Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: BrCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOCCCCCCBr
Temperature: 20 °C
Reaction time: 120 h
Yield: 67.1 %

Procedure:
2-{[tert-Butyl(dimethyl)silyl]oxy}ethanol (1.82 g), 1,6-dibromohexane (7.56 g) and tetrabutylammonium bromide (0.067 g) were stirred under nitrogen and treated with 50% w/v sodium hydroxide (2 g in 4 ml). The mixture was stirred vigorously at 20° C. for 5 days. Water (100 ml) was added, and the product extracted with dichloromethane (3×50 ml). The combined organic layer was separated and dried over Na2SO4 before filtering. The solvent was evaporated in vacuo to give a residue which was purified by flash chromatography on silica. Elution with 5% ether/cyclohexane followed by solvent evaporation in vacuo gave the title compound (2.35 g). LCMS RT=4.32 min, ES+ve 339 (MH)+.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>O1CCOCC1>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([F:30])=[C:23]([Cl:22])[CH:24]=3)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: C1COCCO1
Product: O=C(NCC1CCCCC1)c1cnc(Nc2ccc(F)c(Cl)c2)nc1C(F)(F)F
Yield: 79.9 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (100 mg) in 1,4-dioxan (1 ml) was added 3-chloro-4-fluoroaniline (228 mg, ex Lancaster) and the solution stirred at reflux for 4 hours. Dioxan was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 2N hydrochloric acid (2×3 ml) and water (3×3 ml), dried MgSO4), evaporated and triturated with isohexane to afford the title compound (107 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.ClCCl>CN1C(=O)CCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)S1
Reactant: Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Nc4cccc(Cl)c4)nc23)S1
Temperature: 180 °C

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione (20 mg, 0.06 mmol) in NMP was added 3-chloroaniline (38 μL, 0.36 mmol) and few granules p-toluenesulfonic acid. The reaction was heated in microwave at 180° C. for 1.5 hours. Mixture was filtered and prepared by HPLC then preparative TLC (1% methanol/dichloromethane) to yield 5-((5-(3-chlorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione as a yellow solid. LCMS (M+1=427)
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([C:15](=[O:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:11]=2[O:13]C)[CH:6]=[CH:5][C:3]1=[O:4].O>Br>[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([C:15](=[O:21])[CH2:16][NH:17][CH:18]([CH3:19])[CH3:20])[CH:9]=[CH:10][C:11]=2[OH:13])[CH:6]=[CH:5][C:3]1=[O:4]
Reactant: COc1ccc(C(=O)CNC(C)C)c2ccc(=O)n(C)c12
Agent: Br
Solvent: O
Product: CC(C)NCC(=O)c1ccc(O)c2c1ccc(=O)n2C
Yield: 23.7 %

Procedure:
2.0 g of 1-methyl-5-isopropylaminoacetyl-8-methoxycarbostyril (IIb) hydrochloride prepared as described in Example 3 was dissolved in 30 ml of a 47% aqueous solution of hydrobromic acid, and the solution was heated in an oil bath at a temperature of 120° to 130° C. for 8 hours under refluxing. 10 ml of water was then added to the reaction mixture followed by concentration by distillation. 10 ml of water was again added to the mixture followed by concentration. After allowing the mixture to cool, the precipitate formed was filtered and dissolved in 60 ml of water by heating. The resulting solution was adjusted to a pH of 6.5-7.5 with sodium bicarbonate and the precipitate formed was filtered. Recrystallization of the precipitate from ethanol yielded 0.45 g of white amorphous 1-methyl-5-isopropylaminoacetyl-8-hydroxycarbostyril (IIa) having a melting point of 136° to 138° C (with decomposition). The product thus obtained was confirmed by elemental analysis and IR and NMR spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[N:18]=[C:5]2[N:6]=[C:7](O)[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([CH3:10])[N:4]2[N:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:7]1[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:10])[N:4]2[N:3]=[C:2]([CH3:1])[N:18]=[C:5]2[N:6]=1
Reactant: Cc1nc2nc(O)c(-c3ccccc3)c(C)n2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1nc2nc(Cl)c(-c3ccccc3)c(C)n2n1
Temperature: 100 °C

