Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:2].[CH2:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[C:16]([CH2:18][NH:25][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH:15]=[N:14][CH:13]=2)=[CH:11][C:4]=1[O:3][CH2:1][CH3:2])#[N:7]
Reactant: CCOc1cc(-c2cncc(C=O)c2)ccc1C#N
Reactant: CCS(N)(=O)=O
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CCOc1cc(-c2cncc(CNS(=O)(=O)CC)c2)ccc1C#N
Temperature: 140 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
Titanium(IV) isopropoxide (234 μL, 0.800 mmol) was added dropwise to a mixture of 2-ethoxy-4-(5-formylpyridin-3-yl)benzonitrile (101 mg, 0.400 mmol), ethanesulfonamide (52.4 mg, 0.480 mmol) in toluene (20 mL). The resulting mixture was heated at 140° C. for 2 hr. After concentration, the residue was dissolved in CH2Cl2 (10 mL) and sodium triacetoxyborohydride (254 mg, 1.200 mmol) was added at room temperature. The resulting mixture was stirred overnight, and quenched with NaHCO3 solution. After filtration, extraction and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 1%-3.5%) and yielded a colorless oil (100 mg) which turned to colorless solid after standing. ESI-MS m/z: 317.9 [M+H]+, 1H NMR (400 MHz, CDCl3): δ 1.40 (t, J=7.4 Hz, 3H), 1.53 (t, J=7 Hz, 3H), 3.08 (q, J=7.4 Hz, 2H), 4.25 (q, J=7 Hz, 2H), 4.43 (d, J=6.2 Hz, 2H), 4.59 (brs, 1H), 7.10 (d, J=1.4 Hz, 1H), 7.19 (dd, J=8, 1.6 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.93 (s, 1H), 8.62 (s, 1H), 8.77 (s, 1H).
Reaction SMILES: O[CH:2]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])[CH3:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH2:2]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:5]=1[CH3:31])[CH3:3]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(C)O)OCC2c1ccc(C(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a mixture of N-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (200 mg, 0.47 mmol) obtained in Example 22 and trifluoroacetic acid (3 mL) was added under ice cooling triethylsilane (0.5 mL, 3.2 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, to the residue was added an aqueous saturated sodium hydrogen carbonate solution and the aqueous layer was made alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) and recrystallized from hexane to obtain 100 mg (yield: 52%) of the title compound. Melting point: 135-136° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16](Cl)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1Cl
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1-c1ccccc1

Procedure:
Ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[h][1,4]oxazin-6-yl)-5-phenylthiazole-4-carboxylate (7E) was prepared following a similar procedure as that described in example 1, except ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-chlorothiazole-4-carboxylate (7D) was used instead of ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-chlorothiazole-4-carboxylate (1J) and phenylboronic acid was used instead of 4-methoxyphenylboronic acid in step 11 of example 1. LC/MS (APCI): m/z 409.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15](=[O:36])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][C:24]5[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][C:28]([C:34]#[N:35])=[CH:27][C:25]=5[N:26]=4)=[CH:18][CH:17]=3)[O:10][C:9]2=[O:37])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:44][C:45]([F:57])([F:56])[O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1B(O)O>O1CCCC1.O.C(P([C-]1C=CC=C1)C(C)(C)C)(C)(C)C.[CH-]1C=CC=C1.[Fe+2].[Pd]>[C:34]([C:28]1[CH:29]=[C:30]([CH:31]([CH3:33])[CH3:32])[C:24]2[O:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH2:13][CH:11]4[O:10][C:9](=[O:37])[N:8]([C:5]5[CH:4]=[CH:3][C:2]([C:48]6[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=6[O:46][C:45]([F:44])([F:57])[F:56])=[CH:7][N:6]=5)[CH2:12]4)=[O:36])=[CH:17][CH:18]=3)=[N:26][C:25]=2[CH:27]=1)#[N:35]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CN(c5ccc(Cl)cn5)C(=O)O4)cc3)oc12
