Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])O)O.[C:13]([O-])(O)=O.[Na+].I([O-])(=O)(=O)=O.[Na+]>C(Cl)Cl>[C:4](=[C:6]([OH:7])[CH:8]([OH:9])[CH:10]=[O:11])([CH3:2])[CH3:13]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)=C(O)C(O)C=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The mannitol derivative of Example 7(a) (81 g, 0.311 mol) was suspended in CH2Cl2 (1.1 L) and saturated NaHCO3 (40 mL) and stirred at ambient temperature. Sodium periodate (100 g, 0.47 mol) was added in four portions over 20 minutes and the solution was stirred vigorously at 0° C. for 3 hours. The solvent was decanted off and the remaining solid was stirred in CH2Cl2 and then filtered to remove the excess solid. The two organic portions were combined and concentrated in vacuo. The resulting oil was distilled at reduced pressure to give the title product as a clear, viscous oil. Yield (59 g, 75%). 1H NMR (CDCl3) δ 4.3 (t, 1 H), 3.9 (m, 2 H), 1.4 (d, 6 H).
Reaction SMILES: CC(OC([N:8]1[C:12]2=[C:13]([Cl:28])[N:14]=[CH:15][C:16]([C:17](=[O:27])[N:18]([CH3:26])[CH2:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[C:11]2[C:10]([CH3:29])=[CH:9]1)=O)(C)C.[Br:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34]>>[ClH:28].[CH3:26][N:18]([CH2:19][CH:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[C:17]([C:16]1[C:11]2[C:10]([CH3:29])=[CH:9][NH:8][C:12]=2[C:13]([NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[C:31]([Br:30])[CH:32]=2)=[N:14][CH:15]=1)=[O:27]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N(C)CC3CCOCC3)c12
Reactant: Nc1cccc(Br)c1
Product: Cc1c[nH]c2c(Nc3cccc(Br)c3)ncc(C(=O)N(C)CC3CCOCC3)c12
Product: Cl

Procedure:
Prepared in a similar manner to Example 4(d) from 7-chloro-3-methyl-4-[methyl-(tetrahydro-pyran-4-ylmethyl)-carbamoyl]-pyrrolo[2,3-c]pyridine-1-carboxylic acid dimethyl-ethyl ester (120 mg) and 3-bromoaniline. Purified by Biotage chromatography over silica gel eluting with ethyl acetate rather than trituration with diethyl ether. The salt formation was as Example 4 (d) to afford the title compound (66 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=O)[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:67]([O:69][CH:70]([O:73][CH2:74][CH3:75])[CH2:71][NH2:72])[CH3:68]>CN(C=O)C.O>[CH2:67]([O:69][CH:70]([O:73][CH2:74][CH3:75])[CH2:71][NH:72][C:29]([C:26]1[CH:25]=[C:24]([C:20]2[CH:19]=[C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])=[O:11])=[CH:33][CH:32]=3)[CH:23]=[CH:22][N:21]=2)[NH:28][CH:27]=1)=[O:31])[CH3:68]
Reactant: CCOC(CN)OCC
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (500 mg, 1.12 mmol), HATU (467 mg, 1.23 mmol) and N,N-diisopropylethylamine (322 mg, 2.5 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of aminoacetaldehyde diethyl acetal (194 mg, 1.46 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give N-(2,2-diethoxyethyl)-5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 580 mg, 92%.
Reaction SMILES: ClC(Cl)(Cl)Cl.C(#N)C.[F:9][C:10]1[CH:15]=[C:14]([C:16](Cl)=C(Cl)Cl)[C:13]([N+:21]([O-:23])=[O:22])=[CH:12][C:11]=1[C:24]([F:27])([F:26])[F:25].I([O-])(=O)(=O)=[O:29].[Na+].[OH2:34]>O.[Ru](Cl)(Cl)Cl>[F:9][C:10]1[C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][C:13]([N+:21]([O-:23])=[O:22])=[C:14]([CH:15]=1)[C:16]([OH:29])=[O:34]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1C(Cl)=C(Cl)Cl
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 300 ml of a solvent mixture of tetrachloromethane, acetonitril and water (10:10:15) are added sequentially 8.5 g (25 mmole) of 1-fluoro-4-nitro-5-trichlorovinyl-2-trifluoromethyl-benzene, 1 g (8 mol%) of ruthenium trichloride monohydrate and 23 g (0.1 mole) of sodium periodate. After stirring at 60° C. for 16 hours additional 1 g of ruthenium trichloride monohydrate and 23 g of sodium periodate are added and stirring at 60° C. is continued for 4 hours. The cooled reaction is filtered over Celite and the filtrate evaporated to dryness. 150 ml of a 1M sodium hydroxide solution are added and extracted two times with 150 ml of dichloro-methane. The aqueous phase is acidified with concentrated hydrochloric acid and extracted four times with 100 ml dichloro-methane. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The residue is recrystallized from acetone/petrolether to give 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid of m.p. 142-145° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[C:13](Cl)(=[O:15])[CH3:14]>ClCCCl>[F:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][C:11]=1[C:13](=[O:15])[CH3:14]
Reactant: Oc1cccc(F)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(O)cc1F
Temperature: 25 °C
Yield: 8.4 %

