Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][CH2:8][C:9]([CH3:28])([CH3:27])[CH2:10][CH:11]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26])[CH2:12][N+:13]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>CO.[Zn]>[NH2:13][CH2:12][CH:11]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26])[CH2:10][C:9]([CH3:28])([CH3:27])[CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:30])[CH3:29]
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC(C[N+](=O)[O-])C1C(=O)Nc2cc(Cl)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC(CN)C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of racemic 3-[5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-1-nitromethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one (0.5 g, 1.1 mmol) in methanol (20 mL) was added an aqueous solution (5 mL) of ammonium chloride (0.6 g, 11 mmol), followed by the addition of Zinc (Aldrich, activated) (0.7 g, 11 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to a small volume, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated to give racemic 3-[1-aminomethyl-5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one as a white foam (0.4 g, 86%)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Cl.N1C=CC=CC=1>CC(O)=O>[C:5]1([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(/C=C/c2cc(OC)cc(OC)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Temperature: 90 °C

Procedure:
To a 250 mL round-bottomed flask equipped with a magnetic stir bar was added 8 (2.7 g, 10 mmol) and pyridine hydrochloride (10.4 g, 90 mmol, 9 equiv). A reflux condenser was equipped and the reaction mixture was refluxed for 2 h under an N2 atmosphere. Afterwards, the mixture was allowed to cool to ˜90° C. and quenched into H2O (200 mL) whereupon a purplish colored solid precipitated. The mixture was extracted with EtOAc (50 mL×3). The extracts were collected and diluted with hexanes (100 mL) and then filtered through a thin pad of silica gel to remove dark colored, polar impurities. The filtrate was evaporated in vacuo leaving an off-white solid. The crude product was slurried with HOAc and filtered to give resveratrol as a tan microcrystalline powder (450 mg, 20%), mp. 258-261° C., lit. 261° C. 1H NMR (DMSO): δ 9.59 (s, OH), 9.23 (s, 20H), 7.41 (d, J=8.9 Hz, 2H), 6.95 (d, Jab=16.3 Hz, 1H), 6.82 (d, Jab=16.3 Hz, 1H), 6.76 (d, J=8.9 Hz, 2H), 6.39 (d, J=2.0 Hz, 2H), 6.13 (t, J=2.1 Hz, 1H); 13C NMR (DMSO): δ 158.58, 157.28, 139.36, 128.15, 127.96, 127.92, 125.74, 115.61, 104.41, 101.87. Anal. Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.40; H, 5.44.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1(/[CH:14]=[CH:15]/[C:16]([O:18][CH:19]2[C:36]([CH3:38])([CH3:37])[O:35][C:34]3[C:21](=[C:22]4[C:31](=[C:32]([O:39][CH3:40])[CH:33]=3)[C:30](=[O:41])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]5[CH:45]=[CH:44][CH:43]=[CH:42][C:28]5=3)[N:23]4[CH3:46])[CH:20]2[OH:47])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1(/[CH:14]=[CH:15]/[C:16]([O:18][CH:19]2[C:36]([CH3:38])([CH3:37])[O:35][C:34]3[C:21](=[C:22]4[C:31](=[C:32]([O:39][CH3:40])[CH:33]=3)[C:30](=[O:41])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]5[CH:45]=[CH:44][CH:43]=[CH:42][C:28]5=3)[N:23]4[CH3:46])[CH:20]2[O:47][C:1](=[O:3])[CH3:2])=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(O)C(OC(=O)/C=C/c1ccccc1)C(C)(C)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(OC(C)=O)C(OC(=O)/C=C/c1ccccc1)C(C)(C)O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
31 mmol of acetic anhydride are added to a previously cooled solution of 0.18 mmol of the compound of Example 35 in 3 ml of pyridine. After stirring at ambient temperature for 3 days, the reaction mixture is evaporated under reduced pressure. Chromatography over silica gel (cyclohexane/acetone: 94/6) allows the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4]([CH:3]=1)=[C:5]([Cl:16])[CH:6]=[CH:7][N:8]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2nccc(O)c2cc1Br
Product: Cc1nc2nccc(Cl)c2cc1Br
Temperature: 95 °C
Reaction time: 1 h

Procedure:
In a similar manner to Example B1, a mixture of 6-bromo-7-methyl-1,8-naphthyridin-4-ol (3.7 g) and phosphorus oxychloride (25 ml) was stirred at 95° C. for 1 hour to give 3-bromo-5-chloro-2-methyl-1,8-naphthyridine, m.p. 160°-164° C.
Reaction SMILES: [C:1]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CC[CH2:21][CH2:20]1.[H-].[Na+].C(I)C>O>[CH2:20]([N:13]1[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12]1)[CH3:21]
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2ccccc2)c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCI
Product: CCOC(=O)c1cc(C(=O)c2ccccc2)n(CC)c1
Reaction time: 0.5 h

