Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[O:9]=[C:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]1[CH2:27][C:28]([F:31])([F:30])[F:29].FC(F)(F)C(O)=O>C(Cl)(Cl)(Cl)Cl>[OH:7][CH:16]1[N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]([F:31])([F:29])[F:30])[C:10]1=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1C(O)N=C(c2ccccc2)c2ccccc2N1CC(F)(F)F
Reaction time: 0.25 h

Procedure:
N-Bromosuccinimide (0.335 g, 1.88 mmol) was added to a solution of 2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (H. G. Selnick et al., J. Med. Chem., 1997, 40, 3865-3868) (0.500 g, 1.57 mmol) in carbon tetrachloride (20 mL) at room temperature. After 15 min, trifluoroacetic acid (1.0 mL) was added, and the reaction refluxed for 5 h. The reaction was cooled and concentrated. The residue was dissolved in 5% aqueous sodium acetate (15 mL) and acetone (10 mL) and stirred overnight. The reaction was concentrated and worked up, and the crude product purified by chromatography (silica gel, 0-30% ethyl acetate in hexane gradient elution), providing the title compound. MS 335 (M+1) 1H NMR (500 MHz, CDCl3) □ 7.92-7.30 (9H, m), 5.21 (dq, J=15, 8 Hz, 1H), 5.07 (d, J=10 Hz, 0.5H), 4.51 (d, J=10 Hz, 0.5H), 4.22 (t, dq, J=15, 8 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([I:12])[C:3]=1N.OS(O)(=O)=O.N([O-])=O.[Na+]>C(O)C>[I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([I:12])[CH:3]=1
Reactant: Nc1c(I)cc([N+](=O)[O-])cc1I
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc(I)cc(I)c1
Temperature: 60 °C
Yield: 75.6 %

Procedure:
To an ice-cold solution of 2,6-diiodo-4-nitro-aniline (25.0 g, 0.06 mol) in ethanol (625 mL) was added dropwise conc. H2SO4 (50.0 ml, 0.90 mol) over 30-45 min with constant stirring. The reaction mixture was heated to 60° C. and sodium nitrite (9.70 g, 0.14 mol) was added to the reaction mixture portion wise. The resulting yellow colored reaction mixture was heated slowly to 90° C. and refluxed for 2 to 2.5 h. After cooling to room temperature, the mixture was poured into ice water. The reddish brown solid thus obtained was filtered, washed with water and dried to give the desired compound as a yellow solid (17.0 g, 72%).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@@H]([C@@H](CO)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
3.0%, L-xylose: 2.3%, D-arabinose: 3.0%,
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:28])[CH2:16][CH:15]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C:13]([CH3:27])([CH3:26])[NH:12]1>C1(C)C(C)=CC=CC=1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[C:13]([CH3:27])([CH3:26])[CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16][C:11]2([CH3:28])[CH3:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Solvent: Cc1ccccc1C
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1c1nc(Cl)nc(Cl)n1

