Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[I-:18].[Na+].C(OC)(C)(C)C>CC(C)=O>[I:18][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: Cc1oc(-c2ccc(C(C)C)cc2)nc1CI

Procedure:
1.74 g of 4-Chloromethyl-5-methyl-2-(4-(2-propyl)-phenyl)-oxazole and 3 g of sodium iodide in 150 ml of acetone are heated under reflux for 2 hours. After the reaction mixture has been cooled, 300 ml of methyl tert-butyl ether are added, the mixture is washed three times with saturated Na2S2O3 solution and dried over MgSO4 and the solvents are then removed under reduced pressure. This gives 2.64 g of 4-iodomethyl-5-methyl-2-(4-(2-propyl)-phenyl)-oxazole as a yellowish solid. C14H16INO (341.19), MS(ESI): 342 (M+H+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:11]=2)[C:6]([CH2:21][C:22]([N:24]2[C@H:29]([C:30](=[O:41])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=3[F:40])[CH2:28][C@@H:27]3[C@H:25]2[CH2:26]3)=[O:23])=[CH:5]1)(=[O:3])[NH2:2].[CH3:42][NH:43][CH3:44]>CCO>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([CH:38]=[CH:37][CH:36]=1)[CH2:32][NH:31][C:30]([C@@H:29]1[CH2:28][C@@H:27]2[C@@H:25]([CH2:26]2)[N:24]1[C:22](=[O:23])[CH2:21][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][N:43]([CH3:44])[CH3:42])[CH:8]=2)[N:4]([C:1]([NH2:2])=[O:3])[CH:5]=1)=[O:41]
Reactant: CS(=O)(=O)OCCOc1ccc2c(c1)c(CC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1cccc(Cl)c1F)cn2C(N)=O
Reactant: CNC
Solvent: CCO
Product: CN(C)CCOc1ccc2c(c1)c(CC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1cccc(Cl)c1F)cn2C(N)=O
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-(1-carbamoyl-3-{2-[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hex-2-yl]-2-oxo-ethyl}-1H-indol-5-yloxy)-ethyl ester in a solution of dimethylamine 5.6 M in EtOH (1 mL) was sealed in a microwave vial and heated at 70° C. for 2 h (Emrys Optimizer; personal chemistry). The reaction mixture was quenched by addition of saturated aqueous NaHCO3, extracted with EtOAc, dried (Na2SO4) and evaporated in vacuo. Then crude residue was purified by catch-release (SCX Tosic Acid-1 g from Silicycle; eluent MeOH (10 mL) to 2M ammonia in MeOH (10 mL)) to give the desired material which was precipitated in Et2O. MS (UPLC/MS): 556.5/558.5 [M+H]+, 600.4/602.5 [M+HCOO]−; tR (HPLC conditions f): 1.46 min.
Reaction SMILES: Cl.[NH:2]1[C@H:6]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH2:5][C@@H:4]2[CH2:17][CH2:18][CH2:19][C@H:3]12.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH:4]2[CH2:17][CH2:18][CH2:19][CH:3]12
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)C1CC2CCCC2N1
Reaction time: 16 h

Procedure:
To a solution of commercially available (2S,3aS,6aS)-benzyl octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride (4.70 g, 16.68 mmol) in methylene chloride (42 mL) was added Di-tert-butyl dicarbonate (7.28 g, 33.36 mmol), N,N-diisopropylethylamine (5.82 mL, 33.36 mmol) and 4-(Dimethylamino)pyridine (0.20 g, 1.67 mmol). The solution was stirred under air for 16 hours. Upon completion, the reaction was concentrated in vacuo, diluted in ethyl acetate, and washed with 1N HCl. The aqueous layers were backextracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (5-40% ethyl acetate in hexanes) to afford (2S,3aS,6aS)-1-tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid which was used without further purification. MS (ESI) m/z 368.47 [M+Na]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH:18]=1)[CH:16]=O>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:19])=[C:15]([CH2:16][C:5]2[S:4][C:3]([C:2]([F:9])([F:8])[F:1])=[CH:7][CH:6]=2)[CH:18]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: FC(F)(F)c1cccs1
Product: FC(F)(F)c1ccc(Cc2cc(Br)ccc2Cl)s1

