Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH2:24])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[N:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[C:33]=[O:34]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][C:33]([NH:32][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:34])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a round bottom flask was added (1R,2R)—N1-(1-(4-nitrophenyl)azepan-4-yl)cyclohexane-1,2-diamine (70 mg, 0.211 mmol), THF (3 mL), and Et3N (0.029 mL, 0.211 mmol). To the resulting solution was added isocyanatobenzene (25.08 mg, 0.211 mmol). The reaction was stirred at rt overnight. After this time, the reaction mixture was concentrated. The resulting crude product was purified by RP prep-HPLC to give a mixture of 2 diastereomers. The mixture of two diastereomers was separated by chiral HPLC (chiral separation method A) to give the desired product, 1-((1R,2R)-2-((S)-1-(4-nitrophenyl)azepan-4-ylamino)cyclohexyl)-3-phenylurea (7 mg, 0.019 mmol, 6.7% yield) as a yellow solid. Anal. Calcd. for C25H33N5O3 m/z 451.5, found: 452.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.10 (d, J=9.35 Hz, 2H), 7.30-7.27 (m, 2H), 7.22 (t, J=7.70 Hz, 2H), 6.99 (t, J=7.15 Hz, 1H), 6.60 (d, J=9.35 Hz, 2H), 4.57 (br. s., 1H), 3.66-3.53 (m, 2H), 3.53-3.45 (m, 1H), 3.44-3.35 (m, 1H), 3.21 (d, J=4.95 Hz, 1H), 2.85-2.73 (m, 1H), 2.24 (td, J=10.31, 3.57 Hz, 1H), 2.09 (d, J=9.35 Hz, 2H), 1.97 (d, J=12.10 Hz, 1H), 1.90 (d, J=11.55 Hz, 2H), 1.73 (d, J=9.90 Hz, 2H), 1.69-1.61 (m, 2H), 1.44-1.34 (m, 2H), 1.23-1.07 (m, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 157.11, 153.29, 139.21, 136.84, 129.12, 126.49, 123.13, 120.06, 110.01, 60.75, 56.99, 56.15, 49.50, 45.82, 34.95, 33.49, 33.29, 32.63, 25.06, 24.85, 23.76.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[F:13])[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[I-:14].[Na+].O>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[F:13])[CH2:8][I:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)c1cc(CBr)ccc1F
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(CI)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of 3-tert-butyl-4-fluorobenzyl bromide (1.49 g, 6.08 mmol) in acetone (50 ml), sodium iodide (9.1 g, 60.8 mmol) was added, followed by stirring at room temperature overnight. The reaction mixture was mixed with water and extracted with n-hexane. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine, dried over sodium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane) to give the titled compound (1.18 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccc(F)cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].[CH:21](I)([CH3:23])[CH3:22].Cl>CN(C=O)C.O>[CH:21]([O:11][C:9]1[CH:8]=[C:7]2[C:2]([CH:3]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[CH:4]3[CH2:5][O:6]2)=[CH:1][CH:10]=1)([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)OCC1c3ccccc3OC21
Yield: 50.6 %

Procedure:
Compound 6a,11a-Dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by isopropyl iodide (149 mg, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 3-isopropoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (60 mg, 51%) as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-])=O.C(O)C.O.NN>[C].[Pd].O>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(ccc3ccccc32)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
First, 134 g of 2-nitrophenanthrene, 1.00 g of palladium carbon, and 1.2 L of ethanol were loaded, and then 70 mL of hydrazine monohydrate were added to the mixture. The reaction solution was stirred for 4 hours under heating reflux. After having been cooled to room temperature, the reaction solution was poured into 3 L of water. Then, the mixture was extracted with 2 L of toluene. After the water layer had been removed, the organic layer was dried with magnesium sulfate. After magnesium sulfate had been separated by filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 100 g of a pale yellow solid were obtained (in 86% yield).
