Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[NH:6]1[C:10]2=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[CH:7]1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:3][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:6][CH:7]=[CH:8][C:9]=12
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccnc2[nH]ccc12
Temperature: 25 °C

Procedure:
To a cooled POCl3 (50 mL) in a dried round bottom flask, 1H-pyrrolo[2,3-b]pyridine 7-oxide (5.73 g, step A) was added in potions. The mixture was heated to reflux for 5 h. After cooled down to RT, POCl3 was evaporated under high vacuum under gentle heating (40-50° C.) to obtain black residue. 50 mL of H2O was added slowly and pH was adjusted to 8-9 with Na2CO3 (first with solid, then saturated aqueous solution) The resulting priticipate was collected by filtration, washed with cold H2O and dried in a vacuum oven (50° C.) to give 4-chloro-1H-pyrrolo[2,3-b]pyridine as tan powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([C:18]([F:21])([F:20])[F:19])=[CH:11][C:10]=1[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.[Fe]>[CH2:1]([O:8][C:9]1[C:10]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11][C:12]([C:18]([F:21])([F:19])[F:20])=[C:13]([CH:14]=1)[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c(C2CCCC2)cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cc(OCc2ccccc2)c(C2CCCC2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 4 h
Yield: 109.1 %

Procedure:
To a mixture of 1-(benzyloxy)-2-cyclopentyl-5-nitro-4-(trifluoromethyl)benzene (3.0 g, 8.2 mmol) and Fe (2.8 g, 49.3 mmol) in 25% aqueous ethanol (40 mL) was added concentrated HCl (2.1 g, 1.8 mL, 58.7 mmol). The mixture was stirred at 50° C. for 4 h. The reaction was filtered hot and washed with ethanol (2×5 mL). The filtrate was concentrated to =20 mL volume, resulting in the precipitation of a yellow crystalline solid. The solid was filtered, washed with water and dried to provide 5-(benzyloxy)-4-cyclopentyl-2-(trifluoromethyl)aniline as a yellow-brown crystalline solid (3.0 g, 98% yield). 1H NMR (400.0 MHz, CDCl3) δ 7.40-7.35 (m, 5H), 7.25 (d, J=6.7 Hz, 1H), 6.24 (s, 1H), 5.06 (s, 2H), 4.03 (s, 2H), 3.28-3.20 (m, 1H), 1.99-1.95 (m, 2H), 1.74-1.65 (m, 2H), 1.67-1.62 (m, 2H), 1.58-1.54 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[C:4]([CH3:12])[S:3][C:2]=1[NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:8])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)c1cc(C)sc1N
Solvent: CCO
Product: CCOC(=O)C(=CNc1sc(C)cc1C(=O)OCC)C(=O)OCC
Temperature: 110 °C

Procedure:
A mixture of 3.7 parts of ethyl 2-amino-5-methylthiophene-3-carboxylate and 4.4 parts of diethyl ethoxymethylenemalonate is heated at 110° C for 1.5 hour. After cooling ethanol is added and the crystals are collected by filtration, whereby diethyl (3-ethoxycarbonyl-5-methylthienyl)aminomethylenemalonate is obtained as crystals. Recrystallization from ethanol gives pale yellow needles melting at 67°-68° C
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1([CH2:19][CH3:20])[CH2:18][O:17][CH2:16]1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([C:15]1([CH2:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:18][O:17][CH2:16]1)[CH3:20]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCC1(COCCCCCCBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(COCCCCCCOc2ccc(C(=O)O)cc2)COC1
Yield: 66.4 %

