Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[OH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([OH:20])[CH2:22]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: OC1CCCNC1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCC(O)C3)c(F)c21
Yield: 53.7 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (0.43 g), 3-hydroxypiperidine (1.6 g), and pyridine (3 ml) was refluxed for 6 hours. The mixture was evaporated to dryness, treated with water, acidified with acetic acid, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from a mixture of DMF and ethanol to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-hydroxy-1-piperidinyl)-4-oxoquinoline-3-carboxylic acid (0.3 g), mp 232°-234° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][C:19]([Cl:29])=[CH:18][CH:17]=2>O1CCCC1>[Cl:29][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:11])=[C:22]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cnc2ccc(Cl)cc2c1-c1ccccc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)Nc1cnc2ccc(Cl)cc2c1-c1ccccc1
Reaction time: 20 h
Yield: 77.8 %

Procedure:
2,4-Difluorophenyl isocyanate (0.24 ml) was added to a solution of 3-amino-6-chloro-4-phenylquinoline (509 mg) in anhydrous tetrahydrofuran (8 ml), and the mixture was allowed to stand at room temperature for 20 hrs. The precipitated crystals were collected by filtration. The filtrate was concentrated and the precipitated crystals were collected by filtration. Thus obtained crystals were combined and recrystallized from ethanol to give 6-chloro-3-[3-(2,4-difluorophenyl)ureido]-4-phenylquinoline as colorless crystals (638 mg, 77.8 %). m.p. 206°14 207° C.
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]3[CH2:23][C:24]4([CH2:29][CH:20]3[CH2:19]2)[O:28][CH2:27][CH2:26][O:25]4)=[C:14]([F:30])[CH:13]=1)=[O:10])C1C=CC=CC=1.C([Li])CCC.[C:36](OC[C@@H]1OC1)(=[O:40])[CH2:37][CH2:38]C>O1CCCC1>[F:30][C:14]1[CH:13]=[C:12]([N:11]2[CH2:38][C@H:37]([CH2:36][OH:40])[O:8][C:9]2=[O:10])[CH:17]=[CH:16][C:15]=1[N:18]1[CH2:19][CH:20]2[CH2:29][C:24]3([CH2:23][CH:21]2[CH2:22]1)[O:25][CH2:26][CH2:27][O:28]3
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: O=C(Nc1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
24.12 g (58.5 mmol) of 2-[4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 6 was dissolved in 250 ml of tetrahydrofuran, the temperature was cooled to −78° C., and 44 ml (70.4 mmol) of 1.6 M n-butyllithium was slowly added over 30 minutes. After the reaction mixture was stirred for 1 hour, 9.11 ml (60.0 mmol) of (−)-(R)-glycidyl butyrate was added dropwise over 30 minutes, and the mixture was stirred for 12 hours while raising the temperature to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, 250 ml of ethyl acetate was added, the mixture was washed with a saturated aqueous solution of ammonium chloride and distilled water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 21.4 g (97%) of the title compound, of which NMR data is as follows.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O:12]C)=O)[CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([NH2:2])=[O:12])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 50 °C
Yield: 72 %

Procedure:
Ammonium hydroxide (2 ml) was added to methyl 4-chloropyridine-2-carboxylate (100 mg, 0.58 mmol) in MeOH (4 ml) in a sealed tube and heated at 50° C. for 4 hours. The reaction was cooled to room temperature and concentrated at reduced pressure. The residue was dissolved in dichloromethane (20 ml), washed with water (2×10 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give the title compound (66 mg, 72%).