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][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:32]=1)(C)(C)C>>[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][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a yellow solid (410 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][OH:40])=[CH:35][CH:34]=3)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].Cl>O1CCOCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][OH:40])=[CH:37][CH:38]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(-c3ccc(CO)cc3)s1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To compound 34D (0.14 g) in 1,4-dioxane (2 mL) was added 4 N HCl in 1,4-dioxane (2 mL) and MeOH (0.5 mL). The solution was stirred for 1 hour at rt, concentrated under reduced pressure, and added 1.0 N LiOH (2 mL) in 1,4-dioxane (2 mL). The solution was stirred at 60° C. for 1 hour, concentrated under reduced pressure and purified by Prep HPLC to provide the desired product 34: 1H NMR (DMSO-d6): δ 8.02 (d, J=7.98 Hz, 1H), 7.79 (d, J=7.98 Hz, 1H), 7.69 (d, J=7.36 Hz, 1H), 7.29-7.49 (m, 8H), 4.90 (s, 2H), 4.50 (s, 2H), 3.78 (t, J=5.98 Hz, 2H), 3.98 (t, J=5.98 Hz, 2H); MS (ESI(+)): m/z 543 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.Cl.Cl.[NH:50]1[CH2:54][CH2:53][CH:52]([C:55]2[CH:60]=[N:59][CH:58]=[CH:57][N:56]=2)[CH2:51]1>C(#N)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:50]2[CH2:54][CH2:53][CH:52]([C:55]3[CH:60]=[N:59][CH:58]=[CH:57][N:56]=3)[CH2:51]2)=[O:16])=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: c1cnc(C2CCNC2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2cnccn2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 2-pyrrolidin-3-yl-pyrazine trihydrochloride (36 mg, 0.14 mmol), and stirred at 60° C. for 30 min. The residue was purified on reversed phase HPLC to yield the title compound (26 mg). HRMS (ESI, pos. ion) m/z calcd for C19H15F3N4O2: 388.1147, found 388.1152.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([Cl:16])[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20].[CH3:21][O-:22].[Na+]>CN(C)C=O>[Cl-:16].[NH2:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([C:14]#[N:15])=[C:5]([O:22][CH3:21])[N+:4]=1[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C[O-]
Reactant: CCCCNc1cc(N)[n+](CCCC)c(Cl)c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNc1cc(N)[n+](CCCC)c(OC)c1C#N
Yield: 32 %

Procedure:
3.2 gms (.01 mole) of 2-amino-1-n-butyl-4-n-butylamino-6-chloro-5-cyano-pyridinium chloride (compound 6 - Table 1) was dissolved in dry dimethylformamide, 0.06 gms (0.01 mole) of sodium methoxide added, and the mixture refluxed for 60 minutes, filtered and solvent evaporated off. The solid was recrystallised from acetone to give 1.0 gm (30% yield) of 2-amino-1-n-butyl-4-n-butylamino-5-cyano-6-methoxy pyridinium chloride (MPt 187° - 189°C.)