Procedure:
1.34 g of the product of step 1 are suspended in 20 ml POCl3. 1.06 ml N,N-dimethylaniline is added and the mixture is heated to 100° C. for 45 min. The excess of POCl3 is removed by distillation and the residue is treated with ice. The desired product precipitates and is collected by filtration.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[NH:4][N:3]=1.[CH:14]1([CH:17]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[NH2:18])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH:14]1([CH:17]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[NH:18][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[I:1])=[O:13])[CH2:16][CH2:15]1
Reactant: NC(c1nccs1)C1CC1
Reactant: O=C(O)c1ccc2[nH]nc(I)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1nccs1)C1CC1)c1ccc2[nH]nc(I)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
The title compound was synthesized according to General Method A utilizing 3-iodo-1H-indazole-5-carboxylic acid (255 mg, 0.88 mmol), cyclopropyl(thiazol-2-yl)methanamine (150 mg, 0.97 mmol), TBTU (310 mg, 0.97 mmol), DIPEA (0.31 mL, 1.8 mmol), and DMF (8 mL). The reaction was stirred at 0° C. for 1 h. The crude reaction was subsequently diluted with H2O. A filtration and washing (H2O) of the precipitate provided the desired product as a beige solid (195 mg, 52%). The product used without further purification. 1H NMR (400 MHz, CD3OD) δ ppm 8.16 (br. s., 1H), 7.99 (m., 1H), 7.77 (br. s., 1H), 7.46-7.67 (m, 2H), 1.45-1.68 (m, 1H), 0.46-0.90 (m, 4H); MS ESI 425.0 [M+H]+, calcd for [C15H13IN4OS+H]+ 425.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]2[N:9]=[C:8]3[C:14]4[C:19]([CH2:20][C:7]3([CH3:21])[C:6]=2[C:5]=1[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH3:2].O1CCC[CH2:24]1>C[Li].CCOCC>[CH2:1]([O:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]2[NH:9][C@:8]3([CH3:24])[C:14]4[C:19]([CH2:20][C@:7]3([CH3:21])[C:6]=2[C:5]=1[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH3:2]
Reactant: CCOc1c(C)cc2c(c1C)C1(C)Cc3ccccc3C1=N2
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCOCC
Product: CCOc1c(C)cc2c(c1C)[C@@]1(C)Cc3ccccc3[C@@]1(C)N2
Reaction time: 1 h
Yield: 96 %

Procedure:
To a cold (-78° C.) solution of 2.0 g (0.0063 mol) of 9b,10-dihydro-8-ethoxy-7,9,9b-trimethylindeno[1,2-b]indole in 20 ml of dry tetrahydrofuran, 10 ml of methyllithium (1.6N) in ether was added dropwise with stirring and under argon. After the addition was complete the stirring was continued for 1 hour at -20° C. and then for 1 hour at room temperature. The reaction mixture was quenched by addition of 20 ml of saturated ammonium chloride solution. After addition of 100 ml of ether the organic phase was separated and washed twice with ammonium chloride solution. Drying (Na2SO4) and evaporation gave 2.0 g (96%) of the product. 1H NMR (CDCl3): 1.35 (3H,t), 1.4 (6H,d), 2.1 (3H,s), 2.35 (3H,s), 2.95-3.05 (1H,d), 3.55-3.75 (3H,m), 6.1 (1H,s), 7.0-7.3 (4H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH2:11])=[N:7][CH:6]=1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]([NH:11][C:28]([C:25]2([C:23]3[CH:22]=[CH:21][C:20]4[O:16][CH2:17][O:18][C:19]=4[CH:24]=3)[CH2:27][CH2:26]2)=[O:29])=[N:7][CH:6]=1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Cn1c(Cc2ccccc2Cl)cnc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1c(Cc2ccccc2Cl)cnc1NC(=O)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 16 h
Yield: 22 %