Reaction SMILES: [C:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Zn+2:19].[CH2:20](OC(=O)CCC([O-])=O)[CH2:21]CCCCCCCC.C(OCCCCCCCCCCC)(=O)CCC([O-])=O.[Zn+2].C(OC(=O)CCC([O-])=O)CCCCCCCCCC.C(OCCCCCCCCCCCCCC)(=O)CCC([O-])=O.[Zn+2].C(OC(=O)CCC([O-])=O)CCCCCCCCCCCCC.C(OCCCCCCCCCCCCCCCC)(=O)CCC([O-])=O.[Zn+2].C(OC(=O)CCC([O-])=O)CCCCCCCCCCCCCCC.C(OCCCCCCCCCCCCCCCCCC)(=O)CCC([O-])=O.[Zn+2].C(OC(=O)CCC([O-])=O)CCCCCCCCCCCCCCCCC.C(OCCCCCCCCCCCCCCCCCCCCCC)(=O)CCC([O-])=O.[Zn+2].C(OC(=O)CCC([O-])=O)CCCCCCCCCCCCCCCCCCCCC>>[C:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:20][CH3:21])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Zn+2:19].[CH2:9]([O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:20][CH3:21]
Reactant: CCCCCCCCCCOC(=O)CCC(=O)[O-]
Agent: CCCCCCCCCCCCCCCCCCCCCCOC(=O)CCC(=O)[O-]
Agent: CCCCCCCCCCCCCCCCCCOC(=O)CCC(=O)[O-]
Agent: CCCCCCCCCCCCCCCCOC(=O)CCC(=O)[O-]
Product: CCCCCCCCCCCCOC(=O)CCC(=O)[O-]

Procedure:
In a similar way were prepared, zinc decyl succinate (m.p. 123°C), zinc undecyl succinate (m.p. 121°C), zinc tetradecyl succinate (m.p. 123°C), zinc hexadecyl succinate (m.p. 124°C), zinc octadecyl succinate (m.p. 123°C), zinc docosyl succinate (m.p. 123°C), ##EQU1##
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(O)=O)C(=O)C[C@H]1O.[CH3:26][CH2:27][CH2:28][CH2:29][C:30]([C@H:33]([OH:52])/[CH:34]=[CH:35]/[C@@H:36]1[C@@H:41]([CH2:42]/[CH:43]=[CH:44]\[CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:39](=[O:40])[CH2:38][C@H:37]1[OH:51])([CH3:32])[CH3:31]>>[CH3:26][CH2:27][CH2:28][CH2:29][C:30]([C@H:33]([OH:52])/[CH:34]=[CH:35]/[C@@H:36]1[C@@H:41]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[C:39](=[O:40])[CH2:38][C@H:37]1[OH:51])([CH3:32])[CH3:31]
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
Further, following the procedure of Preparation 16, but using in place of the C-15 unsubstituted PGE2 -type compound of Preparation 16 and above, the 15-methyl and 15-methyl ether PGE2 -type compounds described above, there are obtained the corresponding 15-methyl and 15-methyl ether PGE1 -type compounds of either 15-epimeric configuration in both free acid and methyl ester form. Further, following the procedure of Preparation 16 but using in place of the C-16 unsubstituted PGE2 -type compound therein the 16-methyl or 16,16-dimethyl-PGE2 -type compounds described above there are obtained the corresponding 16-methyl or 16,16-dimethyl-PGE1 -type compounds of this invention. Finally, following the procedure of Preparation 16, but using the various 17-substituted phenyl PGE2 -type compounds described above there are obtained the corresponding 17-substituted phenyl-PGE1 -type compounds. The compounds in this paragraph represent the nvel PGE1 -type compounds of this invention.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11]([OH:13])=O)[S:9][CH:10]=1)=[O:5])[CH3:2].CN(C)CCCN=C=NCC.Cl.[CH3:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[CH2:30][NH2:31]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11](=[O:13])[NH:31][CH2:30][C:29]2[CH:32]=[C:33]([CH3:35])[CH:34]=[C:27]([CH3:26])[CH:28]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(C(=O)O)c1
Reactant: Cc1cc(C)cc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1csc(C(=O)NCc2cc(C)cc(C)c2)c1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
0.5 g 2-carboxy-thiophen-4-carboxylic acid ethyl ester (M. Janda, J. Srogl, M. Nemec, I. Stibor; Org. Prep. and Proced. Int. 3 (6) (1971) 295.) and 0.67 g N′-(3-dimethylaminopropyl)-N-ethylcarbodiimid×HCl are stirred in 50 mL DCM for 15 min. Then, 0.338 g 3,5-dimethylbenzylamin are added and the mixture is stirred overnight. The solution is extracted with 2N HCl and water, then evaporated. The residue is titurated with isohexan, and the resulting crystals are filtrated and air-dried, yielding 0.58 g (73%) crude 5-(3,5-Dimethyl-benzylcarbamoyl)-thiophene-3-carboxylic acid ethyl ester (7b). This ester in converted to title compound by reaction with hydroxylamine hydrochloride in a manner similar to that described for the conversion of 4b into 4a in example 4. After chromatography (silica, ethylacetate), thiophene-2,4-dicarboxylic acid 2-(3,5-dimethyl-benzylamide) 4-hydroxyamide (7a) is obtained as crystals; 44 mg, 9%, mp: 181° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[CH:22](O)=O>ClCCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[CH:22]=[N:16][CH:15]=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: NCc1cc(OCc2ccccc2)ccn1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(COc2ccn3cncc3c2)cc1

