Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]2[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]2)[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:31][C:29]1[CH:28]=[N:27][N:26]([C@H:23]2[CH2:22][CH2:21][C@H:20]([NH:19][CH3:18])[CH2:25][CH2:24]2)[CH:30]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN[C@H]1CC[C@H](n2cc(N)cn2)CC1
Product: CN[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (310 mg, 1.00 mmol) was reacted with 1-[trans-4-(methylamino)cyclohexyl]-1H-pyrazol-4-amine (388 mg, 2.00 mmol) to afford the desired product (65 mg, 14%) as an orange solid: ESI MS m/z 468 [C23H26BrN5O+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH:6]=1)[CH3:2].[Br:18]Br>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:16]=[C:15]([Br:18])[CH:14]=[N:13]2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(-n2cccn2)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C)c(-n2cc(Br)cn2)c1
Yield: 102.6 %

Procedure:
A solution of 3-hydrazino-4-methyl benzoic acid (See U.S. provisional application 60/570,284) (1.0 g, 4.93 mmol), malonaldehyde(bismethylacetate) (0.82 mL, 4.93 mmol), and concentrated HCl (1 mL) in EtOH (20 mL) was heated to reflux for 4 h. After cooling to room temperature, the reaction was poured into ice water, neutralized with 2N NaOH, and extracted with CH2Cl2 (3×). The organic layers were dried over Na2SO4, filtered and concentrated to afford 4-methyl-3-pyrazol-1-yl-benzoic acid ethyl ester (536 mg, 47%) as a yellow oil. A solution of the pyrazole (536 mg, 2.33 mmol) and bromine (0.167 mL, 3.26 mmol) in CHCl3 (15 mL) was refluxed for 4.5 h then cooled and concentrated. Chromatography (1:1 EtOAc/hexanes) yielded 3-(4-bromo-pyrazol-1-yl)-4-methyl-benzoic acid ethyl ester (0.739 g, 99%). The bromopyrazole (366 mg, 1.18 mmol) was dissolved in dioxane (2 mL) and flushed with N2. 1-Methyl-5-tributylstannanyl-1H-imidazole (366 mg, 0.986 mmol) was added to the reaction flask in dioxane (0.5 mL) then the flask was purged with N2. After Pd(PPh3)4 (85 mg, 0.074 mmol) was added, the reaction was heated to 100° C. in a sealed tube. The reaction mixture was stirred with a 10% KF solution for 30 min then diluted with EtOAc. The layers were separated and the aqueous layer extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The resulting residue was purified by chromatography on silica gel (5% MeOH/CH2Cl2) to give 4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzoic acid ethyl ester (81 mg, 22%).
Reaction SMILES: [C@@H:1]1([N:10]2[C:18]3[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=3[N:12]=[CH:11]2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(O[C:24](=[O:26])[CH3:25])(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:2]([O:3][C@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:24](=[O:26])[CH3:25])[O:7][C@H:1]1[N:10]1[C:18]2[CH:17]=[CH:16][NH:15][C:14](=[O:19])[C:13]=2[N:12]=[CH:11]1)(=[O:3])[CH3:1]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]ccc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]ccc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 3.0 g of 1-β-D-arabinofuranosyl-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one, eight ml of acetic anhydride, 150 ml of pyridine, and 50 mg of p-dimethylaminopyridine is stirred at room temperature for 24 hours, evaporated in vacuo, co-evaporated with xylenes, and distributed between water and ethyl acetate. The ethyl acetate layer is washed with saturated NaHCO3 and dried with MgSO4. Removal of the ethyl acetate provides 1-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-1,5-dihydro-4H-imidazo[4,5-c]pyridin-4-one. This is dissolved in 150 ml of dry pyridine, treated with 8.8 g phosphorus pentasulfide, and heated under reflux for 5 hours. The pyridine is removed in vacuo and the residue is treated with water. The precipitate is filtered, washed with water, and recrystallized from ethanol to afford 1-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-1,5-dihydro-4H-imidazo-[4,5-cl]pyridine-4-thione.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)[CH:6]=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:9]([C:8]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:26][CH:28]4[CH2:29][O:30]4)=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)=[CH:6][N:7]=1)[CH3:10]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cnc1CC
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nc(-c3cc(C)c(OCC4CO4)c(CC)c3)no2)cnc1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.5 %

Procedure:
To a solution of 4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (150 mg, 0.445 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), epichlorhydrine (164 mg, 1.78 mmol) is added. The mixture is stirred at rt for 20 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA-heptane to give (RS)-2,3-diethyl-5-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-pyridine (92 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:13]O>OS(O)(=O)=O>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[N:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)nc(OC)c1
Temperature: 0 °C