Procedure:
2-Trifluoromethylthiophene (see Japanese Unexamined Patent Publication No. 2000-34239) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]([C:14]#[N:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[O:9][C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:20]>O>[OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]([C:14]([NH2:15])=[O:20])=[C:8]([C:10]([F:13])([F:11])[F:12])[O:9][C:4]=2[CH:3]=1
Reactant: N#Cc1c(C(F)(F)F)oc2cc(O)ccc2c1=O
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1c(C(F)(F)F)oc2cc(O)ccc2c1=O

Procedure:
A mixture of 3 g of 7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-1-benzopyran-3-carbonitrile, 4 ml of conc. sulfuric acid and 1 ml of water was heated for 11/2 hours at an internal temperature of 120°-135°C. The clear dark solution was poured onto ice. The solid was filtered and recrystallized from methanol, mp > 310° C.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[O:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][N:14]=1)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:11]([C:13]1[CH:18]=[N:17][C:16]([NH:19][C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:15][N:14]=1)=[O:10])([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Temperature: -20 °C
Reaction time: 0.67 h

Procedure:
A 3-necked 1-L round bottomed flask equipped with a magnetic stirrer, addition funnel, thermocouple probe and nitrogen inlet/outlet was charged with 25.00 mL (185.5 mmol) of tert-butyl acetate, 20.00 g (84.30 mmol) of the compound prepared in step 2 and 20 mL of THF. After cooling to −20° C., a solution of 261.4 mL (261.4 mmol) of 10M lithium bis(trimethylsilyl)amide (LHMDS) in THF was added dropwise, while maintaining the temperature of the reaction mixture between −20° C. and 0° C. The resulting red solution was stirred at −20° C. for 40 min. HPLC analysis indicated complete reaction. The mixture was allowed to warm to 0° C., then quenched by the addition of pre-cooled 200 mL (260.3 mmol) of 25 wt % citric acid solution. The organic layer was separated, washed with 2×200 mL of saturated sodium chloride solution and concentrated at 30° C./60 mmHg to a volume of ca. 50 mL. The concentrated solution was diluted with 200 mL of butanone and again concentrated at 30° C./60 mmHg to ca. 50 mL. The concentrate was again diluted with 200 mL of butanone and concentrated at 30° C./60 mmHg to a volume of ca. 100 mL. NMR analysis indicated the absence of THF. The resulting butanone solution of the title compound was used directly in the next step.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[C:38]([F:40])[C:37]([O:41][CH3:42])=[CH:36][C:35]=1[F:43])[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:43][C:35]1[CH:36]=[C:37]([O:41][CH3:42])[C:38]([F:40])=[CH:39][C:34]=1[C@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[CH2:18][NH:19][CH2:32][CH3:33]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CCN(C[C@@H](N)c1cc(F)c(OC)cc1F)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cc(F)c(OC)cc1F

Procedure:
Compound 31 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(2,5-difluoro-4-methoxy-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a pale yellow solid. LC/MS [403 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.03 (d, J=26.0 Hz, 1H), 8.98 (s, 1H), 8.56 (s, 1H), 8.37 (d, J=4.5 Hz, 1H), 8.16 (s, 1H), 7.40 (dd, J=12.1, 7.0 Hz, 1H), 7.09 (dd, J=11.5, 7.3 Hz, 1H), 5.69 (s, 1H), 3.82 (s, 3H), 3.13 (dd, J=12.3, 8.5 Hz, 1H), 2.91 (dd, J=12.4, 5.2 Hz, 1H), 2.63-2.53 (m, 2H), 1.85 (s, 1H), 0.97 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[F:30])[N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:30][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:24]=1[N:6]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CN(c1ccncc1F)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCN(c1ccncc1F)n1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a solution of N-(3-fluoro-4-pyridinyl)-N-(5-benzyloxy-1H-indol-1-yl)glycine ethyl ester (18.7 g) in 100 ml of tetrahydrofuran cooled to ice bath temperature, was added lithium aluminum hydride (89.16 ml) dropwise to the cool solution. The solution was stirred for 0.5 hour, then quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, MgSO4). After filtering, the solvent was evaporated to yield a solid (12.5 g) which was eluted with 50% ethyl acetate/dichloromethane on a silica gel column via HPLC. The desired fractions were evaporated to yield 9.65 g of a solid, m.p. 130°-132° C.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1C(F)(F)F
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-2-trifluoromethylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H10ClF3N4, 364. Found, 363, 365.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Reactant: NCc1ccc2c(c1)OCO2
Product: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine gives 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=3[CH3:36])[CH:20]=[C:21]([C:26](=[O:28])[CH:27]=2)[C:22]([O:24]C)=[O:23])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.[CH3:37]O>[C].[Pd]>[CH3:9][N:11]([CH3:37])[CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]=3[CH3:36])[CH:20]=[C:21]([C:26](=[O:28])[CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:14][CH2:13]1
Reactant: COC(=O)c1cn(-c2ccc(O)cc2C)c(C2CCC(NC(=O)OCc3ccccc3)CC2)cc1=O
Reactant: CO
Agent: [Pd]
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1CCC(N(C)C)CC1