Procedure:
46.1 g of cyanuric chloride and 136.0 g of 2,2,6,6-tetramethyl-4-benzoyloxypiperidine are reacted in 300 ml of xylene as described in Example 1 and worked up. After recrystallization from isopropanol, 2,4-dichloro-6-(2,2,6,6-tetramethyl-4-benzoyloxy-piperidin-1-yl)-1,3,5-triazine are obtained as colorless crystals having a melting point of 145°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:9]=[C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])[N:11]=1)=[O:6].C(N(CC)CC)C.[Br:42][CH2:43][C:44](Cl)=[O:45].C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:42][CH2:43][C:44]([O:1][CH2:2][CH2:3][O:4][C:5]([C:7]1[N:8]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[CH:9]=[C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])[N:11]=1)=[O:6])=[O:45]
Reactant: O=C(Cl)CBr
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCO)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)OCCOC(=O)CBr)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 g (2 mmol) of 2-hydroxyethyl-4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylate (Example 125) are dissolved in a mixture of 25 ml of dichloromethane and 12 ml of DMF, and 1570 μl (1.14 g, 11.2 mmol) of triethylamine are added. While cooling in ice, 804 μl (1.52 g, 9.6 mmol) of bromoacetyl chloride and a catalytic amount of DMAP are added. After stirring at RT for 16 h, a further 0.57 g (5.6 mmol) of triethylamine, 0.76 g (4.8 mmol) of bromoacetyl chloride and a few crystals of DMAP are added while cooling in ice. The reaction mixture is stirred at RT for 2.5 h, poured into saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The combined extracts are washed twice with water and once with saturated sodium chloride solution, dried with magnesium sulphate and evaporated in vacuo. The residue from evaporation is purified by chromatography on silica gel with dichloromethane/methanol as eluent.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][O:38][CH3:39])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(OCC)C>ClCCl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][O:38][CH3:39])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)=[O:43])[CH2:3][CH2:2]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To 338 (0.19 g, 0.31 mmol) in dichloromethane (40 mL) was added TFA (3 mL). The solution was stirred for 6 h, then concentrated. The residue was partitioned between 98:2 dichloromethane/methanol mixture and 1M NaOH(aq), washed with brine, dried over MgSO4, filtered and concentrated. The resulting oil was triturated with diethyl ether and ethyl acetate providing 339 (0.13 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1H: 8.80 (s, 1H); 8.57 (s, 1H); 8.51 (d, J=5.5, 1H); 8.31 (s, 1H); 8.23 (d, J=8.0, 1H); 7.89 (dd, J=8.0, 1.5, 1H); 7.73 (dd, J=13.5, 2.2, 1H); 7.38 (t, J=9.0, 1H); 7.20 (d, J=8.2, 1H); 6.66-6.62 (m, 2H); 3.78 (s, 2H); 3.41 (t, J=5.7, 2H); 3.24 (s, 3H); 2.65 (d, J=5.7, 2H); 2.57-2.51 (m, 1H); 0.66-0.62 (m, 2H); 0.44-0.41 (m, 2H). MS (m/z): 508.3 (M+H).
Reaction SMILES: [OH:1][CH:2]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:32])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:31])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.FC(F)(F)C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>CS(C)=O.C1C=CC=CC=1>[O:4]([CH2:3][C:2]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:32])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:31])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(COc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: O=C(COc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.4 %

Procedure:
(2S)-2-(1-Hydroxy-2-phenoxyethyl)-1-[N-(phenoxyacetyl)-L-prolyl]pyrrolidine (998 mg) was dissolved in a mixture of DMSO (6 ml) and benzene (3 ml), and thereto were added pyridine (0.18 ml) and trifluoroacetic acid (0.09 ml). After ice-cooling the mixture, DCC (941 mg) was added thereto, and the mixture was stirred at room temperature for 2.5 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was poured into ice-cold 1N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine successively, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 759 mg of the title compound.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:31])[C@H:15]([CH2:28][CH2:29][CH3:30])[CH2:16]/[CH:17]=[CH:18]/[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.OO.O.[OH-].[Li+].S([O-])([O-])(=[O:39])=S.[Na+].[Na+]>O.O1CCCC1>[CH2:21]([O:20][CH2:19]/[CH:18]=[CH:17]/[CH2:16][C@@H:15]([CH2:28][CH2:29][CH3:30])[C:14]([OH:31])=[O:39])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=S([O-])([O-])=S
Reactant: CCC[C@H](C/C=C/COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H](C/C=C/COCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 24.1 g of (S)-4-benzyl-3-[(2R,4E)-6-benzyloxy-2-propylhex-4-enoyl]oxazolidin-2-one (57.2 mmol) obtained in Example (116a) in a mixed solvent of tetrahydrofuran (800 ml) and water (260 ml) was cooled in an ice bath, and then 35.0 ml of a 30% hydrogen peroxide aqueous solution and 4.83 g of lithium hydroxide monohydrate (115 mmol) were added thereto. The mixture was stirred at the same temperature for 30 minutes, and then raised to room temperature and further stirred for 16 hours. After cooling in an ice bath, 250 ml of a 1.5 M sodium thiosulfate aqueous solution was added to the reaction mixture. The mixture was further stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, diluted with 500 ml of water and washed with ethyl acetate. Then, the aqueous layer was made acidic with 30 g of sodium dihydrogenphosphate, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 13.6 g of the crude title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[O:17].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:58][C:59]1[CH:64]=[CH:63][C:62]([NH2:65])=[C:61]([NH2:66])[CH:60]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:65][C:62]1[CH:63]=[CH:64][C:59]([F:58])=[CH:60][C:61]=1[NH2:66])=[O:25])=[O:17]
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)ccc1NC(=O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.8 %

