Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][CH:10]=1.Br[C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH:41]=[CH:42][NH:43]2.C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C.C(O)C>[F:8][C:9]1[CH:37]=[CH:36][C:12]([NH:13][C:14]2[CH:26]=[C:25]([C:39]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:40]=3[CH:41]=[CH:42][NH:43]4)[CH:24]=[CH:23][C:15]=2[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[CH:11][CH:10]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Nc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc3[nH]ccc23)cc1Nc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To toluene 1.6 mL solution of tert-butyl 2-(4-fluoroanilino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 60 mg were added ethanol 0.60 mL, water 0.30 mL, 4-bromoindole 0.034 mL, sodium hydrogen carbonate 30 mg and tetrakis(triphenylphosphine)palladium(0) 8.4 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=5:1] to give tert-butyl 2-(4-fluoroanilino)-4-(1H-indol-4-yl)benzoate.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.[CH2:40](C1C=CC=CC=1B(O)O)[CH3:41]>CCCCCCC.CCOC(C)=O>[CH2:40]([C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:32])[CH3:41]
Reactant: CCc1ccccc1B(O)O
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCc1ccccc1-c1ccncc1NC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 36, intermediate b) and 2-ethylphenylboronic acid (CAS RN 90002-36-1) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (87%). MS (ESI): m/z=213.138 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[C:10]([O-])(O)=O.[Na+].[Na+].[Cl-]>CO>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:10])=[O:7]
Reactant: NCCCCC(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-aminovaleric acid (5 g, 42.68 mmol) in MeOH (100 mL) at room temperature was added HCl conc. (37%, 16 mL). The solution was stirred for 48 h at room temperature and monitored by HPLC-MS. The resulting solution was treated with a saturated aqueous solution of NaHCO3 then the solvents were evaporated under reduced pressure. The aqueous layer was washed several times with CH2Cl2 and AcOEt. The aqueous phase was concentrated to produce a solid containing the desired product, NaCl, and NaHCO3. The solid was washed with MeOH, and the organic filtrate was concentrated to afford the title compound (36) as a white solid (7.88 g, 100%): 1H NMR: (300 MHz, CD3OD) δ 3.34 (s, 3H), 2.61 (br. s, 2H), 2.10-2.06 (m, 2H), 1.39-1.34 (m, 4H); MS (ES) m/z 132.2 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[N:34]([C:10](=[O:12])/[CH:9]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(=O)/C=C/c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (E)-3-(3-bromophenyl)acrylic acid (100 g, 0.44 mol) and triethylamine (0.48 mol) in toluene (1000 mL) was added diphenylphosphoryl azide (127.4 g, 0.45 mol) dropwise at 0-10° C. The mixture was stirred at room temperature overnight. Thin layer chromatography (petroleum ether/ethyl acetate=8:1) indicated completion of reaction. The resulting mixture was washed with 1N sodium hydroxide (500 mL) and extracted with ethyl acetate (2000 mL×3). The organic layer was concentrated to give crude (E)-1-azido-3-(3-bromophenyl)prop-2-en-1-one, which was used in the next step directly.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C([O-])(=O)C.C(N(CC)CC)C>ClCCl.[Cu]>[N+:8]([C:7]1[C:2]([CH3:1])=[CH:3][C:4]([O:12][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=2)=[CH:5][C:6]=1[CH3:11])([O-:10])=[O:9]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3,5-dimethyl-4-nitrophenol (1.67 g), 3-trifluoromethylbenzene boronic acid (3.8 g), copper (1 acetate (1.82 g) and triethylamine (2.02 g) in dichloromethane (50 ml) was stirred at room temperature for 48 hours. The mixture was evaporated to dryness and purified by silica gel chromatography eluting with light petroleum (b.p. 60-80° C.)/ethyl acetate (19:1) to give the title product as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[C:21](=[N:23]S(Cl)(=O)=O)=[O:22].[OH-].[K+]>O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:21]([NH2:23])=[O:22])=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1c[nH]c2cccc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.4 g. 4-Benzyloxyindole (see Helv. Chim. Acta, 54. 2411/1971) are dissolved in 20 ml. anhydrous acetonitrile, cooled to 0° C. and mixed with 1.8 ml. N-carbonylsulphamoyl chloride in 20 ml. acetonitrile. After a reaction period of about 1 hour, a solution of 3.4 g. potassium hydroxide in 34 ml. water is added thereto and the reaction mixture then stirred for 1 hour at ambient temperature. After evaporating the solvent, the residue is taken up in 200 ml. 2 N hydrochloric acid and extracted with methylene chloride. From the methylene chloride extract there are obtained 4.8 g. (45% of theory) 4-benzyloxy-3-aminocarbonylindole, which is recrystallized from ethyl acetate; m.p. 176° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([OH:21])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][S:25][CH2:26]Cl.O>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:24][S:25][CH3:26])=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCCl
Reactant: O=C(OCc1ccccc1)N1CCc2ccc(O)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCOc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (2.5 g) in dimethylformamide (25 ml) was added 60% sodium hydride (390 mg) with ice-cooling and under an argon atmosphere, and the mixture was stirred at the same temperature for 30 min. Then, chloromethyl methyl sulfide (0.96 ml) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained oil was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) and dried under reduced pressure to give the title compound (2.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][C:9]1([CH3:19])[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23].CCN=C=NCCCN(C)C.Cl>>[CH3:31][O:30][C:28]([C:27]1[CH:32]=[CH:33][C:24]([C@@H:22]([NH:21][C:16]([C:9]2([CH3:19])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][CH2:14][C:11]3([CH2:12][CH2:13]3)[CH2:10]2)=[O:17])[CH3:23])=[CH:25][CH:26]=1)=[O:29]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)CC1(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2(C)CC3(CCN2C(=O)OC(C)(C)C)CC3)cc1
Yield: 27.4 %

