Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCOCC>[CH2:24]([O:23][C:21]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1)=[O:22])[CH3:25]
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cc(C)nc(C(Cl)(Cl)Cl)n1
Yield: 67 %

Procedure:
To a solution of 3.0 g (0.013 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 1.4 g (0.013 mole) triethylamine, and 75 ml ether was added 1.4 g (0.013 mole) ethyl chloroformate. The reaction mixture was refluxed for 2 hours, filtered, and rotary evaporated under aspiration to give a dark oil. This was triturated with petroleum ether and the solution decanted from tars. The solvent was stripped in vacuo and the product distilled to give 2.7 g (67% yield; bp0.5 mm 125° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][OH:31])[O:27][C:26]5=[O:32])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCCCCC.CCO>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:20][CH2:19][N:18]3[C@H:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N:25]5[CH2:29][C@H:28]([CH2:30][OH:31])[O:27][C:26]5=[O:32])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)N1CCN2c3ccc(N4C[C@H](CO)OC4=O)cc3OCC2C1
Solvent: CCO
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)N1CCN2c3ccc(N4C[C@H](CO)OC4=O)cc3OC[C@@H]2C1

Procedure:
A solution of 50 mg/mL of a mixture of diastereomers 1, 2, 4a, 5-Tetrahydro-8-[5-(R)-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-pyrazino[2, 1-c][1, 4]benzoxazine-3(4 H)-carboxylic acid phenylmethyl ester (EXAMPLE 1, Step 8) is made in the mobile phase that consisted of 35% EtOH in hexane (V/V). The solution (200 mg) is injected into a 5.1×50 cm Chiralcel OD column at 30° C. The column is eluted at 45 ml/min and monitored at 305 nm. The two diastereomers are collected using a peak recognition program and fractions are pooled appropriately. Each diastereomer is obtained at >98% diastereomer excess. Diastereomeric excess is determined on a 0.46×25 cm Chiralcel OD-H column at ambient column temperature, using the mobile phase consisted of 0.1% TEA in EtOH and the monitor set at 218 nm detection. The retention times are 58.9 and 65.6 minutes. (α=1.14; 0.2 mL/min).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([C:21]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][C@@H:33]2[C:37](O)=[O:38])=[O:31])=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:37]([C@H:33]3[CH2:34][CH2:35][CH2:36][N:32]3[C:30]([C@@H:26]3[CH2:27][CH2:28][CH2:29][N:25]3[C:23](=[O:24])[CH2:22][C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)=[O:31])=[O:38])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)[C@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1CCN(CC2CCCCC2)CC1
Product: O=C(NC1CCN(CC2CCCCC2)CC1)[C@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by a method similar to Step 5 of Example 1, using 1-cyclohexylmethyl-4-piperidinamine (JP 52122378) and (2R)-1-{(2S)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxylic acid. The compound was obtained as a white solid.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:15])([F:14])[C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]>O>[N+:10]([C:9]1[CH:8]=[CH:7][C:6]([NH2:1])=[CH:5][C:4]=1[C:3]([F:15])([F:14])[F:2])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: N
Solvent: O
Product: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
A solution of ammonia in water (100 cm3, s.g. 0.88) was added to 3-trifluoromethyl-4-nitrofluorobenzene (5 g) and the mixture was heated in a bomb at 150° for 2 hours. Solvent was removed in vacuo to yield a yellow solid. Recrystallisation of this solid from hexane/ethyl acetate afforded yellow crystals of 4-nitro-3-trifluoromethylaniline, m.p. 134°, (3.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.C(NC(C)C)(C)C.C[Si](C)(C)[C:38]#[C:39][C:40]1([CH3:44])[CH2:43][O:42][CH2:41]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I.CN(C=O)C>[F:24][C:23]([F:26])([F:25])[C:22]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[C:2]([C:38]#[C:39][C:40]2([CH3:44])[CH2:43][O:42][CH2:41]2)[CH:3]=1)([OH:28])[CH3:27]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)c(Br)c1)C(F)(F)F
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC1(C#Cc2cc(C(C)(O)C(F)(F)F)ccc2N2CCN(S(=O)(=O)c3cccs3)CC2)COC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A 20 mL vial was charged with 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (0.500 g, 1.00 mmol), diisopropylamine (2.14 mL, 15.0 mmol), 2 mL of DMF, tetrakis(triphenylphosphine)palladium (0) (0.116 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), copper (I) iodide (0.019 g, 0.100 mmol, Strem Chemical Inc, Newburyport, Mass.), and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.506 g, 3.00 mmol, published PCT patent application no. WO2010030954). The vial was sealed and heated at 100° C. for 3 h. After that time, an additional 20 mol % of both tetrakis(triphenylphosphine)palladium (0) and copper (I) iodide were added and heating was continued for an additional 12 h. The mixture was concentrated and purified by column chromatography (40 g of silica, 0 to 60% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g) as a mixture of two enantiomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[N:18]2[C:13]([CH:14]=[N:15][C:16](S(C)=O)=[N:17]2)=[CH:12][CH:11]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[N:18]2[C:13]([CH:14]=[N:15][C:16]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([NH2:38])=[O:37])[CH2:33][CH2:34]4)=[CH:25][CH:24]=3)=[N:17]2)=[CH:12][CH:11]=1
Reactant: COc1cccc(F)c1-c1ccc2cnc(S(C)=O)nn12
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Product: COc1cccc(F)c1-c1ccc2cnc(Nc3ccc(C4CCN(CC(N)=O)CC4)cc3)nn12
Reaction time: 6 h