Procedure:
To a stirred suspension of aluminum chloride (42 g, 312 mmol) in 1,2-dichloroethane (100 ml) was added 3-fluorophenol (31 g, 276 mmol) dropwise at 0° C. After addition acetyl chloride (24 g, 306 mmol) was added dropwise and then the mixture was heated at reflux temperature for 16 hours. The mixture was cooled down to room temperature, and poured into ice. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with hexane to give title compound (3.57 g, 8% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[C:14]([F:15])=[CH:13][C:12](Br)=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1B(O)O.CCN(CC)CC.C[CH2:38][OH:39]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([C:19]2[O:18][C:22]3[CH:23]=[CH:24][C:25]([O:39][CH3:38])=[CH:26][C:21]=3[CH:20]=2)=[CH:11][N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CN(C(=O)OC(C)(C)C)c1ncc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2oc(-c3cnc(N(C)C(=O)OC(C)(C)C)c(F)c3)cc2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a degassed solution of (5-bromo-3-fluoro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester (310 mg, 1.01 mmol) in EtOH (10 mL) were added Pd(PPh3)2Cl2 (142 mg, 0.20 mmol), bezofuran boronic acid (291 mg, 1.52 mmol) and Et3N (283 μL, 2.03 mmol). The reaction was stirred in a microwave reactor for 30 minutes at 100° C. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography using 10% EtOAc in hexane to obtain title compound (130 mg) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.68 (br. s, 1 H) 7.80 (d, J=11.71 Hz, 1 H) 7.42 (d, J=8.98 Hz, 1 H) 7.04 (s, 2 H) 6.93 (dd, J=8.98, 2.34 Hz, 1 H) 3.85 (s, 3H) 3.35 (s, 3 H) 1.46 (s, 9 H). ESMS: m/z 359.41 (M+1)
Reaction SMILES: FC(=C)C([O-])=O.[F:7][C:8]([F:31])([C:12]([F:30])([F:29])C(F)(F)C(F)(F)[C:15]([F:24])([F:23])[C:16](F)([F:21])[C:17]([F:20])([F:19])[F:18])C([O-])=O.[NH4+]>O>[F:7][C:8]([F:31])=[C:12]([F:30])[F:29].[F:18][C:17]([F:20])([F:19])[C:16]([F:21])=[C:15]([F:24])[F:23]
Reactant: O=C([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C=C(F)C(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: FC(F)=C(F)C(F)(F)F
Product: FC(F)=C(F)F
Reaction time: 3.9 h