Procedure:
5-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)pentanoic acid (382 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (372 mg, 76% yield) as a brown solid. LC-MS (m/z) 491 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[N-:14]=[N+:15]=[N-:16].[Na+]>CC(C)=O>[N:14]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[N+:15]=[N-:16]
Reactant: O=C(O)CCCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCCCCCCCCCC(=O)O
Yield: 94.7 %

Procedure:
10-Bromodecanoic acid (2.51 g, 10 mmol) in acetone (50 mL) is treated with sodium azide (0.75 g, 11 mmol) at reflux for 2 h. The reaction is then concentrated in vacuo to a gum that is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase is separated, dried over sodium sulfate and concentrated in vacuo to give 10-azidodecanoic acid (2.02 g, 95%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.[OH:23][C:24]1[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][C:25]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH2:29]1)=[O:27]>>[CH3:45][O:44][C:42]([C:39]1[CH:40]=[CH:41][C:24]([O:23][CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:7][CH:6]=2)=[C:25]([CH:38]=1)[C:26]([N:28]1[CH2:29][CH2:30][CH:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:33]1)=[O:27])=[O:43]
Reactant: COC(=O)c1ccc(O)c(C(=O)N2CCC(C(=O)OC)CC2)c1
Reactant: BrCCCc1ccc(OCCCCOc2ccccc2)cc1
Product: COC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Methyl 1-(5-(methoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}-benzoyl)-4-piperidinecarboxylate is prepared in analogy to the process described in Example 2 from 1-(3-bromopropyl)-4-(4-phenoxybutoxy)benzene and methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:51]2[CH:52]=[N:53][NH:54][CH:55]=2)O1>>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:5]2[C:4]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:3][C:2]([C:51]3[CH:52]=[N:53][NH:54][CH:55]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COc1ccc(Nc2ncc(-c3cn[nH]c3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Strem Chemicals), and was isolated as an orange amorphous solid (95%). m/z (ESI, +ve ion) 376.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.98 (1H, br. s.); 11.70 (1H, s); 8.89 (1H, br. s.); 8.59 (2H, br. s.); 8.17 (2H, br. s.); 7.87 (2H, br. s.); 7.74 (1H, br s.); 6.84 (1H, s); 3.85 (3H, s); 2.46 (3H, br. s.).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[CH:8][N:7]=1)=[O:5])C.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][CH:29]([NH:28][C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[C:15]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[N:16][O:17][C:18]=3[CH2:19][OH:20])=[CH:8][N:7]=2)=[O:5])[CH2:30][CH2:31]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Yield: 10 %

Procedure:
As described for example 29e, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (75 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (9 mg, 10%), which was obtained as a colourless gum. MS: m/e=428.3 [M+H]+.
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.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26]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]([CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Fc1cccc(CCBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3cccc(F)c3)C2=O)cn1
Yield: 22 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-fluorophenethyl bromide. Yield: 22%. 1H NMR (DMSO-d6, 400 MHz): 2.11 (s, 3H), 2.38 (s, 3H), 2.80 (t, J=7.2 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 4.06 (s, 2H), 5.17 (s, 2H), 6.85 (dt, J=8.4, 2.0 Hz, 1H), 7.11 (t, J=8.4 Hz, 2H), 7.32 (q, J=7.8 Hz, 1H), 7.73 (s, 1H), 8.12 (s, 1H). MS M+H calculated 398.2; found 398.1. Melting point: 110-111° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 μM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=1)[CH:8]=[CH:7]2
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)c2c(ccn2Cc2ccc(C(F)(F)F)cc2)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
7-bromo-5-fluoro-1H-indole (900 mg, 4.20 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.6 g, 6.7 mmol) were dissolved in DMF (20 ml). The mixture was cooled to −10° C. and NaH (185 mg, 4.6 mmol) was added portion wise over 5 min. The mixture was stirred for 1 hour at this temperature. Quenched with NH4Cl (½ sat.) and 1N HCl. The mixture was diluted with water and the aqueous phase was extracted 3× with ether. The combined organic layers were washed with 3× water, 1× brine and dried over MgSO4. The product was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 7.70 (m, 3H), 7.45 (dd, 1H), 7.25 (dd, 1H), 7.10 (d, 2H), 6.65 (d, 1H), 5.90 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].C1(C)C=CC=CC=1.S(=O)(=O)(O)[OH:30].[OH-].[Na+]>O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:7]=[CH:8][C:3]=1[C:1]([NH2:2])=[O:30]
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(N)=O
Temperature: 70 °C
Yield: 101.5 %