Procedure:
5-(2-Chloro-benzyl)-1-methyl-1H-imidazol-2-ylamine (21 mg, 0.10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (22 mg, 0.10 mmol) were dissolved in acetonitrile (1.5 mL) containing triethylamine (42 L, 0.30 mmol). Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 49 mg, 0.11 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product as a trifluoroacetic acid salt (11 mg, 0.022 mmol, 22%). ESI-MS m/z calc. 409.1. found; 410.1 (M+1)+ Retention time 2.40 minutes.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][C:13]1[C:14]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](OC)=[O:23])[C:15]=2[S:16][CH:17]=1)=O)C.C(OCC)(=O)C.O>C1COCC1>[OH:23][CH2:22][C:18]1[C:15]2[S:16][CH:17]=[C:13]([CH2:12][CH2:10][OH:9])[C:14]=2[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cc1csc2c(C(=O)OC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCCc1csc2c(CO)cccc12
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
Under a nitrogen stream, to a solution (38 mL) of lithium aluminum hydride (0.74 g, 19.5 mmol) in THF was added a solution (30 mL) of methyl 3-ethoxycarbonylmethyl-benzo[b]thiophene-7-carboxylate (2.7 g, 9.7 mmol) in THF at 0° C., and the resultant solution was stirred for 10 minutes at the same temperature. To the solution was further added lithium aluminum hydride (0.74 g, 19.5 mmol) at 0° C., and the resultant solution was stirred for 10 minutes at the same temperature. Ethyl acetate was added to the solution, and then water (5.2 mL) was added thereto at 0° C. The temperature of the resultant solution was raised to room temperature, and then the solution was stirred for 10 minutes. The reaction mixture was filtered through Celite. Solvent was then removed by distillation under reduced pressure. The resulting residue was treated by addition of ethyl acetate and n-hexane (1:2), to thereby obtain the titled compound (1.97 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].F[B-](F)(F)F.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]#[N:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O.C(O)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([Br:1])[C:7]([N:26]=[N:25][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)=[N:6][CH:5]=1
Reactant: Oc1cncc(Br)c1
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Agent: F[B-](F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N=Nc2ncc(O)cc2Br)cc1
Reaction time: 1 h
Yield: 33.7 %

Procedure:
5-bromo-3-pyridinol (8.7 g, 0.05 mol) and potassium hydroxide (Fisher Scientific) were dissolved in water (200 ml). A suspension of p-nitrobenzenediazonium tetrafluoroborate (J. Org. Chem., Vol. 44, No 9. 1979 p 1572-1573) (11.845 g, 0.5 mol) was added, and the mixture was stirred for 1 hour, diluted with acetic acid (50 ml) and filtered. The crude product was allowed to dry in air, then was chromatographed (silica gel; CHCl3/MeOH, 95:5 to 90:10) provided 5.45g (33.7 %) of the title compound. MS (CI/NH3) m/e 323/325 (M+H)+. 1H NMR (DMSO-d6, 300 MHz) δ8.48-8.43 (m, 2H), 8.21-8.20 (d, J=2.37 Hz, 1H) 8.09-8.06 (m, 2H), 7.72-7.71 (d, J=2.37 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([CH:28]3[CH2:30][CH2:29]3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C1CC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C3CC3)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=347.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH3:7])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)([CH2:8][O:9]CC=C)[C:4](=[O:20])[N:3]1[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1>C(Cl)Cl>[O:1]=[C:2]1[N:6]([CH3:7])[C:5]([CH2:8][OH:9])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)[C:4](=[O:20])[N:3]1[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:22]=1
Reactant: C=CCOCC1(c2cccc(C)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Solvent: ClCCl
Product: Cc1cccc(C2(CO)C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)N2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 856 mg of 4-[2,5-dioxo-3-methyl-4-(3-methylphenyl)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in DCM (5 mL) is added trifluoroborane-dimethylsulfide complex (812 μL). The mixture is stirred 4 hours at rt, diluted with DCM, washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:11]=2[C:10]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][CH:8]=1.N([O-])=[O:27].[Na+].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[OH-].[NH4+]>O>[OH:27][C:7]1[C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:11]=2[C:10]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][CH:8]=1
Reactant: CN1CCc2c(N)ccc(Sc3ccccc3)c2CC1
Reactant: O=N[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: CN1CCc2c(O)ccc(Sc3ccccc3)c2CC1