Procedure:
0.7 g (3.27 mmol) of 1-[4-(benzyloxy)pyridin-2-yl]methanamine (described in stage B) in 16 ml of formic acid is heated at reflux for 5 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 7 ml of 1,2-dichloroethane. 0.6 ml (6.54 mmol) of phosphoryl chloride dissolved in 7 ml of 1,2-dichloroethane is added. After heating at reflux for 4 hours, the reaction medium is concentrated under reduced pressure and the residue is then taken up in dichloromethane. The organic phase is washed with a saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. 0.97 g of a brown oil is collected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].Cl.[NH2:12][CH2:13][C:14](=[O:20])[CH2:15][CH2:16][C:17](O)=[O:18]>>[ClH:1].[NH2:12][CH2:13][C:14](=[O:20])[CH2:15][CH2:16][C:17]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)=[O:18]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc(Cl)c(Cl)c1
Reaction time: 45 h

Procedure:
From 3,4-dichlorobenzyl alcohol (5.0 g; 28 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 45 h at 100° C. The yield was 1.12 g (57%).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([O:13]CC)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([S:22][C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1OC)(=[O:21])[CH3:20].C(OCC)(=O)C>C1(C)C=CC=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([N:26]2[C@H:23]([S:22][C:19](=[O:21])[CH3:20])[CH2:24][C:25]2=[O:27])[OH:13])=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(C)=O
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)S[C@@H]1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
200 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester and 2 g of molecular sieves A4 are added to a solution of 54.5 mg of (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 4 ml of toluene and 1 ml of dimethylformamide, and the mixture is stirred for 2 hours at 50°. The molecular sieves are filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed over silica gel, and by elution with toluene/ethyl acetate (9:1) the title compound, contaminated with some glyoxylate, is obtained. TLC: Rf =0.48 (ethyl acetate); IR spectrum (in CH2Cl2): absorption bands at 2.89 (broad), 5.64, 5.73, 5.91, 6.24, 6.56, 7.44, 7.62, 7.83-8.15 (broad, sh), 8.26, 8.39 and 8.80-9.30 (broad) μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:30]1[CH:31]=[C:32]([NH:36][C:37](=O)[O:38]C2C=CC=CC=2)[CH:33]=[CH:34][CH:35]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:31]=[C:32]([NH:36][C:37]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c2cc1OC
Yield: 46.7 %

Procedure:
The title compound was prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (103 mg, 0.3 mmol) and phenyl 3-tert-butylphenylcarbamate from Example 118A (114 mg, 0.42 mmol) using Example 115C. The final product was purified by silica gel column chromatography (25-100% EtOAc/hexanes) to give 1-(3-tert-butylphenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (74 mg, 0.14 mmol, 48%). 1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.70 (s, 1H), 8.56 (s, 1H), 7.61-7.58 (m, 2H), 7.49-7.36 (m, 3H), 7.27-7.16 (m, 3H), 7.03 (d, 1H), 6.92 (d, 1H), 4.38-4.32 (m, 2H), 4.00 (s, 3H), 3.81-3.73 (m, 2H), 3.33 (s, 3H), 1.26 (s, 9H); LC-MS (ESI) m/z 517 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](F)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.C(#N)C.O>[F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: C1CCNCC1
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)N2CCCCC2)cc1)C(F)(F)F
Temperature: 22 °C
Yield: 82.9 %

Procedure:
A solution of 3,3,3-trifluoro-N-[4-(fluorosulfonyl)phenyl]-2-hydroxy-2-methylpropanamide (0.2 g), piperidine (0.1 g), and 4-dimethylaminopyridine (5 mg) in dry acetonitrile (4 ml) was heated at reflux for 3 hours. After cooling to 22° C., the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl, brine, dried (Na2SO4), and the solvent evaporated under reduced pressure. Recrystallization from methyl-t-butyl ether/hexane gave the title compound as a colourless crystalline solid, (0.2 g); mp 164°-166° C.; MS: m/z=381(M+1); NMR (250 MHz, CDCl3): 1.42 (m, 2), 1.64 (m, 4), 1.77 (s,3), 2.97 (t,4), 3.79 (s,1), 7.73 (s), 8.67 (s,1). Analysis for C15H19F3N2 04S: Calculated: C, 47.36; H, 5.03; N, 7.37. Found: C, 47.38; H, 5.16; N, 7.30.
