Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[OH:3][CH:4]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8](=O)[C:7]([CH3:14])=[CH:6][CH:5]1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.Cl.[CH3:22][O:23][NH2:24].[OH-].[Na+]>O.N1C=CC=CC=1>[CH3:22][O:23][N:24]=[C:8]1[CH2:9][C:10]([CH3:12])([CH3:11])[CH:4]([OH:3])[CH:5]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[C:7]1[CH3:14]
Reactant: CON
Reactant: CC1=CC(N2CCCCC2)C(O)C(C)(C)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CON=C1CC(C)(C)C(O)C(N2CCCCC2)C=C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a methanol solution (30 ml) containing the 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1-one obtained in Example 16 (3 g, 12.5 millimoles) were added methoxyamine hydrochloride (1.57 g, 18.8 millimoles) and pyridine (3.0 g), and the mixture was stirred first at room temperature and then while slowly heating to 55° C., and after 5 hours of stirring at that temperature, it was allowed to stand at room temperature overnight. The reaction solution was then poured into water and alkalified with a 10% aqueous sodium hydroxide solution (20 ml). The aqueous solution was subjected to extraction with benzene and dried over anhydrous magnesium sulfate. The benzene solution was concentrated under reduced pressure, to obtain 3.49 g of 5-hydroxy-4-piperidino-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime as crude crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:6]=2[CH:20]=1.C[O-].[Na+].CI.[C:26](O)(=O)C>CN(C)C=O.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:26])[C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:6]=2[CH:20]=1
Reactant: CC(=O)O
Reactant: O=C1CN=C(c2ccc(O)cc2)c2cc(Cl)ccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: CN(C)C=O
Product: CN1C(=O)CN=C(c2ccc(O)cc2)c2cc(Cl)ccc21
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a solution of 6.5 g (0.022 mole) of 7-chloro-1,3-dihyro-5-(4-hydroxyphenyl)-2H-1,4-benzodiazepin-2-one in 40 ml of dimethylformamide was added 11.6 ml (0.055 mole) of 4.74 M sodium methoxide in methanol. After 90 min, the mixture was cooled in an ice bath and 9.4 g (0.066 mole) of methyl iodide was added dropwise with stirring. After 18 hr at room temperature the reaction mixture was acidified with acetic acid, and partitioned between 100 ml of dichloromethane and 100 ml of water. The water layer was extracted once more with dichloromethane. The combined dichloromethane extracts were evaporated to dryness. The residual product mixture was separated on a column of Florisil. The column was eluted with dichloromethane, ether and then ethyl acetate. The ethyl acetate fraction was evaporated and crystallized from methanol to give 0.40 g (6%) of product as colorless prisms, mp 225°-259°.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:35][CH2:36]1)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(Cl)c1
Temperature: 100 °C
Yield: 85.5 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (150 mg, 0.643 mmol), 3-chloro-N-cyclopropyl-4-(piperazin-1-yl)benzamide (216 mg, 0.772 mmol), (cyanomethyl)trimethylphosphonium iodide (250 mg, 1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22 mmol) were suspended in Propiononitrile (Volume: 1931 μl) and heated in a closed vial at 100° C. for 4 h. The reaction mixture became a dark brown solution with a precipitate. It was cooled to room temperature and the precipitate was filtered off, washed with MeCN (2 mL) and suspended in MeCN (15 mL) with heating and sonication. It was then cooled to ambient temperature, the precipitate was filtered off, washed with MeCN (2 mL) and dried in vacuum to afford (S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (272.4 mg, 0.550 mmol, 86% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 8.39 (d, J=4.3 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.3, 2.0 Hz, 1H), 7.66 (s, 1H), 7.16 (d, J=8.6 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.38 (s, 2H), 3.02 (br. s., 4H), 2.77-2.88 (m, J=0.8 Hz, 1H), 2.60 (td, J=12.6, 2.5 Hz, 1H), 2.49-2.55 (m, J=3.5, 1.8, 1.8 Hz, 4H), 2.04 (br. d, J=12.6 Hz, 1H), 1.86-1.87 (m, 0H), 1.84 (br. s., 1H), 1.64 (br. d, J=12.6 Hz, 1H), 1.32-1.57 (m, 3H), 0.61-0.72 (m, 2H), 0.51-0.61 (m, 2H); [M+H] calc'd for C26H31ClN6O2, 495; found, 495.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH3:23])[C:14]=2[C:18]([F:21])([F:20])[F:19])[C:9]=1[C:24]([N:26]([CH3:32])[CH2:27][C:28]([O:30]C)=[O:29])=[O:25])[CH2:4][CH2:5][CH3:6]>C1COCC1.CO>[CH2:3]([O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:22][CH3:23])[C:14]=2[C:18]([F:21])([F:20])[F:19])[C:9]=1[C:24]([N:26]([CH3:32])[CH2:27][C:28]([OH:30])=[O:29])=[O:25])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ccc2c(C(F)(F)F)c(OC)ccc2c1C(=O)N(C)CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc2c(C(F)(F)F)c(OC)ccc2c1C(=O)N(C)CC(=O)O
Yield: 69.1 %

