Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[F:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH2:22][CH2:21][CH2:20][F:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NCCCF
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCCCF

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 3-fluoro-propylamine following general procedure B to afford 4-(3-fluoro-propylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (262 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (196 mg) following general procedure E. The above ethylamide (0.64 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-1-(3-fluoro-propyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (138 mg). LCMS: m/z 332 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:14]([CH3:16])[C:8]([CH:9](O)[C:10]([OH:12])=[O:11])=[C:7]([CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(C1C=C(C)C(C(O)C(O)=O)=C(C)C=1)(C)(C)C.Cl>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH3:17])[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[C:14]([CH3:16])[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1C(O)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C(C)(C)C)cc(C)c1CC(=O)O
Temperature: 100 °C
Yield: 86 %

Procedure:
A mixture of 2.89 g of 4-tert-butyl-2,6-dimethylmandelic acid and 7.75 g of 4-tert-butyl-2,6-dimethylmandelic acid acetate, 4.5 g of 37% strength hydrochloric acid, 1.86 g of red phosphorus and 0.66 g of KI in 30 ml of glacial acetic acid is heated at 100° C. for 16 hours. Excess phosphorus is filtered off with suction and washed three times with in each case 10 ml of glacial acetic acid. The filtrate is substantially concentrated on a rotary evaporator at a bath temperature of 50° C./60 mbar. The resulting residue is diluted with 25 ml of water and, by addition of 10% strength aqueous sodium hydroxide solution, dissolved. This solution is extracted twice with in each case 20 ml of MTBE and then adjusted to pH 1 using 48% strength sulfuric acid. The resulting greasy solid is taken up in methylene chloride. This solution is extracted with 25 ml of water, dried over sodium sulfate and concentrated using a rotary evaporator. This gives 7.66 g of 4-tert-butyl-2,6-dimethylphenylacetic acid in a purity of 99.0 GC area % (yield about 86% of theory).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]([CH2:21][CH2:22][CH2:23][CH:24]([O:30]C(=O)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([S:17]([CH3:20])(=[O:19])=[O:18])C(OCC)=O)=[O:4].[Cl-].[Na+].C(=O)=O>CCOCC.O.CS(C)=O>[CH3:20][S:17]([CH:11]([CH2:21][CH2:22][CH2:23][CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3]([OH:4])=[O:2])(=[O:18])=[O:19]
Reactant: CCCCCC(CCCC(CC#CCCCC(=O)OC)(C(=O)OCC)S(C)(=O)=O)OC(C)=O
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(O)CCCC(CC#CCCCC(=O)O)S(C)(=O)=O

Procedure:
A solution of ethyl 2-(6-methoxycarbonyl-2-hexyn-1-yl)-2-(4-acetoxynonyl)-2-(methylsulfonyl)-acetate (48.8 g., 0.1 mole), water (3.6 g., 0.2 mole), and sodium chloride (6.5 g., 0.11 mole) in 120 ml. of dimethyl sulfoxide is heated at 130°-150° C. for 6 hours until evolution of carbon dioxide is completed. The mixture is cooled, treated with 400 ml. of water and the oily product taken up in ether, washed with water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a yellow viscous oil.
Reaction SMILES: C([O:5][C:6]([C@H:8]([OH:33])[C@H:9]([NH:18][C:19]([CH2:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[O:7])CCC.C1COCC1.[OH-].[Na+]>CC(O)=O>[C:6]([C@H:8]([OH:33])[C@H:9]([NH:18][C:19]([CH2:21][CH2:22][CH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])([OH:7])=[O:5]
Reactant: CCCCOC(=O)[C@H](O)[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(CCCc1ccccc1C(=O)O)N[C@H](Cc1ccccc1Cl)[C@@H](O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
2-{3-[(1R,2R)-2-Butoxycarbonyl-1-(2-chloro-benzyl)-2-hydroxy-ethylcarbamoyl]-propyl}-benzoic acid (110 mg, 230 μmol, 1.0 eq.) was combined with THF (2.1 mL), and 1 M aqueous NaOH (480 μL, 2.0 eq.). The mixture was stirred at room temperature for 1 hour. Upon completion of the reaction was completed, AcOH (1 mL) was added and the product was purified by preparative HPLC. The clean fractions were combined and lyophilized to yield the title compound (95 mg, 99% purity). MS m/z [M+H]+ calc'd for C21H22ClNO6, 420.11. found 420.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[N:18][NH:19][CH:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:31]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=4)=[N:18][N:19]([CH3:31])[CH:20]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Nc2nccc(-c3c[nH]nc3-c3ccc(C(F)(F)F)cc3)n2)c1
Reactant: CO
Product: COc1cccc(Nc2nccc(-c3cn(C)nc3-c3ccc(C(F)(F)F)cc3)n2)c1

