Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH2:2]([N:9]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:29][O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][O:32]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Agent: Cl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2)NOC1CCCCO1

Procedure:
(−)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid hydrochloride salt (110 mg, 0.275 mmol) was treated with NH2OTHP following the procedure described in Example 1, Step C, giving (E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (80 mg) as a light yellow solid.
Reaction SMILES: [N+](=[C:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])=[N-].[CH3:16][OH:17]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:3]([O:17][CH3:16])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)=[N+]=[N-]
Reactant: CO
Agent: [Rh]
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(O)cc1)OC
Reaction time: 15 h

Procedure:
A solution of methyl 2-diazo-3-(4-hydroxyphenyl)propanoate (cf Tetrahedron Lett., 1971, 4495) (8.58 g) in methanol (120 mL) was added over 10 minutes to a mixture of rhodium (II) acetate dimer (0.18 g) in methanol (50 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was heated at reflux for 5 hrs, allowed to stand at room temperature for 15 hrs, then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL), washed with water (3×300 mL) and brine (500 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with a gradient of 4% ethyl acetate to 6% ethyl acetate in dichloromethane as eluent to afford the title compound. mp 61°-3° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][CH2:14][CH:15](O)[CH3:16])=[CH:4][N:5]2[C:10]=1[C:9]([S:11][CH3:12])=[N:8][CH:7]=[N:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:63]=[N+:64]=[N-:65])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:63]([CH:15]([CH3:16])[CH2:14][O:13][C:3]1[C:2]([CH3:1])=[C:10]2[N:5]([CH:4]=1)[N:6]=[CH:7][N:8]=[C:9]2[S:11][CH3:12])=[N+:64]=[N-:65]
Reactant: CSc1ncnn2cc(OCC(C)O)c(C)c12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1ncnn2cc(OCC(C)N=[N+]=[N-])c(C)c12
Temperature: 0 °C
Reaction time: 15 h
Yield: 57.2 %

Procedure:
Procedures given in Tetrahedron Lett, 1977, 1977, and JACS, 1999, 3637 were modified. Thus, a 10 mL flask was charged with 1-(5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol (249 mg, 0.98 mmol), and tetrahydrofuran (4.91 mL) and cooled to 0° C. Triphenylphosphine (516 mg, 1.96 mmoles), diethyl azodicarboxylate (310 μL, 1.96 mmol) and diphenylphosphoryl azide (424 μL, 1.96 mmol) were added in order. The mixture was stirred at 23° C. for 15 h and then concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 20% ethyl acetate in hexane to give (156 mg, 57%) of 6-(2-azidopropoxy)-5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazine as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (1H, s), 7.85 (1H, s), 4.16 (1H, dd, J=2.8, 9.6 Hz), 4.05-3.96 (m, 2H), 2.60 (3H, s), 2.37 (3H, s), 1.21 (3H, d, J=6.3 Hz). LCMS m/z 254 (M+H+). B. 6-(2-Azido-propoxy)-5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine and 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol were reacted together according to the procedure described in Example 7 to afford 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine. The crude material was purified by preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ 12.18 (1H, s), 8.32 (1H, d, J=9.6 Hz), 8.02 (1H, s) 7.96 (1H, s), 6.60 (1H, d, J=3.6 Hz), 4.21 (1H, d, J=7.0 Hz), 4.09-4.02 (2H, m), 2.42 (3H, s), 1.23 (3H, d, J=6.3 Hz). LCMS m/z 382 (M+H+). C. A solution of 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.05 mmol) in ethyl acetate (2.0 mL) was stirred in the presence of hydrogen (14 psi) and 10% Pd/C (10 mg) for 12 h. Excess hydrogen was removed and the mixture was filtered through Celite® and evaporated. The residue was purified by preparative HPLC to afford (10 mg, 54%) of the title compound. LCMS: m/z 357 (M+H+). Dihydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ 12.19 (1H, s), 8.31 (1H, d, J=8.9 Hz), 8.16 (2H, br. s), 8.05 (1H, m), s), 7.97 (1H, s), 7.60 (1H, s), 6.60 (1H, s), 4.19 (2H, m), 4.03 (2H, m), 3.65 (1H, m), 1.30 (3H, d, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27]1([CH:33]=[CH:34][C:35](Cl)=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:35](=[O:36])[CH:34]=[CH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(c2ccc(Cl)cc2)n2ccnc2)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(C=Cc1ccccc1)Nc1ccc(C(c2ccc(Cl)cc2)n2ccnc2)cc1
Yield: 83.8 %

