Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@:20]([O:52][CH3:53])([NH:21][C:22](=[O:51])[C:23](=[N:30][O:31]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19](=[O:54])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1>>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([NH:21][C:22](=[O:51])[C:23](=[N:30][OH:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([O:52][CH3:53])[C:19](=[O:54])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CO[C@@]1(NC(=O)C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc2)C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21
Solvent: COc1ccccc1
Product: CO[C@@]1(NC(=O)C(=NO)c2ccccc2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21

Procedure:
t-Butyl (6R,7S)-3-acetoxymethyl-7methoxy- 7-[2-triphenylmethoxyimino-2-phenylacetamido]-ceph-3-em-4-carboxylate (syn isomer) (400 mg, 0,535 mmole) was treated with anisole (2ml) and rifluoroacetic acid (8 ml) as described in Example 1(b) to give (6R,7S)-3-acetoxymethyl-7-[2-hydroxyimino-2-phenylacetamido]-7-methoxyceph-3-em-4-carboxylic acid (syn isomer) as an electrostatic white solid. (135 mg, 0.30 mmole). This acid was converted into the title compound by dissolving it in water containing sodium bicarbonate (25 mg, 0.298 mmole), filtering the solution and freeze-drying the filtrate to give the product as an amorphous solid (120 mg, 0.255 mmole, 51%), paper chromatography Rf 0.40 Rf/Rf cephaloram 0.78, λmax (pH6 buffer) 254 nm (ε 10,400).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C@H:5]([CH3:10])[CH2:6][C:7](O)=[O:8].[CH3:12][Si:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][OH:16].C1CCC(N=C=NC2CCCCC2)CC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:12][Si:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][O:16][C:7](=[O:8])[CH2:6][C@@H:5]([CH3:10])[CH2:4][C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)C[C@H](C)CC(=O)O
Reactant: C[Si](C)(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: ClCCl
Product: COC(=O)C[C@H](C)CC(=O)OCC[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
To the solution of 3-(R)-Methyl-pentanedioic acid monomethyl ester in methylene chloride was added 2-Trimethylsilanyl-ethanol followed by DCC and DMAP and was stirred for 30 minutes. The reaction mixture was treated with sodium bicarbonate and methylene chloride. The product was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[C:4]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:28]>>[Cl:1][C:2]1[C:3]([F:25])=[C:4]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8]([Cl:28])[CH3:9])[CH:7]=1
Reactant: CCOc1c(C(C)O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: CCOc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1

Procedure:
This compound was prepared according to the procedure of Example 13 step 6, using tert-butyl 3-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]azetidine-1-carboxylate (racemic) and cyanuric chloride as the starting materials.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2nc1-c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2ccccc2nc1-c1ccccc1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A mixture of 2-methyl-3-phenylquinoxaline (2.00 g, 9.08 mmol), NBS (1.45 g, 8.17 mmol) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (75 mL) was heated at reflux for 5 h, then allowed to cool to r.t. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue purified by column chromatography (SiO2, 0-20% EtOAc in heptane) to give the title compound (1.22 g, 45%) as a cream-coloured solid. δH (CDCl3) 8.11-8.19 (m, 2H), 7.75-7.85 (m, 4H), 7.52-7.62 (m, 3H), 4.76 (s, 2H). LCMS (ES+) 299.1, 301.1 (M+H)+, RT 4.10 minutes (Method 3).
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH2:11][NH:12][CH2:13][CH2:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-].[K+]>C(O)(C)(C)C.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]1([NH:15][C:2]2[C:10]3[C:9]4[CH2:11][NH:12][CH2:13][CH2:14][C:8]=4[NH:7][C:6]=3[N:5]=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccnc2[nH]c3c(c12)CNCC3
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
4-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (100 mg, 0.48 mmol), aniline (0.13 mL, 1.44 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), X-Phos (23 mg, 0.05 mmol), and KOH (162 mg, 2.89 mmol) were dissolved in tert-butanol (2.0 mL), and stirred overnight at 100° C. The reaction mixture diluted with EtOAc/H2O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude material was triturated with EtOAc, filtered, washed with EtOAc, and dried under vacuum to provide 3 (63 mg, 50% yield) as a tan solid. LC-MS (M+H=265, obsd.=265).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].[NH2:14][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>ClCCl>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:14][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[O:6])[CH3:3]
Reactant: COC(=O)[C@H](C)N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C