Procedure:
The title compound is prepared as described in Example 55 starting from (3-methoxy-phenyl)-{4-[3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4yl]-pyrimidin-2-yl}-amine (Example 87) and using methanol instead.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:33][CH3:34])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]3[C:28]([O:30][CH3:31])=[O:29])=[O:14])=[CH:8][C:7]=2[CH:32]=1.[ClH:35].C(OCC)(=O)C>>[ClH:35].[CH3:1][O:2][C:3]1[C:4]([O:33][CH3:34])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH:16]3[C:28]([O:30][CH3:31])=[O:29])=[O:14])=[CH:8][C:7]=2[CH:32]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)C1CNCCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Reaction time: 5 h

Procedure:
To a solution of 4.5N HCl-ethyl acetate solution (10 ml) is added methyl 1-(2,3-dimethoxy-6,7-dihydro- 5H-benzocyclohepten-8-ylcarbonyl)-4-tert-butoxycarbonylpiperazine-2-carboxylate (1.7 g). The reaction mixture is left standing at room temperature for 5 hours. Then the solvent is distilled off under reduced pressure. To the residue is added ethyl ether. Resulting precipitates are collected and dried to afford methyl 1-(2,3-dimethoxy-6,7-dihydro-5H-benzo-cyclohepten-8-ylcarbonyl}piperazine-2-carboxylate hydrochloride as colorless powder (1.2 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][OH:29])=[CH:23][CH:22]=2)=[O:18])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:34]([O:33][C:32](=[O:38])[NH:31][CH:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=1)[C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][OH:29])=[CH:23][CH:22]=1)=[O:18])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OCc2ccccc2)cn1)C(=O)NCc1ccc(C(=O)NO)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(O)cn1)C(=O)NCc1ccc(C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
A mixture of t-butyl 3-(5-(benzyloxy)pyridin-2-yl)-1-(4-(hydroxyl-carbamoyl)benzylamino)-1-oxopropan-2-ylcarbamate (Compound 7) (0.26 g, 0.5 mmol) and 26 mg of 10% Pd/C in 2 mL of methanol was vigorously stirred under H2 for 4 h at room temperature and then filtered through Celite. The solvent was evaporated. The residue was purified by chromatography to give oily Compound 9 (0.16 g, 73%). NMR (400 MHz in CDCl3, Bruker AVANCE-400) : 1.28 (s, 9H, Boc), 3.15 (m, 2H, CH2), 4.28 (t, 2H, CH2, J=5.12 Hz), 4.36 (m, 1H, CH), 7.05-7.25 (m, 4H, Ar—H), 7.64-7.84 (m, 3H, Ar—H), 8.23 (br, 1H, NH), 8.51 (br, 1H, NH), 10.18 (br, 1H, NH), 11.16 (br, 1H, OH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1)[NH2:5].Cl[C:15]1[N:20]=[C:19]([CH:21]2[CH2:23][CH2:22]2)[C:18]([F:24])=[CH:17][N:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]1([C:19]2[C:18]([F:24])=[CH:17][N:16]=[C:15]([NH:5][C:4]3[CH:6]=[C:7]([C:9]4[S:13][CH:12]=[N:11][CH:10]=4)[CH:8]=[C:2]([F:1])[CH:3]=3)[N:20]=2)[CH2:23][CH2:22]1
Reactant: Fc1cnc(Cl)nc1C1CC1
Reactant: Nc1cc(F)cc(-c2cncs2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Product: Fc1cc(Nc2ncc(F)c(C3CC3)n2)cc(-c2cncs2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
3-Fluoro-5-(1,3-thiazol-5-yl)aniline (0.91 g, 4.69 mmol), 2-chloro-4-cyclopropyl-5-fluoropyrimidine (0.809 g, 4.69 mmol), palladium(II) acetate (0.105 g, 0.469 mmol), Xantphos (0.407 g, 0.703 mmol), and cesium carbonate (3.05 g, 9.37 mmol) were added to a dry flask. Degassed with argon, and then added dioxane (20 mL). The reaction mixture was degassed with argon for five minutes, and then heated to 90° C. After 2 hours, the reaction mixture was cooled, diluted with ethyl acetate, filtered through celite, and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate and hexanes to afford solids. The solids were dissolved in hot ethyl acetate (25 mL) and then triturated with hexanes (50 mL) while cooling. After 2 hours, the mixture was filtered to afford 4-cyclopropyl-5-fluoro-N-[3-fluoro-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (1.2 g, 3.6 mmol, 78%). MS ESI: [M+H]+ m/z 331.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1I>>[Cl:19][C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(I)c(Cl)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cc(Cl)ccc2OCc2ccccc2)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 144 step (i) using the product from example 16 step (ii) and the product from example 145 step (ii). Yield 1.08 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](Cl)[C:15]3[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([NH:27][C:16]1[C:15]2[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:17]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccc2c(Cl)nc(-c3ccc(Br)cc3)nc2c1
Solvent: C1CCOC1
Product: Clc1ccc2c(NCc3ccccc3)nc(-c3ccc(Br)cc3)nc2c1
Temperature: 25 °C