Procedure:
In a 2-liter reactor were added 1000 gram of deionized water, 70 gram of fluoroacrylate (Zonyl TA-N from dupont), 130 gram of ammonium perfluorooctanoate (Fluororad FC-143, 3M). The mixture is a transparent microemulsion at 50° C. and maintained at a stirring speed of about 1200 rpm. The rector was then vacuumed and purged with tetrafluoroethylene gas three times to ensure oxygen content in the mixture to be below 30 ppm. Then the temperature of the mixture was raised and maintained to be about 90° C. A mixture of tetrafluoroethylene and hexafluoropropylene gas was charged to the reactor and the pressure inside the reactor was about 1500 kPa, in which the mole ratio of tetrafluoroethylene to hexafluoroethylene is about 70:30. Then, 0.4 gram of ammonium persulfate in 40 gram of water was pumped into the reactor to start the reaction. Reaction proceeded for about 234 minutes and was stopped. At the end of the reaction, the pressure of the reactor was about 600 kPa.
Reaction SMILES: [H][H].O.[CH3:4][O:5][C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([O:15][CH3:16])[C:9]([N+:17]([O-])=O)=[CH:8][C:7]=1[Cl:20]>[Fe].C(O)(=O)C>[ClH:20].[CH3:4][O:5][C:6]1[C:11]([NH2:12])=[C:10]([O:15][CH3:16])[C:9]([NH2:17])=[CH:8][C:7]=1[Cl:20]
Reactant: [H][H]
Reactant: COc1c(Cl)cc([N+](=O)[O-])c(OC)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(N)cc(Cl)c(OC)c1N
Product: Cl
Temperature: 80 °C

Procedure:
100 g of powdered iron which had been reduced with hydrogen were added to 270 ml of water containing 27 ml of acetic acid which had been previously heated to 80° C., and then 0.25 mole (66 g) of 2,4-dimethoxy-3,5-dinitrochlorobenzene was added gradually, with stirring. Upon completion of the additions, the reaction mixture was maintained in a boiling water bath for 30 additional minutes. After cooling, the reaction mixture was centrifuged. The iron slurries which contained the expected product were taken up with acetone under vigorous mixing. Upon filtration of the iron slurries followed by washing with acetone, the expected product precipitated from the acetone filtrate upon addition of a hydrochloric acid solution in ethanol. After thorough draining and washing, the expected product was recrystallized while hot from a hydrochloric acid and water mixture.
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:6]1[CH:7]=[CH:8][C:3]([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1(c2ccc(Br)cc2)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
At 5° C. bromine (1.5 mL, 30 mmol) is added dropwise to a solution of 1-phenyl-1-cyclopropylcarboxylic acid (5 g, 30 mmol) and sodiumacetate (2.7 g, 33 mmol) in 30 mL glacial acetic acid. Then the mixture is heated to 50° C. and stirred for 2 days. The reaction mixture is diluted with 100 mL water, and the precipitate formed is filtered off and washed with 50% acetic acid. Yield: 5.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1CNC(=O)C1.[Br:22][Br-]Br>O1CCCC1>[Br:22][CH2:14][C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: COc1cc(C(=O)CBr)cc(OC)c1OC
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
3',4',5'-Trimethoxyacetophenone (15.0 g) and pyrrolidone hydrotribromide (35.39 g) were dissolved in tetrahydrofuran (225 ml), followed by stirring at 40° C. for one hour. The reaction solution was cooled to room temperature, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained crude crystals were washed with hexane (100 ml) to give 2-bromo-3',4',5'-trimethoxyacetophenone (Compound VII-1, 12.2 g).
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C@@H:7]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][CH:25]=1.[OH-:36].[Na+].N1C=CN=C1.[Si:43](Cl)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>O1CCOCC1.CN(C)C=O>[C:18]([O:17][C:16]([NH:15][C@@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@@H:5]([O:6][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:4][CH:3]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][CH:25]=1)[C:2]([OH:36])=[O:1])=[O:22])([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccn3)cc2)C(=O)O1
Reactant: [OH-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](CC(Cc1ccc(-c2ccccn2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A solution of the product from Example 1A (21.4 g) in dioxane (100 mL) was treated with sodium hydroxide solution (57 mL, 1N), stirred at 25° C. for 30 minutes and concentrated. The concentrate was cooled to 0° C., and acidified to pH 5 with 4N HCl. The mixture was partitioned between dichloromethane and water, and the organic phase layer was washed with brine, dried over MgSO4, filtered and concentrated. A solution of the residue in N,N-dimethylformamide (100 mL) was treated with imidazole (21 g, 308.5 mmol) and t-butyldimethylsilyl chloride (23 g, 152.6 mmol), stirred at 25° C. for 16 hours and concentrated. The residue was combined with ice and acidified with 4N HCl to pH 3. Ethyl acetate (50 mL) was added to permit stirring during the acidification. The mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel eluting with a gradient of 200%-100% ethyl acetate in chloroform, followed by elution with 5% methanol in ethyl acetate to give the title product (11.3 g, 49% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12](O)=[O:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1.[Cl:25][C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[Cl:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:12]([C:10]2[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]3=[N:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:4]=[C:5]3[CH:11]=2)=[O:13])=[CH:28][N:27]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Reactant: Nc1cnc(Cl)nc1
Product: O=C(Nc1cnc(Cl)nc1)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Yield: 22.9 %

