Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCCC1=O.[CH2:8]([N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1Cl)[C:9]#[C:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O>[CH2:8]([N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1[N:33]1[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34]1)[C:9]#[C:10][CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(Cl)nc2cnn(C)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Temperature: 130 °C
Yield: 99.2 %

Procedure:
5 ml of 1-methyl-2-pyrrolidone was added to a mixture consisting of 1.183 g of 3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one, 0.829 g of potassium carbonate, and 1.395 g of t-butyl piperazine-1-carboxylate under a nitrogen atmosphere. The resulting mixture was heated at 130° C. for 6 hours. The reaction mixture was cooled, and 50 ml of water was added thereto. Then, the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed twice with 50 ml of water and then with 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. Thus, 1.916 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].O[NH3+:20].C([O-])(=O)C.[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:20])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
A mixture of 4-benzyloxy-3-hydroxybenzaldehyde (19.0 g), hydroxylammonium chloride (8.6 g), sodium acetate (13.7 g), water (30 mL) and ethanol (150 mL) was stirred at 80° C. for 8 hours. Water (100 mL) was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and then pyridine (20 mL) was added. Trifluoroacetic anhydride (35.3 mL) was added dropwise under ice-cooling, and the resulting mixture was stirred at room temperature for 6 hours. Two mol/L hydrochloric acid was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/10) to give the title compound (1.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[C:31]([O:33][CH3:34])=[O:32])[C:13]1=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C@H:20]1[CH2:19][C@@H:18]([C:31]([O:33][CH3:34])=[O:32])[C@@H:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:13]2=[O:35])[CH2:22][CH2:21]1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)-cyclohexanecarboxylate in CH2Cl2 (10 mL) was treated with TFA (15 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue dissolved in CH2Cl2 and washed with NaHCO3(aq), brine, and dried over MgSO4. The solution was filtered and concentrated in vacuo to give 0.75 g (59%) of (1R,2S,5R)-methyl 5-amino-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexanecarboxylate as a white solid. MS found: (M+H)+=390.3.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CS([C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:27]=[C:28]([S:32]([N:35]4[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36]4)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)[N:19]2[N:18]=1)=O>CS(C)=O>[OH:40][C@H:37]1[CH2:38][CH2:39][N:35]([S:32]([C:28]2[CH:27]=[C:26]([C:25]3[N:19]4[C:20]([CH:21]=[N:22][C:17]([NH:13][C:10]5[CH:11]=[C:12]6[C:7]([CH2:6][CH2:5][N:4]6[C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=5)=[N:18]4)=[CH:23][CH:24]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH2:36]1
Reactant: CC(=O)N1CCc2ccc(N)cc21
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)N4CC[C@H](O)C4)c3)n2n1
Solvent: CS(C)=O
Product: CC(=O)N1CCc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)N6CC[C@H](O)C6)c5)n4n3)cc21
Yield: 17 %