Procedure:
To a stirred and cooled (0° C.) mixture of 14.6 parts of 4-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]benzenamine, 60.9 parts of benzene and 6.86 parts of pyridine was added a solution of 10.6 parts of 3-phenyl-2-propenoyl chloride in 17.4 parts of benzene under a nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was basified and extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from dichloromethane. The product was filtered off and dried, yielding 17.7 parts (83.8%) of N-[4-[(4-chlorophenyl) (1H-imidazol-1-yl)methyl]phenyl]-3-phenyl-2-propenamide; top. 244° C.(interm. 50).
Reaction SMILES: CC(C)(C)CO[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9]2.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][OH:23]>>[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][O:23][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9]2
Reactant: CC(C)(C)CCO
Reactant: CC(C)(C)COc1cccc2[nH]c(C(=O)O)cc12
Product: CC(C)(C)CCOc1cccc2[nH]c(C(=O)O)cc12

Procedure:
This compound is synthesized analogously to (85) from 3,3-dimethyl-butan-1-ol.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[C:1]([CH2:3][C:4]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:6])#[N:2]
Reactant: Nc1ccccc1
Reactant: N#CCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Cyanoacetic acid (1.0 g, 11.7 mmol) is added to a stirred suspension of PCl5 (2.4 g, 11.7 mmol) in dry dichloromethane (200 ml). The reaction mixture is heated to reflux and kept stirring for 30 min. After cooling to rt, aniline (1.07 ml, 11.7 mmol) is added dropwise and the reaction is stirred at reflux for additional 2 h, then cooled to 0° C. and neutralized by addition of aqueous saturated Na2CO3 solution. The precipitate is filtered off, washed with water and dried under high vacuum to give title compound (1.54 g) as a white solid in 82% yield: tR (LC-2) 1.50 min; ESI-MS(+): m/z 183.33 [M+Na]+ (calcd 160.17 for C9H8N2O).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](C1NC=CN=1)=[O:29])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl-].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][S:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][NH3+:64].CCN(CC)CC>CN(C=O)C>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][P:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:29])[NH:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][S:43][S:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=2)(=[O:5])[O:3][CH2:1][CH3:2])=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)Oc1ccc([N+](=O)[O-])cc1
Reactant: [NH3+]CCOCCOCCOCCCCCCCCCCCSSc1ccccn1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)NCCOCCOCCOCCCCCCCCCCCSSc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 66 h