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CN(c5ccc(-c6ccccc6OC(F)(F)F)cn5)C(=O)O4)cc3)oc12
Temperature: 150 °C
Yield: 82 %

Procedure:
To a mixture of N-{[3-(5-chloropyridin-2-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (52 mg) and potassium carbonate (55 mg) in 1 ml of tetrahydrofuran and 1 ml of water was added 2-trifluoromethoxyphenylboronic acid (82 mg) and palladium di-tert-butylphosphinoferrocene (13 mg). The mixture was heated via microwave for 15 min at 150° C. The sample was cooled to room temperature, and purified was purified via column chromatography on a Biotage Horizon 40M column eluting with 0% ethyl acetate in hexanes (1 column volumes), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 3 column volumes to provide the title compound as an off-white solid (53 mg, 83%). Mass spectrum (ESI) 642.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.43 (s, 1H), 8.35 (d, J=7.8 Hz, 2H), 8.28 (d, J=8.7 Hz, 1H), 7.98 (d, J=8.3 Hz, 2H), 7.94 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.52 (s, 1H), 7.40 (m, 4H), 6.76 (bs, 1H), 4.98 (m, 1H), 4.48 (dd, J=9.1 Hz, 10.7 Hz, 1H), 4.13 (m, 2H), 3.72 (m, 1H), 3.49 (sept, J=6.9 Hz, 1H), 1.46 (d, J=7.1 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.[CH3:28][O:29][C:30](=[O:57])[CH2:31][CH2:32][C@H:33]([C@@H:35]1[C@:52]2([CH3:53])[C@H:38]([C@H:39]3[C@H:49]([CH2:50][C@@H:51]2[OH:54])[C@:47]2([CH3:48])[C@@H:42]([CH2:43][C@@H:44]([NH2:55])[CH2:45][CH2:46]2)[CH2:41][C@H:40]3[OH:56])[CH2:37][CH2:36]1)[CH3:34]>C1COCC1.CCOCC>[CH3:28][O:29][C:30](=[O:57])[CH2:31][CH2:32][C@H:33]([C@@H:35]1[C@:52]2([CH3:53])[C@H:38]([C@H:39]3[C@H:49]([CH2:50][C@@H:51]2[OH:54])[C@:47]2([CH3:48])[C@@H:42]([CH2:43][C@@H:44]([NH:55][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:45][CH2:46]2)[CH2:41][C@H:40]3[OH:56])[CH2:37][CH2:36]1)[CH3:34]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](NC(=O)CNC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 0.33 h
Yield: 62.4 %

Procedure:
To a solution of N-(t-butoxycarbonyl)glycine (marketed product) (14.7 g; 84.0 mmol) and Et3N (8.50 g; 11.6 ml; 84.0 mmol) in THF (400 ml), at 0° C. and under nitrogen, was added dropwise isobutyl chloroformate (11.5 g; 10.9 ml; 84.0 mmol). After 15 min a solution of (3β,5β,7α,12α)-3-amino-7,12-dihydroxy-cholan-24-oic acid methyl ester (prepared according to Example 5) (29.5 g; 70.0 mmol) in THF (100 ml) was added dropwise to the reaction mixture at 0° C. After 20 min the reaction mixture was allowed to rise to room temperature and stirred overnight. The suspension was filtered through a sintered funnel and the filtrate was evaporated under reduced pressure to give a residue that was dissolved in Et2O and washed with a saturated aqueous solution of NaHCO3 and H2O. The organic phase was separated, dried and then evaporated under reduced pressure. The solid residue was purified by flash chromatography to give the desired product as a white solid (25.3 g; 43.7 mmol).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([NH:23][CH3:24])=[C:17]([NH2:25])[CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C.NC(N)=S.IC.C(OC(C1C=C(OC2C=CC3N(C)[C:51]([NH:53][C:54]4[CH:59]=[CH:58][C:57]([Br:60])=[C:56]([CH3:61])[CH:55]=4)=NC=3C=2)C=CN=1)=O)(C)(C)C.FC(F)(F)C(O)=O>CO.C(Cl)Cl>[Br:60][C:57]1[CH:58]=[CH:59][C:54]([NH:53][C:51]2[N:23]([CH3:24])[C:18]3[CH:19]=[C:20]([O:21][CH3:22])[C:15]([O:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([C:6]([OH:5])=[O:7])[CH:13]=4)=[CH:16][C:17]=3[N:25]=2)=[CH:55][C:56]=1[CH3:61]