Procedure:
A mixture of 5-cyano-4-(2-methylphenyl)-2-(4-morpholinyl)pyridine (17.71 g), 18 mL of toluene, and 17.0 mL (33.1 g, 319 mmol) of concentrated sulfuric acid was heated at 70° C. for 12 hours, cooled to room temperature, and quenched by addition of 100 mL of cold H2O. Ethyl acetate (100 mL) was added followed by a solution of 25.5 g (638 mmol) of sodium hydroxide in 50 mL of H2O. The aqueous layer was separated and extracted three times with 50 mL of ethyl acetate. The organic layers were combined and concentrated to afford 19.14 g of 4-(2-methylphenyl)-6-(4-morpholinyl)-3-pyridinecarboxamide as a colorless solid (LC assay 87.7 wt %) (yield 94.9–97%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH2:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH:25][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: COC(=O)C(N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3(4-hydroxy phenyl) propionic acid (10 grams, 60.17 mmol) and Example 1 (11.7 grams, 60.00 mmol) in anhydrous dichloro methane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide(31 grams, 150.24 mmol) in dichloro methane (75 mL). The mixture is stirred at room temperature for 6 hours. The resulting solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 23, which can be purified in appropriate solvent.
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:14]([CH:16]([CH3:18])[CH3:17])=[N:15][C:11]=2[CH2:10][CH2:9][CH2:8]1)(=O)=O.[C-:27]#[N:28].[Na+]>CS(C)=O.O.C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:13]2[C:12]3[CH:7]([CH2:6][C:27]#[N:28])[CH2:8][CH2:9][CH2:10][C:11]=3[N:15]=[C:14]2[CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(COS(C)(=O)=O)CCC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CC#N)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Intermediate 41 (3.8 g) and sodium cyanide (1.41 g) was dissolved in dimethyl sulfoxide (20 mL) and the mixture was stirred at 60° overnight. The reaction was stopped (only 1 g nitrile required) and cooled to RT before diluting with water/DCM. The aqueous was further extracted with DCM, and the combined organic extracts were passed though a hydrophobic frit, reduced in volume in vacuo, and the residue purified by flash column chromatography (0-15% MeOH in DCM, silica, repeated chromatography required). The appropriate fractions were combined to give the title compound (1.57 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:25])[CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH:25][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:12])[CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CCCC(N)c1ccc(OC)cc1
Product: CCCC(NC(=O)c1ccc2c(c1)OCO2)c1ccc(OC)cc1

Procedure:
Prepared in a similar manner to example 4 using benzo[1,3]dioxole-5-carboxylic acid and 1-(4-methoxy-phenyl)-butylamine 1H NMR (500 MHz, CDCl3): δ 0.93-0.95 (t, 3H), 1.30-1.39 (m, 2H), 1.80-1.90 (m, 2H), 3.79 (s, 3H), 5.08-5.09 (dd, 1H), 6.00 (s, 2H), 6.10-6.12 (d, 1H), 6.79-6.80 (d, 1H), 6.87 (s, 1H), 6.88 (s, 1H), 7.25-7.28 (m, 4H). MS (M+H, 328.1).