Procedure:
A solution of phosphonate 17 (68 mg, 0.14 mmol), amino disulfide 18 (60 mg, 0.13 mmol), and Et3N (35 mL, 0.25 mmol) dissolved in DMF was stirred at 60° C. for 66 h. After concentration of the reaction mixture, the crude residue was purified by column chromatography (hexane/EA=1:1) to afford the disulfide, which contained approximately 20% starting materials. ′H NMR (CDCl3, 500 MHz) δ 8.44 (s, 1H), 8.32 (s, 1H), 8.21 (d, J=9 Hz, 2H), 7.78 (br s, 1H), 7.70 (br s, 1H), 7.32 (d, J=9.0 Hz, 2H), 7.07 (br s, 1H), 4.15 (m, 2H), 3.98 (m, 2H), 3.62-3.49 (br m, 10H), 3.45 (m, 2H), 3.32 (m, 2H), 2.78 (t, J=7.5 Hz, 2H), 1.90 (m, 2H), 1.79 (m, 2H), 1.71-1.44 (br m, 4H), 1.40-1.07 (br, 33H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:32])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:32])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
10-bromo-2-ethoxycarbonylmethyloxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (2 g) obtained in Example 5 was suspended in ethanol (100 ml), and to the suspension was added 1N aqueous solution of sodium hydroxide (20 ml), and the mixture was stirred at room temperature for 12 hours. After evaporate the solvent under reduced pressure, 4N sodium hydroxide and methylene chloride were added to the residue for phase separation. To the aqueous layer was added 4N hydrochloric acid to a pH of 6, and the precipitated crystals were recovered by filtration to obtain the title compound (1.8 g, 96%).
Reaction SMILES: [CH:1]1([N:7]([CH3:32])[C:8](=[O:31])[CH2:9][CH2:10][CH:11]([C:29]#[N:30])[CH2:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:15][C:14]=2[N+:26]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>[Zn].CO>[CH:1]1([N:7]([CH3:32])[C:8](=[O:31])[CH2:9][CH2:10][CH:11]([C:29]#[N:30])[CH2:12][C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:16]=[CH:15][C:14]=2[NH2:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)CCC(C#N)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CN(C(=O)CCC(C#N)Cc1cc(Oc2ccccc2)ccc1N)C1CCCCC1

Procedure:
4-cyano-5-(2-nitro-5-phenoxy-phenyl)-pentanoic acid cyclohexyl-methyl-amide (0.200 g, 0.46 mmol), ammonium chloride (0.31 g, 5.75 mmol) and methanol (3.0 mL) were added to a round bottom flask followed by addition of powdered zinc (0.4 g). The vessel was equipped with a condenser and the reaction was headed to reflux for 2 h followed by filtration through a pad of Celite®. The solvent was removed and the resulting residue was dissolved in ethyl acetate, then washed 3 times with 10% aqueous sodium carbonate solution. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting residue was used in subsequent steps without further purification.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5]CC)=O.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18]Br)[C:14]([NH2:17])=[N:15][CH:16]=1>C1COCC1.C(OCC)(=O)C.[Zn]>[Br:10][C:11]1[CH:12]=[C:13]2[C:14](=[N:15][CH:16]=1)[NH:17][C:3](=[O:5])[C:2]([CH3:8])([CH3:9])[CH2:18]2
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of activated Zn (1.0 g, 15 mmol) and ethyl 2-bromo-2-methylpropanoate (1.24 mL, 6.4 mmol) in THF (8 mL) were added together at 0° C. and stirred for 6 h while warming to room temperature. To this mixture a dropwise solution of 5-bromo-3-(bromomethyl)pyridin-2-amine in THF (5 mL) was added via canula and the reaction mixture was stirred for a further 19 h at rt. The mixture was diluted with ethyl acetate (25 mL) and washed with saturated aqueous NH4Cl (50 mL) and brine (50 mL), dried over magnesium sulphate, and concentrated in vacuo. The crude yellow solid product was triturated with diethyl ether and filtered to obtain the white solid product. Yield 158 mg (49%); 1H NMR (300 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.23 (s, 1H), 7.87 (s, 1H), 2.81 (s, 2H), 1.04 (s, 6H); ESI MS m/z 255, 257 [C10H11N2OBr+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:29]=O>C1(C)C=CC=CC=1.C(OCC)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[O:21]=[C:20]1[O:22][CH2:29][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[C@H:19]1[CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: C=O
Reactant: O=C(N[C@@H](Cc1cscn1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C1OCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]1Cc1cscn1
Temperature: 80 °C
Reaction time: 48 h
Yield: 77.5 %

