Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:10])[O:9][C:6]([CH3:8])([CH3:7])[O:5][C:3](=[O:4])[CH2:2]1.N1C=CC=CC=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([CH2:18][C:17]([CH:2]1[C:1](=[O:10])[O:9][C:6]([CH3:8])([CH3:7])[O:5][C:3]1=[O:4])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)CCc2ccccc2)C(=O)O1
Temperature: 3 °C
Reaction time: 0.05 h
Yield: 97.3 %

Procedure:
To a stirred mixture of isopropylidene malonate (5.00 g, 34.7 mmol) in anhydrous dichloromethane (15 ml), cooled under nitrogen to 3° C., was added dropwise, over 7 min, dried pyridine (6.81 ml, 84.2 mmol). The resulting colourless solution was stirred at 3° C. for 3 min, then a solution of hydrocinnamoyl chloride (5.00 ml, 33.7 mmol) in anhydrous dichloromethane (13 ml) was added dropwise over 2.5 h, whilst maintaining the temperature below 6° C. The resulting orange cloudy mixture was stirred at 3° C. for 1 h, then at room temperature for 2.5 h. The mixture was diluted with dichloromethane (20 ml) and poured into ice-cold 1M aqueous HCl (42 ml). The aqueous layer was further extracted with dichloromethane (2×25 ml), and the combined organic extracts were washed with 1M aqueous HCl (2×25 ml), then saturated aqueous NaCl (25 ml), dried (Na2SO4) and evaporated in vacuo to leave 9.06 g of crude 5-benzylacetyl-2,2-dimethyl-1,3-dioxane-4,6-dione as an orange oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]([OH:16])=O)=[N:3]1.C[N:18]1[C:26](C(O)=O)=[C:25]2[C:20]([CH:21]=C([N+]([O-])=O)C=C2)=N1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14]([N:18]2[CH2:21][CH2:20][CH2:25][CH2:26]2)=[O:16])=[N:3]1
Reactant: Cn1nc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Reactant: Cn1nc2cc([N+](=O)[O-])ccc2c1C(=O)O
Product: Cn1nc(C(=O)N2CCCC2)c2ccc([N+](=O)[O-])cc21

Procedure:
is obtained by reacting a mixture of 1-methyl-6-nitro-1H-indazole-3-carboxylic acid and 2-methyl-6-nitro-2H-indazole-3-carboxylic acid. The product is purified by chromatography on silica gel.
Reaction SMILES: O[C@H:2]1[CH2:7][C@@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.C(P(CCCC)CCCC)CCC.[CH2:27]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])(=[O:32])=[O:31])[CH3:28]>>[CH2:27]([N:29]([C@H:2]1[CH2:7][C@H:6]([CH3:8])[S:5](=[O:10])(=[O:9])[C:4]2[S:11][CH:12]=[CH:13][C:3]1=2)[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])(=[O:31])=[O:32])[CH3:28]
Reactant: C[C@@H]1C[C@H](O)c2ccsc2S1(=O)=O
Reactant: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Product: CCN([C@H]1C[C@H](C)S(=O)(=O)c2sccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 4 h
Yield: 20.4 %