Procedure:
Boc-(L)-Ala-(L)-Ala-OMe was prepared as follows. Boc-(L)-Ala-OH (2.06 g, 10.63 mmol) was dissolved in distilled dichloromethane (5 mL). To the resulting solution was added H2N-(L)-Ala-OMe (0.996 g, 9.67 mmol) in 5 mL of distilled dichloromethane. Dicyclohexylcarbodiimide (abbr. DCC; 2.19 g, 10.63 mmol) was dissolved in 3 mL distilled dichloromethane and added to the solution. Dicyclohexylurea (abbr. DCU) precipitation was noted immediately after DCC addition. Triethylamine (3 mL, 21.52 mmol) and additional distilled dichloromethane (4 mL) were added to the reaction mixture. The reaction proceeded for a total of three hours, when TLC analysis indicated consumption of H2N-(L)-Ala-OMe starting material and formation of a new component. DCU precipitation was promoted by storing the reaction at −20° C. The precipitate was filtered through a Buchner funnel and rinsed with cold dichloromethane. The combined filtrate and rinses were dried under vacuum and purified by Silica chromatography to yield dipeptide Boc-(L)-Ala-(L)-Ala-OMe (2.03 g, 7.14 mmol, 74%). 1H-NMR (chloroform-d) δ (ppm): 1.34 (d, J=14.1 Hz, 3H); 1.38 (d, J=14.3 Hz, 3H); 1.40 (s, 9H); 3.73 (s, 3H); 4.14 (s-broad, 1H); 4.55 (quintet, J=14.5 Hz, 1H); 4.97 (s-broad, 1H); 6.59 (s-broad, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[C:22]([C:24]([O:26]CC)=[O:25])[N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[OH-].[Na+].O1CCCC1>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[N:23]=1)=[CH:15]2)(=[O:8])=[O:7]
Reactant: CCOC(=O)c1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1csc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A mixture of ethyl 2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazole-4-carboxylate (0.30 g), 8N aqueous sodium hydroxide solution (0.3 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were dissolved in tetrahydrofuran, treated with activated carbon, and concentrated to give the title compound (0.20 g, yield 71%) as yellow crystals. melting point>273° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C(OCC)C>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([B:20]([OH:25])[OH:21])=[CH:7][N:6]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc(B(O)O)cn1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 5-bromo-2-methyl-pyridine (992 mg, 5.8 mmol) in diethyl ether (5 mL) was slowly added n-butyl lithium in hexane (1.4 M, 5 mL, 7 mmol) at −78° C. over a span of 10 minutes under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 90 minutes. At this time, tri-isopropyl borate (1.30 g, 6.9 mmol) was slowly added, and the resulting mixture was allowed to warm to room temperature and stirred for an additional 90 minutes. The reaction was quenched with 5% aqueous sodium hydroxide solution (6 mL) at 0° C. and was extracted with diethyl ether (25 mL×4). The pH of the aqueous solution was adjusted to about 7 by the slow addition of 2N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-methyl-5-pyridinylbronic acid, which was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1>C(O)CC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:12][CH2:11][CH2:3][CH3:2])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Solvent: CCCO
Product: CCCOc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 44a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (400 mg, 1.2 mmol) in propanol (2 ml) the subtitle compound was obtained (325 mg, 73%). MS 375 m/z (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1.Cl.NC1(C)CCCC1NC(=O)C1C=CC=CC=1N1N=CC=N1.ClC1C=NC(C(F)(F)F)=CN=1>>[CH3:1][C@@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[N:19]=[CH:18][CH:17]=[N:16]1
Reactant: CC1(Nc2cnc(C(F)(F)F)cn2)CCCC1NC(=O)c1ccccc1-n1nccn1
Agent: CC1(N)CCCC1NC(=O)c1ccccc1-n1nccn1
Agent: Cl
Agent: FC(F)(F)c1cnc(Cl)cn1
Product: C[C@@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 82) from N-(2-amino-2-methylcyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 26; 287 mg, 1.01 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 202 mg, 1.11 mmol) except this was then chirally separated using SFC (Waters prep30/MS system using 20% Ethanol, column AY) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][Sn](CCCC)(CCCC)CCCC.C([Li])CCC.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:43]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[O:51][CH3:52])=[C:42]([O:53][CH2:54][CH2:55][OH:56])[N:41]=[C:40](S(C)(=O)=O)[N:39]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:43]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[O:51][CH3:52])=[C:42]([O:53][CH2:54][CH2:55][OH:56])[N:41]=[C:40]([CH2:5][O:4][CH2:3][O:2][CH3:1])[N:39]=2)(=[O:35])=[O:36])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(S(C)(=O)=O)nc1OCCO
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2ccccc2OC)c(OCCO)n1
Reaction time: 0.07 h

