Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>C(O)C.[C].[Pd]>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C1CCC(=O)CC1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Yield: 57.8 %

Procedure:
1.97 g of dibenzylamine, 1.68 g of 1,4-cyclohexanedione and 40 mg of 10% palladium-carbon were heated with stirring in 40 ml of ethanol at 50° C. to 60° C. and reacted for 8 hours under air bubbling. During the reaction, ethanol was added as needed. After the completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resultant was purified by silica gel column chromatography (n-hexane:ethyl acetate=30:1) and further separated by silica gel column chromatography (n-hexane:ethyl acetate=10:1), and 1.67 g of N-(4-hydroxyphenyl)dibenzylamine was obtained (yield 57%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH3:6])=[O:4].C[S:8][C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=S>C(#N)C>[CH3:6][NH:5][C:3](=[O:4])[CH2:2][NH:1][C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[S:8]
Reactant: CSC(=S)c1cccnc1
Reactant: CNC(=O)CN
Solvent: CC#N
Product: CNC(=O)CNC(=S)c1cccnc1
Temperature: 47.5 °C
Reaction time: 0.33 h
Yield: 70.9 %

Procedure:
A 5 liter three-necked round bottom flask was fitted with a nitrogen inlet over a dropping funnel, a mechanical stirrer, and a reflux condenser. A tube from the top of the condenser was plumbed through a 1 liter bump flask and then into a sparge tube in another 5 liter three-neck stirred flask filled with 2.5 liter of 12% pool bleach. The outlet of the bleach flask was plumbed through an alligator trap with about 250 mL of 12% bleach solution. The reactor was charged with 2-amino-N-methylacetamide (160 g, 1.81 mol) and acetonitrile (3 L) to give a cloudy solution. The dropping funnel was charged with methylpyridine-3-carbodithioate (307 g, 1.81 mol) and acetonitrile (200 mL). The addition of the dithioate took about 20 min and the reaction was swept with a good stream of nitrogen. A slight exotherm was noted upon the addition (about 3° C.). After the addition was complete, the dropping funnel was rinsed with 550 mL of acetonitrile to bring the total volume of acetonitrile to 3750 mL. After stirring for about 10 min, the red solution precipitated to give a cottage cheese-like solid which would not stir. The dropping funnel was replaced with a ¼ inch straight tube to bubble nitrogen into the reactor. The reactor was heated slowly to about 45-50° C. to form a reddish solution and then allowed to cool back down slowly to room temperature and crystallize to a fine yellowish needle-like solid which stirred easily. The needles were collected by vacuum filtration and washed with 100 mL of acetonitrile. The solid was dried under vacuum at 40° C. for 16 h to give N-methyl-2-(pyridine-3-carbothioamido)acetamide (268.6 g, 71%) as a light yellow solid: mp 135-137° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.95 (dd, J=2.4, 0.7 Hz, 1H), 8.67 (dd, J=4.8, 1.6 Hz, 1H), 8.14 (ddd, J=8.0, 2.3, 1.7 Hz, 1H), 7.95 (d, J=4.3 Hz, 1H), 7.48 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 4.34 (s, 2H), 2.62 (d, J=4.6 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 194.98, 165.77, 150.37, 146.40, 135.25, 134.04, 121.51, 47.66, 24.41; Anal. Calcd. for C9H11N3OS: C, 51.65; H, 5.30; N, 20.08; S, 15.32. Found: C, 51.47: H, 5.30; N, 20.01; S, 15.53.
Reaction SMILES: [F-:1].[K+].[CH3:3][N:4]1[C:8](Cl)=[C:7]([CH:10]=[O:11])[C:6]([C:12]([F:15])([F:14])[F:13])=[N:5]1>CN(C=O)C>[F:1][C:8]1[N:4]([CH3:3])[N:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]=1[CH:10]=[O:11]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(C=O)c1F
Temperature: 150 °C
Yield: 102.3 %

Procedure:
A suspension of anhydrous KF (4 g) in anhydrous DMF (20 mL) was stirred under N2 and 1-methyl-3-trifluoromethyl-5-chloropyrazole-4-carboxaldehyde (10.6 g) added. The mixture was heated at 150 ° C. for 6 h. The mixture was poured onto ice (250 g) and was mixed thoroughly. The mixture was extracted with ether (5×50 mL). The ether solution was dried (MgSO4) and concentrated in vacuo leaving an amber liquid (10 g). The liquid was distilled under reduced pressure to give one fraction, 8.0 g yellow liquid b.p. 68-74 ° C. @ 0.4 Torr.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](\[NH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])/[CH3:7])[CH3:2].[C:19](#[N:26])[C:20]1C=CC=C[CH:21]=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([O:3][C:4]([C:5]1[C:19]([CH2:20][CH3:21])=[N:26][N:8]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:6]=1[CH3:7])=[O:18])[CH3:2]
Reactant: CCOC(=O)/C=C(/C)Nc1c(C)cc(C)cc1C
Reactant: N#Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)c1c(CC)nn(-c2c(C)cc(C)cc2C)c1C
Yield: 83 %

