Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH2:40])[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH:40][C:4]4[N:9]=[CH:8][C:7]5=[CH:10][CH:11]=[C:12]([C:13]6[CH:14]=[C:15]([CH2:19][CH2:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=6)[N:6]5[N:5]=4)[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(CCC#N)c3)n2n1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: N#CCCc1cccc(-c2ccc3cnc(Nc4ccc5c(c4)CCC(N4CCOCC4)CC5)nn23)c1

Procedure:
Into a microwave vial, 3-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-propionitrile (0.0964 g, 0.310 mmol), 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (0.168 g, 0.683 mmol), 1-Methoxy-2-propanol (0.747 mL) and N,N-Diisopropylethylamine (0.119 mL) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded 3-{3-[2-(7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-propionitrile as a yellow solid (35 mg, 23%). LCMS (E/I+) 493.20 (M+H). MP 184-186° C. NMR 1H (DMSO-d6)-9.34 (s, 1H), 8.97 (s, 1H), 8.18 (d, 1H, J=8.44 Hz), 8.02 (s, 1H), 7.56 (s, 1H), 7.97 (d, 2H, J=7.23 Hz), 7.35 (d, 1H, J=7.23 Hz), 7.18 (d, 1H, J=4.51 Hz), 7.05 (d, 1H, J=7.89), 6.95 (d, 1H, J=4.51 Hz), 3.54 (bs, 4H), 2.98 (t, 2H, J=7.32 Hz), 2.87 (t, 2H, J=7.04 Hz), 2.53-2.81 (m, 5H), 2.43-2.48 (m, 4H), 1.89-2.07 (m, 2H), 1.22-1.43 (m, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].C[O:15][P:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([P:16]1(=[O:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17]1)=[O:12]
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: O=C(c1ccc2ccccc2c1)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 125 °C

Procedure:
50 g (0.262 mol) of 2-naphthoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 60.3 g (0.262 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise over the course of two hours while stirring. The internal temperature was subsequently increased gradually to 125° C. When the reaction was complete, 110 ml of toluene were added. After crystallization, 87 g (90% of theory) of the abovementioned compound of melting point 151° to 153° C. were obtained.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][N:21]1[CH2:38][C:39](O)=[O:40].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([C:39](=[O:40])[CH2:38][N:21]3[CH2:22][CH2:23][CH2:24][C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:19])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,4-diphenylpiperidine (Matrix, 0.24 g, 1.00 mmol) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.308 g, 1.00 mmol), under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.15-7.34 (m, 20H), 4.23 (s, 2H), 3.68-3.73 (m, 2H), 3.45-3.52 (m, 4H), 2.60-2.66 (m, 2H), 2.37-2.45 (m, 4H), 1.78-1.88 (m, 2H); MS (DCI+) m/z 529 (M+H)+.
Reaction SMILES: S([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(O)(=O)=O.CNCCCCC=CCC.C(N1C[C@@H](O)C[C@H]1C(O)=O)(OC(C)(C)C)=O.[CH2:38]([N:44]([CH3:60])[C:45]([C@@H:47]1[CH2:51][C@@H:50]([OH:52])[CH2:49][N:48]1[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:46])CCCC=C>>[CH2:38]([N:44]([CH3:60])[C:45]([C@@H:47]1[CH2:51][C@@H:50]([OH:52])[CH2:49][N:48]1[C:53]([O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[O:54])=[O:46])[CH2:7][CH2:6][CH2:5][CH2:11][CH:10]=[CH:8][CH3:9]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: CCC=CCCCCNC
Product: CC=CCCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C

Procedure:
Compound 70b was synthesized from compound 32c and cis-N-Boc-4-hydroxy-L-proline as yellow oil in quantitative yield, following the procedure as described for compound 48.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Br[CH2:68][CH:69]1[CH2:72][CH2:71][CH2:70]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH2:68][CH:69]2[CH2:72][CH2:71][CH2:70]2)=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N(CC2CCC2)C(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was reacted with bromomethyl cyclobutane and K2CO3 in DMF afforded (S)-2-({(S)-7-[2-(acetyl-cyclobutylmethyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester according to General Procedure O. This product (20 mg) was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 979.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][NH2:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2>C(OC)(OC)(OC)CCC>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH2:5][CH2:6][CH3:7])=[N:17][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(NN)c(Cl)nc2c1
Agent: CCCC(OC)(OC)OC
Product: CCCc1nnc2c(Cl)nc3cc(C(=O)OC)ccc3n12
Yield: 145 %