Procedure:
cis-4-hydroxy-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide (5 g), tributylphosphine (6.6 mL) and N-ethyl-2-nitrobenzenesulfonamide (6.17 g) are mixed under nitrogen atmosphere. It is cooled at −20/−30° C. Diisopropyl azadicarboxylate (4.8 mL) is added, maintaining the temperature. It is maintained under stirring, maintaining the temperature, for 4 hours. Tributylphosphine (1.5 mL) and diisopropyl azadicarboxylate (1.5 mL) are added. It is left to reach 20-25° C. and maintained for 30 minutes. It is cooled at 0-5° C.; it is filtered, washed with cold toluene and dried. After purifying by resuspension in methanol, 2.01 g of trans-4-[N-ethyl-N-(2-nitrobenzenesulfonyl)amino]-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide are obtained.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=1>>[CH3:29][C:27]1[CH:26]=[CH:25][N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[N:28]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Cc1ccnc(Cl)n1
Product: Cc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-methyl-pyrimidine. MS (ESI) mass calcd. for C22H22N4OS, 390.51; m/z found, 391.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7](=[O:13])[C:8]([O:10]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1>C(O)C>[CH2:21]([N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:8](=[O:10])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:13])[CH2:16][CH2:17]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)C(=O)c1ccccc1
Solvent: CCO
Product: O=C(NC1CCN(Cc2ccccc2)CC1)C(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
Added to 4.28 g of ethyl phenylglyoxylate were 9.12 g of 4-amino-1-benzylpiperidine. The mixture was heated and stirred at 120° C. for 3 hours on an oil bath. Thereafter, ethanol formed was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel, thereby obtaining 6.3 g (yield: 81.4%) of N-(1-benzyl-4-piperidinyl)phenyl-glyoxylic acid amide.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:78]=[CH:79][CH:80]=1)[CH2:32][NH:33][C:34](=[O:77])[CH:35]([C:62]1[CH:76]=[CH:75][C:65]([CH2:66][N:67]([CH2:71][C:72](O)=[O:73])[C:68](=[O:70])[CH3:69])=[CH:64][CH:63]=1)[NH:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([N:47]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:42][CH:41]=[CH:40]2>C(Cl)Cl.CN(C=O)C>[C:68]([N:67]1[CH2:66][C:65]2=[CH:64][CH:63]=[C:62]([CH:76]=[CH:75]2)[CH:35]([NH:36][C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[C:43]([N:47]([C:48]([O:50][C:51]([CH3:53])([CH3:54])[CH3:52])=[O:49])[C:55]([O:57][C:58]([CH3:60])([CH3:59])[CH3:61])=[O:56])=[N:42][CH:41]=[CH:40]3)[C:34](=[O:77])[NH:33][CH2:32][C:31]2[CH:30]=[C:29]([CH:80]=[CH:79][CH:78]=2)[NH:28][C:72](=[O:73])[CH2:71]1)(=[O:70])[CH3:69]
Reactant: CC(=O)N(CC(=O)O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc(N)c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CC(=O)Nc2cccc(c2)CNC(=O)C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)c2ccc(cc2)C1
Yield: 53.9 %

Procedure:
To a solution of BOP (30 mg, 0.065), TEA (0.07 mL, 0.5 mmol) in 40 mL of CH2Cl2, was added a solution of 80F (40 mg, 0.055 mmol) in DMF (8 mL) via a syringe pump over 6 h. The mixture was stirred r.t over night, then was quenched with sat. NH4Cl and extracted with EtOAc (3×20 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-10% MeOH/CH2Cl2) afforded 80G (21 mg, 54%). MS (ESI) m/z 709.5 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[I:12][C:13]1[N:14]=[C:15]([CH3:18])[NH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[I:12][C:13]1[N:14]=[C:15]([CH3:18])[N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH:17]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cc1nc(I)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-n2cc(I)nc2C)ccc1[N+](=O)[O-]

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (7.9 g), 4-iodo-2-methylimidazole (9.0 g) and sodium carbonate (4.5 g) was heated with stirring in dimethylformamide (50 cm3) at 120° for 16 hours under nitrogen. The mixture was poured into water (50 cm3) and extracted with chloroform (3×100 cm3). The combined and dried (MgSO4) organic extracts were concentrated in vacuo to give a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:toluene, 1:5 by volume. Combination and evaporation of appropriate fractions afforded a solid which was recrystallised from dichloromethane-hexane to give the title compound, m.p. 146°-8°, (4.0 g).
Reaction SMILES: [I:1]I.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1>C(OCC)C.O1CCOCC1>[I:1][CH2:28][C@@H:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CI)C1
Yield: 93.1 %

Procedure:
Iodine (1.91 g) was added in portions to a vigorously stirred, ice cooled suspension of imidazole (0.681 g) and triphenylphosphine (1.97 g) in diethyl ether (12 mL). The mixture was then stirred for 10 minutes before a solution of tert butyl (R)-3-hydroxymethylpyrrolidine-1-carboxylate (1 g) in dioxane (6 mL) was added dropwise. The resulting mixture was stirred at room temperature overnight, then diluted with diethyl ether and filtered. The solid was washed with diethyl ether and the combined filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 0-20% to give tert-butyl (R)-3-iodomethylpyrrolidine-1-carboxylate (1.44 g) as an oil.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]1[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[C:44]([O:51][CH3:52])[CH:43]=[CH:42][CH:41]=1>CC#N>[CH2:49]([O:48][C:46](=[O:47])[C:45]1[C:44]([O:51][CH3:52])=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:39][N:18]([CH2:17][C:9]1[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)[CH3:50]
Reactant: CCOC(=O)c1c(CBr)cccc1OC
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cccc1OC
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.409 g, 1.08 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.38 mL, 2.18 mmol) followed by a solution of ethyl 6-(bromomethyl)-2-methoxybenzoate (0.454 g, 1.66 mmol) in CH3CN (6 mL). The resultant mixture was heated to 60° C. for 22 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (50 mL) and brine (10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (25:1 CH2Cl2—CH3OH) followed a further chromatographic purification by column chromatography on silica gel (2:1 hexanes-EtOAc) and radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.38 g (62%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N+:3]=1[O-:11].[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>OS(O)(=O)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=[C:4]([CH3:10])[N+:3]=1[O-:11]
Reactant: COc1ccc(C)[n+]([O-])c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1c([N+](=O)[O-])cc(C)[n+]([O-])c1Br
Temperature: 60 °C

