:22][CH3:23])[CH3:20].C(OCC)(=[O:62])C>O1CCCC1>[CH2:19]([C:21]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@H:51]([OH:62])[CH2:52][CH2:53][C:54]([OH:55])=[O:56])=[C:47]([CH3:59])[CH:46]=1)([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])([CH3:37])[CH3:43])=[CH:32][CH:31]=2)=[C:26]([CH3:44])[CH:25]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2ccc(C(C)(C)O[Si](C)(C)C)cc2)c(C)c1
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OC[C@H](O)CCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(C)(C)O)cc2)c(C)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (0.1 mL, 0.1 mmol) was added to a solution of (R)-5-(4-{1-ethyl-1-[2-methyl-4′-(1-methyl-1-trimethylsilanyloxy-ethyl)-biphenyl-4-yl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(4); 16 mg, 0.028 mmol) in tetrahydrofuran (0.1 mL) at room temperature, and the mixture was stirred at 75° C. for two hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with a potassium bisulfate aqueous solution and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol=10/1, developed three times) to give the title compound (11.3 mg, 78%).
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[C:19]4[C:24]([CH3:25])=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[OH-].[Na+].O>O1CCOCC1.CCOC(C)=O>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:48][CH3:49])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[C:24]([CH3:25])[C:19]4=[C:18]([NH:36][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:38]=4[C:39]([NH:41][CH3:42])=[O:40])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1c(C)cn2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2ncc(C)c1-2
Temperature: 120 °C
Yield: 70.7 %

Procedure:
2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (225 mg, 0.321 mmol) was dissolved in dioxane (6 mL), 6N NaOH (2 mL) and water (2 mL) was added in a microwave safe vessel. The reaction was then heated in a microwave at 120° C. for 23 min. Reaction was diluted with EtOAc and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (124 mg, 0.227 mmol) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 6 H) 2.41 (s, 3 H) 2.81 (d, J=4.39 Hz, 3 H) 3.12 (t, J=8.24 Hz, 2 H) 3.17 (s, 2 H) 3.76 (s, 3 H) 4.18 (t, J=8.33 Hz, 2 H) 6.68 (s, 1 H) 6.86 (t, J=9.25 Hz, 1 H) 6.95 (s, 1 H) 7.25 (d, J=7.14 Hz, 1 H) 7.52 (s, 1 H) 8.45 (d, J=8.42 Hz, 1 H) 8.57 (s, 1 H) 8.66 (d, J=4.39 Hz, 1 H) 9.44 (s, 1 H) 10.92 (s, 1 H). ESIMS (M+H)+=547.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:21])=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: O=C(Cc1cccc(Cl)c1)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O

Procedure:
The product from Example 68B and 2-(3-chlorophenyl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.87-11.90 (m, 1H), 8.56 (d, J=8.1 Hz, 1H), 8.38 (dd, J=7.9, 1.3 Hz, 1H), 8.09-8.14 (m, 1H), 7.99-8.03 (m, 3H), 7.78-7.83 (m, 1H), 7.66-7.70 (m, 2H), 7.34-7.41 (m, 3H), 7.24-7.27 (m, 1H), 3.71 (s, 2H); MS (APCI+) M/Z 454 (M+H)+.
Reaction SMILES: C1(NC2C=CC=CC=2)C=CC=CC=1.NC1C=CC=CC=1.P(=O)(O)(O)O.C(OCC)(=O)C.[O:32]=[CH:33][C@@H:34]([C@H:36]([C@@H:38]([C@@H:40]([CH2:42][OH:43])[OH:41])[OH:39])[OH:37])[OH:35]>>[CH2:42]([OH:43])[C@@H:40]([OH:41])[C@@H:38]([OH:39])[C@H:36]([OH:37])[C:34]([CH:33]=[O:32])=[O:35]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P(O)(O)O
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=CC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 100 °C

Procedure:
Thin layer chromatography (TLC)--Avicel coated glass plates are developed with an 8:8:2:4 (by volume); isopropanol:pyridine:acetic acid:water solvent system. Glucose has Rf 's 0.5-0.6; D-glucosone has an Rf 0.4-0.5 streak. (Rf =the distance substance migrates from origin/solvent front distance from origin). When the plates are sprayed with triphenyltetrazolium chloride (2% TTC in 0.5 N NaOH), D-glucosone instantly yields a red spot; glucose yields a red spot only upon heating for ten minutes at 100° C. When the plates are sprayed with diphenylamine/aniline/phosphoric acid/ethyl acetate reagent, (0.15 g/0.8 ml/11 ml/100 ml), glucose yields a brown spot; D-glucosone yields a purple streak upon heating for 10 minutes at 95° C.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[C:8]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])#[N:9].[H-].[Na+].C([Li])CCC.C(I)C.Cl>CN(C)C=O.CCCCCC.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:13]([CH:15]([CH2:1][CH3:2])[CH2:16][C:17]([OH:19])=[O:18])=[O:14])#[N:9]
Reactant: CC(C)NC(C)C
Reactant: N#Cc1cc(C(=O)CCC(=O)O)ccc1N1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC(=O)O)C(=O)c1ccc(N2CCOCC2)c(C#N)c1
Reaction time: 0.17 h