Procedure:
Aqueous sodium hydroxide (2.5N, 2.7 mL, 1.2 eq) was added to a stirred solution of N-[[2-butoxy-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-methylglycine, methyl ester (2.35 g, 5.50 mmol) in THF (22 mL) and methanol (6 mL) at room temperature. After 11/2 hours the organic solvents were removed and the residue was taken up in water (250 mL). The aqueous phase was acidified to pH 1 with 10% HCl, then extracted with ethyl acetate. The extracts were combined, dried over MgSO4, and concentrated to give a solid which was triturated with petroleum ether to provide the title compound as a white solid (1.57 g, 69%), m.p. 152°-155° C.
Reaction SMILES: OC(C)(C)[C@@H]([NH:5]C(C1C2C(=NC=C(C3CCCCC3)N=2)NC=1)=O)C.[C:25]([O:28][CH2:29][CH2:30][C@:31]([OH:73])([C@@H:35]([C:53](=[O:72])[NH:54][C@H:55]([C:68]([O:70][CH3:71])=[O:69])[CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]#[C:66][CH3:67])=[CH:59][CH:58]=1)/[CH:36]=[CH:37]/[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:32](O)=[O:33])(=[O:27])[CH3:26].[CH2:74]([O:78][C:79]1[CH:84]=[CH:83][C:82]([CH2:85][C@H:86]([NH:91][C:92]([C@H:94]([C@@:112]([OH:124])([CH2:120][C:121]([O-])=[O:122])[C:113]([O:115]C(C)(C)C)=[O:114])/[CH:95]=[CH:96]/[CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][C:103](=[O:111])[CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110])=[O:93])[C:87](OC)=[O:88])=[CH:81][CH:80]=1)[C:75]#[C:76][CH3:77]>>[C:25]([O:28][CH2:29][CH2:30][C@:31]([C@H:35](/[CH:36]=[CH:37]/[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](=[O:52])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:53]([NH:54][C@@H:55]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][C:65]#[C:66][CH3:67])=[CH:59][CH:58]=1)[C:68]([O:70][CH3:71])=[O:69])=[O:72])([C:32](=[O:33])[NH2:5])[OH:73])(=[O:27])[CH3:26].[CH2:74]([O:78][C:79]1[CH:80]=[CH:81][C:82]([CH2:85][C@H:86]([NH:91][C:92]([C@@H:94](/[CH:95]=[CH:96]/[CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][C:103](=[O:111])[CH2:104][CH2:105][CH2:106][CH2:107][CH2:108][CH2:109][CH3:110])[C@@:112]([OH:124])([CH2:120][CH2:121][OH:122])[C:113]([OH:115])=[O:114])=[O:93])[CH2:87][OH:88])=[CH:83][CH:84]=1)[C:75]#[C:76][CH3:77]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)O)C(=O)OC)cc1
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)[O-])C(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: C[C@H](NC(=O)c1c[nH]c2ncc(C3CCCCC3)nc12)C(C)(C)O
Product: CC#CCOc1ccc(C[C@@H](CO)NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)O)cc1
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(N)=O)C(=O)OC)cc1

