Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH2:2]([O:3][C:4](=[O:5])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10]/[C:11](=[CH:19]\[N:20]([CH3:22])[CH3:21])/[C:12]1=[O:13])[CH3:1]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCOC(=O)CC1CCCCC1=O
Product: CCOC(=O)CC1CCC/C(=C\N(C)C)C1=O

Procedure:
Ethyl 2-cyclohexanoneacetate (100 mg, 0.54 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (116 mg) as a brown oil which was used directly in the next step. MS ISP (m/e): 194.2 (100) [(M-EtOH+H)+], 240.2 (90) [(M+H)+].
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[CH:7][C:6]=2[CH:10]=1.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+]>O>[S:9]1[C:5]2[CH:4]=[CH:3][C:2]([OH:12])=[CH:10][C:6]=2[CH:7]=[N:8]1
Reactant: Nc1ccc2sncc2c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc2sncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
5-Aminobenzo[d]isothiazole (217 mg, 1.45 mmol) was suspended/dissolved in water (20 mL) containing concentrated sulphuric acid (1.5 mL) and heated at 90° C. for 2 h. This solution was cooled to 0° C. and sodium nitrite (105 mg, 1.52 mmol) in water (1 mL) was added over 5 min and the mixture allowed to warm to ambient temperature. The diazonium salt was added dropwise over 20 min to a solution of concentrated sulphuric acid (1 mL) in water (12 mL) at 90° C. and stirred at this temperature for 2 h before hot filtering to remove an insoluble solid. The filtrate was extracted with dichloromethane (3×20 mL) and the combined organic extracts washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a brown solid (65 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=3[CH3:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C1C=CC=CN=1)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:39][S:40]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]([O:21][CH3:22])=[S:20])[S:16][C:17]=3[CH3:18])[S:11][CH:12]=2)=[CH:4][CH:3]=1)(=[O:42])=[O:41]
Reactant: COC(=S)c1cc(-c2nc(-c3ccc(N)cc3)cs2)c(C)s1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=S)c1cc(-c2nc(-c3ccc(NS(C)(=O)=O)cc3)cs2)c(C)s1
Temperature: 25 °C
Reaction time: 192 h
Yield: 66.4 %

Procedure:
Methyl 4-(4-(4-aminophenyl)(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (200 mg, 0.55 mmol) was dissolved in dry dichloromethane (20 mL). To this, N-methyl morpholine (150 μL, 1.38 mmol) and dimethylaminopyridine (6.1 mg, 0.055 mmol) were added, the mixture was cooled on an ice bath, and methanesulfonyl chloride (43 μL, 0.55 mmol) was added dropwise. The mixture was then stirred for 8 days at room temperature. The mixture was partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (20 mL). The aqueous layer was extracted with dichloromethane (3×20 mL), and the combined organic layers were washed with saturated sodium bicarbonate (20 mL), brine (2×20 mL), and dried over anhydrous sodium sulfate. The solvent was remove in vacuo. Column chromatrography on silica gel (100 g) eluting with dichloromethane:methanol 99/1 (v:v), gave methyl 4-(4-{4-[(methylsulfonyl)amino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (155 mg, 64%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ9.92 (s, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 8.40 and 6.90 (AB quartet, 2H, J=8.7 Hz), 3.87 (s, 3H), 3.05 (s, 3H), 2.76 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix m/z): Calcd. for C17H16N2O4S4441.0 (M+H), found 441.2.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Li+].[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](Cl)(=[O:16])[CH3:15]>ClC(Cl)C>[CH3:13][C:7]1[CH:12]=[CH:11][C:10]([C:14]([CH3:15])=[O:16])=[CH:9][CH:8]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an agitated mixture of aluminium chloride (20 g., 0.15 mole) and lithium chloride (3.18 g., 0.075 mole) and dichloroethane (20 ml) at -15° C. wash slowly added toluene (4.6 g., 0.05 mole) and acetyl chloride (3.93 g., 0.05 mole) in dichloroethane (10 ml). The reaction mixture was left at -15° C. for one hour then allowed to warm up to room temperature overnight. After working up as described in Example 1, the 4-methylacetophenone obtained (7.17 g.), had a 1H NMR estimated purity of about 95%. 1H NMR showed less than 2% ortho isomers.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2I)=[O:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17])=[O:4]
Reactant: COc1ccccc1O
Reactant: COC(=O)c1ncc2c(I)cccc2c1O
Product: COC(=O)c1ncc2c(Oc3ccccc3OC)cccc2c1O