Procedure:
Following the synthetic and purification procedures of Example 1291c, 7-(2-Fluoro-6-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (79 mg, 0.26 mmol) was coupled to 2-[4-(4-amino-phenyl)-piperidin-1-yl]-acetamide (91 mg, 0.39 mmol) in a sealed vial at 125° C. for 96 h followed by 6 h in a microwave reactor at 170° C. Yield of
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20]([C:22]([C:27]#[N:28])=[CH:23]OCC)#[N:21]>C(O)(=O)C>[NH2:28][C:27]1[N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[C:3]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:2]2[N:1]=[CH:23][C:22]=1[C:20]#[N:21]
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CCOC=C(C#N)C#N
Solvent: CC(=O)O
Product: N#Cc1cnc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1N
Yield: 59.3 %

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (100 mg) and 1,1-dicyano-2-ethoxyethylene (49 mg) in acetic acid (2 ml) was refluxed for 1 hour. The reaction mixture was concentrated in vacuo and the residue was crystallized from ethanol to give 7-amino-6-cyano-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (77 mg).
Reaction SMILES: Br.Br[CH:3]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=O.C(N(CC)CC)C.[NH2:24][C:25]([NH2:27])=[S:26].C(=O)([O-])O.[Na+]>C(O)C>[NH2:27][C:25]1[S:26][C:3]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[N:24]=1
Reactant: O=C(c1ccco1)C(Br)c1ccncc1
Reactant: NC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(-c2ccco2)c(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-1-(2-furyl)-2-(4-pyridyl)ethanone hydrobromide (7.59 g, 21.9 mmol) was suspended in ethanol (110 mL), and triethylamine (3.35 mL, 24.1 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Thiourea (1.83 g, 24.1 mmol) was added to the reaction mixture, followed by stirring under heating and reflux for 30 minutes. The reaction mixture was allowed to cool down to room temperature, and then a saturated aqueous solution of sodium hydrogencarbonate was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=10:1) to afford the entitled Compound a (5.10 g, 96%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].C(OC([N:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26]OS1(=O)=O)=O)(C)(C)C>>[NH2:23][C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3](=[O:4])[C:2]([F:1])([F:14])[F:15])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=C(c1ccc2[nH]ccc2c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Product: CC(C)(N)CCn1ccc2cc(C(=O)C(F)(F)F)ccc21