Procedure:
A dimethylformamide (3 L) solution of 3-[(6-bromohexyloxy)methyl]-3-ethyloxetane 500 g, 4-hydroxybenzoic acid 297 g and potassium carbonate 490 g was stirred at 90° C. for 8 hours. Water 4 L was added to the reaction mixture, and then it was extracted with toluene 4 L. The organic layer was washed with water, and the solvent was distilled off. Sodium hydroxide 200 g, water 1 L and ethanol 2.5 L were added to the resulting residue and refluxed for 4 hours. Ethanol (1 L) was distilled off at atmospheric pressure, and then the solution was acidified by hydrochloric acid to obtain a slurry. The slurry was filtered and dried to thereby obtain 400 g of 4-[6-(3-ethyloxetane-3-ylmethoxy)hexyloxy]benzoic acid. Melting point: 58.5° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([CH2:20][CH2:21][CH3:22])[CH3:19])[CH:13]=[CH:12]2)C1C=CC=CC=1>CO.[Pd]>[CH3:19][CH:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(C)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Product: CCCC(C)n1ccc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-(Benzyloxy)-1-(pentan-2-yl)-1H-indole (8) (10.67 g, 36.4 mmol, 1.0 equiv.) was dissolved in MeOH (90 mL), and 10% wt. Pd/C was added (3.87 g, 3.64 mmol, 0.10 equiv). The reaction mixture was placed under a hydrogen atmosphere using double balloons, and stirred for 24 h at room temperature. The mixture was filtered through a Celite® pad and washed with (800 mL). The filtrate was concentrated to afford 1-(pentan-2-yl)-1H-indol-5-ol (9) as a brown oil, which was used without any further purification in the next step. 1H NMR (500 MHz, CDCl3) δ7.23 (d, J=8.8 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H), 7.03 (d, J=1.8 Hz, 1H), 6.77 (dd, J=8.7, 2.0 Hz, 1H), 6.39 (d, J=2.8 Hz, 1H), 4.52 (br, 1H), 4.42 (m, 1H), 1.87 (m, 1H), 1.76 (m, 1H), 1.49 (d, J=6.8 Hz, 3H), 1.23 (m, 2H), 0.88 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([O:11]C)=[O:10])=[CH:5][N:4]=1.O.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[CH:5][N:4]=1
Reactant: COC(=O)c1cnc(OC)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(C(=O)O)cn1
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A solution of methyl 2-methoxypyrimidine-5-carboxylate (944 mg) (Z. Budesinsky and J. Vavrina, Collect. Czech. Chem. Commun. 37 (1972)1721-1733) in dioxan (33 ml)/water (33 ml) was treated with 2N NaOH (3.37 ml), left overnight and evaporated to low volume. The residue was taken up in water (30 ml), the pH adjusted to 2 by addition of 2N HCl and the mixture extracted with EtOAc (4×30 ml). The EtOAc was dried and evaporated to give the title compound as a white solid (605 mg) 1HNMR δ(DMSO) 4.00(3H,s), 9.03(2H,s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:13]=[N:14][C:15]([C:16](O)=[O:17])=[C:11]3[CH2:10][N:9]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[CH:25]=1)#[CH:2].[ClH:26].[CH2:27]([N:29]=C=NCCCN(C)C)[CH3:28].N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.C(N)C>CN(C=O)C>[ClH:26].[ClH:26].[CH2:27]([NH:29][C:16]([C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:25][C:7]=3[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:9][CH2:10][C:11]=12)=[O:17])[CH3:28]
Reactant: CCN=C=NCCCN(C)C
Reactant: C#Cc1ccc2c(c1)C(c1ccccc1)=NCc1c(C(=O)O)ncn1-2
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc2c(c1)C(c1ccccc1)=NCc1c(C(=O)NCC)ncn1-2
Reaction time: 0.25 h

Procedure:
8-Ethynyl-6-phenyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylic acid (82 mg, 0.251 mmol) was dissolved in DMF (6 ml) and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (48 mg, 0.251 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (33.8 mg, 0.251 mmol), and triethylamine (70 μL, 0.501 mmol) were added. The solution was stirred for 15 min and then ethylamine hydrochloride (20.4 mg, 0.251 mmol) was added. The solution was stirred at room temperature for 3 days. The DMF was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with water twice, then dried with brine. The ethyl acetate layer was then condensed with a stream of nitrogen, and dried in vacuo. The residue was dissolved in methylene chloride, and applied to a silica gel column. The product was eluted with ethyl acetate. The product fractions were concentrated in vacuo. The oily residue was dissolved in acetonitrile and several drops of concentrated HCl were added to give the HCl salt. The acetonitrile was removed in vacuo and the HCl salt was dried under high vacuum to give a yellow powder (75 mg, 77%).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:17][CH2:16]3)[C:8]=2[CH:7]=1)=O)C.[Cl-].[NH4+:31].C[Al](C)C.C1(C)C=CC=CC=1>>[ClH:29].[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][N:15]([C:14]3[C:8]4[CH:7]=[C:6]([C:4]#[N:31])[S:10][C:9]=4[CH:11]=[CH:12][CH:13]=3)[CH2:16][CH2:17]2)=[CH:28][CH:27]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc2c(N3CCN(CCc4ccc(Cl)cc4)CC3)cccc2s1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cl
Product: N#Cc1cc2c(N3CCN(CCc4ccc(Cl)cc4)CC3)cccc2s1
Yield: 50 %