Procedure:
700 mg of methyl 3-chloro-2-hydrazinoquinoxaline-6-carboxylate was suspended in 3.7 mL of trimethyl orthobutyrate, followed by heating and refluxing for 2 hours. The suspension was ice-cooled, and the solid was collected by filtration and washed with cold ethyl acetate. The obtained solid was washed with hot ethyl acetate to obtain 612 mg of methyl 4-chloro-1-propyl[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:18](Br)([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)cc(N2CCNCC2)c1
Reactant: CC(C)Br
Product: CC(C)N1CCN(c2cc(Cl)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-Chloro-5-trifluoromethyl-phenyl)-piperazine and iso-propylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 306 (M+, 30), 291 (bp), 206 (25), 193 (15), 179 (20).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO>C(Cl)Cl>[C:30]1([NH:36][C:37]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccccc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.80 mmol) and DIEA (0.314 mL, 1.80 mmol) in DCM (9 mL) was added phenyl isocyanate (0.196 mL, 1.80 mmol). The resulting mixture was stirred at RT for 3 h. Then, MeOH (50 mL) was added and the mixture was concentrated. The residue was purified by silica gel flash column chromatography (0%-50% EtOAc/hexane) to give the title compound as a light yellow solid. The solid was then washed with MeOH (3×20 mL) to give 440 mg of the title compound as a white solid. MS (ESI, positive ion) m/z: 397 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[O:14](S(C(F)(F)F)(=O)=O)[S:15]([C:18]([F:21])([F:20])[F:19])(=O)=[O:16]>ClCCl.N1C=CC=CC=1>[F:19][C:18]([F:21])([F:20])[S:15]([O:12][C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:13])[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:14]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc2ncccc2c(Br)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2ncccc2c(Br)c1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To the solution of 5-bromo-7-methylquinolin-6-ol (238 mg, 1.0 mmol) in dichloromethane (10 mL) and pyridine (2 mL) was added Tf2O (0.34 mL, 2.0 mmol) at −30° C. The mixture was stirred and warmed to 0° C. over a period of 2 hours. The reaction was quenched with slow addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 5-bromo-7-methylquinolin-6-yl trifluoromethanesulfonate. LCMS-ESI+ (m/z): 369.9, 371.9 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].N1CCCCC1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=[C:29]4[NH:23][C:24](=[O:25])[NH:26][C:27]4=[O:28])=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1cccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-tert-butylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (39 mg, 0.133 mmol) in EtOH was added hydantoin (28 mg, 0.280 mmol) and piperidine (13 μL, 0.133 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and air dried to yield 5-((5-(3-tert-butylphenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=377)
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: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
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, 1H), 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.90 μM.
Reaction SMILES: [N:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:5]=1)=[N+]=[N-]>C1COCC1.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:5]=1
Reactant: [N-]=[N+]=Nc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc3[nH]ccc3c2)ncn1

Procedure:
480 mg (1.9 mMol) 5-(6-azido-pyrimidin-4-yloxy)-1H-indole in 25 ml THF are hydrogenated in presence of 75 mg Pd/C 10%. Filtration, concentration of the filtrate and column chromatography (SiO2; EtOAc/hexane 3:1→EtOAc) gives the title compound: MS: [M+1]+=227; TLC(EtOAc): Rf=0.11
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCCBr)cc1

Procedure:
In analogy to example 1.4, reaction of (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester with 1,4-dibromobutane yielded [4-(4-Bromo-butoxy)-phenyl]-carbamic acid tert-butyl ester, MS: 344 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.[NH2:25][O:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29]>>[OH:30][C:28]([CH3:31])([CH3:29])[CH2:27][O:26]/[N:25]=[C:22](/[C:19]1[N:20]=[C:21]2[N:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)[N:14]=[N:15][C:16]2=[N:17][CH:18]=1)\[CH3:23]
Reactant: CC(C)(O)CON
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Product: C/C(=N\OCC(C)(C)O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 97.7 %