Procedure:
Prepared analogously to Component V by alkylation of 2,2,2-trifluoro-1-(1H-indol-5-yl)-ethanone with N-tert-butoxycarbonyl-4,4-dimethyl-[1,2,3]oxathiazinane-2,2-dioxide (Component XI) and subsequent cleaving of the acid protecting group.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([O:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([F:30])[CH:8]=1)(=[O:5])=[O:4].C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:35])C>C(O)(=O)C.C(OC(=O)C)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:2]([F:1])([F:31])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:35])[C:10]([C:13]2[N:14]=[N:15][C:16]([O:19][CH:20]3[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:28])([CH3:29])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([F:30])[CH:8]=1)(=[O:4])=[O:5]
Reactant: CC1(C)CC(Oc2ccc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3F)nn2)CC(C)(C)N1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CC(Oc2ccc(-c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3F)nn2)CC(C)(C)N1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
3-Fluoro-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate (0.48 g, 1.01 mmol), PhI(OAc)2 (0.46 g, 1.41 mmol), and Pd(OAc)2(68 mg, 0.10 mmol) were dissolved in a mixture of acetic acid (4 mL) and acetic anhydride (4 mL). The mixture was stirred at 80° C. for 3 h. The crude reaction was purified by catch and release using SiliaBond Propylsulfonic Acid® (5 eq, CH3CN as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo and 3-fluoro-5-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate was afforded as a green solid (0.50 g, 100%). [M+H]: 494.3; 1H NMR (400 MHz, MeOD) δ 8.09 (t, J=8.5 Hz, 1H), 7.99 (dd, J=9.5, 2.5 Hz, 1H), 7.50 (dd, J=10.5, 2.5 Hz, 1H), 7.45 (dd, J=8.5, 2.5 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 5.82 (tt, J=11.0, 4.0 Hz, 1H), 2.24 (dd, J=12.5, 4.0 Hz, 2H), 1.43 (t, J=12.0 Hz, 2H), 1.36 (s, 6H), 1.25 (s, 6H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:20]([C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)#[C:21][CH3:22]>C(NCC)C.[Cu](I)I>[CH2:20]([C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]#[C:10][C:7]3[CH:6]=[CH:5][C:4]([C:1]#[C:2][CH3:3])=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[CH2:25][CH2:24]1)[CH2:21][CH3:22]
Reactant: CC#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(CC[C@H]2CC[C@H](CCC)CC2)cc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CC#Cc1ccc(C#Cc2ccc(CC[C@H]3CC[C@H](CCC)CC3)cc2)cc1

Procedure:
4-[2-(Trans-4-propylcyclohexyl)ethyl]phenylacetylene (2.54 g, 0.01 mol) and 4-(1-propynyl)iodobenzene (2.4 g, 0.01 mol) were dissolved in diethylamine (20 ml), and then copper iodide (0.11 g, 0.15 mmol) and dichlorobistriphenylphosphinepalladium dichloride (0.21 g, 0.3 mmol) were added. The resulting mixture was subjected to reaction and purification operations in the same manner as in Example 1, to obtain the objective 4-[2-(trans-4-propylcyclohexyl)ethyl]-4'-(1-propynyl)tolan (compound
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24]1>C(#N)C>[NH2:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:8]([C:12]([NH:14][CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=3[N:3]=2)[CH2:24]1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: N[C@H]1CCNC1
Solvent: CC#N
Product: N[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 100 °C

Procedure:
A stirred suspension of 2,6-dichloro-N-(cyclohexylmethyl)quinoline-5-carboxamide (Example 43(a)) (500 mg) and (3S)-3-pyrrolidinamine (0.60 mL) in acetonitrile (3 mL) was heated at 100° C. in a microwave for 40 minutes after which it was cooled to room temperature and concentrated. Purification by chromatography (SiO2, dichloromethane:methanol:ammonia in methanol (7 M) 95:5:0.5 as eluant) and subsequent recrystallisation (acetonitrile) afforded the title compound as a solid (280 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:4]=1/[CH:5]=[CH:6]/[S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])[CH:16]=1)(=[O:9])=[O:8].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:4]=1/[CH:5]=[CH:6]/[S:7]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:24][CH3:25])=[C:15]([NH:17][CH:18]([CH3:23])[C:19]([OH:21])=[O:20])[CH:16]=1)(=[O:8])=[O:9]
Reactant: COC(=O)C(C)Nc1cc(CS(=O)(=O)/C=C/c2c(OC)cc(OC)cc2OC)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(NC(C)C(=O)O)c2)c(OC)c1