Procedure:
In 15 ml of methanol was dissolved 0.2 g of methyl 6-(4-benzyloxycarbonylaminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate, and 0.05 g of 5% by weight palladium carbon was added to the resulting solution, and the above ester was hydrogenated under atmospheric pressure for 1.5 hours. Then, the catalyst was removed by filtration, and the solvent was removed by distillation under reduced pressure. To the residue was added 0.4 g of 37% by weight formalin and 0.1 g of formic acid, and they were reacted at 100° C. for 7.5 hours. After completion of this reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (3:1 by volume) mixture) to obtain 0.04 g of 6-(4-dimethylaminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 207°-215° C.
Reaction SMILES: [SH:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:34][C:35]([CH3:43])([CH3:42])[CH2:36]OS([O-])(=O)=O>CN(C)C=O>[NH2:34][C:35]([CH3:43])([CH3:42])[CH2:36][S:1][C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1
Reactant: CC(C)(N)COS(=O)(=O)[O-]
Reactant: CC(C)=CCn1c(S)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(SCC(C)(C)N)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Reaction time: 0.25 h

Procedure:
30 mg of 8-mercapto-3-methyl-7-(3-methylbut-2-enyl)-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydropurine-2,6-dione were introduced into 2 ml of dimethyl-formamide and, after addition of 37 mg of potassium carbonate, stirred for 15 minutes. Then 13.5 mg of mono(2-amino-2-methylpropyl)sulfate were added, and the mixture was stirred at 80° C. for 29 hours. The volatile fractions were removed in vacuum at 40° C., and the residue was purified by column chromatography (silica gel, mobile phase: methylene chloride: methanol =95:5).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.S(O[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(C1C=CC(C)=CC=1)(=O)=O>>[CH3:1][C:2]1[N:3]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1CC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared according to the method described for Preparation 146 using 2-methyl-1H-imidazole and tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:20]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])[CH2:19][CH2:18][N:17]=1>>[O:11]=[C:9]1[N:17]2[CH2:18][CH2:19][CH:20]([N:21]3[C:29](=[O:30])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:31])[C:16]2=[N:15][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:8]1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1=NCCC1N1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1C1CCn2c1nc(-c1ccncc1)cc2=O

Procedure:
By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyridinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) and using 2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound was obtained as a white powder.
Reaction SMILES: CCN(C1C=CC=CC=1)CC.O[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([CH2:22][CH3:23])[N:16]=[CH:15][N:14]=1.C(OCC)(=O)C.P(Cl)(Cl)[Cl:31]>>[Cl:31][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([CH2:22][CH3:23])[N:16]=[CH:15][N:14]=1
Reactant: ClP(Cl)Cl
Reactant: CCc1ncnc(O)c1[N+](=O)[O-]
Solvent: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
18.7 g (0.125 mol) of diethylaniline are dissolved in 18 ml of phosphorus chloride, and then 8.46 g (0.05 mol) of 4-hydroxy-5-nitro-6-ethylpyrimidine are stirred in. During the addition, the temperature rises from 22° to 47° C. A solution is formed which is heated at 60° C. for 2 hours. It is then stirred with ice-water and ethyl acetate for 30 minutes for the purpose of hydrolysis. The organic phase is separated off and combined with the extracts obtained by extraction, and the mixture is washed with NaHCO3 solution. Removal of the solvent yields 9.1 g of crude product, which is purified by column chromatography on silica gel (eluant:ethyl acetate/hexane 20:80 parts). 6.76 g (72.1% of the theoretical yield) of pure product are obtained in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:9])=[O:8])=[CH:13][CH:12]=1
Reactant: O=C(O)c1sccc1Br
Reactant: OB(O)c1ccc(F)cc1
Product: O=C(O)c1sccc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 3-bromo-thiophene-2-carboxylic acid with 4-fluorophenyl-boronic acid. LC-MS (basic): tR=0.47 min; [M−H]−=221.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:44]>CN(C=O)C.C(N(CC)CC)C.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.[Cu]I>[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:29]=[C:30]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][CH:4]=3)[CH:31]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:33]=2)=[CH:20][C:19]=1[CH3:44]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-ethynyl-4-trifluoromethyl-benzene (159 mg, 0.94 mmol), (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (160 mg, 0.31 mmol, example 6), Pd(PPh3)2Cl2 (36 mg, 0.031 mmol), CuI (16 mg, 0.087 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 1 hour at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (2-methyl-4-{3-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-(4-trifluoromethyl-phenylethynyl)-phenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester in 18 mg (10%) yield.
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16][CH:17]([OH:20])[CH2:18][Cl:19]>C1(C)C=CC=CC=1>[Cl:15][CH2:16][CH:17]([O:20][CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][Cl:19]
Reactant: OC(CCl)CCl
Reactant: ClC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: ClCC(CCl)OC(c1ccccc1)c1ccccc1
Yield: 79.5 %