Procedure:
1-acetyl-6-aminoindoline and (S)-1-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonyl]-pyrrolidin-3-ol were reacted in an analogous manner to Example 881D. The mixture was then taken up in DMSO and purified by Gilson prep HPLC to afford the product as a TFA salt (16 mg, 17%). HPLC purity=94%, rt=2.636 min, LCMS=519.2 (M+H). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.41 (s, 1H0, 9.01 (s, 1H), 8.58 (d, J=8.3 Hz, 1H), 8.31 (s, 1H), 8.26 (s, 1H0, 7.76 (d, J=8.1 Hz, 1H), 7.68 (dd, J=8.1 Hz, 8.1 Hz, 1H), 7.52 (dd, J=8.3 Hz, 1.8 Hz, 1H), 7.27 (d, J=4.7 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 6.97 (d, J=4.9 Hz, 1H), 4.18-4.08 (m, 4H), 3.31-3.20 (m, 3H), 3.12-3.02 (m, 3H), 2.17 (s, 3H), 1.80-1.70 (m, 1H), 1.68-1.60 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:9][C@@H:8]2[C@@H:4]([C@@H:5]([OH:12])[C@@H:6]([CH2:10][OH:11])[O:7]2)[O:3]1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.O>[OH:12][CH:5]1[CH:4]2[CH:8]([O:9][C:2]([CH3:13])([CH3:1])[O:3]2)[O:7][CH:6]1[CH2:10][O:11][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)O[C@H]2O[C@H](CO)[C@H](O)[C@H]2O1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC2OC(COC(=O)c3ccccc3)C(O)C2O1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
1,2-O-Isopropylidene-α-D-xylofuranose (Aldrich, 20 g, 100 mmol) in CH2Cl2 (300 mL) and TEA (44 mL, 310 mmol) was cooled to 0° C. The solution was treated with benzoyl chloride (12.8 mL, 110 mmol) in CH2Cl2 (10 mL) dropwise and stirred for 2 h. The solution was diluted with H2O (30 mL) and washed with saturated NaHCO3 (2×30 mL). The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was treated to flash column chromatography (SiO2, 4×20 cm, 0-100% EtOAc-hexanes gradient) to afford compound 9.2 (22.0 g, 71% yield). (Taken from: Johnson, C. R.; Bhumralkar, D. R. Nucleosides & Nucleotides 1995, 14, 185.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:13][CH2:14][O:15][CH3:16].O>CN(C)C=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH2:13][CH2:14][O:15][CH3:16])=[CH:3][C:2]=1[F:1]
Reactant: COCCBr
Reactant: Oc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 3,4-difluoro-phenol (10 g, 76.9 mmol) (Aldrich) in N,N-dimethylformamide (100 mL) was added sodium hydride (4.6 g, 115 mmol) and 1-bromo-2-methoxy-ethane (12.8 g, 92.2 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 2 h, then heated at 80 ° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over dried over MgSO4, filtered and concentrated. The residue was purified with chromatography (EtOAc:Hexane=1:10) to give 1,2-difluoro-4-(2-methoxy-ethoxy)-benzene as colorless oil (Yield 6.3 g, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[C:9](N(OC)C)=[O:10])=[CH:4][C:3]=1[O:17][CH3:18].[Li][CH3:20]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:16])[C:9](=[O:10])[CH3:20])=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(C(C)(C)C(=O)N(C)OC)ccc1F
Reactant: [Li]C
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C(C)=O)ccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-fluoro-3-methoxyphenyl)-N-methoxy-N,2-dimethylpropanamide (123 g, 0.48 mol) in THF (1 L)-78° C. was added 3M ethereal solution of MeLi (210 mL, 0.627 mol). The resulting solution was warmed to ambient temperature and stirred 16 h. The reaction mixture was quenched with 3N HCl (400 mL) and extracted with EtOAc (600 mL×2). The combined extracts were washed with satd NaHCO3 (1.0 L) and brine (1.0 L), then dried over MgSO4 and concentrated at reduced pressure to give 3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one as yellow color oil (92.5 g, 91%). 1H NMR (400 MHz, CDCl3): δ 7.05 (m, 1H), 6.83-6.78 (m, 2H), 3.88 (s, 3H), 1.95 (s, 3H), 1.47 (s, 6H).
Reaction SMILES: [Cl:1][C:2]([Cl:20])([Cl:19])[CH2:3][O:4][C:5]([O:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1)=[O:6].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:20][C:2]([Cl:1])([Cl:19])[CH2:3][O:4][C:5]([O:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=[O:15])[N:13]=1)=[O:6]
Reactant: CCOC(=O)c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of ethyl 2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazole-4-carboxylate (23 g) in CH2Cl2 (200 mL) is added a solution of diisobutylaluminum hydride (1.0 M in CH2Cl2, 120 mL) at −78° C. over 30 minutes. The resulting mixture is kept at −78 ° C. for 10 hours. The excess hydride is quenched with acetic acid (5 mL) and the reaction is warmed to ambient temperature, and the mixture is stirred with sat. aq. Rochelle's salt (150 mL) until the suspension clears. The organic layer is washed with 10% aq NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. Purification by column chromatography on SiO2 (toluene/ethyl acetate, 6:1) affords the product as a light yellow syrup.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C#N)c3)C2=O)cn1
Yield: 21 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-(bromomethyl)benzonitrile. Yield 21%. MS M+H calculated 411.1. Found 411.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1 uM.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[F:30][C:29]([F:32])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:13](=[O:14])[N:2]([C:3]3[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=3[C:5](=[O:6])[NH2:7])[CH3:1])=[CH:17][CH:18]=2)=[N:24][CH:25]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CNc1ccccc1C(N)=O
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1C(N)=O