Procedure:
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(thiazol-4-yl)propanoic acid (Fmoc-Ala(4-Thz)-OH, Compound SP818) (50 g, 127 mmol), camphorsulfonic acid (2.10 g, 9.04 mmol) and paraformaldehyde (110 g, 3.66 mol) were dissolved in toluene (2 l) under a nitrogen atmosphere, and the mixture was stirred at 80° C. for two days. The reaction solution was diluted with diethyl ether and sequentially washed with an aqueous sodium bicarbonate solution and brine. The resulting organic extract was dried over sodium sulfate and then concentrated under reduced pressure to afford (S)-(9H-fluoren-9-yl)methyl 5-oxo-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (Compound SP817) (40.0 g, 98%) as a crude product.
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.[CH2:21](Br)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[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]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[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: BrCCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccccc3)C2=O)cn1
Yield: 37 %

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 phenethylbromide. Yield: 37%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.83 (t, J=6.4 Hz, 2H), 3.55 (t, J=7.4 Hz, 2H), 4.03 (s, 2H), 5.17 (s, 2H), 7.18-7.30 (m, 5H), 7.73 (s, 1H), 8.13 (s, 1H). MS M+H calculated 380.2. found 380.1. Melting point: 95-96° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.14 μM.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1)#[N:2].[N-:27]=[N+:28]=[N-:29].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]3[NH:29][N:28]=[N:27][N:2]=3)=[CH:26][CH:25]=2)=[O:24])=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(-c2nnn[nH]2)cc1)c1cccnc1Oc1ccc(F)cc1
Temperature: 110 °C

Procedure:
N-(4-Cyano-benzyl)-2-(4-fluoro-phenoxy)-nicotinamide (0.090 g) was placed in a sealable tube with anhydrous toluene (2 mL). Timethylsilyl azide (0.10 mL) was added, followed dibutyltin oxide (0.010 g) and the reaction mixture heated to 110° C. for 20 h. The reaction mixture was allowed to cool to ambient temperature, and quenched with 30% sodium bicarbonate (10 mL). Ethyl acetate (10 mL) was added and the aqueous layer collected. The organic layer was subsequently extracted with 30% sodium bicarbonate (2×10 mL). The combined aqueous portions were brought to pH 2 with 3N hydrochloric acid, and extracted with ethyl acetate (5×25 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated to dryness in vacuo to yield the title compound (0.040 g).
Reaction SMILES: C([O:3][C:4]([C@:6]1([CH3:22])[C@H:10]([CH2:11][F:12])[CH2:9][N:8]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:7]1=[O:21])=[O:5])C.[OH-].[Na+].O>C(O)C>[F:12][CH2:11][C@@H:10]1[CH2:9][N:8]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:7](=[O:21])[C@:6]1([CH3:22])[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@@]1(C)C(=O)N([C@H](C)c2ccccc2)C[C@H]1CF
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](c1ccccc1)N1C[C@@H](CF)[C@@](C)(C(=O)O)C1=O
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of (3R,4S)-3-ethoxycarbonyl-4-fluoromethyl-3-methyl-1-[(1R)-1-phenylethyl]-2-pyrrolidone (1.05 g, 3.42 mmol) in ethanol (20 mL), 10 mol/l aqueous solution of sodium hydroxide (3.42 mL, 34.2 mmol) was added dropwise in an ice bath, and the mixture was stirred for 30 minutes. Water (20 mL) was added to the reaction mixture in an ice bath, and the aqueous solution was washed with diethylether (50 mL). To the aqueous layer was added concentrated hydrochloric acid to pH 2 to 3 in an ice bath, and the solution was extracted with chloroform (50 mL×3). The organic layer was washed with saturated aqueous solution of sodium chloride (50 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was azeotropically distilled by adding toluene (20 mL), and dried under reduced pressure to obtain 950 mg (99%) of the title compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)C#N)=[CH:4][CH:3]=1.OS(O)(=O)=O.O.[C:25]([O-:28])([O-])=[O:26].[Na+].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[C:25]([OH:28])=[O:26])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CCC(CC(C#N)c2ccc(Br)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CCC(CC(C(=O)O)c2ccc(Br)cc2)CC1