Procedure:
A solution of 2-(4-bromo-phenyl)-4,7-dichloro-quinazoline (0.085 mmol, 30 mg) [prepared analogously to example 1] in 2 ml THF is treated with benzylamine (0.174 mmol, 0.019 ml). The mixture is heated at 60° for 6 hrs. After cooling to rt, the reaction mixture is filtered through a tentacle ion exchanger (LiChrolut® SCX: Merck ChromBook, 2nd ed. page 31). Evaporation of the solvent afforded benzyl-[2-(4-bromo-phenyl)-7-chloroquinazolin-4-yl]-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18]C)[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=2)=[N:10]1.[Cl:29]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:29][C:16]1[C:17]2[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:12]=2[C:13](=[O:18])[NH:14][CH:15]=1
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
To a solution of (4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (322.3 mg) obtained in Step A of Example 39 in DMF (10 mL) was added N-chlorosuccinimide (252 mg) at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred for 1 day, and then at 100° C. for 1 day, and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane/methanol) to give the title compound (156 mg).
Reaction SMILES: [K].Cl[CH:3]([CH:9]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[N:13]=1.C(O)(=O)C>C(O)C>[NH2:18][C:14]1[N:13]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(N)n1
Reactant: CCOC(=O)C(Cl)C=O
Agent: [K]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2cccc(N)n12
Yield: 40.2 %

Procedure:
In 1250 ml of ether was suspended 56.0 g (500 mM) of potassium tert-butoxide and while the suspension was stirred vigorously, a solution of 37.0 g (500 mM) of ethyl formate and 61.3 g (500 mM) of ethyl chloroacetate in 100 ml of ether was added dropwise at room temperature over 15 minutes. The reaction mixture was stirred at room temperature for 30 minutes and the precipitate that formed was recovered by filtration. The precipitate was rinsed with 50 ml of ether and dried in vacuo to give 93.13 g of ethyl 2-chloro-2-formylacetate potassium salt as light-yellow solid. In 40 ml of ethanol was suspended 7.59 g (40.0 mM) of this ethyl 2-chloro-2-formylacetate potassium salt as well as 2.18 g (20.0 mM) of 2,6-diaminopyridine and following addition of 2.3 ml (40 mM) of acetic acid, the mixture was refluxed for 3 hours. After completion of the reaction, the precipitate that formed was recovered by filtration and rinsed with 10 ml of ethanol. The filtrate and the washes were pooled and neutralized with aqueous NaCO3 solution, and the solvent was distilled off under reduced pressure. The residue was extracted with 100 ml of ethyl acetate and the organic layer was washed with 100 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was distilled off under reduced pressure and the residue was washed with ether to provide 1.65 g of the title compound as light-yellow solid. The washes were concentrated and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 0.61 g of the title compound (total yield 2.26 g, percent yield 55.1%).
Reaction SMILES: [C:1]1([SH:7]2(=[O:19])[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:12]1[SH:7](=[O:19])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8][CH:9]=[N:10][C:11]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=CN1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=[SH]1(c2ccccc2)NC=NC(c2ccccc2)=C1Br
Reaction time: 0.5 h
Yield: 160.3 %

Procedure:
To a solution of 4.5 g (16 mmole) of 1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide of Example 1 in 225 ml of chloroform was added over 20 minutes a solution of 2.8 g, (7.5 mmole) of bromine in 25 ml of chloroform. After the addition was complete, the mixture was stirred for 30 minutes before reducing to an oil which was subjected to flash chromatography (SiO2, petrol:chloroform 1:1) to obtain 4.2 g of (73%) 6-bromo-1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 135°-136° C. after crystallization from ethyl acetate/ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(C)c(C)cc4nc3OC)CC2)c1
Yield: 75 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3,5-di methoxyphenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 75%). 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.39 (s, 3H), 3.21-3.29 (m, 4H), 3.75 (m, 4H), 3.79 (s, 3H), 4.11-4.13 (m, 3H), 6.06 (s, 1H), 6.12 (s, 2H), 7.52 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH3:16])[CH2:11][C:10]2[C:5](=[C:6]([Cl:14])[C:7]([Cl:13])=[C:8]([OH:12])[CH:9]=2)[C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27]CC)=[O:26].[OH-].[Na+].Cl>CN(C=O)C.O>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH2:24][C:25]([OH:27])=[O:26])=[C:7]([Cl:13])[C:6]=2[Cl:14])[CH2:11][C:3]1([CH2:1][CH3:2])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: CCC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 55 °C