Reactant: Cc1cc(Nc2nc3cc(Oc4ccnc(C(=O)OC(C)(C)C)c4)ccc3n2C)ccc1Br
Reactant: CNc1cc(OC)c(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Agent: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: CI
Solvent: CO
Product: COc1cc2c(cc1Oc1ccnc(C(=O)O)c1)nc(Nc1ccc(Br)c(C)c1)n2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-6-methoxy-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-bromo-3-methylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-bromo-3-methylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-bromo-3-methylphenyl]amino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=482.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:16])([C:10](N(OC)C)=[O:11])[CH2:5][C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)#[N:2].[C:24]([Mg]Br)#[CH:25]>O1CCCC1>[CH3:16][C:6]1([C:10](=[O:11])[C:24]#[CH:25])[NH:7][C:8](=[O:9])[C:3]([C:1]#[N:2])=[C:4]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH2:5]1
Reactant: CON(C)C(=O)C1(C)CC(c2ccc(C)cc2)=C(C#N)C(=O)N1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(=O)C1(C)CC(c2ccc(C)cc2)=C(C#N)C(=O)N1
Temperature: 35 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
Intermediate 109A (0.0887 g, 0.283 mmol) was dissolved in tetrahydrofuran (1 mL) in a 25 mL 1 neck pear shaped flask that was equipped with a magnetic stirrer and an Ar inlet. Ethynylmagnesium bromide (5.66 mL, 2.83 mmol) was added dropwise and the reaction mixture was stirred at 35° C. for 4 h. The reaction mixture was cooled to rt, quenched with sat'd. aq NH4Cl (5 mL) and extracted with EtOAc (2×10 mL). The organic phases were combined and concentrated in vacuo. The residue was purified by silica gel chromatography (24 g silica gel, eluted with 0-100% EtOAc in hexanes) to give the desired product (0.06 g, 78%) as an orange solid. LCMS Anal. Calc'd for C12H14N2O2 278.1, found [M+H] 279.0.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:28]([F:31])([F:30])[F:29])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:27])=[C:22]([N+:24]([O-])=O)[CH:23]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>C(O)C.[Fe]>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:28]([F:30])([F:29])[F:31])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:27])=[C:22]([CH:23]=3)[NH2:24])[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To an aqueous 2.5% acetic acid solution (19 ml) was added an iron powder (10-20 mesh; 1.89 g), followed by a suspension of 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylnitrobenzene (4.62 g) obtained by Reference Production Example 12 in ethanol (29 ml) at 75° C., and then the mixture was stirred at the same temperature for 15 minutes. To the mixture was further added an iron powder (1.80 g) at the same temperature, and the mixture was stirred at the same temperature for 1 hour. After cooling to room temperature, the reaction mixture was filtrated and washed with ethyl acetate. Then, the filtrate was extracted with an aqueous saturated sodium hydrogen carbonate solution and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylaniline (3.18 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=O.[CH:11](NC=O)([NH:15]C=O)[NH:12][CH:13]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N)=O.[OH-].[Na+].Cl>>[Br:10][C:6]1[CH:5]=[C:4]([C:2]2[CH:1]=[CH:13][N:12]=[CH:11][N:15]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: O=CNC(NC=O)NC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: NC=O
Product: Brc1cccc(-c2ccncn2)c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