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1>C(OC)(C)(C)C>[NH2:1][C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1
Reactant: N
Reactant: FC(F)(F)Oc1cc(Cl)nc(Cl)n1
Solvent: COC(C)(C)C
Product: Nc1nc(Cl)cc(OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.3 g (0.25 mol) of gaseous ammonia were passed over the course of 45 minutes into a stirred mixture of 23.3 g (0.1 mol) of 2,4-dichloro-6-trifluoromethoxypyrimidine and 150 ml of methyl tert.-butyl ether at -50° to -45° C. The mixture was stirred at -50° C. for 30 minutes, at -30° C. for 1 hour and at 25° C. for 1 hour. The precipitate was filtered off with suction, washed with water and dried, resulting in 5.4 g (33.1% of theory) of 4-amino-2,4-dichloropyrimidine of melting point 270°-272° C. as by-product. The filtrate was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed with 5:1 petroleum ether/ether, the initial fractions yielding 3 g (12.8% of theory) of starting material as a colorless oil, and subsequent fractions containing 9 g (42% of theory) of the title compound as colorless crystals of melting point 55°-56° C. Conversion was 48.3%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][C@@H:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>ClCCl>[CH:12]([C@@H:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][C@@H:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11]
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A cold (−76° C.), stirred solution of oxalyl chloride (0.8 mole) in dichloromethane (1.4 L) was treated with dimethyl sulfoxide (116 mL, 1.64 mole) over 40 minutes while keeping the internal temperature below −60° C. After stirring the solution for 45 minutes, a solution containing (−)-(4R*,5R*)-5-hydroxymethyl-1-methyl-4-phenylpyrrolidin-2-one (150 g, 0.73 mole) in dichloromethane (1L) was added over a 30 minute period (T<−60° C.) and stirring continued for 45 minutes. Hunig's base (diisopropylethylamine, 509 mL, 2.92 mole) was then added dropwise (T<−60° C.), the mixture was stirred for 45 minutes and then quenched with 1N hydrochloric acid solution (cold, 1.5L) while warming to 0° C. The layers were separated and the organic layer was washed twice with hydrochloric acid (700 mL of 2N, then 500 mL of 1N), dried over magnesium sulfate, filtered and concentrated in vacuo to give (−)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one as tan, crystalline solids, 137 g (93%). NMR (CDCl3) 67 2.81 (m, 2, CH2), 2.91 (s,3H, CH3) 4.02 (q, J=9 Hz, 1H, CH), 4.38 (dd, J=9.1, 1.9 Hz), 7.21-7.39 (m, 5H, Ar), 9.17 (d, J=1.9 Hz, 1H, CHO).
