Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[C:16]([NH:17]C(=O)C)=[CH:15][C:14](C2C=CC=CC=2C([O-])=O)=[C:13]([N+:30]([O-:32])=[O:31])[CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl>C(O)C.O>[CH2:3]([O:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14]([OH:1])=[C:13]([N+:30]([O-:32])=[O:31])[CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [OH-]
Reactant: CCCCCCCOc1cc([N+](=O)[O-])c(-c2ccccc2C(=O)[O-])cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCOc1cc([N+](=O)[O-])c(O)cc1N
Reaction time: 8 h
Yield: 81.3 %

Procedure:
Sodium hydroxide (2.15 g, 53.7mmol) was carefully added to a stirred solution of 50b (890 mg, 2.15 mmol) in 80 ml ethanol and 20 ml water. The reaction mixture was stirred overnight and was then acidified with concentrated HCl. Extracted three times with dichloromethane, and the combined organic layers were washed with brine and dried over MgSO4. The crude product was adsorbed onto silica gel and purified via flash chromatography with gradual elutions from 85/10/5 to 75/20/5 (Hex/EtOAc/dichloromethane). Evaporation of solvent yielded 469 mg (81%) of an orange solid.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].O[CH:12]1[CH:19]2[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][C:13]1([OH:22])[CH2:14]3)[CH2:18]2.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([O:6][CH2:7][C:8]([O:10][C:19]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:21][C:13]([OH:22])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC(=O)O
Reactant: OC1C2CC3CC(C2)CC1(O)C3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(=O)OC12CC3CC(CC(O)(C3)C1)C2

Procedure:
Hydroxycarbonylmethyl methacrylate (30 g) and dihydroxyadamantane (16.8) were added into dichloromethane (500 ml), and p-toluenesulfonic acid (1 g) was added thereto. Then, the mixture was refluxed for 15 hours while removing water generated. After the reaction, conventional after-treatments were carried out to obtain oil (21.2 g), which was identified to be Monomer A described above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-].B(F)(F)F>CCOCC>[O:14]=[C:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12][CH:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
tert-Butyl-4-oxo-1-piperidinecarboxylate (10 g, 50.19 mmol) was dissolved in Et2O (100 ml) and cooled to −78° C. Ethyl diazoacetate (7.3 ml, 70.26 mmol) and BF3.EtO were sequentially added over 30 min. After stirring at the same temperature for 2 h, the reaction was quenched by careful addition of aqueous potassium bicarbonate, during which the cold bath was removed. After warming up to room temperature, the organic layer was washed with water, dried over Na2SO4 and concentrated. Purification with flash chromatography provided the titled compound (13 g, Yield: 91%). MS (DCI/NH3) m/z 286 (M+H)+.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].[N-]=C=S>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCC
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: [N-]=C=S
Solvent: CCCCC
Product: CCN(CC)C(=S)NC1(N=NC(C)(C)C)CCCCC1

Procedure:
To 9.12 grams (.0395 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane cooled to 10° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.89 grams (.0395 moles) of diethylamine. The reaction mixture was stirred for 3 hours at room temperature, adding pentane periodically to keep the viscosity low. The pentane was stripped from the reaction mixture to leave a yellow viscous oil weighing 11.4 grams (95% crude yield). The infrared spectrum of the product had a strong broad band at 1520 cm-1 and a sharp NH band at 3300 cm-1 and the isothiocyanate band at 2040 cm-1 was very weak indicating there was a trace of the starting material still present.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([O:24][CH2:25][CH3:26])[CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=[N:37][C:36]2[N:39](O)N=NC=2C=1.CC(C)N=C=NC(C)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:22])[CH3:23])=[C:16]([O:24][CH2:25][CH3:26])[CH:15]=2)[C:11]([O:13][N:37]=[C:36]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH2:39])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOc1cc(C(Nc2ccc(C#N)cc2)C(=O)O)ccc1OC(C)C
Reactant: On1nnc2cccnc21