Procedure:
According to a method similar to that described in Stage 1.4, starting from 1.08 g (3.2 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, described in Stage 1.3, and 0.46 g (3.52 mmol) of 2-chloro-5-aminopyrimidine, we obtain 0.33 g of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[O:25]1[CH2:29][C:28](=O)[N:27]=[C-:26]1.[H-].[Na+].[O:33]1CCOCC1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][N:27]2[CH2:28][CH2:29][O:25][C:26]2=[O:33])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Reactant: C1COCCO1
Reactant: O=C1CO[C-]=N1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CN2CCOC2=O)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
[3-(2-Bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.15 g, 0.36 mmol), 2-oxazolidone (0.063 g, 0.72 mmol), and sodium hydride (60% in mineral oil; 0.03 g, 0.72 mmol) were combined in 1,4-dioxane (10 mL) and stirred at 80° C. for 2 hours. The mixture was cooled to room temperature to give the title compound, which was used directly as a crude solution in the hydrolysis step.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[OH:8][C@@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[C:22](=[O:28])[CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:29]([OH:31])=[O:30])[CH2:10]1.ClCC#N>CC(C)=O>[C:6]([CH2:7][O:31][C:29]([C@H:18]1[CH2:17][CH2:16][C@H:15]2[C@H:14]3[C@H:23]([C:22](=[O:28])[CH2:21][C@:19]12[CH3:20])[C@:24]1([CH3:27])[C@H:11]([CH2:10][C@H:9]([OH:8])[CH2:26][CH2:25]1)[CH2:12][CH2:13]3)=[O:30])#[N:3]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCC#N)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 4 h

Procedure:
Triethylamine (4.5 mmole) was added to a solution of 3α-hydroxy-5α-androstan-11-one 17β-carboxylic acid (1.025g.) in warm acetone (50 ml.) followed by chloroacetonitrile (6 mmole). After refluxing this mixture for 3 hr. further chloroacetonitrile (6 mmole) was added and refluxing continued for 4 hr. Removal of the solvent afforded a residue which was partitioned between ether and water. The ethereal solution was washed with water, dried (MgSO4) and evaporated, to give a foam (1.187g.) which was purified by preparative t.l.c. to afford the pure title compound; m.p. 142°-146°; [α]D + 74°,.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]1[N:16]=[C:17]([C:21]([O:23]CC)=O)[NH:18][C:19](=[O:20])[C:8]1=[CH:7]2>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]1[N:16]=[C:17]([C:21]([NH2:1])=[O:23])[NH:18][C:19](=[O:20])[C:8]1=[CH:7]2
Reactant: N
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Solvent: CCO
Product: COc1cc2cc3c(=O)[nH]c(C(N)=O)nc3nc2cc1OC
Temperature: 95 °C