A mixture of 9.0 g (59.9 mmol) of 3-bromoacetophenone, 17.1 g (118 mmol) of N,N′,N″-methylidynetrisformamide, 0.57 g (3.0 mmol) of p-toluenesulfonic acid and 27 g of formamide was stirred at 160° C. for 2 hours. After the reaction mixture was cooled to room temperature, a 5% aqueous solution of caustic soda was added thereto, and the mixture was adjusted to pH 4 with a 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of ammonium chloride and saturated brine, then dried and concentrated. The resultant solid residue was recrystallized from a mixture ethanol:water=1:2 to obtain 2.49 g of 4-(3-bromophenyl)pyrimidine.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:28]([C:31]1[C:32]([CH:41]2[CH2:44][CH2:43][CH2:42]2)=[CH:33][C:34]([CH3:40])=[C:35]([CH:39]=1)[C:36](O)=[O:37])(=[O:30])[NH2:29].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([CH:4]2[CH2:5][N:2]([C:36]([C:35]3[C:34]([CH3:40])=[CH:33][C:32]([CH:41]4[CH2:44][CH2:43][CH2:42]4)=[C:31]([CH:39]=3)[C:28]([NH2:29])=[O:30])=[O:37])[CH2:3]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1cc(C2CCC2)c(C(N)=O)cc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(C(N)=O)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 4-mL vial was added 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 27 mg, ˜90% pure, 0.13 mmol), HOBt (20 wt % H2O) (22 mg, 0.13 mmol), EDC (27 mg, 0.14 mmol). A solution of 5-carbamoyl-4-cyclobutyl-2-methylbenzoic acid (compound 6.5, 28 mg, 0.12 mmol) in DMF (500.4) was added followed by DIEA (83 μL, 0.48 mmol). The mixture was sealed and stirred at room temperature for 18 hours. Additional amine (3 mg, ˜0.015 mmol) and EDC (5 mg, ˜0.026 mmol) were added and the mixture was stirred at room temperature for an additional 27 hours. The mixture was diluted with ethyl acetate (5 mL) and washed with brine (8 mL). The aqueous was extracted with ethyl acetate (2 mL) and the combined organics was washed with brine, 1 M NaH2PO4, saturated NaHCO3 and brine (7 mL each). The product began precipitating out of solution after the final brine wash, so the organics was diluted with DCM (3 mL) and MeOH (˜200 μL). The organics was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was triturated with Et2O (1.5 mL), filtered, and washed with Et2O (0.5 mL) to yield the title compound as an off white powder (41.4 mg, 92%). m/z (ES+) 374 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.67 (d with fine str., J=8.4 Hz, 2H), 7.40 (d with fine str., J=8.4 Hz, 2H), 7.32 (s, 1H), 7.25 (s, 1H), 5.79 (br s, 1H), 5.70 (br s, 1H), 4.67-4.57 (m, 1H), 4.39-4.30 (m, 1H), 4.28-4.18 (m, 1H), 4.00-3.86 (m, 3H), 2.46 (s, 3H), 2.42-2.31 (m, 2H), 2.19-1.96 (m, 3H), 1.88-1.77 (m, 1H).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:21]=[CH:20][C:6]([C:7](=[O:19])[CH2:8][N+:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:36](#[N:39])[CH:37]=[CH2:38]>CN(C)C=O>[C:36]([C:37]1[CH:38]=[C:8]([C:7](=[O:19])[C:6]2[CH:20]=[CH:21][C:3]([F:2])=[CH:4][CH:5]=2)[N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=12)#[N:39]
Reactant: O=C(C[n+]1cccc2ccccc21)c1ccc(F)cc1
Reactant: C=CC#N
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12

Procedure:
The title compound was prepared from 1-(4-fluoro-phenacyl)-quinolinium bromide (117 mg, 0.338 mmol), tetrapyridinecobalt(II) dichromate (217 mg, 0.356 mmol), sodium bicarbonate (75.7 mg, 0.901 mmol), acrylonitrile (110 μL, 1.67 mmol), and N,N-dimethylformamide (2.0 mL), similar to Example 1b, and yielded 32.6 mg (30%) as a yellow solid. 1H NMR (CDCl3): 8.11 (m, 2H), 8.04 (dd, J=8.52, 0.55 Hz, 1H), 7.86 (dd, J=7.69, 1.65 Hz, 1H), 7.74 (d, J=9.34 Hz, 1H), 7.68 (d, J=9.07 Hz, 1H), 7.62 (ddd, J=8.31, 7.07, 1.72 Hz, 1H), 7.54 (td, J=7.48, 1.19 Hz, 1H), 7.41 (s, 1H), 7.26 (m, 2H).