Procedure:
Ethyl 5-benzoylpyrrole-3-carboxylate (0.973 g., 4 mmoles) was dissolved in 40 ml. of dry tetrahydrofuran. To the stirred solution, under nitrogen, there was added sodium hydride dispersion in oil (57%, 0.173 g., 4 mmoles), and the mixture was stirred for 0.5 hour. Ethyl iodide (1.25 g., 8 mmoles) was added and stirring continued for 6 hours. Additional sodium hydride (0.17 g.) and ethyl iodide (1.25 g.) was added and reflux continued for an additional 104 hours. Like quantities of sodium hydride and ethyl iodide were added after 16 hours reflux and a like quantity of ethyl iodide after 24 hours reflux. The reaction was cooled and excess sodium hydride decomposed by cautious addition of 40 ml. of water. The product was extracted into 40 ml. of ether, the ether back-washed with 10 ml. of water, and evaporated to dryness to yield ethyl 1-ethyl-5-benzoylpyrrole-3-carboxylate (1 g.), used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:28])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:21][C:22]=1[F:27]
Reactant: COC(=O)CCCBr
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)CCCOc1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2C)cc1F

Procedure:
In analogy to example 221, step 6, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 324, step 1) was reacted with methyl 4-bromobutyrate in N,N-dimethylacetamide in the presence of cesium carbonate to give the title compound as a colourless foam, MS (ESI+): m/z=500.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].[CH3:40][S:41]([OH:44])(=[O:43])=[O:42].[O-]S([O-])(=O)=O.[Zn+2:50]>>[Zn:50].[CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].[CH3:40][S:41]([OH:44])(=[O:43])=[O:42]
Reactant: [Zn+2]
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Agent: CS(=O)(=O)O
Agent: O=S(=O)([O-])[O-]
Product: [Zn]

Procedure:
50 mM solution of Desferal (Desferrioxamine B) is mixed with 1/5 the volume of 50 mM solution of ZnSO4 (zinc sulfate heptahydrate, Aldrich Chemical Co., Inc.). The mixture is heated to for 45 min. to 40° C. and cooled to form the resultant Zn/Desferrioxamine (5 nM) complex. The ratio Zn/Desferal is 0.2:1.0
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C@@H:3]1[C:9]([O-:11])=[O:10]>P([O-])([O-])([O-])=O>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9]([OH:11])=[O:10]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 30 °C
Reaction time: 96 h

Procedure:
Bacillus sp. DC-1 was cultivated in the same manner as in Example 38 and 0.5 g (wet weight) of cells was obtained from 100 ml of the cultured solution by centrifugation. After the harvested cells were suspended in 10 ml of 0.1M phosphate buffer solution (pH 8.0), 1.0 g of methyl (±)-cis, trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylate (cis/trans ratio=45/55) was added to the suspension and the mixture was stirred at 30° C. for 96 hours. Extraction and isolation from the resulting mixture was performed in the same manner as in Example 38, thereby 0.277 g of 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid was obtained. All of the starting methyl 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylate were recovered as it was excluding that which had been converted to 2,2-dimethyl-3(2,2-dichlorovinyl)cyclopropane carboxylic acid.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[NH:8][CH2:7][C@@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(Cl)Cl>[OH:9][C@@H:6]1[CH2:7][N:8]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@@H:3]([CH3:2])[CH2:4][CH2:5]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1CC[C@H](O)CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of ±trans-6-methylpiperidin-3-ol hydrochloride (14.0 g, 0.092 mol) in CH2Cl2 (150 mL) was cooled to 0° C. Triethylamine (51.5 mL, 0.369 mol) was added slowly. CbzCl (13.59 mL, 0.092 mol) was added dropwise, keeping the temperature below 20° C. The reaction was allowed to warm overnight to room temperature. The reaction was quenched by addition of water and diluted further with additional CH2Cl2. The layers were separated and the organics were dried over MgSO4 and concentrated. The crude material was purified by silica gel gradient chromatography (0-75% ethyl acetate in hexanes), providing ±Benzyl trans-5-hydroxy-2-methylpiperidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[OH:10])C=NC=1.[Br:27][C:28]1[N:33]=C(/C=C/C2C=C(F)C=CC=2F)C=C[N:29]=1>>[Br:27][C:28]1[N:33]=[C:4]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[C@@H:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[OH:10])[CH:3]=[CH:2][N:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cncc(Br)c1)[C@H](O)c1cc(F)ccc1F
Reactant: Fc1ccc(F)c(/C=C/c2ccnc(Br)n2)c1
Product: CC(C)(C)OC(=O)N[C@H](c1ccnc(Br)n1)[C@H](O)c1cc(F)ccc1F