Procedure:
4.9 ml of diisopropylamine and 10 g of 3-(3-cyano-4-morpholino-benzoyl)propionic acid are added to a suspension of 1.7 g of a 50% dispersion of sodium hydride in 35 ml of dimethylformamide and the mixture is heated for 5 minutes to reflux temperature. Then 28.9 ml of a 1.2 molar solution of butyllithium in hexane are added dropwise at -70° . The reaction mixture is stirred for a further 10 minutes at -30° and then 2.8 ml of ethyl iodide are added at -70° . The batch is stirred for a further 20 hours at room temperature with the addition of another 5.6 ml of ethyl iodide after the first 3 hours. For working up, water is added and the pH is adjusted to 1 with 120 ml of 1N hydrochloric acid. The aqueous phase is extracted with ether and the ethereal extracts are extracted with 2N sodium carbonate solution. The sodium carbonate extracts are in turn adjusted to pH 1 and then extracted with a 1:1 mixture of ether/ethyl acetate. These extracts are washed with brine, dried over sodium sulfate and concentrated by evaporation, affording 10.5 g of crude 3-(3-cyano-4-morpholinobenzoyl)valeric acid, which is further reacted direct as described above.
Reaction SMILES: COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCN(C(OC(C)(C)C)=O)CC1)CC2=O.[C:30]1([N:36]2[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH3:43][C:44]([C:46]1[CH:51]=[C:50]([Br:52])[CH:49]=[CH:48][C:47]=1O)=[O:45]>>[C:30]1([N:36]2[CH2:37][CH2:38][C:39]3([CH2:43][C:44](=[O:45])[C:46]4[C:47](=[CH:48][CH:49]=[C:50]([Br:52])[CH:51]=4)[O:42]3)[CH2:40][CH2:41]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCN(c2ccccc2)CC1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: O=C1CC2(CCN(c3ccccc3)CC2)Oc2ccc(Br)cc21

Procedure:
1′-Phenyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one was synthesized according to the procedure for preparation of Intermediate 1, Step A, using 1-phenyl-piperidin-4-one (607 mg, 3.47 mmol) and 2-hydroxy-5-bromoacetophenone (746 mg, 3.47 mmol), giving 650 mg as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:21]1([S:24](Cl)(=[O:26])=[O:25])[CH2:23][CH2:22]1>C(Cl)Cl.CN(C1C=CN=CC=1)C.[NH4+].[Cl-].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:24]([CH:21]3[CH2:23][CH2:22]3)(=[O:26])=[O:25])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(4-bromophenyl)piperazine (1 g, 4.15 mmol) was dissolved in DCM (40 ml) and cooled in 0° C. Then DMAP (0.051 g, 0.415 mmol), triethylamine (0.723 ml, 5.18 mmol), and cyclopropanesulfonyl chloride (0.641 g, 4.56 mmol) were added. The reaction was stirred 1 h at rt, then diluted with DCM and saturated NH4Cl/water (1:1). The aqueous phase was separated, extracted with DCM (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired product. LC-MS: calculated for C13H17BrN2O2S 346.02 observed m/e: 346.88 (M+H)+ (Rt 1.16/2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7](=S)/[N:8]=[C:9]1\[S:10][C:11]2[C:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][C:12]=2[N:13]\1[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C.[N:35]#[C:36][NH2:37]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:7](=[N:37][C:36]#[N:35])/[N:8]=[C:9]2\[S:10][C:11]3[C:21]([CH3:23])([CH3:22])[O:20][CH2:19][CH2:18][C:12]=3[N:13]\2[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:25]=1
Reactant: N#CN
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=NC#N)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of Example 89H (0.18 g, 0.42 mmol) in acetonitrile (10 mL) were added mercuric acetate (0.18 g, 0.55 mmol, Aldrich), triethylamine (0.18 mL, 1.27 mmol) and cyanamide (0.04 g, 0.85 mmol, Aldrich). After stirring at 80° C. for 16 hr, the reaction mixture was cooled and quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined the organic extracts were washed with water (1×25 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% ethyl acetate in hexanes) and followed by crystallization from ethyl acetate/hexanes to afford 0.04 g (21%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.8 Hz, 6H), 1.51 (s, 6H), 2.06-2.35 (m, 1H), 2.66-2.87 (m, 2H), 3.81 (s, 3H), 3.94-4.14 (m, 4H), 7.21 (d, J=9.2 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.52 (dd, J=9.2, 2.7 Hz, 1H); MS (ESI+) m/z 433 (M+H)+; Anal. Calculated C21H25ClN4O2S: C, 58.25; H, 5.82; N, 12.94. Found: C, 58.30; H, 5.79; N, 12.64.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[C:9]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[NH:6][C:5]1=O)[CH:2]=[CH2:3].P(Cl)(Cl)([Cl:22])=O>C(OCC)(=O)C>[CH2:1]([N:4]1[C:8]2[C:9]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[N:6]=[C:5]1[Cl:22])[CH:2]=[CH2:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: C=CCn1c(=O)[nH]c2c(Cl)ccc(C(CC)CC)c21
Solvent: CCOC(C)=O
Product: C=CCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 95 %

Procedure:
A solution of 1-allyl-4-chloro-7-(1-ethylpropyl)-1,3-dihydro-2H-benzimidazol-2-one (9.80 g, 35.1 mmol) in phosphoryl chloride (35 mL) was stirred at 100° C. for 2 hr. The mixture was concentrated in vacuo to give a residue which was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (9.90 g, 33.3 mmol, 95%) as a colorless solid.