Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27](/[CH:28]=[CH:29]/B(O)O)=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.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>[Cl:23][C:24]1[CH:34]=[CH:33][C:27](/[CH:28]=[CH:29]/[C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-n2cnc(/C=C/c3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 55 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one Part A of Procedure 11 (40 mg, 0.12 mmol), (E)-4-chlorostyrylboronic acid (56 mg, 0.30 mmol), potassium phosphate, tribasic (78 mg, 0.37 mmol), and palladiumtetrakis (7 mg, 6.16 μmol) in DMF (1 mL) was stirred under nitrogen at 55° C. for 1 hour. The mixture was diluted with DCM, washed with water, sat. NaHCO3 and brine, then dried (Na2SO4) and concentrated to afford the crude product. The crude product was purified using ISCO flash chromatography (silica gel/hexanes-ethyl acetate 100:0 to 0:100 gradient). The product was re-purified using HPLC (C18 column/10:90 to 90:10 MeOH—H2O) to afford the desired product (E)-6-(4-chlorostyryl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one J-1 (16.8 mg, 0.039 mmol, 31% yield) as a light yellow solid. LC/MS 427 (M+H)+, tR 0.97 min (method 5); 1H NMR (400 MHz, CHLOROFORM-d) δ 8.15 (1H, s), 7.76 (1H, d, J=15.56 Hz), 7.53 (2H, d, J=8.28 Hz), 7.38 (2H, d, J=8.28 Hz), 7.01 (1H, d, J=8.03 Hz), 6.82-6.98 (3H, m), 6.46 (1H, s), 3.89 (5H, br. s.), 1.37 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([O-])=O.[NH4+]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]1[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=1[F:1])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccccc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2n1Cc1ccccc1F

Procedure:
27.84 g (81.33 mmol) of ethyl 1-(2-fluorobenzyl)-5-nitro-1H-indole-2-carboxylate from Example II are initially charged in 750 ml of ethyl acetate and 750 ml of ethanol. 20.51 g (325.31 mmol) of ammonium formate and 2.78 g of palladium on activated carbon are added. The mixture is boiled at reflux and, after one hour, cooled and filtered off through kieselguhr. The filter cake is washed with ethyl acetate. The solvent is removed under reduced pressure and the residue is dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:29]=[C:30]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:29]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) according to the general procedure K. Obtained as a light yellow solid (489 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH2:13]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11][CH3:12])=[CH:20][CH:19]=1)=[O:17])[CH3:14]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2OC)cc1
Yield: 76.8 %

Procedure:
A mixture of 2-bromo-1-methoxy-4-nitro-benzene (1 g), 4-ethoxycarbonyl-phenyl boronic acid (836 mg), cesium carbonate (1.4 g) and tetrakis(triphenylphosphine)palladium0 (catalytic quantity), in 1:2 aqueous DME (45 ml) was heated to reflux for 18 h. The mixture was then cooled and partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue purified on silica gel. Elution with 5-40% ethyl acetate:petrol gave a yellow solid (997 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C@H:12]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:11][C@@H:10]1[OH:29].CCN(CC)CC.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C@H:9]1[C@@H:10]([O:29][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11][C@@H:12]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:4])=[O:3]
Reactant: CCCCCCCC[C@@H]1[C@@H](CCO)[C@@H](O)C[C@H]1OC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC[C@@H]1[C@@H](CCOS(C)(=O)=O)[C@@H](OS(C)(=O)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
MsCl (0.60 mL, 7.72 mmol) was added to an ice cold solution of 6-1 (447 mg, 1.31 mmol) and Et3N (1.3 mL, 9.33 mmol) in dichloromethane (5 mL). The reaction was allowed to warm to room temperature and after 3 h, saturated NaHCO3 solution was added. The resulting mixture was extracted with dichloromethane (3×) and the combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (Combiflash unit by Isco) gave the title compound (326 mg, 50%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>C1(C)C=CC=CC=1>[C:22]([NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: C=C(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCCC[Si](OCC)(OCC)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
A solution of 3-aminopropyltriethoxysilane (20.0 g) in toluene (200 ml) was added to a 500 ml three neck flask equipped with magnetic stir bar, addition funnel, and nitrogen inlet. A total of 9.11 g of triethylamine was added to the solution and the solution was cooled to 0° C. in an ice bath. A total of 9.41 g of methacryloyl chloride was added dropwise to the reaction by the addition funnel at a rate such that the temperature did not exceed 5° C. The reaction was stirred overnight with gradual warming to room temperature. The reaction mixture was then washed 4 times with 200 ml of ice water, dried over magnesium sulfate and concentrated under vacuum. The yield was 38.4 percent and the reaction product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH2:43])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:44]N>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH:43][NH2:44])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(N)=O)cc1
Reactant: NN
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)NN)cc1
Reaction time: 3 h
Yield: 60 %