Procedure:
Prepared according to the same procedure as tert-butyl (1R,2R)-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate, starting with (E)-2-bromo-4-(2,5-difluorostyryl)pyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=5.2 Hz, 1H), 7.65 (d, J=5.2 Hz, 1H), 7.45 (d, J=9.8 Hz, 1H), 7.29 (ddd, J=9.0, 5.3, 3.4 Hz, 1H), 7.22-7.10 (m, 2H), 5.82 (d, J=5.2 Hz, 1H), 5.46-5.30 (m, 1H), 4.85 (dd, J=9.8, 3.1 Hz, 1H), 1.29-1.03 (m, 9H), Mass spec.: 432.1 (MH)+.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:35])(=[O:34])[NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:13][CH:12]=2)=[C:8]([C:36]([O:38]CC)=[O:37])[N:7]([C:41]2[CH:46]=[C:45]([NH:47][C:48](=[O:53])[CH2:49][CH2:50][CH2:51][CH3:52])[CH:44]=[CH:43][C:42]=2[Cl:54])[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CO.Cl>O>[CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:35])(=[O:34])[NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:13][CH:12]=2)=[C:8]([C:36]([OH:38])=[O:37])[N:7]([C:41]2[CH:46]=[C:45]([NH:47][C:48](=[O:53])[CH2:49][CH2:50][CH2:51][CH3:52])[CH:44]=[CH:43][C:42]=2[Cl:54])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Nc1ccc(Cl)c(-n2nc(CCCC)c(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCC(=O)Nc1ccc(Cl)c(-n2nc(CCCC)c(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2C(=O)O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 39.5 mg (0.05 mmol) of ethyl 3-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-1-[2-chloro-5-(valerylamino)phenyl]-1H-pyrazole-5-carboxylate (from Example 1), 200 μL (0.5 mmol) of 2.5N NaOH, and 600 μL of methanol was stirred under N2 at 60° C. for 2 hours. The solution was cooled, diluted with 5 mL of H2O, and adjusted to approximately pH 2 by gradual addition of 2N HCl, resulting in precipitation. The precipitate was collected on a filter and dried to yield 37.8 mg (97%) of the title compound as a nearly white solid, mp>110° C. (gradual); homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 761 (M+1)+. 400 MHz 1H NMR (DMSO-d6) δ0.80 (t, J=7.3 Hz, 3H), 0.88, (t, J=7.3 Hz, 3H), 1.24, 1.31 (overlapping m, each 2H), 1.47 (m, 2H), 1.57 (m, 2H), 2.31 (t, J=7.4 Hz, 2H), 2.48 (t, 2H, partially obscured by DMSO peak), 4.18 (br, 2H), 7.09 (d, J=7.4 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 7.27-7.74 (m, 10H), 7.87 (d, J=2.5 Hz, 1H), 8.17 (dd, J=8.0, 1.3 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)(=[N:4]C(=O)C(F)(F)F)=[O:3].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][S:2]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)(=[NH:4])=[O:3]
Reactant: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CCc1ccc(S(C)(=N)=O)cc1
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
Methyl 3-{4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}propanoate (0.200 g, 0.653 mmol) was dissolved in MeOH (3 mL). K2CO3 (0.450 g, 3.27 mmol) was added to the solution, and the resulting suspension was allowed to stir for 5 minutes. The suspension was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc and dried over anhydrous Na2SO4(S) to give the title compound (0.147 g, 93%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[N:9]=[C:4]2[NH:3]1.[H-].[Na+].[N:22]1[C:30]2[CH2:29][C@H:28]([CH2:31]OS(C)(=O)=O)[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>CN(C)C=O>[N:22]1[C:30]2[CH2:29][C@H:28]([CH2:31][N:3]3[C:4]4=[N:9][C:8]([C:10]5[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=5)=[CH:7][C:6](=[O:16])[N:5]4[CH2:17][CH2:18][C:2]3([CH3:19])[CH3:1])[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)CCn2c(nc(-c3ccncc3)cc2=O)N1
Reactant: CS(=O)(=O)OC[C@@H]1Cc2cccnc2C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC1(C)CCn2c(nc(-c3ccncc3)cc2=O)N1C[C@@H]1Cc2cccnc2C1
Temperature: 45 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a solution of 0.226 g (0.88 mmol) of 8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 5 ml of anhydrous dimethylformamide was added 0.040 g (0.97 mmol) of sodium hydride (60% suspension in mineral oil) and the mixture was allowed to stir at 45° C. for 3 hours. 0.20 g (0.88 mmol) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl ester was added and the stirring continued at 80° C. for 18 h. The mixture was cooled and a solution of saturated ammonium chloride was added. The mixture was extracted with trichloromethane/methanol 90/10. The extracts were washed with a saturated aqueous solution of sodium chloride, dried and evaporated to give crude product. Purification by chromatography on silica gel eluting with a mixture of ethyl acetate/ethanol in the proportions 100/0 to 70/20, gives 0.197 g (58%) of the compound in the form of free base. Mp.: 202-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=O)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:18]([N:20](CC)CC)C.C(Cl)(=O)OCC.CN>C1COCC1.O>[CH3:18][NH:20][C:15](=[O:17])[CH2:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)CCc1nc(-c2ccc(Cl)cc2)co1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.4 g) in THF (20 ml) were added triethylamine (0.33 ml) and ethyl chlorocarbonate (0.23 ml) at -30° C., followed by stirring for 30 minutes at the same temperature. The mixture was poured into 30% methylamine aqueous solution (10 ml), and the resultant was stirred for 15 minutes at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4. The solvent was distilled off to give crystals of N-methyl-4-(4-chlorophenyl)-2-oxazolepropion-amide (0.375 g, 89%). Recrystallization from dichloromethane-ethanol gave colorless prism crystals of mp 169°-170° C.
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[CH:13]1([CH2:18][CH2:19][OH:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:18][CH2:19][O:20][NH2:2])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OCCC1CCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: NOCCC1CCCC1