Procedure:
The title product was prepared from 2-(methylamino)benzamide and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (57%, light yellow oil). HPLC-MS m/z=454.2 (M+Na), Rt: 3.66 min.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[N:10]=1)[CH2:2]2.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(O)C.C1(C)C=CC=CC=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>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[N:12]=2)=[CH:26][CH:25]=1
Reactant: O=C1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: Nc1ccc(B(O)O)cc1
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: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2nc(N3CCC(=O)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
A suspension of 1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one (1.0 g, 3.1 mmol), 4-aminophenylboronic acid, pinacol ester (1.0 g, 4.7 mmol), and tetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound as a golden yellow foam.
Reaction SMILES: C(OC1C(F)=CC=C2C=1C([C:19](=[O:25])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=CN2)C1C=CC=CC=1.[Br:26][C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[CH:32][N:33]2[CH2:36][CH3:37])=[C:29]([O:38][CH3:39])[CH:28]=1>>[Br:26][C:27]1[CH:35]=[C:34]2[C:30]([C:31]([C:19](=[O:25])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])=[CH:32][N:33]2[CH2:36][CH3:37])=[C:29]([O:38][CH3:39])[CH:28]=1
Reactant: CCn1ccc2c(OC)cc(Br)cc21
Reactant: CN(C)C(=O)C(=O)c1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Product: CCn1cc(C(=O)C(=O)N(C)C)c2c(OC)cc(Br)cc21
Yield: 88 %

Procedure:
Following the procedure (step 5, scheme 1) used to prepare compound 1-6a, compound 36-2 gave compound 36-3 (669 mg, 88%) as a pale pink solid. LCMS: calc 352.0 and found: 353.0 [MH]+.
Reaction SMILES: [CH2:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[K+]>CO>[CH2:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: C=C(Cc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
The ethyl α-methylenebenzenepropanoate of Step 8 (4.6 g, 24.3 mmol) was dissolved in methanol (12 mL) and then reacted with 2N potassium hydroxide (24 mL) solution. The mixture was stirred at room temperature for 4 hours and concentrated by evaporation. The residue was diluted with water and washed with ether. The aqueous layer was acidified to pH 2 with 1N HCl, and then extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated to give the title compound as colorless oil (2.8 g, 66% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F-].[Cs+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:17][C@H:18]1[O:20][CH2:19]1)(=O)=O.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:17][C@H:18]2[O:20][CH2:19]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OC[C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
3-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF, and cesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature, and (S)-glycidyl nosylate (1.71 g, 6.6 mmol) was added. The reaction mixture was stirred for 20 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent to give (S)-glycidyl m-nitrophenyl ether (1.02 g 80% yield, m.p 44-5° C.) as a yellowish solid.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C=O)C>>[C:21]1([S:27]([N:18]2[CH2:17][CH:16]=[C:15]([C:7]3[N:6]=[C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[N:9]4[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=34)[CH2:20][CH2:19]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nccn2c(C3CCC3)nc(C3=CCNCC3)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(C3=CCN(S(=O)(=O)c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-cyclobutyl-1-(1,2,3,6-tetrahydropyridin-4-yl)-imidazo[1,5-a]pyrazin-8-ylamine (20.0 mg, 0.0742 mmol), benzenesulfonyl chloride (9.48 uL, 0.0742 mmol), DIEA (0.0647 mL, 0.371 mmol) and DMF (1 mL, 0.01 mol) was stirred at rt for 10 min. The reaction mixture was directly given for Gilson HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=2.03 (dt, J=8.84, 2.65 Hz, 1H) 2.09-2.24 (m, 1H) 239-2.59 (m, 4H) 2.81 (d, J=1.77 Hz, 2H) 3.50 (t, J=5.68 Hz, 2H) 3.72 (quin, J=8.53 Hz, 1H) 3.85 (t, J=2.91 Hz, 2H) 5.93 (t, J=1.52 Hz, 1H) 6.82 (d, J=5.56 Hz, 1H) 6.99 (d, J=5.56 Hz, 1H) 7.55-7.69 (m, 3H) 7.86-7.90 (m, 2H). MS (ES+): m/z 409.99 (100) [MH+]. HPLC: tR=2.29 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[NH2:8].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[C:17](O)=[O:18]>>[OH:10][CH2:9][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[NH:8][C:17](=[O:18])[C:16]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[N:1]2
Reactant: Nc1ccc(CO)cc1N
Reactant: O=C(O)C(=O)c1cccs1
Product: O=c1[nH]c2ccc(CO)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared with (3,4-Diamino-phenyl)-methanol and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-Hydroxymethyl-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1C(=O)C2=CC=CC=C2C1=O)=[N:8]3.O.NN>C(O)C>[NH2:18][CH2:17][CH2:16][CH2:15][CH2:14][S:13][C:7]1[C:6]2=[C:2]([CH3:1])[N:3]=[C:4]3[N:5]2[C:9](=[CH:10][CH:11]=[CH:12]3)[N:8]=1
Reactant: Cc1nc2cccc3nc(SCCCCN4C(=O)c5ccccc5C4=O)c1n23
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc2cccc3nc(SCCCCN)c1n23
Yield: 72.6 %