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13].[OH-].[Na+]>CO>[CH2:18]([O:17][C:15]([NH:14][C@@H:4]([CH2:5][C:6]1[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=1[F:12])[C:3]([OH:25])=[O:2])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](Cc1c(F)cccc1F)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1c(F)cccc1F)C(=O)O)OCc1ccccc1
Reaction time: 4 h
Yield: 95.1 %

Procedure:
2(S)-Benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid methyl ester (5 g, 14.4 mmol) was dissolved in methanol (60 mL) and cooled on ice. 1 N NaOH (22 mL, 22 mmol) was added dropwise over 15 min. The reaction mixture was removed from cooling bath and stirring was continued at room temperature for 4 h. The solvent was then removed by rotary evaporation and the residue was treated with water (100 mL) and then with 1 N HCl to adjust the pH to 4. The product was extracted with ethyl acetate (300 mL, 200 mL). Evaporation of the solvent and crystallization of the residue from methylene chloride/hexane gave 2(S)-benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid (4.6 g, 13.7 mmol, 94% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[CH3:25][O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29]>>[CH3:25][O:26][C:27](=[O:37])[C@@H:28]([NH:29][C:19]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)=[O:21])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 88 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (111 mg, 0.36 mmol) was converted, using L-phenylalanine methylester hydrochloride instead of 2-aminoethyl isopropylether, to the title compound (148 mg, 88%) which was obtained as a white solid. MS: m/e=470.1 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[N:14]([CH3:18])[CH2:13][C@@H:12]1C.F[C:21]1C=C([N+]([O-])=O)C=CC=1N1C[C@H](C)N[C@H](C)C1>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][C@@H:13]([CH3:21])[N:14]([CH3:18])[C@@H:15]([CH3:17])[CH2:16]1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1C
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)C[C@H](C)N1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)C[C@H](C)N1C
Yield: 100 %

Procedure:
Crude cis-4-(2-Fluoro-4-nitrophenyl)-1,2,6-trimethylpiperazine (6.1 g, 100% recovery) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,4,5-trimethylpiperazine from 1-(2-fluoro-4-nitrophenyl)-cis-3,5-dimethylpiperazine (5.71 g, 24.2 mmol). LCMS-ESI (m/z): calcd for C13HBFN3O2, 267; [M+H]+ found, 268.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N+:10]2[O-].C(OC(=O)C)(=[O:25])C.N>>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:25])[NH:10]2
Reactant: COc1ccc2c(ccc[n+]2[O-])c1Oc1ccc(F)cc1F
Reactant: CC(=O)OC(C)=O
Agent: N
Product: COc1ccc2[nH]c(=O)ccc2c1Oc1ccc(F)cc1F
Temperature: 75 °C
Reaction time: 22 h
Yield: 22.2 %

Procedure:
5-(2,4-Difluoro-phenoxy)-6-methoxy-quinoline N-oxide (1.35 g, 4.5 mmol) was mixed with 5 mL of acetic anhydride and stirred at 75° C. for 22 hours. The reaction mixture was poured on ice, neutralized with aqueous ammonia, and the resultant precipitate was filtered and washed with water. The aqueous layer was extracted with dichloromethane and the organic extract was dried over MgSO4. The solvent was removed under vacuum. The dry residue, combined with the filtered precipitate, was dissolved in a minimum amount of CH2Cl2 and purified using a Biotage system, eluting with 10–30% EtOAc/hexane to give 0.3 g (22.2%) of 5-(2,4-difluoro-phenoxy)-6-methoxy-1H-quinolin-2-one.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17].O.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:25]=[O:26])=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]([F:19])([F:17])[F:18]
Reactant: FC(F)(F)c1cc2cc[nH]c2cc1Cl
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cc(Cl)c(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Phosphorus oxychloride (1.83 ml) was added dropwise to dimethylformamide (16 ml) under ice-cooling, and the mixture was stirred at 0° C. for 20 min. 6-Chloro-5-(trifluoromethyl)-1H-indole (3.24 g) dissolved in dimethylformamide (10 ml) was added to the reaction mixture, and the mixture was stirred at 0° C. for 3 hr. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr, and the mixture was alkalified with a 1N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, washed with water and dried to give 6-chloro-5-(trifluoromethyl)indole-3-carbaldehyde (3.25 g, yield 89%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([S:9]([CH:12]([CH:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:27](#N)C>>[CH3:27][C:12]([CH:14]1[CH2:15][NH:16][CH2:17]1)([S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:25])([F:26])[F:1])[CH:4]=1)(=[O:10])=[O:11])[CH3:13]