Procedure:
According to AVV A, (Z-3-(2,4,6-trimethylphenylamino)-but-2-enoic acid ethylester (247.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into benzonitrile (3.0 ml, 29.4 mmol, 29.4 equiv.) for 14 hours at 120° C. The brown oil obtained as raw product (524.3 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→0:100). The product was obtained in the form of a white solid (289.4 mg, 0.83 mmol, 83%).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:17])[C@@H:10]([OH:24])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40](O)=[O:41]>>[C:25]1([C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:40](=[O:41])[CH2:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([OH:17])[C@@H:10]([OH:24])[CH2:9]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: O[C@H]1CC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]2[C@]1(O)c1ccccc1
Agent: Cl
Product: COc1ccccc1CC(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)C[C@H](O)[C@@]2(O)c1ccccc1
Yield: 63.3 %

Procedure:
By working in accordance with Use Example 18, starting from 0.5 g of (3aS,4S,5S,7aS)-7,7-diphenyl-4-phenyl-perhydroisoindole-4,5-diol hydrochloride and 0.39 g of (2-methoxyphenyl)-acetic acid, 0.4 g of (3aS,4S,5S,7aS)-7,7-diphenyl-4-phenyl-2-[(2-methoxyphenyl)-acetyl]-perhydroisoindole-4,5-diol is obtained in the form of a white solid which melts with decomposition at 150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[CH:5][CH:4]=1.[Br:18]Br.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:18][C:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:13][C:12]=1[C:14]([F:17])([F:15])[F:16]
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(Br)c(C(F)(F)F)[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.8 %

Procedure:
To a solution of 7 (5 g, 0.025 mol) in CHCl3 (200 ml) was added dropwise a solution of Br2 (1.3 mol, d=3.1, 4.0 g, 0.25 mol) in 100 ml CHCl3. After the addition, the solution was stirred at room temperature for 5 h, poured onto saturated Na2CO3 solution, and separated. The aqueous layer was extracted with CHCl3 (3 x). The organic layers were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with CHCl3 to yield 4.4 g (65%) of 8. An analytical sample was prepared by crystallization from petroleum ether-CHCl3, m.p. 177°-178° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:21]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:15]=2)=[O:22])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-chlorobenzoic acid (0.86 g, 5 mmol) in anhydrous CH2Cl2 (40 mL) was added 1-(trifluoromethyl)-3-isocyanatobenzene (1.03 g, 5.5 mmol). The mixture was stirred overnight at room temperature. The saturated NaHCO3 (40 mL) was added and the mixture was stirred for 5 min. The organic layer was separated and aqueous was extracted with CH2Cl2 (3×20 mL). The combined organic solution was dried (Na2SO4). The solvent was removed in vacuo. The title compound was afforded as a white solid (1.68 g, 94%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][NH2:34])[CH2:29]1)[CH3:27].C(N(CC)CC)C>CS(C)=O>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([CH2:33][NH:34][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: CCN1CC[C@H](CN)C1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCN1CC[C@H](CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 140 °C
Yield: 22 %

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.105 g), ((R)-1-ethylpyrrolidin-3-yl)methyl-amine (Intermediate 163, 0.5 g) and triethylamine (0.5 g) in DMSO (1 mL) was stirred and heated at 140° C. overnight. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatogrpahy on silica, eluting with a mixture of methanol and DCM (5%). The product was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]-chromene-4-carboxylic acid (0.03 g) as a white solid,
Reaction SMILES: C1N=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])C=1.CN.Cl.N1CC(N2[CH:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([S:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)(=[O:37])=[O:36])[CH:26]=3)[CH:22]=[N:21]2)C1.CCN(CC)CC>C1COCC1>[F:34][C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:23]3[CH:22]=[N:21][N:11]([CH:10]4[CH2:9][N:8]([C:6]([NH:3][CH3:4])=[O:7])[CH2:12]4)[CH:24]=3)=[CH:26][N:27]2[S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])=[CH:32][CH:31]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CNC3)c2)c2ccc(F)cc21
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)N1CC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Reaction time: 1 h
Yield: 101 %

Procedure:
A mixture of CDI (62 mg; 0.38 mmol) and MeNH2 (0.20 ml; 0.40 mmol; 2.0 M in THF) of THF (10 mL) was stirred for 1 hour and added a premixed mixture of 3-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole hydrochloride (Intermediate 24; 200 mg; 0.46 mmol) and Et3N (0.10 ml; 0.72 mmol) in THF (2 mL) was stirred at rt for 10 min. The reaction mixture was stirred overnight and concentrated. The residue was diluted with EtOAc (50 mL), washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 174 mg (100%) of the title compound as a yellow oil, which was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:20])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=2)[CH:9]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([OH:20])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]2
Reactant: COc1ccc2cc(-c3ccc(O)cc3Cl)ccc2c1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2)c(Cl)c1