Procedure:
Anhydrous ammonia is bubbled into a mixture of ethyl 7,8-dimethoxy-pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (300 mg., 9.00 millimoles) in absolute ethanol (75 ml.) for 15 minutes. A clear solution formed, followed, after a few minutes, by formation of a precipitate. The reaction mixture is transferred to a pressure bomb (Monel) and heated in a 95° C. oil bath overnight. The bomb is then cooled to room temperature and the contents removed. The bomb is washed with ethanol and the combined reaction mixture plus wash filtered to recover the product. The filter cake is washed with ethanol and then dried in air. Yield = 260 mg. (95%); m.p. 310° C. (dec.)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[CH:10][C:2]1=2.CC(OC(C)=O)=O.[N+:23]([O-])([OH:25])=[O:24]>CC(O)=O>[N+:23]([C:9]1[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:3]2[O:4][CH2:5][CH2:6][O:1][C:2]=2[CH:10]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)c1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 50 °C
Yield: 99 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of ethyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.42 g, 6.8 mmol) and Ac2O (3 mL), in AcOH (15 mL) was dropped fuming nitric acid (1 mL). The reaction was heated at 50° C. for 2 hours, to afford ethyl 7-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as a solid (1.720 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H), 7.18 (s, 1H), 4.36 (m, 6H), 1.33 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([F:16])[CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([C:18]([F:28])([F:17])[F:27])=[CH:24][CH:23]=3)[C:6]3[CH:11]([F:16])[CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1Cc2c([nH]c3ccc(Cl)cc23)C(F)C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1Cc2c(n(CCc3ccc(C(F)(F)F)nc3)c3ccc(Cl)cc23)C(F)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-4-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]2[CH2:16][CH2:17][CH:7]1[C:8]1[CH:9]=[C:10]([NH2:18])[CH:11]=[CH:12][C:13]=1[CH2:14]2)=[O:5])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1.Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[CH2:1]([O:3][C:4]([N:6]1[CH:15]2[CH2:16][CH2:17][CH:7]1[C:8]1[CH:9]=[C:10]([NH:18][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=4[C:29](=[O:30])[NH:31][CH3:32])[C:23]([Cl:37])=[CH:22][N:21]=3)[CH:11]=[CH:12][C:13]=1[CH2:14]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1c1cc(N)ccc1C2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)N1C2CCC1c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc1C2
Temperature: 140 °C
Yield: 49.3 %

Procedure:
4-Amino-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid ethyl ester (J. Med. Chem. 1988, 31, 433-444)(30 mg, 0.12 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (36 mg, 0.12 mmol) were combined with 4 N HCl (0.030 mL, 0.12 mmol) in isopropanol (1 mL). The resulting mixture was heated in a microwave at 140° C. for 30 min. The resulting mixture was then made basic with saturated aqueous NaHCO3, extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered, and concentrated. The resulting residue was purified with silica gel chromatography (0-100% EtOAc in hexanes) to obtain 4-[5-Chloro-4-(2-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-triene-12-carboxylic acid ethyl ester as a yellow solid (30 mg, 49%). 1HNMR (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 9.4 (s, 1H), 8.8 (d, 1H, J=4.6 Hz), 8.7 (d, 1H, J=8.1 Hz), 8.2 (s, 1H), 7.8 (d, 1H, J=7.1 Hz), 7.7-7.5 (m, 2H), 7.4 (m, 1H), 7.1 (t, 1H, J=7.1 Hz), 7.0 (d, 1H, J=8.3 Hz), 4.7 (m, 1H), 4.4 (m, 1H), 4.1-3.9 (m, 2H), 3.2 (d, 1H, J=14.1H), 2.8 (d, 3H, J=4.6 Hz), 2.2-2.0 (m, 2H), 1.7 (t, 1H, J=9.4 Hz), 1.6 (m, 1H), 1.2 (m, 1H), 1.2-1.0 (m, 3H); MS (m/e) 507 (M+1); mp 140-144° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[S:8])[O:6][CH:7]=1)[CH3:2].C(N1C(=O)C2=CC=CC=[C:13]2[C:12]1=[S:21])C>>[CH2:1]([C:3]1[N:4]=[C:5]([S:8][S:21][CH2:12][CH3:13])[O:6][CH:7]=1)[CH3:2]
Reactant: CCc1coc(=S)[nH]1
Reactant: CCN1C(=O)c2ccccc2C1=S
Product: CCSSc1nc(CC)co1

Procedure:
Starting from 4-ethyl-2-thiono-4-oxazoline and N-ethylthiophthalimide there is obtained (4-ethyl-2-oxazolyl)ethyl-disulphide. nD20 =1.5549. IR (liq.): bands inter alia at 3000, 2970, 1590, 1485, 1250, 1135, 1080, 950, 760 cm-1.