Procedure:
A portion of the crude intermediate of example 58 above, (50 mg, 0.06 mmol) was added to a solution of hydrazine in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 25 mg, 60% of the desired material.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28][CH2:29][CH2:30][C:31]([NH:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[N:9][N:8]2[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)=[O:32]
Reactant: O=C(O)CCSc1ccc2ccccc2c1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Product: O=C(CCSc1ccc2ccccc2c1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(naphthalen-2-ylsulfanyl)-propionic acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H), 1.99 (m, 2 H), 2.79 (t, J=7.02 Hz, 2 H), 3.04 (m, 2 H), 3.40 (t, J=7.02 Hz, 2 H), 3.53 (m, 2 H), 3.71 (q, J=6.10 Hz, 2 H), 4.68 (t, J=6.26 Hz, 2 H), 7.06 (m, 1 H), 7.50 (m, 3 H), 7.70 (m, 1 H), 7.88 (m, 4 H), 8.09 (s, 1 H), 8.30 (s, 1 H), 9.62 (br s, N H); MS (DCI/NH3) m/z 445 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1>CO.[C].[Pd]>[OH:23][C:16]1[C:15]([CH2:14][NH:13][C:11]([C:10]2[C:5]3[CH:4]=[N:3][CH:2]=[N:7][C:6]=3[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:9]=2[CH3:24])=[O:12])=[C:20]([CH3:21])[CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3ncncc23)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
To a solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (140 mg, 0.30 mmol) in MeOH (10 mL). Palladium-carbon catalyst (10%, 20 mg) was added, the mixture solution was stirred at 25° C. for 12 hours under hydrogen atmosphere (4 bar). The mixture was filtered and concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (93 mg, 72%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH2:13]>C(O)(=O)C.C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[O:11][C:7](=[O:13])[NH:8][C:9]=2[CH:10]=1
Reactant: O
Reactant: O=C1Nc2cc(I)ccc2C1=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2cc(I)ccc2c(=O)o1
Temperature: 80 °C
Yield: 81.8 %

Procedure:
To a stirred warm (80° C.) solution of 6-iodo-1H-indole-2,3-dione (3.0 g, 11 mM) in acetic acid (10 mL) and acetic anhydride (10 mL) was added in small portions chromium trioxide (1.83 g, 18.3 mM) while maintaining the temperature of the reaction mixture at 80°-90° C. The reaction mixture was then heated at 80° C. for 10 min, cooled and poured into water. The resulting mixture was filtered and the collected solids dried to provide the title compound as a yellow solid (2.6 g, 81.8%); MS(CI): 290 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[NH2:29].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:29][C@@H:24]2[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]2[CH3:22])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: C[C@@H]1CCCC[C@H]1N
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c([N+](=O)[O-])c1
Reaction time: 1.5 h
Yield: 97.7 %

Procedure:
To a solution of 6.47 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 35 ml of abs. DMF was added 13.47 g of potassium carbonate, followed by 4.96 g of (1R,2R)-2-Methyl-cyclohexylamine-hydrochloride. After 1.5 h at 60° C., the mixture was poured into water, the pH was adjusted to 5-6 by the addition of 2 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 9.28 g (98%) of 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-nitro-benzoic acid methyl ester.
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:37])=[C:12]([CH2:32][O:33]C(=O)C)[C:13]([I:31])=[C:14]([C:29]=2[I:30])[C:15]([NH:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][O:21]C(=O)C)=[O:16])=[O:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:6][CH:5]([CH2:4][OH:3])[C:7]([NH:9][C:10]1[C:11]([I:37])=[C:12]([CH2:32][OH:33])[C:13]([I:31])=[C:14]([C:29]=1[I:30])[C:15]([NH:17][CH2:18][CH:19]([OH:25])[CH2:20][OH:21])=[O:16])=[O:8]
Reactant: CC(=O)OCc1c(I)c(NC(=O)C2COC(C)(C)O2)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(NCC(O)CO)c1c(I)c(CO)c(I)c(NC(=O)C(O)CO)c1I
Temperature: 25 °C
Reaction time: 17 h