Procedure:
In an analogous manner to example 3, the title compound (0.39 g) as a white solid, mp 267°-269° C., is prepared from ethyl-4-[4-[2-(4-chlorophenyl)ethyl]-1-piperazinyl]-benzo[b]thiophene-2-carboxylate (1.60 g, 3.73 mmol, prepared in example 18), dry ammonium chloride (0.60 g, 11.2 mmol) and 2M trimethyl aluminum in toluene (5.6 mL, 11.2 mmol). The free base of the title compound is isolated by flash chromatography (ethyl acetate:hexane, 50:50, then ethyl acetate followed by ethanol:ethyl acetate, 50:50, Rf =0.4 in ethyl acetate:hexane, 40:60); 1H NMR (DMSO-d6) δ 11.35 (1H, bs), 8.50 (1H, s), 7.82 (1H, d, J=8.2 Hz), 7.57 (1H, t, J=8.0 Hz), 7.45 (2H, d, J=8.4 Hz), 7.36 (2H, d, J=8.4 Hz), 7.10 (1H, d, J=7.6 Hz), 3.63 (4H, m), 3.37 (6H, m), 3.17 (2H, m); 13C NMR (DMSO-d6) δ 148.02, 142.47, 136.12, 134.77, 131.45, 131.41, 130.58, 129.21, 128.58, 117.53, 114.72, 113.99, 107.10, 55.75, 51.10, 48.53, 28.61; IR (KBr) 2430, 2218, 1458, 958 cm-1 ; CI/MS (CH4) 382(100%). IC50 =13 nM (5HT1ABinding Affinity) IC50 =31 nM (5HT1DBinding Affinity) pA2 =7.37 (34%) (blocking of 5-HTl-like-mediated contraction in canine saphenous vein)
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)CCl>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:17](=[O:19])[CH3:18])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
In a 5 L 4-neck round bottom flask, EDC (2 L) was added to the 4,4-dimethylthiochroman from the previous step. The contents were stirred and cooled to a temperature of about −10° C. Aluminum chloride (252 g) was slowly added to the reaction mixture. Acetyl chloride (152.7 g) was added at a temperature ranging from about −10° C. to about −5° C. over about 1.5 hours. After the addition, the reaction mixture was maintained at a temperature ranging from about −5° C. to about 0° C. for about 2 hours. The reaction was monitored by TLC. [If the reaction is incomplete as determined by TLC, bring the reaction mixture to a temperature ranging from about 25° C. to about 35° C. under stirring for about 4 hours.] The reaction mixture was quenched with ice (4.87 kg) and hydrochloric acid (1.63 L), and the reaction mass was stirred for about 30 minutes. EDC (2.5 L) was added to the reaction mass. The layers were separated. The aqueous layer was extracted with MDC (2×2 L). The organic layers were combined and washed with 5% sodium bicarbonate solution (2×2 L) and water (2×2 L) until the pH is about 7. This was followed by a washing with brine (1.5 L). The EDC and MDC layer were distilled out under reduced pressure until the moisture content was less than about 0.1%. There was a residual volume of about 3 L.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[Li]CCCC.[C:14]1([P:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Br:8][C:4]1[CH:3]=[C:2]([P:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1cccc(P(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.5 %