Procedure:
A solution of 124C (7.0 g, 32.4 mmol) in concentrate H2SO4 (9.5 mL) was added to a solution of concentrate H2SO4 (9.5 mL) and fuming HNO3 (13 mL) and the mixture was heated at 60° C. for 30 min. After cooling to room temperature, the reaction mixture was added to iced 6M solution of NaOH (150 mL) and neutralized to pH 6 with 1N NaOH solution. The reaction mixture was extracted with dichloromethane (4×100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 124D as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:35])=[CH:17][N:16]=1>>[Cl:35][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][C:29]([N:32]([CH3:33])[CH3:34])=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: CNC(=O)c1cc(N(C)C)ccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(N(C)C)ccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-5-dimethylamino-N-methyl-benzamide was prepared from 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-5-dimethylamino-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow solid (155 mg, 81%). m.p.=253-255° C.; LCMS (m/e) 480 (M+H); 1HNMR (d6-DMSO, 400 MHz) δ 11.46 (bs, 1H), 9.80-9.66 (m, 1H), 9.51 (s, 1H), 8.87-8.77 (m, 1H), 8.53-8.40 (m, 1H), 8.21 (s, 1H), 7.34 (s, 1H), 7.29-7.09 (m, 1H), 7.25 (d, 1H, J=8.0 Hz), 7.17 (d, 1H, J=8.5 Hz), 7.03-6.81 (m, 1H), 2.99 (s, 6H), 2.81 (d, 3H, J=3.8 Hz), 2.65 (t, 2H, J=6.8 Hz), 2.24-2.15 (m, 2H), 2.15-2.04 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[C:42]=1[S:48](Cl)(=[O:50])=[O:49]>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:48]([C:42]1[C:43]([CH3:47])=[CH:44][CH:45]=[CH:46][C:41]=1[Cl:40])(=[O:50])=[O:49])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Product: Cc1cccc(Cl)c1S(=O)(=O)NCCc1c(CCNc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
The intermediate from example 143 step 12 was treated with 2-chloro-6-methyl-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 85% yield.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>CN(C=O)C.O>[CH3:16][C:11]1[N:12]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=2)[C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[C:10]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(C)N(Cc2cccc(OC)c2)C(=O)CC1c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
The product from Example 5, Step 1 (0.627 g, 2.00 mmol, 1.00 equiv) and cesium carbonate (0.975 g, 3.00 mmol, 1.50 equiv) were combined in DMF (9 mL) for 15 minutes at rt. 3-Methoxybenzyl bromide (0.436 mL, 3.12 mmol, 1.56 equiv) was added and the reaction was heated to 100° C. for 6 hours. The reaction was diluted with H2O and extracted with Et2O. The organic phase was washed with H2O and satd. NaCl, dried over MgSO4 and concentrated en vacuo to provide 0.762 mg (88%) of the title compound as an oil. MS (ES+) m/e 434 [M+H]+
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=2[CH2:11][N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=1)=O.[CH:30]([C:33]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[C:34]=1[NH2:35])([CH3:32])[CH3:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:33]([CH:30]([CH3:32])[CH3:31])[C:34]=1/[N:35]=[CH:1]/[C:3]1[N:8]=[C:7]([C:9]2[CH:29]=[CH:28][CH:27]=[CH:26][C:10]=2[CH2:11][N:12]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:6]=[CH:5][CH:4]=1)([CH3:42])[CH3:41]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1-c1cccc(C=O)n1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(-c2ccccc2CN(C(=O)OC(C)(C)C)c2ccccc2)n1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Tetrahydrofuran (50 mL) and 4 angstrom molecular sieves (ca. 15 mL) were added to tert-butyl 2-(6-formylpyridin-2-yl)benzyl(phenyl)carbamate (11) (03.63 g, 9.34 mmol). Then 2,6-diisopropylaniline (1.66 g, 9.34 mmol) was added followed by a catalytic amount of p-toluenesulfonic acid monohydrate (0.003 g, 0.015 mmol). The mixture was stirred overnight then filtered and evaporated to a thick yellow oil. After several days the oil began to crystallize. Methanol (40 mL) was added and the mixture was stirred to give a yellow crystalline solid. The mixture was cooled to 5° C. for a couple of hours then the solid was collected on a glass frit and dried under reduced pressure. Yield: 3.93 g, 76.8%. 1H NMR (CD2Cl2, 500 MHz): 8.26 (s, 1H), 8.19 (d, 1H), 7.87 (t, 1H), 7.54 (d, 1H), 7.32-7.42 (m, 4H), 7.02-7.20 (m, 8H), 5.11 (s, 2H), 2.99 (sept, 2H), 1.34 (s, 9H), 1.18 (d, 12H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:15].[Na+].[OH-].[Na+].Cl[O-].[Na+]>O.CO>[CH2:1]([C:8]1[CH:13]=[C:12]([I:15])[CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: Oc1ccccc1Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Oc1ccc(I)cc1Cc1ccccc1
Reaction time: 8 h
Yield: 87.3 %