Procedure:
No. 6801995, methyl (S)-2-[(E)-(S)-2-((S)-3-acetoxy-1-carbamoyl-1-hydroxy-propyl)-11-oxo-octadec-3-enoylamino]-3-(4-but-2-ynyloxy-phenyl)-propionate (ESI (LC/MS positive mode) m/z 685 (M+H); Rt 3.40 min.) was synthesized by the synthesis similar to that of No. 5453635, 2-cyclohexyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-hydroxy-1,2-dimethyl-propyl)-amide, except that No. 5214354, (E)-(2S,3S)-2-(2-acetoxy-ethyl)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-12-oxo-nonadec-4-enoic acid was used instead of No. 5317776, 1-tert-butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate. From methyl (S)-2-[(E)-(S)-2-((S)-3-acetoxy-1-carbamoyl-1-hydroxy-propyl)-11-oxo-octadec-3-enoylamino]-3-(4-but-2-ynyloxy-phenyl)-propionate, the title compound was obtained by the synthesis by a synthetic method similar to that of No. 5257016, (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-hydroxymethyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoic acid.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:31])OCC(Cl)(Cl)Cl)[C:5]=1[CH3:32])(=[O:3])[CH3:2].[OH:33][CH2:34][CH2:35][NH2:36]>>[C:1]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24]([NH:36][CH2:35][CH2:34][OH:33])=[O:31])[C:5]=1[CH3:32])(=[O:3])[CH3:2]
Reactant: NCCO
Reactant: CC(=O)c1c(C)c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Product: CC(=O)c1c(C)c(NC(=O)NCCO)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 66 %

Procedure:
Using 2,2,2-trichloroethyl (7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 206 and 2-hydroxyethylamine, the title compound was obtained in the same manner as in Example 143. Yield: 66%.
Reaction SMILES: COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:40][CH:39]([N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[NH:43][C:42]3=[O:50])[CH2:38]2)[CH2:33][CH2:32]1)=[O:30].C(Cl)(=O)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[CH3:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:40][CH:39]([N:41]3[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]([S:56]([CH3:55])(=[O:58])=[O:57])[C:42]3=[O:50])[CH2:38]2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N1CCC(N2CC(n3c(=O)[nH]c4ccccc43)C2)CC1
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CC(=O)Cl
Product: COC(=O)N1CCC(N2CC(n3c(=O)n(S(C)(=O)=O)c4ccccc43)C2)CC1

Procedure:
Example 12 was repeated except that the 1-[1-(1-methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-methoxycarbonylpiperidin-4-yl)-azetidin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 4 and that acetyl chloride was replaced with methanesulfonyl chloride. The title compound was obtained which was colorless and amorphous.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(OC(C)C)OC(C)C>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Fc1ccc(Nc2ncnc3ccc(Br)cc23)cc1Cl
Reactant: CC(C)OB(OC(C)C)c1cccs1
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(-c4cccs4)cc23)cc1Cl
Yield: 36 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was heated to reflux for 3 hours, 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 2-thienylboronate to give 4-(3-chloro-4-fluoroanilino)-6-(2-thienyl)quinazoline in 36% yield, m.p. 205-208° C.;
Reaction SMILES: I[C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][C:9]([CH:14]=[O:15])=[CH:10][CH:11]=3)[C:4]=2[NH:5][N:6]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)(O)[O-].[Na+]>COCCOC.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>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[C:3]3[CH2:13][C:12]4[C:7](=[CH:8][C:9]([CH:14]=[O:15])=[CH:10][CH:11]=4)[C:4]=3[NH:5][N:6]=2)=[CH:17]1
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1ccc2c(c1)-c1[nH]nc(I)c1C2
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: COCCOC
Solvent: O
Product: O=Cc1ccc2c(c1)-c1[nH]nc(-c3ccsc3)c1C2
Yield: 30 %