Procedure:
The title compound (12.0 mg, 89%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and 1-aminooxy-2-methyl-propan-2-ol (6.5 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.29 (s, 1H), 8.93 (dd, 1H), 8.41 (dd, 1H), 8.19 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.23 (s, 2H), 4.60 (s, 1H), 4.12 (d, 2H), 2.30 (s, 3H), 1.17 (s, 6H). LCMS (method A): [MH]+=410, tR=5.40 min.
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@@H:6]2[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH3:10])[C@H:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N+:66]([C:69]1[CH:82]=[CH:81][C:72]([CH2:73][O:74][C:75]([NH:77][CH2:78][CH2:79][SH:80])=[O:76])=[CH:71][CH:70]=1)([O-:68])=[O:67]>C(#N)C.C(OCC)(=O)C>[CH3:25][C:9]([C@H:6]1[C:5](=[O:26])[N:4]2[C@@H:7]1[CH2:8][C:2]([S:80][CH2:79][CH2:78][NH:77][C:75]([O:74][CH2:73][C:72]1[CH:81]=[CH:82][C:69]([N+:66]([O-:68])=[O:67])=[CH:70][CH:71]=1)=[O:76])=[C:3]2[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([O:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:10]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 4-nitrobenzyl(2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (148.5 mg) and 4-N,N-dimethylaminopyridine (3.35 mg) in acetonitrile (7.4 ml) was added dropwise a solution of di-isopropylethylamine (57.3 μl) in acetonitrile (0.516 ml). To the mixture was further added a solution of diphenyl chlorophosphate (59.6 μl) in acetonitrile (0.536 ml) at 0° C. After stirring for an hour at 0° C., a solution of diisopropylethylamine (190.9 μl) in acetonitrile (1.72 ml) was added to the mixture. To the mixture was further added a solution of N-(4-nitrobenzyloxycarbonyl)cysteamine (73.8 mg) in acetonitrile (0.664 ml) at -15° C. The mixture was allowed to stand overnight at -15° C. The resulting solution was diluted with ethyl acetate (15 ml) and washed in turn with water and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residue was chromatographed on silica gel (3 g) eluting with a mixture of methylene chloride and ethyl acetate (50:1 to 5:1) to give 4-nitrobenzyl(5R,6S)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)-ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (167.8 mg) as an amorphous solid.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH:18]([C:12]1[CH:17]=[CH:16][C:15]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)([CH3:20])[CH3:19]
Reactant: O=CC(=O)c1ccccc1
Reactant: CC(C)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)c1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and cumene (0.56 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 4 hours. Using the same procedure as in Example 1, 4'-iso-propylbenzoin was obtained as crystal (300.6 mg, 59.6% yield).
Reaction SMILES: [N:1]1([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[N:7]=[C:6]3[N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: c1ccc2[nH]c(N3CCCC3)nc2c1
Product: C/C(C#N)=C1/c2ccc(Cn3c(N4CCCC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 89.3 %

Procedure:
Using commercially available 2-(pyrrolidin-1-yl)-1H-benzo[d]imidazole (63 mg, 0.34 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.34 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (141 mg, 91%) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[C:8]1[C:18]([O:20]CC)=[O:19].[OH-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[C:8]1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1ccc(-c2ccccc2)n1CCCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCn1c(C(=O)O)ccc1-c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 107.7 %

Procedure:
Ethyl 1-(4-methoxybutyl)-5-phenyl-1H-pyrrole-2-carboxylate (430 mg) was dissolved in methanol (2 ml), 2M aqueous sodium hydroxide solution (4 ml) was added and the mixture was stirred at 60° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, and the aqueous layer of the mixture was adjusted to pH 3 with 6M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (420 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[N:6][CH:7]=1.Br[C:18]1[C:29]([Cl:30])=[CH:28][C:21]2[O:22][C:23]([F:27])([F:26])[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCOCC1.CC#N.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:30][C:29]1[C:18]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:19][C:20]2[O:25][CH2:24][C:23]([F:27])([F:26])[O:22][C:21]=2[CH:28]=1
Reactant: CC1(C)OB(c2cnc(N)cn2)OC1(C)C
Reactant: FC1(F)COc2cc(Br)c(Cl)cc2O1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: CC#N
Solvent: C1COCCO1
Product: Nc1cnc(-c2cc3c(cc2Cl)OC(F)(F)CO3)cn1
Temperature: 85 °C
Yield: 8.7 %

Procedure:
5-Aminopyrazine-2-boronic acid pinacol ester (62 mg, 0.28 mmol) and 254 (67 mg, 0.23 mmol) were dissolved in 2 mL 1,4-dioxane and 2 mL MeCN. Next 1 ml of 2 M K3PO3 was added and the mixture was then bubbled with Ar for 2 min before bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (A-Phos, 70 mg, 0.1 mmol) was added. The reaction was then heated at 85° C. for 2 h. The reaction mixture was cooled and then worked-up with EtOAc extraction. The product was purified by flash column and afforded 256 (6 mg, 9%) as a yellow wax.