Procedure:
The title compound was synthesized from 4-hydroxy-8-iodo-isoquinoline-3-carboxylic acid methyl ester and 2-methoxy-phenol in analogy to example 19d; MS-(+)-ion: M+1=326.4.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH:25]1[CH:29]([CH3:30])[CH2:28][NH:27][CH2:26]1)[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH:29]([CH3:30])[CH:25]([CH2:24][NH:23][CH2:21][CH3:22])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CNCC1C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-ethylaminomethyl-4-methylpyrrolidine (0.38 g) and DBU (0.27 g) was refluxed for an hour and allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and ether successively and recrystallized from chloroform-methanol-concentrated aqueous ammonia to give the title compound (0.47 g) as pale yellow powder, mp 224°-226° C.
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])[CH:16]([CH2:19][C:20]([OH:22])=O)[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.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])[CH:16]([CH2:19][C:20]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:22])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)Nc3ccccc3)C2=O)cn1
Temperature: 65 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) (100 mg, 0.3 mmol), aniline (33 mg, 0.36 mmol), Pybop (187 mg, 0.36 mmol) and triethyl ammine (0.05 mL, 0.36 mmol) were mixed in DMF (1 mL). The reaction stirred at 65° C. for 4 hours. The reaction was allowed to cool to room temperature and then diluted with ethyl aceate (2 mL). The organic phase was washed with saturated sodium bicarbonate solution (2×, 2 mL) and then with saturated NaCl solution (1 ml). The organic phase was extracted, dried over anhydrous Na2SO4, and filtered. The crude product was re-suspended in MeOH (1 mL) and purified by reversed phase HPLC (5-95% acetonitrile in H2O; 16 minute gradient). The pure fractions were combined and solvent was removed on the rotovap to afford 2-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)-N-phenylacetamide as a white solid (50%). 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.40 (s, 3H), 2.72 (m, 1 H), 3.14-3.13 (d, 1H, J=4 Hz), 4.54-4.51 (d, J=8 Hz 1H), 5.04 (s, 2H), 6.53 (bs, 1H), 7.15-7.13 (m, 1H), 7.33-7.22 (m, 2H), 7.47-7.45 (d, J=8 Hz, 2H), 7.78 (bs, 1H), 7.09 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.75 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([C:25]#[N:26])([CH3:24])[CH3:23])[CH:17]=3)[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[S-:30][C:31]#[N:32].[K+].BrBr>>[NH2:32][C:31]1[S:30][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:14][C:15](=[O:27])[C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([C:25]#[N:26])([CH3:24])[CH3:23])[CH:17]=4)[CH:10]=[CH:11][C:12]=3[CH3:13])[CH:28]=[CH:29][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Yield: 45.2 %

Procedure:
Using N-[3-(4-aminophenoxy)-4-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (1.93 g, 5.0 mmol), potassium thiocyanate (1.94 g, 20.0 mmol) and bromine (1.20 g, 7.50 mmol), and in the same manner as in Example A25(v), the title compound (1.00 g, 45%) was obtained as a pale-yellow powder.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:32])[C@@H:9]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[C:12]2=[O:31])[CH3:10])[CH2:3]1.[C:33](O)(=[O:36])[C:34]#[CH:35].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:17]([NH:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@@H:9]([CH3:10])[C:8]([N:4]3[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:33](=[O:36])[C:34]#[CH:35])[CH2:3]3)=[O:32])[C:12]1=[O:31])(=[O:19])=[O:18])[CH:29]=[CH:28]2
Reactant: C[C@@H](C(=O)N1CCCC(N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C#CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CC(=O)NC1CCCN(C(=O)[C@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 115.5 %