Procedure:
A mixture of Example 319 (930 mg, 3.0 mmol), 3-thienylboronic acid (384 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.21 mmol) and sodium bicarbonate (630 mg, 7.5 mmol) in 1,2-dimethoxyethane (18 mL) and water (6 mL) was stirred under nitrogen in a heavy walled process vial in a microwave synthesizer at about 160° C. for about 10 minutes. The mixture was concentrated under vacuum and the residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (3:1) as eluent to provide 240 mg (30%) of the desired product. MS (ESI): m/z 267 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:11]=1[C:12]([O:14]CC)=O.C[CH:25]([C:29](Cl)=[O:30])[C:26](Cl)=[O:27].[Na].C[C:34]([CH3:36])=[O:35]>C(O)C>[OH:14][C:12]1[C:11]2[C:10](=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][CH:17]=2)[NH:9][C:26](=[O:27])[C:25]=1[C:29]([O:35][CH2:34][CH3:36])=[O:30]
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: CC(C)=O
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ccc([N+](=O)[O-])cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
7.7 ml of triethylamine (55 mmol) were added dropwise to a suspension of 10.0 g of ethyl 2-amino-4-nitrobenzoate hydrochloride (4.3 mmol) in 100 ml of acetone. Subsequently, 6.55 ml of methylmalonyl chloride (52 mmol) were added. The reaction mixture was left to stir at room temperature for 48 hrs., concentrated and then treated with a solution of 4.2 g of sodium (183 mmol) in 110 ml of ethanol. The reaction mixture was boiled at reflux for 2.5 hrs. After removing the solvent the residue was taken up in 200 ml of water and heated to 60° C. for 1 hr. Subsequently, the mixture was filtered over Dicalite and thereafter the pH value was adjusted to pH=3.5 with 3N HCl. The precipitate which thereby separated was filtered off, washed with water and dried in a high vacuum. There were obtained 7.2 g of ethyl 4-hydroxy-7-nitro-2-oxo-1,2-dihydro-quinoline-3-carboxylate (60%) as beige crystals.
Reaction SMILES: ClC1C=C(CCC[N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])NC2SC(SCC(O)=O)=CN=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][C:42](O)=O)[CH:37]=[CH:38][CH:39]=1.C([O:47][C:48](=[O:59])[C:49]([S:52][C:53]1[S:57][C:56]([NH2:58])=[N:55][CH:54]=1)([CH3:51])[CH3:50])C>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][CH2:42][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:58][C:56]2[S:57][C:53]([S:52][C:49]([CH3:50])([CH3:51])[C:48]([OH:47])=[O:59])=[CH:54][N:55]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: COc1cccc(CCC(=O)O)c1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Product: COc1cccc(CCCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)c1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 3-(3-methoxy-phenyl)-propionic acid and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(C)C.[OH-].[K+]>CO.C1(C)C=CC=CC=1>[C:6]([C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: C#Cc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Reaction time: 2 h

Procedure:
To a solution of 6-trimethylsilylethynyl-8-(3-nitrophenyl)-1,7-naphthyridine (77 mg, 0.22 mmol) in methanol (0.5 ml) and toluene (0.5 ml) is added 1N potassium hydroxide (0.22 ml). The mixture was stirred for 2 h. The suspension is filtered and the product washed with water and ether affording the title compound. Mass M+H 276; mp 215° C. decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.CN(C)C=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.C(OCC)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)=[CH:26][CH:25]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1ccc(C(O)c2cc(F)ccc2F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 62.6 %