Procedure:
To a suspension of 2-chloro-6-methoxy-isonicotinic acid (244 g, 1.30 mol) in methanol (2.5 L), H2SO4 (20 mL) is added. The mixture is stirred at reflux for 24 h before it is cooled to 0° C. The solid material is collected, washed with methanol (200 mL) and water (500 mL) and dried under HV to give 2-chloro-6-methoxy-isonicotinic acid methyl ester (165 g) as a white solid; LC-MS: tR=0.94 min, [M+1]+=201.89.
Reaction SMILES: O[CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:25])[CH:24]=2)[CH:3]1[CH3:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:51]I>C1(C)C=CC=CC=1>[I:51][CH:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:5](=[O:19])[N:4]([C:20]2[CH2:21][O:22][C:23](=[O:25])[CH:24]=2)[CH:3]1[CH3:26]
Reactant: II
Reactant: CC1C(O)C2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1C(I)C2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1C1=CC(=O)OC1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a solution of the compound of step C (370 mg, 1.01 mmol) in toluene (20 mL) at rt was added PPh3 (397 mg, 1.515 mmol), imidazole (137 mg, 2.02 mmol), and I2 (384 mg, 1.515 mmol). The mixture was stirred for 10 h at 100° C., and quenched with NaHCO3 aqueous solution. The organic layer was diluted with DCM, separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried (MgSO4) and purified by column chromatography (0-100% EtOAc/hex) to give the title compound. LC/MS: [(M+1−56)]+=421
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:39])[CH:13]([N:15]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)[CH3:14])=[CH:8][CH:7]=1)(=O)=O.O.[OH-].[K+].Cl>CC(C)=O>[CH2:32]([N:15]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:23]=1)[CH:13]([CH3:14])[C:12]([C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C(=O)c1ccc(OS(C)(=O)=O)cc1)N(CCc1ccc(OCc2ccccc2)cc1)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C(=O)c1ccc(O)cc1)N(CCc1ccc(OCc2ccccc2)cc1)Cc1ccccc1
Temperature: 59 °C
Yield: 96.7 %

Procedure:
50 g of 4-(2-{benzyl-[2-(4-benzyloxyphenyl)-ethyl]-amino}-propionyl)phenyl methanesulfonate (B), 100 ml of water, 355 ml of acetone and 18.4 g of potassium hydroxide are introduced into a one liter glass reactor at room temperature. The mixture is heated to reflux temperature (about 59° C.) and kept at such a temperature for two hours. Subsequently, the mixture is cooled down to 45-50° C. and 30% hydrochloric acid is added until a pH of around 7 is obtained. The lower phase is separated and the organic phase is diluted with 100 ml of water. A suspension is obtained that is cooled down to 0° C. The solid is isolated through filtration and washed and then vacuum dried at 40° C. 41.4 g of 2-{Benzyl-[2-(4-benzyloxy-phenyl)-ethyl]-amino}-1-(4-hydroxy-phenyl)-propan-1-one (C) as a white solid, are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[O:9]=[C:5]1[NH:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][NH:1][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: NCCN1CCNC1=O
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: O=C(NCCN1CCNC1=O)Nc1ccccc1
Reaction time: 4 h

Procedure:
To a mixture of 6.5 g of commercially available 1-(2-aminoethyl)-2-imidazolidone and 50 ml benzene was added 5.5 ml of phenyl isocyanate. The strongly exothermic reaction was moderated by cooling to 25°. The mixture was stirred at 25° for 4 hr. It was cooled in ice and the mixture was filtered. The solid product was crystallized from 250 ml of acetone to give 6.8 g of white 1-[2-(2-oxo-1-imidazolidinyl)ethyl]-3-phenylurea, mp 162°-164°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:14]([O:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[O:10][CH3:9])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)COc1ccccc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)Oc1ccccc1OC
Reaction time: 7 h
Yield: 105.9 %