Procedure:
The title compound was prepared by reacting 3-chloro-4-(6-methoxy-2-naphthyl)phenol (2.4 g, 8.43 mmol) with boron tribromide (21.9 mL of 1.0 M solution in CH2Cl2, 21.9 mmol) according to method D to yield 2.1 g (92%) of a yellowish solid: mp 209–210° C.; 1H NMR (DMDO-d6): δ 6.86 (1H, dd, J=8.42 Hz, J=2.45 Hz), 6.97 (1H, d, 2.41 Hz), 7.11 (1H, dd, J=8.78 Hz, J=2.35 Hz), 7.16 (1H, d, J=2.15 Hz), 7.30 (1H, d, J=8.40 Hz), 7.42 (1H, dd, J=8.51 Hz, J=1.71 Hz), 7.71 (1H, d, J=8.59 Hz), 7.76 (1H, s), 7.80 (1H, d, J=8.82 Hz), 9.82 (1H, s), 10.01 (1H,s); 13C NMR (DMDO-d6): δ 108.45, 114.79, 116.21, 118.90, 125.53, 127.43, 127.77, 127.92, 129.56, 130.70, 131.73, 132.34, 133.18, 133.52, 155.56, 157.46; MS (ESI) m/z 269/271 (M−H)−.
Reaction SMILES: [Mg].C(O[CH2:5][CH3:6])C.[CH3:7][C:8]12[CH2:18][CH:12]3[CH2:13][C:14]([CH3:17])([CH2:16][C:10](Br)([CH2:11]3)[CH2:9]1)[CH2:15]2>ClCCl.O>[CH3:7][C:8]12[CH2:18][CH:12]3[CH2:13][C:14]([CH3:17])([CH2:16][C:10]([C:14]45[CH2:15][C:8]6([CH3:18])[CH2:9][CH:10]([CH2:11][C:5]([CH3:6])([CH2:7]6)[CH2:13]4)[CH2:16]5)([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Reactant: CCOCC
Agent: [Mg]
Solvent: O
Solvent: ClCCl
Product: CC12CC3CC(C)(C1)CC(C14CC5CC(C)(CC(C)(C5)C1)C4)(C3)C2
Yield: 47 %