Reactant: CC#N
Reactant: CC(C1CN(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Product: CC(C)(C1CNC1)S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
To a 100 ml round bottom flask equipped with a reflux condenser was added tert-butyl 3-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)azetidine-1-carboxylate (0.85 g, 2.09 mmol), ceric ammonium nitrate (1.37 g, 2.5 mmol) and 15 ml acetonitrile. The resulting reaction mixture was refluxed for 3 hours. The volatiles were removed. The residue was diluted with 60 ml ethyl acetate and 50 ml saturated sodium carbonate. It was filtered through a pad of celite. The organic portion from the filtrate was washed with 50 ml brine, dried over sodium sulfate, filtered and concentrated. The residue was redissolved in hexane/CH2Cl2 (9:1), filtered and concentrated to give 0.62 g yellow sticky solid. It is about 90% pure based on 1H NMR spectra. It was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[C:5]([NH:26][C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[O:4][N:3]=1.O[CH:36]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:37]([O:39][CH3:40])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[N:26]([C:27]([O:29][CH2:30][C:31]([Cl:32])([Cl:33])[Cl:34])=[O:28])[C@H:36]([C:37]([O:39][CH3:40])=[O:38])[CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)C(O)CC(C)C
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1onc(C)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To tert-butyl 4-[4-(3-methyl-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}isoxazol-4-yl)phenyl]piperazine-1-carboxylate (617 mg, 1.16 mmol), methyl 2-hydroxy-4-methylpentanoate (255 mg, 1.74 mmol) and triphenyl phosphine (460 mg, 1.74 mmol) in dry DMF (15 mL) at 0° C. under dry nitrogen was added diisopropyl azodicarboxylate (0.35 mL, 1.74 mmol) dropwise over ½ hour and the reaction mixture was stirred for 2 days at rt. The reaction was poured into water and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 25/75) to afford methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[CH2:17][CH2:16][NH:15][C:14]3=[O:18])[CH:10]=[N:9]2)=[C:5]([CH3:19])[O:4][N:3]=1.[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([N:15]1[CH2:16][CH2:17][N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:19])[CH:12]=2)[C:14]1=[O:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1noc(C)c1Cn1cc(N2CCNC2=O)cn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2CCN(Cc3ccccc3)C2=O)cn1
Temperature: 0 °C
Yield: 31.5 %

Procedure:
1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidin-2-one (example 10-88a) (50 mg, 0.19 mmol) and 60% sodium hydride (8 mg, 0.21 mmol) in DMF (3 mL) were stirred at room temperature for 15 minutes then cooled to 0° C. Benzyl bromide (33 mg, 0.19 mmol) was added to the mixture and allowed to warm up at room temperature for 2 hours. The reaction was quenched with methanol and concentrated on the rotovap. The reaction was diluted with brine (50 mL) and extracted with dichloromethane (2×, 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidin-2-one (21 mg, 31%) as a white solid. MS M+H calculated 352.17. Found 352.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.71 μM.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:19][O:18][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[NH:7][C:6]2=[O:17])[O:4][CH2:3]1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:3][O:4][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[N:7]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:6]2=[O:17])[O:18][CH2:19]1
Reactant: CC1(C)COC2(OC1)C(=O)Nc1ccc([N+](=O)[O-])cc12
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Crude 5,5-dimethyl-5′-nitrospiro[[1,3]dioxane-2,3′-indolin]-2′-one (obtained as described in Example 17, Step 1) (361 mg) was dissolved in dry DMF (11 ml) and cooled to 0° C.; NaH (60% w/w dispersion in mineral oil, 83 mg, 2.076 mmol) was added; and the mixture was stirred at 0° C. for 10 minutes (the reaction turned dark orange). Methyl 2-bromoacetate (0.144 ml, 1.557 mmol) was then added, the reaction was warmed to room temperature and stirred for 3 hours. The solvent was evaporated, water was added and extracted with EtOAc; the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc from 95:5 to 85:15) affording methyl 2-(5,5-dimethyl-5′-nitro-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (344 mg, 0.982 mmol, 84% yield). MS/ESI+ 351.0 [MH]+.