Procedure:
Prepared by a similar procedure as described for preparation 31. Starting materials: N-hydroxyphthalimide and 2-cyclopentylethanol (Lancaster). 13C-NMR (CDCl3) δ 75.7, 37.0, 34.6, 32.8, 25.1.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:9]([C:10](O)=[O:11])[CH:8]=1)=[O:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>O1CCCC1.CN(C)C=O>[CH:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:9]([C:10]([NH:20][C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[O:11])[CH:8]=1)=[O:2]
Reactant: O=COCCOc1cc(C(=O)O)nc2ccccc12
Reactant: Nc1nnn[nH]1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=COCCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12

Procedure:
N,N'-Carbonyldiimidazole (1.55 g) was added to 4(2-formyloxyethoxy)quinaldic acid (2.5 g) in hot tetrahydrofuran (200 ml) and the solution was heated under reflux for 1.5 hours. 5-Aminotetrazole (0.85 g) in dimethylformamide (4 ml) was added and the mixture was heated under reflux for 2.5 hours. 4(2-Formyloxyethoxy)-N(1H-tetrazol- 5-yl)quinaldamide was filtered off and dried, m.p. 263° .
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[S-:17].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[SH:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: N#Cc1ccc(-c2ccc(I)cc2)cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(-c2ccc(S)cc2)cc1
Temperature: 100 °C
Yield: 106.6 %

Procedure:
3.25 g (10.8.10-3 mol) of 4-(4-iodophenyl)benzonitrile are dissolved in 50 ml of hexamethylphosphoramide, and 3.05 g (43.4.10-3 mol) of sodium thiomethylate are then added to the solution. The reaction mixture is heated at 100° C. for 1.5 hours and then, after cooling, hydrolyzed in a 1N hydrochloric acid/ice mixture. The expected product is extracted with ethyl acetate. The resulting organic phase is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and then evaporated under reduced pressure to give 2.4 g (quantitative yield) of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.[CH3:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([C:23](OC)=[O:24])=[N:21][CH:22]=1)(=[O:16])=[O:15].Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23](=[O:24])[C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][N:21]=1
Reactant: Nc1ccccc1Cl
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cn1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)nc1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Chloroaniline (1.20 g, 0.0093 mol) in toluene (20 mL) was added to trimethylaluminum (2.0 M 4.6 mL) then methyl 5-(methylsulfonyl)picolinate 4 (1.0 g, 4.65 mol) was added and the mixture was heated to 80-90° C. for 2 h. The reaction was cooled down and 1N HCl solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 as a light yellow solid. Yield: 1.26 g, 87.2%.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[S:12][CH2:13][CH2:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+]>CCO>[F:24][C:15]([F:23])([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:14][CH2:13][S:12][C:7]1[N:8]=[C:9]([CH3:11])[S:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(C)nc1SCCC(F)(F)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(SCCC(F)(F)c2ccc(F)cc2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
To a solution of 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.6 g, 1.6 mmol) in EtOH (1.5 ml) is added an aqueous solution (1.5 ml) of potassium carbonate (0.22 g, 4.0 mmol) and the mixture is stirred at RT for 16 h. After completion of the reaction, the solvent is evaporated and the residue is diluted with water (30 ml), acidified with 2M hydrochloric acid to pH 3 and extracted with EtOAc (3×40 ml) yielding 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-2-methyl-thiazole-5-carboxylic acid (0.41 g, 1.19 mmol, 74%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C@@H:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C@@H:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: COCCN(C)C(=O)CCl
Product: COCCN(C)CCOc1ccc(CCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1F
Yield: 45.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.5 mg) was obtained.