Procedure:
To a solution of 1,3-dibromobenzene (7.4 mL, 61 mmol, 1.05 equiv) in THF (70 mL, 0.9 M) at −90° C. was added n-BuLi (2.5 M) (25.5 mL, 64 mmol, 1.10 equiv) dropwise. The reaction mixture was stirred 45 min then diphenylchlorophosphine (10.7 mL, 58 mmol, 1.0 equiv) was added dropwise and the resulting dark brown solution was warmed to room temperature for 15 min and filtered through a small pad of Celite. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (Et2O/hexane, 0:100-5:95) to afford (3-bromophenyl)diphenylphosphine (2) (18.1 g, 91%) as a viscous colorless oil, which was characterized as follows:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.CN(C)C=O.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>O1CCCC1>[Cl:16][C:17]1[N:22]=[C:21]([O:1][CH2:2][C:3]2([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]2)[CH:20]=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OCC1(CO)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCC1(COc2ccnc(Cl)n2)CCC1
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of 1.00 g (8.62 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 20 ml of (1:1) tetrahydrofuran:dimethylforamide was added a 60% dispersion of 0.413 g (8.62 mmol) of sodium hydride in oil. The reaction was stirred for 15 min and 1.28 g (8.62 mmol) of 2,4-dichloropyrimidine was added. After stirring for 2 h, the reaction was concentrated under vacuum and the residue was purified using silica gel chromatography eluting with ethyl acetate:hexane (4:6) to afford 0.9 g (51%) of (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J=6 Hz, 1H), 6.69 (d, J=7 Hz, 1H), 4.51 (s, 2H), 3.67 (s, 2H), 2.35 (br s, 1H), 2.05-1.87 (m, 6H).
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])#[N:7].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1>[CH3:12][O:11][C:9](=[O:10])[C:8]([C:6]#[N:7])=[CH:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)C(C#N)=CC(C)C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of isobutyraldehyde (18.2 mL, 200 mmol) in dry benzene (20 mL) was added methyl cyanoacetate (18 mL, 200 mmol), ammonium acetate (2 g) and glacial acetic acid (4 mL). The reaction mixture was' stirred at 60° C. for 30 minutes and allowed to cool to room temperature. Excess of solvents was removed in vacuo and the residue was dissolved in EtOAc (200 mL). The organic layer was washed with water, dried over sodium sulfate and evaporated to give 2-cyano-4-methyl-pent-2-enoic acid methyl ester as pale yellow oil. Further purification of the pale yellow oil by distillation (7 mm Hg) gave product 2 (27.4 g, 56%) as colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.16 (d, J=6.6 Hz, 6H), 2.96-3.04 (m, 1H), 3.87 (s, 3H), 7.47 (d, J=10.5 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:11][CH:7]([CH2:8][NH:9][CH2:10]1)[CH2:6][S:5][CH2:4]2.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>O.C(Cl)Cl>[C:12]([N:9]1[CH2:8][CH:7]2[CH2:11][CH:3]([CH2:4][S:5][CH2:6]2)[CH2:10]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1NCC2CSCC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)N1CC2CSCC(C2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
A 10-mL, two-necked, round-bottomed flask was equipped with a magnetic stirrer, an ice bath, a standard condenser with a N2 inlet, and a glass stopper. To a chilled (5° C.) solution of NaOH pellets (0.1 g, 2.38 mmol) in H2O (1.7 mL) was added a solution of the amine (28, 0.17 g, 1.19 mmol) in CH2Cl2 (1 mL). This was followed by the dropwise addition of a solution of benzoyl chloride (0.2 g, 1.43 mmol) over ~5 min. After stirring for 30 min at 0°-5° C., 30 min at RT, and then 15 min over a steam bath, the mixture was diluted with H2O (15 mL), and the mixture was extracted (CH2Cl2, 3×15 mL). Combining the extracts, drying (Na2SO4, overnight), filtering, and concentrating the solution gave a viscous yellow oil. Chromatography of the oil on alumina (38 g, 2.4 cm×17 cm) employed ethyl acetate as eluant and afforded amide (29) (Rf =0.47) as white crystals (157 mg, 53.3%); mp 95°-96° C. IR (KBr) cm-1 3065, 3045 (Ar C--H), 3000, 2985, 2940, 2910, 2855, 2835 (C--H), 1635 (C=O), 745, 720 (C--H out of plane, mono); 1H NMR (DCCl3) δ1.78-1.93 [m, 3H, H(9) and H(1)], 2.15 [bs, 1H, H(5)], 2.39 [d, 1H, H(4)ax, J=13.9 Hz], 2.77 [d, 1H, H(6)ax, J=12.3 Hz], 3.12-3.21 [m, 3H, H(4)eq and H(6)eq ], 3.41 [d, 1H, H(2)ax, J=12.8 Hz], 3.89 [d, 1H, H(2)eq, J=13.4 Hz], 4.98 [d, 1H, H(8)eq, J=13.1 Hz], 7.38-7.44 [m, 5H, Ar--H]; 13C NMR (DCCl3) ppm 26.53 [C(1)], 26.87 [C(5)], 31.73 [C(2)], 31.78 [C(9)], 32.34 [C(4)], 46.07 [C(8)], 52.12 [C(6)], 126.46, 128.41, 128.83, 137.35 (Ar--C), 170.38 [C=O]. Anal. Calcd. for C14H17NOS: C, 67.98; H, 6.93. Found: C, 68.01; H, 7.07.
Reaction SMILES: [CH:1]1([CH:6]([OH:10])[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:22]2[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=2[N:20]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:19]1=[O:38])=O)C>>[CH:1]1([CH:6]([OH:10])[C:7]([NH:17][C@H:18]([C:24]([C:18]2([NH2:17])[C:24](=[O:25])[N:23]([CH2:26][CH:27]3[CH2:29][CH2:28]3)[C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[N:20]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:19]2=[O:38])=[O:25])[CH3:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(O)C1CCCC1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O
Agent: Cl
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)C1(N)C(=O)N(CC2CC2)c2ccccc2N(CC2CC2)C1=O