Procedure:
A solution of N-bromosuccinimide (13.35 g), azoisobutyronitrile (200 mg) and ethyl 2-(2-methoxyphenoxy)acetate (15.1 g) in anhydrous carbon tetrachloride (ex. calcium hydride) (100 ml) was irradiated with a 120 W sunlamp under reflux and a nitrogen atmosphere for 7 hours. The resulting suspension was allowed to stand at room temperature for 72 hours and was then filtered to remove the suspended solids, which were washed with toluene (40 ml). The combined filtrates were evaporated under vacuum leaving a brown liquid (22 g) Rf 0.75 (dichloromethane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[NH:30][CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2].[F:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:41][C:40]4[CH:43]=[CH:44][CH:45]=[C:38]([F:37])[CH:39]=4)[CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=Cc1cccc(F)c1
Reactant: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The above free amine (1.23 g, 2.49 mmol, Example 65) and 3-fluorobenzaldehyde (0.62 g, 4.98 mmol) were placed in a 100 mL flask and sealed under nitrogen. Tetrahydrofuran (40 mL) and 0.31 mL of acetic acid (5.47 mmol, 2.20 equiv.) was added. The reaction was stirred at room temperature for 20 minutes, and then sodium triacetoxyborohydride (1.32 g, 6.22 mmol) was added and stirred overnight. The reaction solution was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium hydrogencarbonate (25 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residual dark brown oil (2.01 g) was purified by chromatography on a Biotage column (SiO2-F Flash Cartridge, 8 g, 32-63 μm, 60 A) eluting first with dichloromethane to remove the less polar contaminant, then using 2.5% methanol in dichloromethane. The desired fractions were combined and the solvent was removed under reduced pressure. The title product (4-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperazin-1-yl)-acetic acid ethyl ester was obtained as a light yellow solid (0.75 g, 50%). 1H NMR (300 MHz, d6-DMSO): □ 0.81-1.01 (m, 6H); 1.14-1.19 (t, 3H), 1.89-2.01 (m, 2H); 2.48 (s, 4H); 2.57-2.66 (m, 4H); 3.24 (s, 2H); 3.29-3.36 (m, 4H); 3.50-3.56 (m, 1H); 3.71-3.76 (dd, 1H); 4.03-4.10 (q, 2H); 4.94 (s, 1H); 6.62-6.71 (m, 3H); 6.97-7.19 (m, 4H); 7.29-7.43 (m, 5H); 9.35 (s, 1H). Calculated for C35H43FN4O4.0.12 CH2Cl2: C, 68.82; H, 7.11; N, 9.14; F, 3.10. Found: C, 68.85; H, 7.17; N, 9.11; F, 3.18.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:23]=[C:24]([Cl:26])[N:25]=2)[C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:13])[CH2:5][CH2:4]1.[Cl:27][C:28]1[C:32]([Cl:33])=[C:31]([CH3:34])[NH:30][C:29]=1[C:35](NC1CCN(C2C=CC=C(Cl)N=2)CC1)=[O:36]>>[Cl:26][C:24]1[CH:23]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:35]([C:29]3[NH:30][C:31]([CH3:34])=[C:32]([Cl:33])[C:28]=3[Cl:27])=[O:36])[CH2:8][CH2:7]2)[N:25]=1)[C:12]([NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:13]
Reactant: NC1CCN(c2cc(C(=O)NCCN3CCOCC3)cc(Cl)n2)CC1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cccc(Cl)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NCCN4CCOCC4)cc(Cl)n3)CC2)c(Cl)c1Cl

Procedure:
The title compound was synthesised by an analogous method to Example 18 from 2-(4-aminopiperidin-1-yl)-6-chloro-N-(2-morpholin-4-ylethyl)isonicotinamide hydrochloride salt (Intermediate 218) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:2]1>[Pd].CO.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1
Reactant: O=C(O)/C=C\c1csc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCc1csc2ccccc12
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A suspension of 329a (5.5 g, 27 mmol) and 10% Pd/C (600 mg) in 1:1 methanol/ethyl acetate (100 mL) was hydrogenated in a Parr apparatus at 50 psi for overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give crude 329b as a brown solid (5.0 g, 90%), which was used without further purification for the next step. MS: [M+H]+ 207. 1H NMR (500 MHz, CDCl3) δ 2.81-2.84 (t, J=8.5, 2H), 3.18-3.21 (m, 2H), 7.16 (s, 1H), 7.34-7.41 (m, 2H), 7.74-7.76 (d, 1H), 7.85-7.87 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][C:15]([OH:17])=[O:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(O)CC1(c2ccc(Cl)cc2)CCOCC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1(c2ccc(Cl)cc2)CCOCC1