Procedure:
The oily residue of 2-(4-bromo-phenyl)-3-(1-methyl-piperidin-4-yl)-propionitrile was hydrolyzed by refluxing for 2 h with 4 mL of concentrated H2SO4 and water (38:28). The mixture was neutralized with Na2CO3, then MeOH (20 mL) was added. The solid was filtered and washed with MeOH (3×10 mL). The combined methanol solution was evaporated to give an oil. MS: calc'd 326 (MH+), exp 326 (MH+).
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:17][CH:15]([CH2:16]2)[O:14][C:13](=[O:18])[NH:12]3)=[CH:7][CH:6]=1)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[N:28]=1.C(N(CC)CC)C>C(O)C>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]2[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]45[CH2:17][CH:15]([CH2:16]4)[O:14][C:13](=[O:18])[NH:12]5)=[CH:7][CH:6]=3)[N:33]=[C:29]2[N:28]=1
Reactant: O=C1NC2(c3ccc(C(=O)C(Br)c4ccccc4)cc3)CC(C2)O1
Reactant: COc1ccnc(N)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccn2c(-c3ccccc3)c(-c3ccc(C45CC(C4)OC(=O)N5)cc3)nc2n1
Temperature: 100 °C

Procedure:
A mixture of crude 5-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-2-oxa-4-aza-bicyclo[3.1.1]heptan-3-one (2.5 g), 4-methoxypyrimidin-2-amine (1.26 g), triethylamine (0.84 mL) and ethanol (62 mL), under argon, was heated at 100° C. (bath temperature) for 6 hours. On cooling the reaction was concentrated and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried and concentrated. Purification was achieved by chromatography on silica gel followed by preparative reverse phase HPLC to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[C:6]([S:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=2)=[CH:5][CH:4]=[CH:3]1.CS(O[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=1)(=O)=O>>[O:1]=[C:2]1[C:15]2[N:14]([CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][CH:25]=3)[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:7][C:6]=2[CH:5]=[CH:4][CH2:3]1
Reactant: O=c1cccc2sc3ccccc3nc1-2
Reactant: CS(=O)(=O)OCCOc1ccc(C=O)cc1
Product: O=Cc1ccc(OCCN2C3=C(C=CCC3=O)Sc3ccccc32)cc1
Yield: 65.1 %

Procedure:
The title compound (2.2 g, 67%) was prepared as a thick liquid from 9-oxophenothiazin (2.0 g, 9.3 mmol) and 2-(4-formylphenoxy)ethyl methanesulfonate (2.7 g, 11 mmol) using a similar procedure to that described in preparation 3.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[NH:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:21]=2[N:20]=[CH:19]1.N(CCCC)(CCCC)CCCC.[I-].ClC1C=CC=C[N+]=1C>CN(C)C=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:27]([C:25]3[CH:24]=[CH:23][C:22]4[NH:18][CH:19]=[N:20][C:21]=4[CH:26]=3)=[O:28])=[CH:8][CH:9]=2)[N:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Cc1nn(-c2ccccc2)c2cc(N)ccc12
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: Cc1nn(-c2ccccc2)c2cc(NC(=O)c3ccc4[nH]cnc4c3)ccc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 3-methyl-1-phenyl-1H-indazol-6-amine (520 mg, 2.33 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), 1H-benzo[d]imidazole-5-carboxylic acid (324 mg, 2.00 mmol, 0.86 equiv), NBu3 (925 mg, 5.00 mmol, 2.14 equiv). To the resulting mixture was then added 2-chloro-1-methylpyridiniumiodide (612 mg, 2.40 mmol, 1.03 equiv) at 50° C. The resulting solution was stirred for 2 days at 100° C. in an oil bath, then concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1). The resulting mixture was washed with methanol (1×10 mL) and diethyl ether (1×10 mL) to yield N-(3-methyl-1-phenyl-1H-indazol-6-yl)-1H-benzo[d]imidazole-5-carboxamide as a yellow solid.