Procedure:
The 2-[(2,5-difluorophenyl)-hydroxymethyl]-5-methylpyridine (125 mg, 0.53 mmol) obtained in Referential Example 5 was dissolved in thionyl chloride (1.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration. The residue was dissolved in dimethylformamide (5 ml). To the resulting solution were added 4-chlorobenzenethiol (115 mg, 0.80 mmol) and potassium carbonate (438 mg, 3.18 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (120 mg, 66%) as an oil.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1S[C:15](=[O:24])[CH2:16][CH2:17][C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1>CCOCC.C1COCC1>[C:18]1([CH2:17][CH2:16][C:15]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: O=C(CCC1=CCCCC1)Sc1ccccn1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCC1=CCCCC1)C1CCCC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 72 %

Procedure:
Cyclopentylmagnesium bromide (1.6 mL, 3.15 mmol, 2M soln in ether) was added to a cooled −78° C. solution of 3-Cyclohex-1-enyl-thiopropionic acid S-pyridin-2-yl ester (0.65 g, 2.63 mmol, from Step 3) dissolved in THF (10 mL). The reaction mixture was stirred for 45 min at −78° C. and then warmed up to rt. The reaction was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0% to 5% EtOAc in hexanes) to give the title compound as a clear oil (0.39 g, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.S(OC)(O[CH3:13])(=O)=O.Cl>[OH-].[Na+]>[OH:8][C:6]1[CH:5]=[CH:4][N:3]([CH3:13])[C:2](=[O:1])[CH:7]=1
Reactant: Oc1ccnc(O)c1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc(O)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
2,4-Dihydroxypyridine (3.0 g) was dissolved in 2N aqueous sodium hydroxide solution (30 ml) and dimethyl sulphate (3.7 g) was added dropwise over 90 minutes. The mixture was stirred at room temperature overnight, acidified with concentrated hydrochloric acid, the solvent removed under reduced pressure, the residue stirred in 5% methanol/dichloromethane and filtered. The filtrate was evaporated and the crude product was chromatographed on silica using 7:93 methanol: dichloromethane as the eluent to yield 1,2-dihydro-4-hydroxy-1-methyl-2-oxopyridine (0.77 g) as a yellow solid. m.p. 165-169° C. Found: C,57.28; H,5.47; N,10.89. C6H7NO2 requires C,57.59; H,5.64; N,11.19%.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:10])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][C:15](S)=[CH:14][CH:13]=1.C(N(CC)CC)C.O[O:27][S:28]([O-:30])=O.[K+]>CO.O>[C:1]([NH:4][C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:10][S:28]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)(=[O:30])=[O:27])(=[O:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: Fc1ccc(S)cc1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](CS(=O)(=O)c1ccc(F)cc1)NC(C)=O
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of methyl 2-acetamidoacrylate (10.0 g, 69.9 mmol) in 100 mL of methanol, cooled to zero degrees C., was added 4-fluorothiophenol (7.44 mL, 69.9 mmol) followed by triethylamine (9.74 mL, 69.9 mmol). The mixture stirred under a nitrogen atmosphere for 4 hours. The solution was poured into a slurry of Oxone® (86 g, 140 mmol) in H2O (250 mL) and MeOH (125 mL). After stirring at room temperature for 18 hours, the mixture was partitioned between EtOAc (200 mL) and H2O and washed with saturated NaHCO3 (3×100 mL) and brine (1×100 mL). After concentration in vacuo, trituration with diethyl ether afforded the title compound as a white solid (16.3 g, 77%): MS MH+ calcd. for C12H14NO5SF: 304, found 304. HRMS calcd. for C12H14NO5SF: 303.0577, found: 303.0581.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH:27]1([S:31]([Cl:34])(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28]1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[ClH:34].[NH2:16][C@H:15]([C:24](=[O:26])[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:14][CH2:13][CH2:12][NH:11][S:31]([CH:27]1[CH2:30][CH2:29][CH2:28]1)(=[O:33])=[O:32]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)C1CCC1
Product: Cl
Product: N[C@@H](CCCNS(=O)(=O)C1CCC1)C(=O)N1CCCC1

Procedure:
Starting from (S)-N5-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-ornithine, cyclobutanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 3.