Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9]([NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=2)=[CH:10][C:11]2[C:12]([CH3:20])=[CH:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:33](=O)[CH3:34]>>[CH2:33]([N:21]([C:9]1[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:17][C:16]2[C:15]([CH3:19])([CH3:18])[CH2:14][CH:13]=[C:12]([CH3:20])[C:11]=2[CH:10]=1)[C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1)[CH3:34]
Reactant: CCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Reactant: CC=O
Product: CCCCCCOc1cc2c(cc1N(CC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Yield: 100 %

Procedure:
Following General Procedure D ethyl 4-(3-n-hexyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 112, 0.03 g, 0.07 mmol) was reacted with acetaldehyde and the resulting crude product, residue was purified by flash column chromatography (hexane:ethyl acetate=4:1) to afford 0.030 g (100%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH:11]([CH2:13]O)[N:12]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>N1C=CC=CC=1>[Br:35][CH2:13][CH:11]1[CH2:10][O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:12]1
Reactant: OCC1COC(c2ccc(F)cc2)=N1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: Fc1ccc(C2=NC(CBr)CO2)cc1
Yield: 46.5 %

Procedure:
To a solution of [2-(4-fluorophenyl)-1,3-oxazolin-4-yl]methan-1-ol (500 mg, 2.5 mmol) in pyridine (30 ml) cooled to 0° under inert conditions was added triphenylphosphine (1.3 g, 5.0 mmol). Carbon tetrabromide (817 mg, 2.5 mmol) was added in 4 fractions (˜200 mg each). The reaction mixture was stirred at zero degrees until all starting material was consumed, as shown by TLC (1:1 EtOAc:Hexanes). Methanol (˜5 ml) was added to quench the reaction. The solution was evaporated under reduced pressure, and the residue was purified using column chromatography (1:1 EtOAc:Hexanes) to yield compound 4-(bromomethyl)-2-(4-fluorophenyl)-1,3-oxazoline (300 mg, HNMR).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[N:13]2)[CH:3]=1
Reactant: c1cnc2nn[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1-n1nnc2ncccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
4-Chloro-2-fluoro-1-nitrobenzene (25 g, 142 mmol) and 1H-[1,2,3]triazolo[4,5-b]pyridine (18.8 g, 157 mmol) were slurried in DMF (50 mL) in a 200 mL round-bottom flask fitted with a magnetic stir bar. Potassium carbonate (29.5 g, 214 mmol) was added to the mixture and it was then heates while stirring in a 60°C. oil bath under N2. LCMS analysis after two hours indicated complete consumption of the nitrobenzene and two different isomeric forms of the desired product. Water (250 mL) was subsequently added in a steady stream to the rapidly stirring mixture to precipitate the crude product. The resultant precipitate was collected by vacuum filtration and washed twice with 100 mL water. The resultant damp filter was slurried with 50 mL toluene and the solids collected by vacuum filtration. This action was repeated three additional times and then the resultant solid was dried in vacuo to afford 21.6 g (55% yield) 1-(5-chloro-2-nitrophenyl)-1 H-[1,2,3]triazolo[4,5-b]pyridine as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].N=C=N.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=2)=[O:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Agent: N=C=N
Solvent: ClCCl
Product: CCN(CC(=O)Nc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 11 %