Reactant: c1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(C(Nc2ccc(C#N)cc2)C(=O)ON=C(N)c2ccccc2)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 2-(4-cyanophenylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetic acid (US2004242585, which is incorporated herein by reference) (525 mg, 1.48 mg) and benzene amideoxime (242 mg, 1.78 mmol) in 10 mL CH2Cl2/DMF (9:1) at 0° C., were added HOAt (242 mg, 1.78 mmol), DIC (0.279 mL, 1.78 mmol) and TEA (0.248 mL, 1.78 mmol). The mixture was stirred at 0° C. for 15 min, then at rt for 6 h. The mixture was diluted with EtOAc, washed with H2O, 1 N HCl, H2O, sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 700 mg of Intermediate 187.1 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[S-:12][C:13]#[N:14].[K+].[NH2:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[C:19]([CH3:38])[CH:18]=1.C(O)C>C(#N)C.C(OCC)C>[CH3:38][C:19]1[CH:18]=[C:17]([NH:16][C:13]([NH:14][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[S:12])[CH:37]=[CH:36][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])[CH:23]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: Cc1cc(N)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: CCO
Product: Cc1cc(NC(=S)NC(=O)Cc2ccc(F)cc2)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
To a solution of 2-(4-fluorophenyl)acetyl chloride (66.3 mg) in acetonitrile (30 ml) was added potassium thiocyanate (37.3 mg), followed by stirring under a nitrogen atmosphere at 50° C. for 1 hr. The reaction mixture was cooled down to room temperature, and then pyrrolidine-1-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridin-2-yl]amide (80 mg) was added thereto, followed by stirring under a nitrogen atmosphere for 2 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and water (60 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:3, then ethyl acetate). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether was then added and concentrated under a reduced pressure again to give a solid. The resultant solid was then suspended in diethyl ether (4 ml)-ethanol (0.4 ml), filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (15 mg, 11.5%) as colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CCOCC.CCCCCC.C(OCC)C>[Cl:11][CH2:12][CH2:13][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: OCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: ClCCOc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxyindole (3.99 g, 30 mmol), 2-chloroethanol (6.03 ml, 90 mmol) and triphenylphosphine (23.6 g, 90 mmol) in tetrahydrofuran is treated with diethyl azodicarboxylate (14.1 ml, 90 mmol) under nitrogen at room temperature, stirred for 2 hr at room temperature and concentrated in vacuo to give a residue. Cooled diethyl ether is added to the residue and the solid triphenylphosphine oxide is precipitated and removed by filtration. The filtrate is concentrated and purified by flash chromatography (silica gel, EtOAc/hexane: 1.5/8.5) to give an oil. After trituration with Et2O/hexane (1/10), the title compound is obtained as a white solid, 4.8 g (82%) mp 60° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=5[O:23][C:22]4=[O:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc2c(c1)oc(=O)n2CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 30.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9 mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K2CO3 (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours. The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2.3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31%) of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone, m.p.=152°-154° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8]([CH2:11]P(=O)(OCC)OCC)(=[O:10])=[O:9].[CH:20]([C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=O>O1CCCC1>[CH3:7][S:8]([CH:11]=[CH:20][C@H:22]1[CH2:23][CH2:24][C@H:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:26][CH2:27]1)(=[O:9])=[O:10]
Reactant: CCOP(=O)(CS(C)(=O)=O)OCC
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=CS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 M potassium tert-butoxide in tetrahydrofuran (THF) (1.0 mL, 1.0 mmol) was added diethyl [(methylsulfonyl)methyl]phosphonate (0.21 g, 0.92 mmol) dropwise at 0° C. and the resulting mixture was stirred at 0° C. for 1 h. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate (0.15 g, 0.66 mmol) in tetrahydrofuran (4.6 mL) was added dropwise, then cooling bath was removed and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with water, concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.14 g, 70%) as a mixture of E- and Z-isomers. LCMS calculated for C14H25NO4SNa (M+Na)+: m/z=326.2. Found: 326.1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([Li])CCC.CN(C)[CH:22]=[O:23]>O1CCCC1.[Cl-].[Na+].O>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:10]=[C:2]([CH:22]=[O:23])[C:3]2[CH:4]=[CH:5][NH:6][C:7]=2[CH:8]=1