Procedure:
Following General Procedure I above using cyclopentyl-α-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-U), the title compound was prepared as a white foam. Purification was by L.C. 2000 eluting with CH2Cl2/EtOAc (1:1 gradient to 1:2) then flash chromatography eluting with 2:1 EtOAc/CH2Cl2. Rf=0.47 and 0.37 (CH2Cl2/EtOAc, 1:2).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:23].[O:24]([CH2:31][CH:32]1[NH:37][CH2:36][CH2:35][NH:34][CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[F:23][C:3]1[CH:2]=[CH:11][C:10]([N:9]2[C:12]3[C:17](=[CH:16][C:15]([F:18])=[C:14]([N:34]4[CH2:35][CH2:36][NH:37][CH:32]([CH2:31][O:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:33]4)[CH:13]=3)[C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8]2)=[CH:5][CH:4]=1
Reactant: c1ccc(OCC2CNCCN2)cc1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(N3CCNC(COc4ccccc4)C3)c(F)cc2c1=O
Yield: 33.6 %

Procedure:
A mixture of 0.6 g of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.03 g of 3-(phenoxymethyl)piperazine and 5 ml of pyridine was reacted as described in Example 81, giving 295 mg of the desired product, mp 204°-207° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]2)[C:11]1=[O:25]>S(=O)(=O)(O)O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([N+:1]([O-:4])=[O:2])=[CH:16][CH:17]=2)[C:12]2([C:22](=[O:23])[NH:21][C:20](=[O:24])[NH:19]2)[C:11]1=[O:25]
Reactant: O=[N+]([O-])O
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Agent: O=S(=O)(O)O
Product: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Fuming nitric acid (0.2 ml.) was added during 10 minutes to a stirred solution of 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.79 g.) in concentrated sulphuric acid (1.5 ml.) maintained at a temperature of 0°-5° C. The reaction mixture was then stirred at 0°-5° C. for 1 hour and finally at 5°-20° C. for a further 1 hour. The solution was then poured onto crushed ice (300 g.) and the mixture which formed was extracted with ethyl acetate. The combined extracts were washed with water (3×150 ml.) then with brine (100 ml.) and dried (MgSO4). The extracts were evaporated and the residual oil was redissolved in ethyl acetate (20 ml.). The solution was evaporated on to chromatographic silica gel and the solid residue added to the top of a column of the same silica gel made up in toluene. The column was eluted with increasing concentrations of ethyl acetate in toluene (up to 1:1 v/v). The fractions containing the major component [TLC:Rf~0.6 on SiO2 :eluant 1:1 v/v EtOAc/toluene] were combined and evaporated. The residue was recrystallised from a mixture of toluene, ethyl acetate and petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-5'-nitro-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (Prep. 35) (0.46 g.), m.p. 249°-251° C.
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][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>Cl>[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][CH2:23][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[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: BrCCOc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCOc3ccccc3)C2=O)cn1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (200 mg, 0.7 mmol), (2-bromoethoxy)benzene (200 mg, 1 mmol), and cesium carbonate (325 mg, 1 mmol) were irradiated in the microwave reactor at 85° C. for 20 minutes. The reaction was cooled to room temperature, diluted with aqueous 1N HCl (100 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was taken up in methanol (10 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O: 25 minute gradient). The pure fractions were pooled, concentrated then re-dissolved in absolute ethanol and concentrated on the rotovap (4×) to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(2-phenoxyethyl)imidazolidine-2,4-dione (150 mg, 54%) as a white solid. 1H NMR (CDCl32.18, 400 MHz): δ (s, 3H), 2.41 (s, 3H), 3.86 (t, J=5.2 Hz, 2H), 4.19 (t, J=4.4 Hz, 2H), 4.25 (s, 2H), 5.05 (s, 2H), 6.88 (dd, J=9.2, 1.2 Hz, 2H), 7.00 (dt, J=7.6, 1.2 Hz, 1H), 7.27-7.32 (m, 2H), 7.89 (s, 1H), 8.05 (s, 1H). MS M+H calculated 396.17; found 396.1. Melting point: 117-118° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.