Procedure:
A mixture of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-ethyl glycine, Example 91B (0.074 g, 0.25 mmol), and resin bounded carbodiimide (0.50 g, 1.26 mmol/g) was shaken in CH2Cl2 (15 mL) for 30 min, then 4-fluoroaniline (0.044 g, 0.4 mmol) was added, and the mixture was shaken for another 12 h. The resin was filtered and washed with CH2Cl2 (2×10 mL). The resulting filtrate was concentrated under vacuum. The residue was triturated with Et2O to obtain 0.018 g (11%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.42-7.39 (m, 2H), 7.06-6.99 (m, 4H), 6.85 (dd, J=9.0, 2.7 Hz, 1H), 4.10 (s, 2H), 3.64 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H); MS (APCI) m/z 366 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:32][C:26]1[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=[C:24]([NH:23][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[CH:25]=1
Reactant: CCOC(=O)c1nn(C(C)C)cc1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C(C)C)cc1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-pyrazole-3-carboxylate (Step 41.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.65 min (HPLC 1); tR: 1.07 min (LC-MS 2); ESI-MS: 463 [M+H]+ (LC-MS 2); Rf=0.30 (EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([O:16][CH3:17])[C:12]([NH2:15])=[N:13][CH:14]=1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26]([NH:15][C:12]1[C:11]([O:16][CH3:17])=[N:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][N:13]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1nc(-c2ccc(F)cc2F)cnc1N
Product: COc1nc(-c2ccc(F)cc2F)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 using 5-(2,4-difluorophenyl)-3-methoxy-2-pyrazinamine (0.2 g) and 2,3-dichlorobenzenesulphonyl chloride (0.2 g). Yield 0.06 g.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][C:5](=O)[NH:6][C:7]=1[CH3:8].CN(C=O)C.P(Cl)(Cl)([Cl:24])=O>>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([Cl:24])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: Cc1[nH]c(=O)cc(-c2ccc(Cl)cc2)c1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(-c2ccc(Cl)cc2)c1Br
Temperature: 100 °C
Reaction time: 20 h
Yield: 70 %

Procedure:
To a suspension of 5-bromo-4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one (300 mg, 1.0 mmol) in phosphorus oxychloride (5 mL) was added anhydrous DMF (0.015 mL). The mixture was stirred at 100° C. for 20 h. Analysis by HPLC/MS indicated about 27% of the starting 5-bromo-4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one remained. Additional phosphorus oxychloride (1 mL) was added, followed by anhydrous DMF (0.1 mL). The reaction mixture was stirred at 100° C. for 24 h more. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the phosphorus oxychloride. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (20-40%) in hexanes to obtain 220 mg (70%) of the title compound as a white solid. HPLC/MS: retention time=4.07 min, [M+H]+=316.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:24]1([CH2:27][C:28](O)=[O:29])[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][C:28]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:12]2)=[O:29])[CH2:26][CH2:25]1
Reactant: O=C(O)CC1CC1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)CC3CC3)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 22 mg (0.22 mmol, 1.1 eq.) of cyclopropylacetic acid were reacted according to General Method 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]1=[O:15].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:1][CH2:2][CH2:3][N:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][CH2:13][CH2:14][C:7]3=[N:6][C:5]2=[O:15])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=c1nc2n(c(=O)n1CCO)CCCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCCn2c(=O)nc3n(c2=O)CCCC3)cc1

Procedure:
The entitled compound was prepared as a yellowish solid from 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione prepared in Reference Example 27 and 4-methylbenzenesulfonyl chloride in the manner described in Reference Example 33.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=2)[CH2:16][C:15]1([CH3:26])[CH3:25].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CNC>CN(C=O)C>[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][C:15]([CH3:26])([CH3:25])[C@H:14]2[NH:13][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2ccccc2[nH]1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 72.9 %