Reaction SMILES: C(OCC)(=O)CCC[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:15]1([S:21][CH2:22][C:23]([OH:25])=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(=O)(=O)(O)O>C1(O)CCCCC1>[C:15]1([S:21][CH2:22][C:23]([O:25][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCCCCCC(=O)OCC
Reactant: O=C(O)CSc1ccccc1
Agent: O=S(=O)(O)O
Solvent: OC1CCCCC1
Product: O=C(CSc1ccccc1)OC1CCCCC1

Procedure:
The procedure is as in Example 20 for the preparation of ethyl n-decanoate, starting with (phenylthio)acetic acid (20 g) and 36N aqueous sulphuric acid solution (0.32 cc) in cyclohexanol (100 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (70:30 by volume) as eluent, cyclohexyl (phenylthio)acetate (29 g) is obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:34](=[N:36]O)[NH2:35])[CH:33]=1.CCN(C(C)C)C(C)C>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:34]2[N:35]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[CH3:7])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[O:20][N:36]=2)[CH:33]=1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (106 μL; 1.25 mmol; 3 eq.), Intermediate 24 (120 mg; 0.42 mmol; 1 eq.), Intermediate 23 (77 mg; 0.42 mmol, 1 eq.) and DIEA (216 μL; 1.25 mmol; 3 eq.) were reacted according to general procedure 2. Purification by preparative HPLC (increasing amount of 0.1% TFA in CH3CN, in 0.1% TFA in water) afforded the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Br[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:10])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(Br)ccc1Cl
Reactant: CC(=O)c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1cc(CC(=O)c2ccccc2Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-chlorophenyl)ethanone (1.4 mL, 10.8 mmol), 4-bromo-1-chloro-2-(methyloxy)benzene (2.0 g, 9.0 mmol), sodium tert-butoxide (2.2 g, 22.6 mmol), palladium(II) acetate (20.3 mg, 0.1 mmol), and 2-(dicyclohexylphosphino)-2′-methylbiphenyl (65.8 mg, 0.2 mmol) in 30 mL of toluene was degassed and stirred at 80° C. for 16 h. The reaction mixture was cooled and a mixture of Et2O (100 mL) and H2O (100 mL) was added. The aq layer was separated and extracted with Et2O (3×50 mL). Organic layers were combined, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 1:9 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 3.87 (s, 3H), 4.22 (s, 2H), 6.75 (dd, J=1.7, 8.2, 1H), 6.81 (d, J=1.6, 1H), 7.26-7.31 (m, 2H), 7.37-7.43 (m, 3H).
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][N:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[C:14]3=[O:27])[CH:10]=[N:9]2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][CH2:31][CH2:32]Br>>[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]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:32][CH2:31][O:30][CH3:29])[C:14]3=[O:27])[CH:10]=[N:9]2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COCCBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3O)C2=O)cn1
Product: COCCOc1ccccc1CN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 19 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(2-hydroxybenzyl)imidazolidine-2,4-dione (example 10-11) and 2-bromoethyl methyl ether. Yield 19%. 1H NMR (DMSO, 400 MHz): δ2.11 (s, 3H), 2.08 (s, 3H), 3.25 (s, 3H), 3.64 (t, J=3.6, 2H), 4.00 (s, 2H), 4.11 (t, J=3.2, 2H), 4.27 (s, 2H), 5.17 (s, 2H), 6.90 (m, 1H), 7.00 (m, 1H), 7.26 (m, 2H), 7.76 (s, 1H), 8.15 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.1 uM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH2:32]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([CH:39]1[CH2:44][CH2:43][N:42]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:29])[F:30])[C:9]=4[CH:17]=3)[CH:19]=2)=[O:23])[CH2:41][CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(Cc2ccccc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=605.01 (M+H+); retention time=1.09 minutes.