Reactant: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)cc2[nH]ccc12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-bromo-6-(trifluoromethyl)-1H-indole (5.23 g, 19.81 mmol) in tetrahydrofuran (20 ml) was cooled to −78 ° C. and treated slowly with n-butyllithium (1.6 M solution in hexanes, 39.6 ml, 63.4 mmol). The solution was stirred for 15 min at −78 ° C., and then treated with dimethylformamide (7.67 ml, 99 mmol), and stirred for 30 minutes more, allowing the reaction to warm to ambient temperature. The resulting solution was poured into brine and extracted with ethyl acetate. The pooled organics were dried over sodium sulfate and concentrated to give an amber oil. Column chromatography (ethyl acetate/hexanes gradient elution) afforded 1.17 g, (32%). 1H-NMR (CDCl3, 500 MHz) δ ppm 10.28 (s, 1H), 8.72 (br s, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H). Mass spec.: 214.14 (MH)+.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[Br:9][C:10]1[S:14][C:13]2=[N:15][CH:16]=[CH:17][N:12]2[N:11]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:9][C:10]1[S:14][C:13]2=[N:15][CH:16]=[C:17]([I:8])[N:12]2[N:11]=1
Reactant: Brc1nn2ccnc2s1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1nn2c(I)cnc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
NIS (3.83 g, 16.2 mmol, 1.1 eq) was added to a solution of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (3.0 g, 14.7 mmol, 1 eq) in dry DMF (50 mL). The mixture was stirred at RT for 4 h and then poured into aq. Na2S2O3 (10%) and diluted with EtOAc. The organic phase was washed with water, dried and concentrated to give the desired product (pale brown solid; 4.34 g, yield 89%). 1H (300 MHz, CDCl3): δ/ppm 7.29 (1H, s).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2].[NH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH2:51])=[O:50].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:47][C:48]([C:49](=[O:50])[NH2:51])([CH3:53])[CH3:52])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(N)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole (0.2 g) in N,N-dimethylformamide (3 mL) were added 2-amino-2-methylpropionamide (47 mg), 1-hydroxybenzotriazole (50 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg) and triethylamine (0.13 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carbamoyl-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.12 g). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.06 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.1 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (80 mg).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][C:6]2[C:16]([C:19]([O:21]C)=[O:20])=[CH:17][S:18][C:5]1=2>CO.O1CCOCC1.O>[O:3]=[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:7][C:6]2[C:16]([C:19]([OH:21])=[O:20])=[CH:17][S:18][C:5]1=2
Reactant: COC(=O)c1csc2c(=O)cc(-c3ccccc3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C(O)c1csc2c(=O)cc(-c3ccccc3)oc12
Temperature: 22.5 °C
Yield: 93.6 %

Procedure:
26 mL of 0.6N sodium hydroxide was added to a solution of 3.82 g of Compound 1F in 174 mL of methanol and 87 mL of dioxane at 50° C. while stirring. The mixture was stirred at 50° C. for an additional 20 minutes, cooled to 20-25° C., then diluted with 280 mL of water, filtered and acidified with 1N hydrochloric acid to pH=1. The suspension of that formed precipitate gel was stirred at 60° C. for 2 hours, until a heavier filtrable solid was obtained. This solid was filtered and dried to yield 3.4 g of the title compound, which was suitable for use in the next reaction step without further purification. It was crystallized from ethanol to yield the analytical sample, melting at 282-283° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([Cl:30])=[O:29])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[ClH:30].[N:1]1([CH2:6][C:7]2([C:28](=[O:29])[CH2:27][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:31])([F:19])[F:32])=[CH:26][CH:25]=3)[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c1CCNC2CN1CCCC1
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1CCNC2(CN1CCCC1)C(=O)Cc1ccc(C(F)(F)F)cc1
Product: Cl
Reaction time: 8 h

Procedure:
750 mg (3.05 mmoles) of 1-(pyrrolidin-1-yl)methyl-5-methoxy1,2,3,4-tetrahydroisoquinoline were dissolved in 10 ml of dry chloroform. 810 mg (3.64 mmoles) of 4-trifluoromethylphenyl acetyl chloride, dissolved in 10 ml of chloroform, were added dropwise to the solution at 0° C. The reaction mixture was allowed to reach room temperature and left overnight.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[C:19](Cl)[N:18]=[C:17]([Cl:22])[CH:16]=3)[C:11]2=[O:23])[CH2:3][CH2:2]1.[CH:24]1(B(O)O)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:22][C:17]1[CH:16]=[C:15]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:3][CH2:2]3)[C:11]2=[O:23])[CH:20]=[C:19]([CH:24]2[CH2:26][CH2:25]2)[N:18]=1
Reactant: OB(O)C1CC1
Reactant: O=C1N(c2cc(Cl)nc(Cl)c2)CCN1c1cnccc1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1N(c2cc(Cl)nc(C3CC3)c2)CCN1c1cnccc1C1CC1
Yield: 19.7 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropyl pyridin-3-yl)-3-(2,6-dichloropyridin-4-yl)imidazolidin-2-one (I-46a: 100 mg, 0.2865 mmol) was reacted with cyclopropyl boronic acid (74 mg, 0.8593 mmol), Pd(PPh3)4 (7 mg, 0.0057 mmol), sodium carbonate (69 g, 0.6590 mmol) and toluene (5 mL) in seal tube at 120° C. for 12 hours. Purification by column chromatography on silica gel (1% methanol in chloroform), followed by preparative HPLC afforded 20 mg of the product (20% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:14]C(=O)OC(C)(C)C)([CH2:12][OH:13])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:22].O1CCOCC1>>[Cl-:22].[OH:13][CH2:12][C:3]([CH2:2][OH:1])([NH3+:14])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)C(=O)c1ccccc1
Solvent: C1COCCO1
Product: [Cl-]
Product: [NH3+]C(CO)(CO)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
tert-butyl 3-hydroxy-2-(hydroxymethyl)-1-oxo-1-phenylpropan-2-ylcarbamate (1) (120 mg, 0.4 mmol, 1.0 equiv.) was added to a 10 mL RBF followed by a 4.0 N HCl-Dioxane solution (3.0 mL, 12.0 mmol, 30.0 equiv.). The solution was stirred for 1 h and 2 mL of the solvent was evaporated with a steady stream of N2 (g). The resulting suspension was taken up in Et2O giving a white precipitate. The mixture was filtered, washed with Et2O (3×10 mL) and dried under vacuum to give 77 mg (83%) of 3 as a white solid. Decomposition occurs at 173-174° C.; 1H NMR (500 MHz, DMSO) δ 8.51 (br s, 3H, C—NH3), 7.89 (d, J=7.5 Hz, 2H, Ph-H), 7.64 (t, J=7.5 Hz, 1H Ph-H), 7.53 (t, J=7.5 Hz, 2H, Ph-H), 5.77 (s, 2H, (CH2—OH)2), 4.11 (d, J=12.0 Hz, 2H, C—CH2), 3.89 (d, J=12.0 Hz, 2H, C—CH2); 13C NMR (125 MHz, DMSO) δ 197.6, 135.1, 132.7, 128.7, 128.1, 73.1, 61.2; LRMS (ESI-MS m/z): Mass calcd for C10H14NO3 [M]+, 296.22. Found 296. Anal. calcd for C10H14ClNO3: C, 51.84; H, 6.33; N, 6.05 Found: C, 51.70; H, 6.33; N, 5.84.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:14](=O)[C:15]3[CH:20]=[CH:19][C:18]([C:21]([C:24]#[N:25])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1>CC(O)=O.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]3[N:9]2[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:23])([CH3:22])[C:24]#[N:25])=[CH:17][CH:16]=2)=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1ccc(C(=O)NNc2cnc3ccc(Br)cc3n2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C#N)c1ccc(-c2nnc3cnc4ccc(Br)cc4n23)cc1
Temperature: 25 °C
Yield: 8.5 %

Procedure:
A solution of N′-(7-bromoquinoxalin-2-yl)-4-(2-cyanopropan-2-yl)benzohydrazide (2.2 g, 0.054 mol) in 3 mL of AcOH was stirred at 100° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (5 mL). The solid was collected on a filter, and washed with Sat. NaHCO3 (5 mL) to give 2-(4-(8-bromo-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl) phenyl)-2-methylpropanenitrile as a yellow solid (1.8 g, yield 85.0%). MS (m/z): 392 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([CH:36]1[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[CH:36]1([S:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:18]=[C:19]4[CH:25]=[CH:24][NH:23][C:20]4=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:34])=[O:35])[CH2:38][CH2:37]1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)C1CC1
Product: O=S(=O)(c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1)C1CC1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. for C22H17FN2O2S, 392.10; m/z found, 393.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.62-8.52 (m, 1H), 8.24-8.12 (m, 2H), 7.71-7.63 (m, 1H), 7.62-7.53 (m, 2H), 7.45-7.31 (m, 4H), 6.64-6.55 (m, 1H), 2.19-2.08 (m, 1H), 1.18-1.08 (m, 2H), 0.93-0.82 (m, 2H).