Procedure:
A stirred solution of 508 g (2.5 mol) of diphenylmethylchloride and 387 g (3 mol) of 1,3-dichloro-2-propanol in 700 mL of dry toluene was heated at reflux temperature for 72 hr. The reaction mixture was concentrated in vacuo and the residual oil distilled to give 587 g (80%) of colorless oil; bp 137°-140° C./0.1 mm.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][C:16](=[O:18])[CH3:17])[CH2:12][CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CCO.O=[Pt]=O>[C:16]([O:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1)[CH2:12][CH2:13][CH3:14])(=[O:18])[CH3:17]
Reactant: C=CCC(OC(C)=O)c1ccc(OC(C)=O)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCCC(OC(C)=O)c1ccc(OC(C)=O)cc1

Procedure:
1.0 g (4 mmol) diacetate 9 is dissolved in 19 ml EtOH and hydrogenated over 50 mg PtO2. The catalyst is removed by filtration over Celite and the solvent is evaporated. Flash chromatography of the crude product gave 0.92 g (91% by weight) of compound 15 in the form of a yellowish oil having the following 1H NMR (CDCl3) values: 0.92 g (t, J=7.0, CH3); 1.15-1.45 (m, 2H, CH2); 1.62-2.00 (m, 2H, CH2); 2.05 (s, CH3); 2.30 (s, CH3); 5.74 (t, J=7.0, CH ); 7.06 J=9.0, 2 aromatic H); 7.34 (d, J=9.0, 2 aromatic H); 7.34 (d, J=9.0, 2 aromatic H). MS: 250 (2, [M+]), 208 (19), 165 (32), 123 (68), 43 (100).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][C:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][OH:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Na+].C(O)(=[O:31])C>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][C:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:21]([OH:31])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CCC(CC)(CO)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(CC)(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a cooled mixture of chromic anhydride (8.5 g, 85,2 mmole) in 100 ml acetic acid was added dropwise a solution of 2-(N-benzyloxycarbonyl-L-valyloxymethyl)-2-ethyl-butan-1-ol (10.4 g, 28.4 mmole) in 50 ml acetone and the mixture was stirred 24 hours at room temperature. The mixture was added to 1000 ml 10% sodium chloride solution and extracted four times with ethyl acetate. The organic phase was washed twice with brine, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 7 g=65%. The product can be activated and esterified directly to a drug or further modified as described below.
Reaction SMILES: C.Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C=O)C.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.[Pd]>[C:3]1([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1
Reactant: C=Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
In a miniautoclave, 85 mg of palladium on active charcoal (similar to Example 59, metal content 5%) are suspended in 20 ml of DMF. After 2 mmol of bromobenzene, 2 mmol of styrene, and 4 mmol of tetrabutylammonium acetate have been added, heating at 120° C. is performed with shaking. After 16 h, 267 mg of stilbene can be isolated from the reaction solution. This corresponds to a 74% conversion.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH:12]=2)=[O:7])CCC.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30]>>[C:22]1([S:19]([C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)(=[O:20])=[O:21])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(S(=O)(=O)c3ccccc3)ccc2c1O
Product: C[C@H](NC(=O)c1ncc2cc(S(=O)(=O)c3ccccc3)ccc2c1O)C(=O)O

Procedure:
Prepared in analogy to Example A-63 g) from 7-benzenesulfonyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and L-alanine MS-(−)-ion: M−1=399.1.