Procedure:
A mixture of 1H-indole-2-carboxylic acid (44.0 mg, 0.273 mmol), (R)-3-amino-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (34.0 mg, 0.182 mmol), BOP reagent (157 mg, 0.355 mmol), N-methylmorpholine (0.12 mL, 1.09 mmol) in DMF (0.5 mL) was stirred at 50° C. for 50 min. Dimethylamine (2.0 M in THF, 0.2 mL) was added to the mixture and the resulting mixture was stirred at 50° C. for 30 min. The desired title product (43.7 mg, 73% yield) was isolated as a white solid by prep. LCMS (M+H)+=330.33; HPLC. 1H NMR (500 MHz, DMSO-d6) δ: 11.6 (s, 1H), 8.53 (d, J=9.35 Hz, 1H), 7.70 (d, J=70 Hz, 1H), 7.60 (d, J=7.70 Hz, 1H), 7.62 (s, 1H) 7.46 (d, J=7.70 Hz, 1H), 7.44 (d, J=9.35 Hz, 1H), 7.29 (s, 1H), 7.18 (t, J=7.70 Hz, 1H), 7.03 (t, J=7.70 Hz, 1H), 5.38 (d, J=9.35 Hz, 1H), 2.86 (dd, J=22.5, 16.5 Hz, 2H), 1.21 (s, 3H), 0.94 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ: 161.1, 148.2, 144.1, 136.2, 131.4, 131.0, 127.9, 126.7, 125.7, 123.0, 121.2, 119.4, 118.8, 111.9, 108.8, 103.2, 61.0, 39.4, 39.2, 39.1, 38.9, 27.1, 22.2.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][N:11]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]3)=[O:22])[CH2:12]2)=[CH:19][CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a stirred solution of [(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (860 mg, 1.72 mmol) in CH2Cl2 (8 ml) was added TFA (2 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 680 mg (98%) of the title product as a white solid. ES-MS m/e: 401.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Br:5][C:6]1[CH:7]=[C:8]([CH:16](Br)[C:17]([CH3:19])=O)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[S:3][C:16]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:14])[CH3:15])=[C:6]([Br:5])[CH:7]=2)=[C:17]([CH3:19])[N:4]=1
Reactant: CC(=O)C(Br)c1ccc(OC(C)C)c(Br)c1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N)sc1-c1ccc(OC(C)C)c(Br)c1
Temperature: 40 °C
Yield: 66.4 %

Procedure:
Thiourea (65 mg, 0.857 in mol) was added to 1-(3-bromo-4-isopropoxyphenyl)-1-bromo acetone (200 mg, 0.571 mmol) in 0.5 mL of methanol and the mixture was heated to 40° C. The mixture was then heated to 80° C. And 1.0 mL of methanol was added to facilitate stirring. After refluxing 3 h, the reaction was transferred to a separatory funnel with 50 mL of ethyl acetate and 30 mL of saturate aqueous sodium bicarbonate, the layers were separated, and the organic layer was washed with 30 mL of brine. Drying over sodium sulfate and evaporation gave the crude product. Purification by flash chromatography, eluting with 30-50% ethyl acetate in hexane, gave 124 mg of the title compound as a white solid. Mass spectrum (NH3/CI): m/z=327 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH2:3][CH:4]=[CH2:5].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][C:21]1[CH:26]=[CH:25][C:24]([O:1][CH:2]([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)[CH2:3][CH:4]=[CH2:5])=[CH:23][CH:22]=1
Reactant: Oc1ccc(OC2CCCCO2)cc1
Reactant: C=CCC(O)c1ccc(C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: C=CCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
A cooled (0° C.) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (4.93 g, 28.5 mmol) and 4-(tetrahydro-2H-pyran-2-yloxy)phenol (8.3 g, 42.7 mmol) in dry THF (200 mL) was treated with tributylphosphine (8.85 mL, 42.7 mmol), followed by 1,1′-(azodicarbonyl)dipiperidine (10.77 g, 42.7 mmol). After addition was complete, the reaction mixture was stirred at 0° C. for 10 min, before being stirred at rt overnight. The precipitate of tributylphosphine oxide was removed by filtration and the filtrate was concentrated in vacuo to give 24.6 g of crude product. This was purified by chromatography on silica gel, eluting with IPA:EtOAc:heptane (5:5:90), to give 4.6 g (47%) of the subtitle compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:19][CH:18]=3)[N:14]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]2=[N:12][CH:13]=1)=O)#[N:2].[N-:37]=[N+:38]=[N-:39].[Na+].N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[C:27]([Si:24]([CH3:25])([CH3:26])[O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:14]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]3=[N:12][CH:13]=[C:8]([C:6]4[N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:39]=[N:38][N:37]=4)[CH:9]=[C:10]3[N:16]=2)=[CH:22][CH:21]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C(=O)NCCC#N)cnc3n2C2CCCCC2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(-c4nnnn4CCC#N)cnc3n2C2CCCCC2)cc1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
A solution of intermediate 61 (250 mg, 0.5 mmol), sodium azide (33 mg, 0.5 mmol), and 2,6-lutidine (116 μL, 1.0 mmol) in dichloromethane (3 mL) was cooled to 0° C. and trifluoromethanesulfonic anhydride (84 μL, 0.5 mmol) from a freshly opened ampule was added under a nitrogen atmosphere. The reaction mixture was allowed to warm up slowly to rt over 2 h and stirring continued for 20 h at which point dichloromethane was added (25 mL). The resulting organic phase was washed with saturated NaHCO3 (1×20 mL), dried (Na2SO4), and concentrated on a rotary evaporator. The foamy residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford intermediate 62 as a white solid (48 mg, 18%). ESI-MS m/e 529.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:20])[C@@H:17]([CH3:19])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:21][CH3:22].Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:19][C@H:17]1[NH:18][C:24](=[O:26])[N:15]([C:12]2[CH:13]=[N:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:21][CH3:22])[CH:4]=3)=[CH:10][CH:11]=2)[C:16]1=[O:20]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)ccc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 137.8 %