Procedure:
To a solution of N-{(3S)-1-[(1S)-2-(3-aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide (0.005 g) in DMF (0.5 ml) were added propiolic acid (0.001 g), N,N-diisopropylethylamine (0.0044 ml) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.0049 ). The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The separated organic fraction was concentrated under reduced pressure to give the title compound (0.0064 g) as an oil.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[C:18]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]([NH:36][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:34][CH:35]=1)(=[O:29])=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(S(=O)(=O)NC(=O)c2ccccc2)cc1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)NC(=O)c2ccccc2)cc1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-benzoyl-4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ12.5 (br s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 8.0 (d, 2H), 7.9 (t, 3H), 7.65 (t, 3H), 7.5 (t, 2H), 7.2 (d,1H); ESI−MS m/z 475 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][O:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:23][CH2:22][CH2:21][O:20]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C2(CN)CCCO2)cn1
Product: Cc1ncc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCCO2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and (2-(2-methylpyrimidin-5-yl)tetrahydrofuran-2-yl)methanamine. LCMS (MH+): m/z=366.0, tR (minutes, Method E)=0.52
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][NH:7][C:8]([N:10]1[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[N:11]1)=[O:9]>C(O)(=O)C>[CH3:6][NH:7][C:8]([N:10]1[C:14]([CH2:15][CH3:16])=[C:13]([Cl:4])[C:12]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:26])([F:27])[F:28])=[CH:20][N:19]=2)=[N:11]1)=[O:9]
Reactant: CCc1cc(Oc2ncc(C(F)(F)F)cc2Cl)nn1C(=O)NC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCc1c(Cl)c(Oc2ncc(C(F)(F)F)cc2Cl)nn1C(=O)NC
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
Sulfuryl chloride (0.17 g, 1.2 mmol) was added to a solution of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole-1-carboxamide (0.35 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-4-chloro-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-ethylpyrazole-1-carboxamide (0.31 g, yield: 80.9%). mp: 88-89° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.30 (t, J=7.4 Hz, 3H), 2.96 (d, J=5.0 Hz, 3H), 3.14 (q, J=7.4 Hz, 2H), 6.90-7.10 (m, 1H), 8.04 (d, J=2.0 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: Cl[N:2]1[C:6]2[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:5]=2[N:4]=[CH:3]1.[NH:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[O:18]2)[CH2:14][CH2:13]1.O>CN1C(=O)CCC1>[I:11][C:9]1[CH:8]=[CH:7][C:6]2[NH:2][C:3]([N:12]3[CH2:17][CH2:16][C:15]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19](=[O:26])[O:18]4)[CH2:14][CH2:13]3)=[N:4][C:5]=2[CH:10]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: Cln1cnc2cc(I)ccc21
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1OC2(CCN(c3nc4cc(I)ccc4[nH]3)CC2)c2ccccc21

Procedure:
Heat a solution of 2 chloro-5-iodo-1H-benzimidazole (3.0 g, 10.7 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (2.63 g, 12.9 mmol) in dry NMP (15 mL) at 100° C. for 14 hours. Pour the cooled mixture into water (50 mL) and extract twice with EtOAc (50 mL). Wash the combined extracts with brine (30 mL), dry, and evaporate in vacuo. Purify by flash column chromatography (50% EtOAc-hexane) to obtain 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a beige solid. C. 1′-(5-Pyridin-3-yl-1G-benzimidazol-2-yl)-spiro[isobenzofuran-1,44′-piperidin]-3-one
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[N:15][CH:16]=1)[CH3:10].[S]>>[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:15][CH:16]=1)[CH3:10]
Reactant: CCc1ccc(C)nc1
Reactant: Nc1ccccc1N
Agent: [S]
Product: CCc1ccc(-c2nc3ccccc3[nH]2)nc1

Procedure:
130 g. of o-phenylenediamine, 121 g. of 5-ethyl-2-methylpyridine and 96 g. of sulfur were heated at 160°-170° C. for 20 hours. The reaction mixture was dissolved in 2,000 ml. of chloroform and the solution was washed with water and 6 N hydrochloric acid successively. Chloroform was removed by evaporation in vacuo. The residue was subjected to silica gel column chromatography and recrystallized from ethyl acetate. The product showed no melting point depression upon mixing with the product of the preceding example. Yield, 137 g (61% of theory).
Reaction SMILES: O[C:2]1[O:3][C:4]2[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][C:5]=2[C:6](=[O:11])[C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[Na+].Cl>C(OCC)(=O)C>[N+:8]([C:7]1[C:6](=[O:11])[C:5]2[CH:12]=[C:13]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:4]=2[O:3][CH:2]=1)([O-:10])=[O:9]
Reactant: CS(=O)(=O)Nc1cc2oc(O)c([N+](=O)[O-])c(=O)c2cc1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc2occ([N+](=O)[O-])c(=O)c2cc1Oc1ccccc1
Reaction time: 5 h
Yield: 41 %