Procedure:
6.87 g of 2-benzylphenol, 7.2 g of sodium iodide and 1.7 g of sodium hydroxide were added to 60 ml of methanol and while stirring in an ice bath, 50 ml of an aqueous 5% sodiumhypochlorite solution was added dropwise to the mixture over 30 minutes. The temperature was slowly returned to room temperature and the stirring was continued overnight. Water was added to the reaction mixture, which then was extracted with ethyl acetate, washed with brine and then dried over anhydrous magnesium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give 10.1 g of the title compound.
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][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29]>>[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:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[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: Cc1ccccc1CBr
Product: Cc1ccccc1CN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 21 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-2-methylbenzene. Yield: 21%. MS M+H calculated 380.1; found 380.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.1 uM.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:11])([CH3:10])[C@@H:4]([C:6]([O:8][CH3:9])=[O:7])[NH2:5].N1C=CC=CC=1.[C:18](Cl)(Cl)=[O:19].Cl>C(Cl)Cl>[CH3:2][C:3]([CH3:11])([CH3:10])[C@@H:4]([C:6]([O:8][CH3:9])=[O:7])[N:5]=[C:18]=[O:19]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](N=C=O)C(C)(C)C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of methyl 3-methyl-L-valinate hydrochloride (10.0 g, 54.9 mmol) and pyridine (22.3 mL, 276 mmol) in methylenechloride (300 mL) was cooled in an ice bath under nitrogen. Phosgene (20% in toluene, 41.1 mL, 83.0 mmol) was added dropwise over 0.5 h using an addition funnel. The resulting mixture was stirred 1 h then poured into cold 1M hydrochloric acid and extracted with methylenechloride (3×100 mL). The combined organic extracts were washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. Flash column chromatography eluting with hexane/ethyl acetate 90/10 gave methyl 3-methyl-N-(oxomethylene)-L-valinate as an orange oil, 6.99 g (74% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Product: CNc1ccc(Br)c(Oc2ccccc2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 1, Step 1, using 4-bromo-3-fluoro-N-methyl-2-nitroaniline and phenol as the starting materials. LCMS calculated for C13H12BrN2O3 (M+H)+: m/z=323.0, 325.0. found: 322.9, 325.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:6][CH:7]=1.C([O-])(=O)C.[NH4+:36]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:36][C:11]([CH:12]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(Br)cn2)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 85.5 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-5-[4-(methylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (3.89 g) in acetic acid (40 mL) was added ammonium acetate (9.50 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.20 g, yield 86%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 491 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][OH:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27]C(=O)C(C)(C)C.[C:37](O)(=[O:40])[CH2:38][CH3:39].S(=O)(=O)(O)O>>[NH2:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:34])=[C:3]([CH2:35][O:36][C:37](=[O:40])[CH2:38][CH3:39])[C:2]=1[F:1]
Reactant: CCC(=O)O
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Agent: O=S(=O)(O)O
Product: CCC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Yield: 32 %

Procedure:
Substantially the same manner as that in Example 123 was repeated except that 1.06 g (2.10 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 118 (4), 32 mL of propionic acid and 8 mL of concentrated sulfuric acid were used, and the resulting compound was purified by silica gel column chromatography (chloroform:acetonitrile=20:1) and high performance liquid chromatography, to give 261 mg of Compound 124 (yield: 32%).