Procedure:
To a stirred solution of 114 ml. of water and 15 ml. of concentrated sulfuric acid at 60°-70° C. is added 23.2 g. (0.082 mole) of 9-amino-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting suspension is stirred vigorously and cooled to 0°-5° C. To this suspension is added 6.3 g. (0.091 mole) of sodium nitrite in 10 ml. of water at a rate such that the temperature does not exceed 5° C. The resulting diazonium solution is added dropwise to a boiling solution of 200 g. of cuprous sulfate and 300 ml. of water. After being refluxed for 15 minutes the solution is cooled, a trace of ascorbic acid is added and the pH is adjusted to 7.0 with ammonium hydroxide. The mixture is extracted with ethyl acetate. After being dried the extract is concentrated to afford 9-hydroxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine. Purification is accomplished by chromatography or by recrystallization of an appropriate acid addition salt.
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18](/[CH:26]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]#[CH:25].[N:40]([CH2:43][C:44]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:45])=[N+:41]=[N-:42]>CS(C)=O.O.S([O-])([O-])(=O)=O.[Cu+2].C(C(N(C(C1N=NNC=1)CC1C=CC=CC=1)C(C1N=NNC=1)CC1C=CC=CC=1)C1N=NNC=1)C1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18](/[CH:26]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:42]=[N:41][N:40]([CH2:43][C:44](=[O:45])[NH:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:25]=1
Reactant: [N-]=[N+]=NCC(=O)Nc1ccccc1
Reactant: C#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OCc1cn(CC(=O)Nc2ccccc2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
Sodium ascorbate (28 mg, 140 μmol), tris-(benzyltriazolylmethyl)amine (15 mg, 28 μmol) and copper sulfate (4.5 mg, 28 μmol) were added to a solution of (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.50 g, 1.4 mmol) and 2-azido-N-phenylacetamide (0.25 g, 1.4 mmol) in DMSO (20 mL) and water (5.0 mL). The solution was stirred at rt for 16 h and diluted with water. The suspension was filtered and the filter cake was washed with water and dried. The crude product was recrystallised from acetonitrile to afford (E)-2-[[3-(3-methoxy-4-((1-(2-oxo-2-(phenylamino)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.60 g, 80%) as a colourless solid; mp 220-222° C.; δH (400 MHz, DMSO-d6) 3.82 (s, 3H, OCH3), 5.21 (s, 2H, CH2), 5.36 (s, 2H, CH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.08 (t, J=8.0 Hz, 1H, H4″), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.21-7.28 (m, 2H, H6′, H5′), 7.39 (s, 1H, H2′), 7.31 (t, J2″,3″=J3″,4″=J4″,5″=J5″,6″=8.0 Hz, 2H, H3″, H5″), 7.56-7.63 (m, 4H, CH═CHCO, H5, H2″, H6″), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.27 (s, 1H, C═CHN), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 10.48 (s, 1H, NH), 11.30 (s, 1H, NH), 13.60 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 52.2, 55.6, 61.4, 110.5, 112.9, 116.6, 119.2, 120.1, 120.4, 122.6, 122.8, 123.8, 126.6, 127.6, 129.0, 131.2, 134.1, 138.5, 141.1, 141.7, 142.2, 149.1, 149.4, 164.2, 169.5; HRMS (ESI) calculated for C28H25N5O6 [M+Na]+ 550.1697. found 550.1691; vmax 1239, 1585, 1665, 2605, 3000, 3250 cm−1.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.NO.[CH:9]1([C:12](=[O:28])[C:13](=[CH:24][N:25](C)C)[C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][N:17]=2)=[O:15])[CH2:11][CH2:10]1>C(O)C>[CH:9]1([C:12]([C:13]2[CH:24]=[N:25][O:15][C:14]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][N:17]=2)=[O:28])[CH2:11][CH2:10]1
Reactant: CSc1ccc(C(=O)C(=CN(C)C)C(=O)C2CC2)nc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CCO
Product: CSc1ccc(-c2oncc2C(=O)C2CC2)nc1
Reaction time: 1 h
Yield: 14.1 %