Procedure:
5-(2,2-Dimethyl-1,3-dioxolane-4-carbamido)-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (0.80 g, 9.16 mmol) was dissolved in methanol (7 ml) and potassium carbonate (0.17 g, 12.3 mmol) was added. The mixture was stirred at room temperature for 17 h. The mixture was filtered and pH of the filtrate was adjusted to 1 using aqueous SM hydrochloric acid, and the mixture was stirred for further 5 h at room temperature. The reaction mixture was then evaporated to a solid residue, which was purified by preparative HPLC. Yield: 0.41 g (49%) of a white freeze dried product.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[C:14]([C:17](=[O:19])[CH3:18])[O:15][CH:16]=1.C([O:27][C:28](=O)[C:29]([F:33])([F:32])[CH2:30][CH3:31])C1C=CC=CC=1>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:17](=[O:19])[CH2:18][C:28](=[O:27])[C:29]([F:33])([F:32])[CH2:30][CH3:31])[O:15][CH:16]=1
Reactant: CCC(F)(F)C(=O)OCc1ccccc1
Reactant: CC(=O)c1cc(Br)co1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(F)(F)C(=O)CC(=O)c1cc(Br)co1
Temperature: -78 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
A solution of lithium hexamethyldisilazide (2.4 mL of a 1.0M solution in THF, 2.4 mmol) was diluted with THF (2 mL) and cooled in a −78° C. bath. To this cold solution was added 1-(4-bromo-furan-2-yl)-ethanone (317 mg, 1.68 mmol) dropwise as a solution in THF (4 mL), followed by a THF (1 mL) rinse of the vial and syringe to insure complete transfer. After ˜2 minutes the resulting red enolate solution was treated with a solution of 2,2-difluoro-butyric acid benzyl ester (357 mg, 1.67 mmol) in THF (4 mL), followed by a THF (1 mL) rinse of the vial and syringe to insure complete transfer. After the completion of the addition, the cooling bath was removed and the reaction was allowed to warm to ambient temperature. After stirring for 16 hrs at ambient temperature, the reaction was quenched by the addition of H2O (10 mL), and diluted with ether (50 mL). Phosphoric acid (2M, aqueous) was added to the mixture to bring the pH below 3. The layers were separated and the aqueous was extracted with ether (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a dark brown oil. The crude material was purified by flash chromatography eluting with a gradient from 0% to 30% ethyl acetate/hexane to afford 1-(4-bromo-furan-2-yl)-4,4-difluoro-hexane-1,3-dione (224 mg, 46% yield) as a red oil. The compound exists primarily in its' enolic form. 1H-NMR (400 MHz, CDCl3): δ 14.77 (1H, br s), 7.62 (1H, s), 7.27 (2H, s), 6.45 (1H, s), 2.12 (2H, t of q, JH-H=7.6 Hz, JH-F=16.7 Hz), 1.05 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([O:21]C)=[O:20])=[CH:17][N:18]=3)[CH:15]=2)[CH2:4][CH2:3]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([OH:21])=[O:20])=[CH:17][N:18]=3)[CH:15]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCN(CCc2ccc3ncc(C(=O)O)n3c2)CC1
Temperature: 60 °C