Procedure:
To a solution of N1-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-alaninamide (Intermediate 52, 255 mg) in dry dichloromethane (15 mL), TEA (0.590 mL, 4.23 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (113 mg, 0.381 mmol) in dry dichloromethane (DCM) (5 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by silica gel chromatography (Biotage system, 10 g SNAP column) using as eluent a gradient cyclohexane/ethyl acetate from 70/30 to 30/70. This afforded the title compound as a white solid (172 mg, 0.525 mmol).
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:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[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:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]#[N:26])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: N#Cc1ccccc1CBr
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3C#N)C2=O)cn1
Yield: 27 %

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 2-(bromomethyl)benzonitrile. Yield: 27%. MS M+H calculated 391.1. found 391.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.5 μM.
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5](F)[CH:4]=1.C(C1C=CC(C(N)=O)=CC=1)#[N:17]>>[NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH2:17])=[O:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Product: NC(=O)c1ccc(C(N)=NO)cc1
Yield: 94 %

Procedure:
The title compound was obtained following procedure described for Intermediate 1 step 2 but starting from 4-cyanobenzamide (396.1 mg, 2.71 mmol) (60° C. for 24 h). Solvents were removed under vacuum, solid residue was triturated in water, filtered and dried under vacuum to give the title compound as a white solid (460 mg, 94%). 1H NMR (DMSO-d6, 300 MHz) δ 9.78 (bs, 1H), 7.98 (bs, 1H), 7.87-7.84 (m, 2H), 7.74-7.72 (m, 2H), 7.38 (bs, 1H), 5.88 (bs, 2H).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]>[Pd].C(O)C>[CH3:1][CH2:2][CH:3]([C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][CH:26]5[CH2:27]4)[O:35][CH2:34][CH2:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])[CH3:4]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Agent: [Pd]
Solvent: CCO
Product: CCC(C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4CC5O[C@@H]5OCC[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Yield: 59.1 %

Procedure:
Azadirachtin (30 mg, 0.042 mmol) and 0.5 ml of ethanol was stirred with 20 mg of 5% palladium on alumina at 20° C. under hydrogen (10 atm) for 3 hours. The reaction mixture was then filtered and rotary evaporated in vacuo. The crude product was purified by silica gel preparative HPLC (solvent=2-propanol:n-hexane, 17:83, v/v), followed by ODS preparative HPLC (solvent=methanol:water, 1:1, v/v) to give 2',3',22,23-tetrahydroazadirachtin (18 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>O1CCCC1>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[O:32])=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc(N)cc2)ccnc1N
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccnc1N

Procedure:
Ethyl(E)-3-[2-amino-4-(4-aminophenoxy)-3-pyridyl]-propenoate (230 mg), p-fluorophenyl isocyanate (0.11 ml) and tetrahydrofuran (6 ml) were stirred at room temperature for 30 minutes. After adding NH type silica gel to the reaction solution, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (ethyl acetate). The solvent was distilled off under reduced pressure to obtain 200 mg of a white solid.