Procedure:
Sodium acetate (1.1 g) was added to a solution of hydroxylamine hydrochloride (0.9 g) and 3-cyclopropyl-2-(N,N -dimethylaminomethylene)-1-[5-(methylsulphenyl)-pyrid-2-yl]propan-1,3-dione (3.24 g) in ethanol. The mixture was stirred for 1 hour then cooled and filtered. The solid was washed with cold ethanol and the filtrate was partially evaporated. Water was added and the mixture was stirred at 0° C. for 0.5 hours. It was extracted with dichoromethane washed with water, dried (Na2SO4) and filtered. The flitrate was evaporated to dryness and the residue was purified by chromatography eluted with mixture of ethyl acetate and hexane to give 4-cyclopropylcarbonyl-5-[5-(methylsulphenyl)pyrid-2-yl] isoxazole (compound 13, 0.41 g) as a white solid, m.p. 103°-104° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([OH:32])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:66]1[CH2:71][CH2:70][CH:69]([N:72]2[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]2)[CH2:68][CH2:67]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:29])[C:23]([O:27][CH3:28])=[C:24]([CH3:26])[CH:25]=3)[C:30](=[O:32])[N:75]3[CH2:74][CH2:73][N:72]([CH:69]4[CH2:70][CH2:71][O:66][CH2:67][CH2:68]4)[CH2:77][CH2:76]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: COc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 40 mg (0.08 mmol) (R)-2-(4-methoxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 29 mg (0.09 mmol) TBTU and 14 μL (0.10 mmol)triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 15 mg (0.09 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the mixture was stirred for a further 16 h at RT. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH:7]1[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:8]1=[O:14].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([N:7]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:8]2=[O:14])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a stirred solution of 42.8 parts of sodium hydride dispersion 50% in 200 parts of dimethyl sulfoxide was added dropwise slowly a solution of 50 parts of 2,4(1H,3H)-pyrimidinedione in 800 parts of dimethyl sulfoxide while the temperature was kept constant (20° C.) by cooling in an ice/water bath. 62.9 Parts of 1-fluoro-4-nitrobenzene were added and the whole was stirred overnight at 50° C. After cooling, the reaction mixture was poured into 2500 parts of water. The whole was washed with dichloromethane. The aqueous phase was brought to pH 5-6. The product was filtered off and stirred in 2-propanone. The product was filtered off and dried in vacuo at 60° C., yielding 60 parts (57.6%) of 1-(4-nitrophenyl)-2,4(1H,3H)-pyrimidinedione; mp.>300° C. (int. 23).
Reaction SMILES: CS(O)(=O)=O.[CH:6]([O:9][CH:10]1[C:15](OC)([O:16]C)[CH2:14][CH2:13][N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11]1)([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CC(C)=O>[CH:6]([O:9][CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][N:12]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:11]1)([CH3:8])[CH3:7]
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OC(C)C
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)OC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
Methanesulfonic acid (0.8 mL) was added to a solution of tert-butyl 3-isopropoxy-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (147b) (248 mg, 0.817 mmol) in acetone (3 mL). The mixture was stirred at room temperature overnight and further stirred at 50° C. for 35 minutes. Following cooling, saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the organic substance was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate) to obtain 111 mg of the title compound as a colorless oily substance (53%).