Procedure:
To a stirring solution of methyl 6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxylate (113) (215 mg, 0.68 mmol) in THF:MeOH (4:1, 4 mL) was added 2N LiOH (3 mL). The reaction was heated at 60° C. for 45 minutes. The pH was adjusted between 4-5 with 1N HCl and concentrated. The crude product was purified by preparative HPLC to afford 6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (114). 1H NMR (400 MHz, d6-DMSO) δ 9.25 (s, 1H), 8.35 (s, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.61 (dd, J=1.6, 9.2 Hz, 1H), 4.65-4.19 (m, 8H), 3.49-3.30 (m, 2H), 3.04-2.99 (m, 2H), 2.81 (s, 3H). MS m/z 316.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:15])[CH:10]=[N:9]2)=[C:5]([CH3:25])[O:4][N:3]=1.[C:26](=[O:31])=[N:27][C:28](Cl)=[O:29]>C1COCC1>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:28](=[O:29])[NH:27][C:26](=[O:31])[N:16]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]3=[O:15])[CH:10]=[N:9]2)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: O=C=NC(=O)Cl
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)NCCc2ccccc2)cn1
Solvent: C1CCOC1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]c(=O)n(CCc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3-phenethylurea (example 9-7a) (100 mg, 0.29 mmol) in THF (2 mL) was cooled to 0° C. and n-chlorocarbonyl isocyanate (93 mg, 0.88 mmol) was slowly added. After addition, the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was concentrated and the residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford (1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3-phenethyl-1,3,5-triazinane-2,4,6-trione (100 mg, 83%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.13 (s, 3H), 2.39 (s, 3H), 2.82 (t, J=5.8 Hz, 2H), 3.88 (t, J=8.0 Hz, 2H), 5.17 (s, 2H), 7.19-7.31 (m, 5H), 7.44 (s, 1H), 7.89 (s, 1H), 11.84 (s, 1H). LC/MS; [M+H] calculated for C20H20N6O4; expected 409.15; found 409.20. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 3.03 μM.
Reaction SMILES: [C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Cl:10].[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[C:1](=[O:13])([O:11][CH3:12])[O:2][C:3]1[CH:8]=[C:7]([N+:14]([O-:16])=[O:15])[C:6]([F:9])=[CH:5][C:4]=1[Cl:10]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Oc1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Yield: 90 %

Procedure:
To a suspension of 2-chloro-4-fluorophenyl methyl carbonate (110 g, 0.54 mol) in conc. H2SO4 (50 mL) was slowly added a mixture comprised of conc. H2SO4 (40 mL) and fuming HNO3 (40.8 mL, 0.89 mol). The resultant mixture was stirred for 30 min at 0° C. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluoro-5-nitrophenyl methyl carbonate (120g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J=7.2 Hz, 1H), 8.12 (d, J=10.8 Hz, 1H), 3.89 (s, 3H); MS (ESI) m/z: 250.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:30]=2)=[O:28])=[CH:22][C:18]=1[C:19](O)=[O:20]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:12][C:19](=[O:20])[C:18]3[CH:22]=[C:23]([NH:26][C:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[CH:30]=4)=[O:28])[CH:24]=[CH:25][C:17]=3[Cl:16])[CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccnc(N2CCOCC2)c1
Reactant: CN1CCN(Cc2cccc(N)c2)CC1
Product: CN1CCN(Cc2cccc(NC(=O)c3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3Cl)c2)CC1

Procedure:
Using an analogous procedure to that described in Example 4, 3-(4-methylpiperazin-1-ylmethyl)aniline was reacted with 2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)benzoic acid to give the title compound in 32% yleld; NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.31-2.35 (m, 8H), 3.42 (s, 2H), 3.49-3.53 (m, 4H), 3.69-3.72 (m, 4H), 7.02 (d, 1H), 7.1 (d, 1H), 7.22-7.3 (m, 2H), 7.57-7.65 (m, 3H), 7.84-7.94 (m, 2H), 8.28 (d, 1H), 10.47 (s, 1H), 10.52 (s, 1H); Mass Spectrum: M+H+ 549 and 551.
Reaction SMILES: [O-]CC.[Na+].Cl.[NH2:6][C:7]([NH2:9])=[NH:8].ClCCl.[CH2:13]([O:15][C:16](=[O:27])[C:17]([C:21](=O)[C:22]([F:25])([F:24])[F:23])=[CH:18]OC)[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[C:21]([C:22]([F:23])([F:24])[F:25])=[N:8][C:7]([NH2:9])=[N:6][CH:18]=1)=[O:27])[CH3:14]
Reactant: CCOC(=O)C(=COC)C(=O)C(F)(F)F
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnc(N)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Sodium ethoxide (2 eq, 83.8 mmol, 5.7 g) was added in one portion to a solution of guanidine hydrochloride (4 g, 41.9 mmol) in absolute ethanol (100 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. A dichloromethane solution of 3-methoxy-2-(2,2,2-trifluoro-acetyl)-acrylic acid ethyl ester was then added and the mixture was stirred at ambient temperature for an additional 20 hours. The solvent was then removed by evaporation, water was added to the residue, and the mixture was stirred vigorously for 2 hours then allowed to stand at room temperature. The resulting solid was isolated by filtration, washed with water then dried in vacuo to afford 6.10 g (62% yield) of 2-amino-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester. m/z (M+H)=236.2.