Procedure:
The title compound (D57) (25 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 6-(tert-butoxycarbonyl)-5-methyl-6-azaspiro[2.5]octane-5-carboxylic acid (D6) (57 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (46 mg). EDC.HCl: 1.1 eq, Reaction time: 48 hrs.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]1[O:14][C@@H:13]1[CH2:15]Cl>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:15][C@H:13]2[CH2:12][O:14]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: ClC[C@@H]1CO1
Product: CC(C)(C)c1ccc(OC[C@H]2CO2)cc1

Procedure:
The title compound was prepared from 4-tert-butyl-phenol and S-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([NH:12]C(OCC1C=CC=CC=1)=O)[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([NH2:12])[C:9]([NH2:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](N)C(N)=O
Reaction time: 4 h
Yield: 99.4 %

Procedure:
To a solution 3-benzyloxycarbonylamino-succinamic acid tert-butyl ester (5.0 g, 15.50 mmol) in THF (20 mL) was added 20% Pd/C (150 mg), and the mixture was stirred for 4 h under H2 atmosphere at 50 psi. The catalyst was filtered and the solvent removed. The resulting oil solidifies upon the addition of ether. The solid was dried to give 2.90 g (98%) of (S)-3-amino-succinamic acid tert-butyl ester as an off white solid. The solid was used immediately in the next step. MS (APCI) m/z 189.1 (M+1).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Br:16][C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:28](=[O:38])[CH2:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[C:26]=1O)[C:20]([O:22][CH3:23])=[O:21]>ClCCCl>[Br:16][C:17]1[CH:18]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[CH:24]=[C:25]2[C:26]=1[O:31][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:29][C:28]2=[O:38]
Reactant: COC(=O)c1cc(Br)c(O)c(C(=O)CC(=O)N2CCOCC2)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Trifluoromethanesulfonic anhydride (0.755 L, 4487 mmol) was added to a stirred solution of methyl 3-bromo-4-hydroxy-5-(3-morpholino-3-oxopropanoyl)benzoate (433 g, 1122 mmol, pooled material from several batches) dissolved in 1,2-dichloroethane (1 L) at RT under nitrogen (exotherm). The resulting solution was stirred at 50° C. overnight. The mixture was partially evaporated, and the residue was diluted with MeOH (1.6 L) at 0° C. (exotherm) and stirred for 1 hr at RT. The solvent was evaporated again and the residue was diluted in DCM, quenched with a saturated aqueous solution of sodium carbonate and extracted with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated to afford the crude product. The crude was triturated under MTBE (2×), ethyl acetate (1×) and MTBE (1×). The solid was dried to afford methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (208 g, 50%) as a beige solid. Mass Spectrum: M+H+ 370.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:26]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:26])[C:3](=[O:2])[N:13]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:11]=1[CH3:12])=[O:8]
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)N[C@H](C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n([C@H](C)c2ccccc2)c1C
Temperature: 25 °C
Yield: 51.8 %

Procedure:
MeOH (170 mL) was added to a flask containing (R)-4-[1-(1-phenyl-ethylamino)-ethylidene]-pent-2-enedioic acid dimethyl ester (5.56 g, 18.3 mmol). NaOMe solution (4.2 mL, 18.3 mmol, 4.375 M in MeOH) and N-bromosuccinimide (3.92 g, 22 mmol) were added, and the resulting mixture was refluxed for 7 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-25% EtOAc/hexanes) to give 3.32 g of the title compound as an off-white solid. MS: (+) m/z 372.20, 374.16 (M+Na, 79/81Br).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH-].[K+].[OH:7][C:8]1[C:17]([CH:18]=[O:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].Cl>CS(C)=O>[CH2:1]([O:7][C:8]1[C:17]([CH:18]=[O:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH:2]=[CH2:3]
Reactant: COC(=O)c1ccc(OC)c(C=O)c1O
Reactant: C=CCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCOc1c(C(=O)OC)ccc(OC)c1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.1 %