Procedure:
Into a 2 liter egg plant-shaped flask, 9.8 g (0.4 moles) of magnesium was weighed and placed. Under the stream of nitrogen gas, 80 ml of diethyl ether was added and stirred. Then, a solution prepared by dissolving 97.28 g (0.4 moles) of 3,5-dimethyl-1-bromoadamantane into 40 ml of diethyl ether was added dropwise. After the addition was completed, the resultant mixture was heated under the refluxing condition for 30 minutes. The temperature was adjusted at the room temperature, and diethyl ether was completely removed using a vacuum pump. Then, a solution prepared by dissolving 48.64 g (0.2 moles) of 3,5-dimethyl-1-bromoadamantane into 600 ml of dichloromethane was added dropwise. After the addition was completed, the resultant mixture was heated under the refluxing condition for 5 hours. The reaction fluid was poured into 400 ml of ion-exchanged water and treated by extraction with dichloromethane using a separation funnel. The solvent was removed using an evaporator. The residue was dissolved into 40 ml of hexane and purified in accordance with the silica gel column chromatography (the solvent of development: hexane). The solvent was removed using an evaporator, and 30.70 g of 3,3′,5,5′-tetramethyl-1,1′-biadamantane was obtained (the yield: 47%). Since the molecular weight was 327 in the mass analysis, it was shown that the product was the object compound.
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([C:13]#[N:14])[C:6]=1[F:15])(=O)C.[N+:16]([O-])([OH:18])=[O:17]>>[F:15][C:6]1[C:5]([OH:4])=[C:10]([O:11][CH3:12])[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[C:13]#[N:14]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C#N)c(F)c1OC(C)=O
Product: COc1c([N+](=O)[O-])cc(C#N)c(F)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.8 g of 3-cyano-2-fluoro-6-methoxyphenyl acetate are introduced in three portions at -15° into 5 ml of 96 percent nitric acid, whereupon the mixture is stirred at -10° for 1 hour. Thereupon, the reaction mixture is poured on to 50 g of ice. The mixture is extracted twice with 70 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The thus-obtained residue is dissolved in 50 ml of 1N sodium carbonate solution and 50 ml of methanol, whereupon the solution is stirred at 23° for 1 hour and the methanol is distilled off. The residal aqueous phase is adjusted to pH 2 at 0° with conc. hydrochloric acid and extracted trice with 100 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated, and the residue is chromatographed on 45 g of silica gel with methylene chloride/methanol (97:3). After recrystallization from ether/hexane there is obtained 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile of m.p. 112°-113°.
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH3:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CO>[C:17]([O:6][CH2:5][CH2:4][C:3]([F:8])([F:7])[C:2]([CH3:9])([OH:10])[CH3:1])(=[O:19])[CH3:18]
Reactant: CC(C)(O)C(F)(F)CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OCCC(F)(F)C(C)(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6.92 g (0.045 mol) of 4-methyl-3,3-difluoro-1,4-pentanediol and 28 mL of pyridine at 0° C. was added 16 mL of acetic anhydride and the mixture was stirred at 0° C. for 1 hr and at 25° C. for 1 hr. The mixture was added to 15 mL of methanol and the solution was evaporated to dryness to yield oily 4-methyl-3,3-difluoro-1,4-pentanediol 1-acetate. NMR (CDCl3) δ4.40 (triplet, 2, J=7 Hz), 2.30 (multiplet, 2), 2.06 (singlet, 3) and 1.33 ppm (triplet, 6, J=1 Hz).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH2:54])[CH:49]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:54][C:50]4[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=4)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: Nc1cccnc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2cccnc2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with pyridin-3-ylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H46Cl2N7O3 [(M+H)+] 742.3034, observed 742.3034.
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.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:26][CH2:27]Br>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:26][CH2:27][N:15]1[CH2:16][C:17](=[O:18])[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[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccc(CCBr)cc1OC
Product: COc1ccc(CCN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1OC
Yield: 36 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example10-1) and 3,4-dimethoxyphenethyl bromide. Yield: 36%. MS M+H calculated 440.19. Found 440.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.26 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([OH:25])=[N:23][N:24]=1.[CH3:26][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([O:25][CH3:26])=[N:23][N:24]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3nnc(O)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CO
Solvent: ClCCl
Product: COc1nnc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)s1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-((5-hydroxy-1,3,4-thiadiazol-2-yl)methyl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol (100 mg, 0.26 mmol) from step 2 in dichloromethane (8 mL) and methanol (2 mL) at 0° C. was added (trimethylsilyl)diazomethane (2.0 M in diethyl ether, 0.65 mL, 1.3 mmol). The reaction mixture was stirred with gradual warming to ambient temperature over 1 h and concentrated in vacuo. Purification by reverse phase preparative HPLC (Gilson®, SunFire™ Prep, 5 to 50% acetonitrile in water gradient) provided the title compound (69 mg, 0.17 mmol, 66%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:6]2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1.[OH-].[K+].O.Cl>CCO>[CH3:1][C:2]1([CH3:22])[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1
Reactant: CCOC(=O)c1cnn2c1NC(c1ccccc1)CC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2)Nc2c(C(=O)O)cnn21
Temperature: 90 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A mixture of 1 (0.73 g) obtained in Example 1009, KOH (0.41 g), H2O (20 ml) and EtOH (20 mL) was stirred at 90° C. for 12 h, acidified with 1N HCl, and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo to give 0.55 g (83% yield) of the title compound as colorless prisms ([α]D20° C.=−85.33, in CHCl3, C=0.46). mp 205-206° C., 1H NMR (CDCl3, 300 MHz): 1.59 (3H, s), 1.66 (3H, s), 2.05-2.15 (2H, m), 4.64 (1H, dd, J=9.6, 5.4 Hz), 6.04 (1H, s), 7.30-7.41 (5H, m), 7.73 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH3:15][O:16][C:17]([C:19]#[C:20][C:21](OC)=[O:22])=[O:18].C[O-].[Na+].[Na]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21](=[O:22])[CH:20]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[NH:14]1
Reactant: COC(=O)C#CC(=O)OC
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc(=O)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Reaction time: 2.5 h
Yield: 65 %

Procedure:
To a solution of 30.1 g (0.123 mole) of 2,6-dichloro-4-trifluoromethylphenylhydrazine in 75 ml of methanol was added dropwise with stirring a solution of 18.5 g (0.13 mole) of dimethylacetylene dicarboxylate dissolved in 75 ml of methanol. The reaction mixture was stirred for 2.5 hrs. at 10°-20° C. The brown mixture was then added slowly, over a period of 50 min., to a stirred solution of sodium methoxide (made by dissolving 11.0 g (0.478 mole) of sodium in 400 ml of anhydrous methanol). After stirring for an additional period of 1.5 hr, the solution was concentrated under a partial vacuum and acidified with 100 ml of 4N hydrochloric acid. The precipitated solid was filtered, washed with water and air dried to afford 28.4 g (65 percent yield) of a tan colored solid, mp 245°-246° C., which was recrystallized from methanol to give a solid, mp 249°-250° C.