Procedure:
3.92 g of 2-hydroxy-7-methylsulfonylamino-3-nitro-6-phenoxy-4H-1-benzopyran-4-one was mixed with 80 ml of a 1N aqueous sodium hydroxide solution. The mixture was stirred for 5 hours at 20°-25° C. The mixture was adjusted to pH 5 with 4N hydrochloric acid. 50 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting yellow solid was dissolved in N,N-dimethylformamide. 2.62 g of N,N-dimethylformamide dimethylacetal was added thereto. The mixture was stirred for 1 hour at 20°-25° C. The reaction mixture was introduced into 300 ml of water. The resulting mixture was adjusted to pH 2 with 4N hydrochloric acid. The precipitate was washed with water and then recrystallized from acetonitrile to obtain 1.54 g (yield: 41%) of 3-nitro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 225°-227° C.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])[CH2:25][C:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)=O)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:43][OH:44].C([O-])(O)=O.[Na+]>>[C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])[CH2:25][C:26](=[N:43][OH:44])[C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)N[C@H](C)c4ccccc4)cc3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@@H](c2ccc(-c3ccc(C(=O)N[C@H](C)c4ccccc4)cc3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example example 74, step 7, from 4′-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid ((R)-1-phenyl-ethyl)-amide and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.4:1) as a colorless oil, MS (ESI+): m/z=553.702 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:47]=[CH:46][C:19]([CH2:20][NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:25]=[C:24]([NH:34][C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41]CC)=[O:40])=[CH:37][CH:36]=3)[N:23]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.Cl>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:47]=[CH:46][C:19]([CH2:20][NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[N:25]=[C:24]([NH:34][C:35]3[CH:45]=[CH:44][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=3)[N:23]=2)=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCCCCNC(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 110 °C
Yield: 75.2 %

Procedure:
A mixture of ethyl 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (1.0 g) and K2CO3 (1.25 g) in acetone (12 mL)/water (12 mL) was heated at 110° C. for 24 hours. After cooling to room temperature, the mixture was acidified with 1N HCl to pH=3. The white precipitate was collected, washed with water (20 mL) and dried under vacuum to give 4-(4-(4-(6-(tert-butoxycarbonylamino)hexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (0.72 g).
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:12]1[CH2:17][CH:16]=[CH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:12]1([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH:14]=[CH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: C1=CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=CCC1
Yield: 92.2 %

Procedure:
tert-Butyl dicarbonate (6.55 g) was added to a mixture of 1,2,3,6-tetrahydropyridine (2.50 g) and a 10% aqueous solution (3.0 ml) of sodium carbonate, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture to conduct extraction with ethyl acetate. The resultant organic layer was washed with 0.5N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride in that order and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain the title compound (5.08 g).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:21][CH2:22][C:23]2([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[CH2:24]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[I-].[Na+]>C1C=CC=CC=1>[CH2:36]([CH:26]1[C:25](=[O:30])[CH2:24][C:23]([CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]([Cl:12])[CH:14]=2)([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[O:28][C:27]1=[O:29])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: BrCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cc3ccccc3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14.6 %

Procedure:
DBU (28.6 ul, 0.191 mmol) was added to a solution of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (60.6 mg, 0.172 mmol) in benzene (2.0 ml), under an atmosphere of argon. Benzyl bromide (20.5 ul, 0.172 mmol) was then added. The reaction mixture was stirred at room temperature for 20 minutes, followed by the addition of 5 crystals of sodium iodide. The reaction mixture was stirred for a further 24 hrs, after which time the mixture was filtered through a plug of Celite. The filtrate was concentrated in vacuo and the residue purified by prep HPLC to afford the title compound as a white solid (11.1 mg).