Procedure:
A stirred mixture of 2-ethyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (3.6 g., 0.014 mole), potassium carbonate (4.2 g.), ethyl bromoacetate (5.0 g.) in DMF (40 ml.) is warmed in an inert atmosphere at 55° C. for one hour, then treated with water (40 ml.) and 10N sodium hydroxide (6 ml.) and heated on a steam bath for 11/2 hours. The reaction mixture is poured into dilute aqueous hydrochloric acid, extracted with ether, washed with water and dried over magnesium sulfate. The ether is evaporated at reduced pressure affording the crude product which melts at 168° C. after recrystallization from nitromethane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.C([O:18][C:19]([CH3:21])=[CH2:20])(=O)C.[O-]CCCC.C([Sn+](CCCC)CCCC)CCC.[F-].[K+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:14][C:4]1[CH:3]=[C:2]([CH2:20][C:19](=[O:18])[CH3:21])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: C=C(C)OC(C)=O
Agent: CCCC[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 80 °C
Yield: 77.7 %

Procedure:
150 g of 4-bromo-2-fluorobiphenyl, 89.6 g of isopropenyl acetate, 258 ml of tributyltin butoxide and 4.7 g of a palladium chloride-tri(o-phenyl)phosphine complex were added to 300 ml of toluene and the mixture was stirred under heating at 80° C. for 2 hours under a nitrogen atmosphere. The reaction solution was left to cool to room temperature. Then, 1 l of ethyl acetate and 500 ml of a saturated potassium fluoride aqueous solution were added thereto, and the mixture was vigorously stirred. Insoluble matters were separated by filtration, and then the organic layer was collected by separation. The obtained organic layer was post-treated by a conventional method. The product was treated with hexane to obtain 106 g (yield: 78%) of 1-(2-fluoro-4-biphenylyl)-2-propanone.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][S:16]2(=[O:22])=[O:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(O)C>CN(C)C=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]([C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][S:16]3(=[O:21])=[O:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:26][CH:25]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(N2CCCCS2(=O)=O)n(C)c(=O)c1O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1c(N2CCCCS2(=O)=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Yield: 83.9 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (1.00 g, 3.02 mmol) and 4-fluorobenzylamine (1.31 g, 10.5 mmol) in a mixture of anhydrous ethyl alcohol (40 ml) and N,N-dimethylformamide (10 ml) was heated under reflux for 10 h. The solvent was then evaporated in vacuo and the residue was diluted with dichloromethane (500 ml). The organic phase was washed with 5% aqueous acetic acid, brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and recrystallization of the white solid obtained from dichloromethane and ethanol gave 1.04 g (84% yield) of the title amide as white crystals; mp 227–228° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 and 2.07 (2×1H, m, CH2), 2.28–2.43 (2H, m, CH2), 3.19–3.31 (2H, m, CH2), 3.64 (3H, s, NCH3), 3.6–3.8 (2H, m, CH2), 4.59 (2H, AB part of ABX system, JAB=14.9 Hz, Δν=36.1 Hz, JAX=6.6 Hz, JBX=5.8 Hz, NCH2), 7.06 (2H, m, aromatics), 7.31 (2H, m, aromatics), 7.52 (1H, broad NH). Anal. Calcd for C17H19FN4O5S: C 49.75, H 4.67, N 13.65. Found: C 49.67, H 4.63, N 13.77.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][CH2:16][O:17][C:18]([CH:20]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19].[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>ClCCl>[CH3:15][CH2:16][O:17][C:18]([CH:20]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])[N:21]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:19]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1CCC(C=O)N1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCC(CNCC(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Yield: 47.1 %

Procedure:
Sodium triacetoxyborohydride (2.08 g, 9.86 mmol) was added to a solution of 5-formyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (891 mg, 3.29 mmol) and glycine t-butyl ester (1.65 g, 9.86 mmol) in dichloromethane (20 mL) over 2 minutes—a small amount of gas evolution was observed. After 1 hour the reaction was quenched with saturated ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography with methanol and dichloromethane as the eluant at a gradient of 0-10%. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 5-[(tert-butoxycarbonylmethyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (601 mg, 1.55 mmol, 47%). C19H34N2O6 calculated 386.2, observed [M+1]+ 387.2; rt=1.61 min.