Procedure:
A stirred solution of (4-{4-chloro-phenyl}-tetrahydro-pyran-4-yl)-acetic acid [3.3 g, Reference Example 21(a)] in anhydrous methanol (125 mL), under argon, was treated with concentrated sulfuric acid (8 drops). This mixture was stirred at reflux temperature for 5.5 hours then evaporated. The residue was treated with ethyl acetate (35 mL) and the resulting solution was washed three times with water (10 mL), then dried over magnesium sulfate and then evaporated to give the title compound (3.12 g) as a pale amber oil. LC-MS: RT=3.43 minutes, MS(ES+): 269 and 271(M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[O:3].[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[CH:20]1([NH:26][C:2]([O:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: CC(C)C[C@H](OC(=O)Cl)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C[C@H](OC(=O)NC1CCCCC1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
To a solution of benzyl(2S)-2-chlorocarbonyloxy-4-methylvalerate (0.56 g) in tetrahydrofuran (11 ml) was added cyclohexylamine (0.40 g) at room temperature. After being stirred for 10 minutes, the solvent was removed by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 1N HCl, water and brine successively. The organic layer was dried over magnesium sulfate concentrated in vacuo. The residual solid was triturated with hexane to give benzyl (2S)-2-cyclohexylcarbamoyloxy-4-methylvalerate (0.45 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29](Cl)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][CH2:22][NH:23][C:24]([C:26]2[N:27]=[N:28][C:29]([N:9]3[CH2:10][CH2:11][CH:6]([O:5][C:4]4[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=4[C:2]([F:1])([F:16])[F:17])[CH2:7][CH2:8]3)=[CH:30][CH:31]=2)=[O:25])[CH2:20][CH2:19]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1
Yield: 44 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 4-(2-trifluoromethylphenoxy)piperidine in place of piperidin-4-yl-(2-trifluoromethylphenyl)amine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 44% yield. 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=9.5 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.46 (t, J=7.2 Hz, 1H), 7.00-6.96 (m, 3H), 4.78 (t, J=4.7 Hz, 1H), 4.03-3.95 (m, 2H), 3.83-3.74 (m, 2H), 3.56-3.50 (m, 2H), 2.00-1.98 (m, 4H), 1.51-1.45 (m, 2H), 0.75-0.70 (m, 1H), 0.46-0.40 (m, 2H), 0.09-0.04 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 163.2, 159.9, 154.9, 144.4, 133.2, 127.5, 127.4, 126.8, 120.2, 113.5, 112.1, 71.35, 41.1, 39.6, 34.6, 29.5, 8.7, 4.2 MS (ES+) m/z 457 (M+Na).
Reaction SMILES: [Na].[SH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=2)[CH:15]=1>CN1CCCC1=O>[N+:19]([C:16]1[N:14]2[CH:15]=[C:10]([S:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[CH:11]=[CH:12][C:13]2=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cn12
Reactant: Sc1ccccn1
Agent: [Na]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cnc2ccc(Sc3ccccn3)cn12

Procedure:
A solution of 1.61 g. (0.012 mole) of the sodium salt of 2-mercapto pyridine and 2.42 g. (0.01 mole) of 6-bromo-3-nitroimidazo [1,2-a] pyridine in 10 ml. N-methylpyrolidinone is heated at 150° C. for 40 minutes under a nitrogen atmosphere. The cooled solution is poured onto 100 ml. of ice-water and the resultant suspension is extracted with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent to a small volume and dilution with N-hexane yields crystalline material. The solids are purified by chromatography on silica gel. Elution with methylene chloride yields pure 3-nitro 6-(2-pyridylthio) imidazo [1,2-a] pyridine.
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.O[CH2:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=4)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[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: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(CNC(=O)OC(C)(C)C)c3)C2=O)cn1
Yield: 89.2 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (070 mg, 0.254 mmol), tert-butyl 3-(hydroxymethyl)benzylcarbamate (0.254 mmol, 60 mg), diethyl azodicarboxylate (0.50 mmol, 86 mg), and P-tBu3 (125 mL, 0.50 mmol) were stirred in THF (1 mL) for 4 hours. The reaction was diluted with ethyl acetate (1.5 mL) and washed with saturated sodium bicarbonate solution (2×, 1.5 mL). The organic phase was collected and the mixture was concentrated under a stream of nitrogen. The crude product was purified by column chromatography on silica gel using ethyl acetate as the eluent. The pure fractions were combined and the solvents were removed on the rotovap to afford tert-butyl 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzylcarbamate as a white solid (112 mg, 90%). 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 9H), 2.19 (s, 3H), 2.42 (s, 3H), 3.48 (bs, 1H), 3.84 (s, 2H), 4.31-4.30 (d, J=6 Hz, 1H), 4.60 (s, 2H), 4.87 (bs, 1H), 5.06 (s, 2H), 7.36-7.16 (m, 4H), 7.92 (s, 1 H), 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.90 μM.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:18]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc(N)c1NCCCCO
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(N)c1NCCCCO
Reaction time: 4 h
Yield: 17 %

Procedure:
To a stirred solution of methyl 3-amino-2-[(4-hydroxybutyl)amino]benzoate (29.8 g, 125 mmol) in dichloromethane (500 mL) was added N-chlorosuccinimide (33.3 g, 250 mmol) at room temperature. After 4 h, the reaction mixture was quenched with aqueous sodium hydrogen carbonate and purified by flash column chromatography on silica gel eluting with a 30% ethyl acetate/n-hexane mixture to give the title compound as a pale red solid (5.81 g, 21.3 mmol, 17%).