Reaction SMILES: ClCl.[SiH](CC)(CC)CC.[C:10]([OH:16])([C:12]([F:15])([F:14])[F:13])=[O:11].C(O)(C(F)(F)F)=O.[NH2:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27].[NH2:31][C:32]1[CH:48]=[CH:47][C:35]([C:36]([NH:38][C@H:39]([C:44]([OH:46])=[O:45])[CH2:40][CH2:41][S:42][CH3:43])=[O:37])=[CH:34][C:33]=1[CH3:49]>>[NH2:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27].[OH:16][C:10]([C:12]([F:15])([F:14])[F:13])=[O:11].[NH2:31][C:32]1[C:33]2[C:34](=[CH:26][CH:25]=[CH:28][CH:49]=2)[C:35]([C:36]([NH:38][C@H:39]([C:44]([OH:46])=[O:45])[CH2:40][CH2:41][S:42][CH3:43])=[O:37])=[CH:47][CH:48]=1
Reactant: CSCC[C@H](NC(=O)c1ccc(N)c(C)c1)C(=O)O
Agent: CC[SiH](CC)CC
Agent: ClCl
Agent: N[C@@H](CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)c1ccc(N)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-BOC-S-trityl-cysteine-4-amino-1-naphthoyl methionine methyl ester (83.3 mg, 0.11 mmol) was taken up in THF (0.7 ml) and to this mixture was added 0.5M LiOH (0.43 ml) at 0° C. The mixture was stirred at 0° C. for 35 minutes. The solvent was removed in vacuo using a cold water bath. The residue was worked up as described for TFA-cysteine-4-amino-3-methylbenzoyl methionine in Example 2, and 74.1 mg of the free acid was obtained. This was then dissolved into CH2 Cl2 (1 ml) and Et3SiH (0.015 ml) was added followed by TFA (1 ml). The reaction mixture was stirred at room temperature for 1 h and worked up as further described for TFA-cysteine-4-amino-3-methylbenzoyl methionine in Example 2. After lyophilization, 42.4 mg of crude material was obtained which was then purified on the HPLC using 0.1% TFA in water and acetonitrile. mp 121°-125° C.; [α]25D =+2.4°(c=0.8, H2O); 1H NMR (CD3OD) 2.03-2.13 (4 H, m), 2.22-2.36 (1 H, m), 2.59-2.74 (2 H, m), 3.16-3.33 (2 H, m), 4.42 (1 H, m), 4.84-4.89 (1 H, m), 7.57-7.61 (2 H, m), 7.64 (1 H, d, J=7.7 Hz), 7.70 (1 H, d, J=7.7 Hz), 8.08-8.11 (1 H, m), 8.29-8.32 (1 H, m), 8.98 (1 H, d, J=7.7 Hz); 13C NMR (CD3OD) 15.19, 26.45, 31.50, 31.63, 53.20, 56.72, 122.52, 123.43, 126.43, 126.12, 127.02, 127.96, 128.32, 129.49, 132.27, 134.15, 135.12, 168.11, 172.41, 175.17; anal. calc. for C21H23F3N3O6S2, C: 47.19, H: 4.34, N: 7.86; found, C: 46.53, H: 4.56, N: 7.59; Note: difference for C is 0.65.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.IC1C2C(=O)N(COCC[Si](C)(C)C)N=CC=2N(COCC[Si](C)(C)C)C=1.[CH2:55](B(O)O)[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[CH2:55]([C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1)[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: OB(O)CCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Br)cn2COCC[Si](C)(C)C)c1=O
Agent: C[Si](C)(C)CCOCn1ncc2c(c(I)cn2COCC[Si](C)(C)C)c1=O
Product: C[Si](C)(C)CCOCn1ncc2c(c(CCc3ccccc3)cn2COCC[Si](C)(C)C)c1=O
Yield: 77.6 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 18-(c) except for using 855 mg (1.80 mmol) of 3-bromo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 20-(a) in place of 3-iodo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 965 mg (6.43 mmol) of phenethylboronic acid in place of methylboronic acid, respectively, whereby 698 mg of the title compound was obtained as an orange oil. (Yield: 78%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH2:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]2[O:28][CH2:29][CH2:30][C:26]=2[CH:25]=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:22]([CH2:23][C:24]1[CH:32]=[CH:31][C:27]3[O:28][CH2:29][CH2:30][C:26]=3[CH:25]=1)[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: NCc1ccc2c(c1)CCO2
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A mixture of 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (2.3 g), 5-aminomethyl-2,3-dihydrobenzo[b]furan (2.0 g), triethylamine (2.3 ml) and methanol (23 ml) was stirred at 50° C. for 24 hrs. The reaction mixture was concentrated, 1N-hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4N-Hydrochloric acid-ethyl acetate solution (8 ml) was added to the residue at room temperature, and the mixture was stirred for 12 hrs. The reaction mixture was concentrated under reduced pressure and the obtained crystals were washed with diethyl ether to give the title compound (1.98 g).