Procedure:
At room temperature, 23.2 g (0.192 mol) of allyl bromide were added dropwise to a mixture of 21.0 g (0.375 mol) of potassium hydroxide and 20.2 g (0.096 mol) of methyl 2-hydroxy-3-formyl-4-methoxybenzoate in 500 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 4 hours. The mixture was subsequently stirred into 1.5 l of 3% strength aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with water and dried, and the solvent was removed. Silica gel chromatography using cyclohexane/ethyl acetate=1:2 gave 7.7 g (36%) of methyl 2-allyloxy-3-formyl-4-methoxybenzoate in the form of a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.ClC1C=C2C(C(O[Si](C)(C)C)=NC(O[Si](C)(C)C)=N2)=CC=1.Cl[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].[Br-].[Li+]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[N:9]2[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Agent: C[Si](C)(C)Oc1nc(O[Si](C)(C)C)c2ccc(Cl)cc2n1
Agent: [Br-]
Agent: [Li+]
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reaction time: 18 h

Procedure:
7-Chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (10 g) was treated as in Example 1 to give a concentrate containing 7-chloro-2,4-bis(trimethylsilyloxy)quinazoline. To this concentrate was added an oil prepared from ethyl chloroacetate (15 ml) and lithium bromide (2.21 g), and the reaction was carried out at an internal temperature of 115˜130° C. for 18 hours. This reaction mixture was cooled to ≦70° C. and worked up as in Example 4 to provide ethyl 2-(7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl)acetate (13.66 g).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.O>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH2:10][CH2:11][C:12](=[O:18])[NH:13]4)[CH2:3][CH2:4]2)=[O:33])=[CH:30][CH:29]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (2.6 g) and 2.34 ml of triethylamine were dissolved in 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.5 g of 4-methoxybenzoyl chloride. After completion of addition the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 1.1 g of 5-[4-(4-methoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 219°-220° C., colorless needles.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[C:24]([Br:26])[C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[C:6]=1[Cl:27])=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[Br:26][C:24]1[C:8]2[O:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:11][C:7]=2[C:6]([Cl:27])=[C:5]([C:3]([OH:4])=[O:2])[CH:25]=1
Reactant: COC(=O)c1cc(Br)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c2c(c1Cl)OC(c1ccccc1)(c1ccccc1)O2

Procedure:
7-Bromo-4-chloro-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid methyl ester (520 mg, 1.16 mmol) is dissolved in THF (6 ml). Lithium hydroxide hydrate (190 mg, 4.64 mmol) in water (6 ml) is added. After addition of methanol (2 ml) the reaction is heated to reflux for 5 hours. After cooling the organic solvents are evaporated and the reaction is diluted with water, acidified with 1N aqueous HCl solution and extracted with ethyl acetate. The combined organic layers are washed with brine, dired over sodium sulfate and filtered. The solvent is evaporated in vacuo. The residue is stirred with n-hexane. The product precipitates as a white solid (350 mg, 70%), which is filtered and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[S:22][C:23]([Cl:26])=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:23]1[S:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:25][CH:24]=1
Reactant: [O-]B([O-])Oc1ccc(Cl)s1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(Cl)s3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
In toluene/ethanol/water (10/1/1.2 ml) was dissolved methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (750 mg), and to the solution were added 5-chloro-2-thienyl borate (736 mg) and potassium carbonate (1.0 g). The mixture was stirred at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (210 mg). The mixture was stirred at 100° C. for 15 hours, cooled to room temperature, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-(5-chloro-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (350 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[H-].[Na+].Br[CH2:21][CH2:22][F:23]>CN(C=O)C>[F:23][CH2:22][CH2:21][O:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)C1CC(O)CN1C(=O)OC(C)(C)C
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(OCCF)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
A solution of 2.45 g (10.0 mmol) of 1-tert-butyl 2-methyl 4-[hydroxy]pyrrolidine-1,2-dicarboxylate (24) in DMF (10 ml) was added to a suspension of 0.65 g (15 mmol) of sodium hydride in DMF (20 ml). After 15 min, a solution of 1.90 g (15.0 mmol) of 1-bromo-2-fluoroethane in DMF (10 ml) was added. The batch was subsequently reacted in 3 portions at 100° C. in a microwave for 45 minutes. The batch was concentrated and treated with water and ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate). 2.10 g (48%) of 1-tert-butyl 2-methyl 4-(2-fluoroethoxy)-pyrrolidine-1,2-dicarboxylate were obtained.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([OH:20])=O.C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([N:35]=[N+:36]=[N-:37])=[O:20]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc2ccccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc2ccccc2n1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 263.9 %

Procedure:
47 ml (0.34 mol) of triethylamine are added to a stirred suspension, cooled to -10° C., of 30.0 g (0.17 mol) of quinoline-2-carboxylic acid in 385 ml of anhydrous tetrahydrofuran, and the mixture is stirred at -10° C. for 10 minutes, whereupon a clear solution forms. 73.0 ml (0.34 mol) of diphenylphosphoryl azide are then added dropwise and the reaction mixture is left to stand in a refrigerator at 0° C. for 20 hours. Thereafter, the mixture is stirred into 350 ml of ice-cold dilute NaHCO3 solution. The precipitate formed is separated off by filtration, washed with water and dried in air. 88.9 g (86%) of the title compound are obtained as a pale solid.