Procedure:
To a solution of methyl(E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)propanoate (0.1 mol) in ethanol (200 mL), was added sodium hydroxide (20% aqueous solution, 200 mL). The resulting mixture was heated at reflux for 2.5 h. The reaction was monitored by TLC. When the reaction was complete, the volatiles were removed under vacuum and the resulting residue was acidified to pH 4 by addition of acetic acid. A solid precipitate formed. The precipitate was separated by filtration. The filtered solid was recrystallized twice from acetone to provide the desired (E)-2-(5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenylamino)propanoic acid. m.p. 176-180° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]1=[O:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>O1CCCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]2=[O:27])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CCN(CC)C(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CN1C(=O)C(NC(=O)Nc2cccc(OC)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3-amino-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 222°-224° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13]>C(O)(=O)C>[CH3:13][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[Br:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1Br
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Fuming nitric acid (>90% yellow fuming HNO3) is slowly added to a solution of 2-bromo-m-xylene (20 g, 150 mmol) in acetic acid (100 ml) cooled in an ice bath (above freezing point). The resulting mixture is allowed to warm to room temperature, stirred for 1 hour, and heated at 80° C. for 2 hours or until the reaction is shown to be complete by GC/MS analysis following micro-scale base work-up. The reaction mixture is cooled to room temperature and poured into ice/water with stirring. The resulting yellow precipitates are collected by suction filtration and air dried to obtain 2,6-dimethyl-3-nitrobromobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][OH:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C=O)oc23)c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(CO)oc23)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
1.5 g (3.8 mmol) of 3-(4-chloro-6-fluoro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 10 ml of tetrahydrofuran, and 4.5 ml of diisobutylaluminum hydride (0.94M hexane solution) was dropwise added thereto in a nitrogen stream at 5° C. After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 1.4 g (yield: 90.7%) of the desired product as pale yellow crystals. Melting point: 198-199° C.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35]C(N)=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:14]([N:12]3[C:3](=[O:4])[C:5]4[S:6][C:7]([C:15]([CH:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)=[O:16])=[CH:8][C:9]=4[N:10]=[CH:11]3)=[CH:33][CH:32]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)c1sc(C(=O)C2CCOCC2)cc1N=CN(C)C
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Product: CN1CCCN(c2ccc(-n3cnc4cc(C(=O)C5CCOCC5)sc4c3=O)cc2)CC1

Procedure:
3-(Dimethylaminomethyleneamino)-5-(tetrahydropyran-4-carbonyl)thiophene-2-carboxylic acid methyl ester and 4-(4-methyl[1,4]diazepan-1-yl)phenylamine were reacted by method A1. The product with the molecular weight of 452.58 (C24H28N4O3S) was obtained in this way; MS (EST): 453 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[N:9]=[C:5]2[CH:4]=1
Reactant: COc1ccnc(N)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2cc(OC)ccn12
Yield: 134.5 %

Procedure:
A mixture of 4-methoxy-2-aminopyridine (1.07 g, 8.6 mmol) and ethyl 2-chloroacetoacetate (5.4 g) in EtOH (50 mL) was refluxed for 24 h. The reaction mixture was then concentrated to half its volume, extracted with CH2Cl2, washed with brine and then water, and dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified on a silica gel column eluting with EtOAc and then MeOH/CH2Cl2 (1:9) to give ethyl 7-methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate (2.71 g, 90%).
Reaction SMILES: [CH:1]1[NH:2][C:3](=[O:12])[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7][CH2:6]2.[CH3:13]I>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:13][N:2]1[C:3](=[O:12])[CH:4]=[C:5]2[C:10]([C:9](=[O:11])[CH2:8][CH2:7][CH2:6]2)=[CH:1]1
Reactant: O=C1CCCc2cc(=O)[nH]cc21
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Cn1cc2c(cc1=O)CCCC2=O

Procedure:
The novel compounds of the present invention originate from a novel process which utilizes dihydroresorcinol as the starting material. That substance thus is allowed to react with a chlorinating reagent such as phosphorus trichloride to afford 3-chloro-2-cyclohexen-1-one. Reaction with cycnoacetamide and sodium hydride results in α-cyano-3-oxo-1-cyclohexen-1-acetamide, which is contacted with a dialkylformamide acetal, for example dimethylformamide diethyl acetal or dimethylformamide dineopentyl acetal, to produce 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarbonitrile. Elimination of the cyano group is effected by heating with hydrobromic acid, thus affording 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione. Heating with an alkyl or cycloalkyl halide produces the corresponding 6-alkoxy and 6-cycloalkoxy 7-aza-1-tetralones together with the N-alkylated or N-cycloalkylated derivatives. Typically, 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione is heated in benzene at the reflux temperature with methyl iodide and silver carbonate to yield 7-aza-6-methoxy-1-tetralone together with 2-methyl-2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([CH3:21])[C:13]([N:18]=[C:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=1.CCOC(C)=O>CSC>[CH3:21][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20]
Reactant: Cc1ccccc1N=C=O
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CSC
Solvent: CCOC(C)=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Reaction time: 1 h

Procedure:
To a suspension of p-aminophenylacetic acid (56.8 g, 376 mmol) in DMS (150 mL) was added o-tolyl isocyanate (50 g, 376 mmol) dropwise. The reaction mixture was allowed to stir 1 h, and was poured into EtOAc (1.75 L) with stirring. The precipitate was collected and washed with EtOAc (400 mL) and MeCN (400 mL) to provide oMePUPA (80 g, 75%). ESMS M/z (M+H+) 285.1.