Procedure:
To a suspension of 3.90 g (10.0 mmol) of 3-methyl-[4-(phthalimido)butan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 70 ml of ethanol was added 1.50 g (30.0 mmol) of hydrazine monohydrate. The mixture was heated for 2 hours under reflux. After cooling the resulting precipitates were filtered off. The filtrate was concentrated to give the residue, water was added, extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, then the solvent was distilled off to give 1.89 g of the desired compound (72.7%, pale brown solid)
Reaction SMILES: [C:1]1([C:7]2[C:8]([OH:29])=[C:9]([C:24]([O:26]CC)=O)[C:10]([CH:19]([O:22][CH3:23])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[C:1]1([C:7]2[C:8]([OH:29])=[C:9]([C:24]([NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[O:26])[C:10]([CH:19]([O:22][CH3:23])[CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nccs1
Reactant: CCOC(=O)c1c(C(CC)OC)nc(-c2ccccc2)c(-c2ccccc2)c1O
Product: CCC(OC)c1nc(-c2ccccc2)c(-c2ccccc2)c(O)c1C(=O)Nc1nccs1
Yield: 81.7 %

Procedure:
Using the procedure of Example 5, 9.3 g of the product of Step E and 12 g of 2-aminothiazole were reacted to obtain 8.65 g of the expected product which after crystallization from ether melted at 236° to 238° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>[O-]CC.[Na+]>[C:10]([CH:9]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CSc1ccc(CC#N)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(SC)cc1

Procedure:
By following the procedures outlined in Examples 1 and 3, p-methylthiophenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide solution to give ethyl 3-cyano-3-(p-methylthiophenyl)-pyruvate. This compound is similarly reacted with p-methylthiophenylacetonitrile which results in the formation of 2,5-di-(p-methylthiophenyl)-3,4-dioxoadiponitrile. The latter is refluxed with water, acetic acid and sulfuric acid to obtain 4,4'-dimethylthiopulvinic acid which is treated with acetic anhydride to give the corresponding acid lactone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1I)[OH:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH:27]([C:23]2[NH:24][CH:25]=[CH:26][N:22]=2)[OH:28])(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: OC(c1ncc[nH]1)c1ccccc1I
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1C(O)c1ncc[nH]1
Yield: 51.7 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (193 mg, 0.62 mmol) and 1H-imidazol-2-yl(2-iodophenyl)methanol (171 mg, 0.57 mmol) according to the method of Example 6 Step 4. Purification by flash column chromatography eluting with ethyl acetate gave solid (2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}phenyl)(1H-imidazol-2-yl)methanol (135 mg, 51%). 1H NMR (500 MHz, d6-DMSO) δ 11.94 (1H, s), 8.54 (1H, s), 8.30 (1H, s), 8.19 (1H, d, J=8.6 Hz), 8.11 (1H, d, J=7.9 Hz), 8.07 (1H, d, J=8.7 Hz), 8.02-7.97 (1H, m), 7.94-7.86 (2H, m), 7.84 (1H, d, J=7.7 Hz), 7.78-7.67 (2H, m), 7.61-7.53 (1H, m), 7.41-7.32 (2H, m), 6.88 (1H, s), 6.84 (1H, d, J=5.2 Hz), 6.52 (1H, s), 6.12 (1H, d, J=5.2 Hz); m/z (ES+) 459 [MH+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[CH:18][C:17]([CH:23]3[CH2:25][CH2:24]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:20]1([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([CH:23]3[CH2:25][CH2:24]3)[CH:18]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
4-(3,5-Dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7.4 g), which is the intermediate described in Preparation Example 50, was dissolved in chloroform (54 mL), 4N hydrogen chloride/ethyl acetate (21.5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added chloroform and saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with chloroform. The solvent was evaporated to give the title compound (4.6 g).