Procedure:
##STR150## (1) To a solution of methoxymethyloxymethyltributyltin (655 mg) in tetrahydrofuran (6 ml) is added dropwise a 1.63M solution of n-butyl lithium in n-hexane (1.09 ml) at -78° C. The mixture is stirred at the same temperature for four minutes, and thereto is added a solution of 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxyphenoxy)-2-methylsulfonylpyrimidin-4-yl]benzenesulfonamide obtained in Reference Example 10-(1) (200 mg) in tetrahydrofuran (2 ml), and the mixture is stirred for 40 minutes. To the mixture is added an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1~50:1) to give 4-tert-butyl-N-[6-(2-hydroxyethoxy)-2-methoxymethyloxymethyl-5-(2-methoxy-phenoxy)pyrimidin-4-yl]benzenesulfonamide (111 mg) as a colorless caramel.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>COC(OC)N(C)C>[CH3:8][N:10]([CH3:12])/[CH:11]=[CH:2]/[C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([N:10]([CH3:11])[CH3:12])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(=O)N(C)C)cc1
Agent: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Yield: 27 %

Procedure:
A mixture of crude 4-acetyl-N,N-dimethylbenzamide (24.0 g) and N,N-dimethylformamide dimethyl acetal (100 mL) was heated to reflux for 15 h, cooled to room temperature and concentrated. The residue was washed with ether and dried under vacuum to provide (E)-4-(3-(dimethylamino)acryloyl)-N,N-dimethylbenzamide as brown solid (16 g, 27% yield over 2 steps). MS (ES+) m/z: 247 (M+H).
Reaction SMILES: C(O)=O.[C:4]1([C:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([CH2:26][CH2:27][NH:28][C:29](=O)OC(C)(C)C)=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Si]([O:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH2:63][CH:64]2C[O:65]2)=[CH:58][CH:57]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:65][C@@H:64]([CH2:29][NH:28][CH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([NH:21][CH:18]2[CH2:19][CH2:20][N:15]([C:12]3[S:13][CH:14]=[C:10]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:11]=3)[CH2:16][CH2:17]2)=[CH:37][CH:36]=1)[CH2:63][O:62][C:59]1[CH:60]=[CH:61][C:56]([OH:55])=[CH:57][CH:58]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(c4nc(-c5ccccc5)cs4)CC3)cc2)cc1
Yield: 30.7 %

Procedure:
tert-Butyl 4-{[1-(4-phenyl-1,3-thiazol-2-yl)-4-piperidinyl]amino}phenethylcarbamate formate (0.40 g 1.04 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.42 g, 1.04 mmol) according to Procedure G to give the title compound (0.25 g, 0.319 mmol).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]\[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([OH:15])[CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>N1C=CC=CC=1>[C:22]([O:15][C:8]1[CH:7]=[C:6]([O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=[O:24])[CH3:23]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(OC/C=C(\C)CCC=C(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To 10 ml of a pyridine solution containing 0.82 g (2.82 mmol) of 4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzoic acid was added 0.72 g (7.1 mmol) of acetic anhydride, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into a 2% hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was recrystallized from an ethyl ether/hexane mixed solvent to obtain 0.45 g (yield: 48%) of 2-acetoxy-4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}benzoic acid represented by the following structural formula (hereinafter referred to as compound 45) as white crystals. The analytical results are shown below. ##STR66##
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[C:14]([SiH2:18][O:19][C:20]([CH3:48])([CH3:47])[C:21]1([CH:45]=O)[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[C:36]([CH3:44])[CH:35]=3)=[CH:28][CH:27]=2)[CH2:22]1)([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:45][C:21]1([C:20]([CH3:48])([CH3:47])[O:19][SiH2:18][C:14]([CH3:17])([CH3:16])[CH3:15])[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[C:36]([CH3:44])[CH:35]=3)=[CH:28][CH:27]=2)[CH2:22]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: Cc1cc(COc2ccc(C3=NOC(C=O)(C(C)(C)O[SiH2]C(C)(C)C)C3)cc2)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=CC1(C(C)(C)O[SiH2]C(C)(C)C)CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Trimethyl phosphonoacetate (0.4 g, 2.2 mmol) was added to a suspension of sodium hydride (hexane washed) (0.088 g, 60% in oil, 2.2 mmol) in DMF (7 mL) under a nitrogen atmosphere at 0° C. The reaction was stirred for 0.5 h and the aldehyde from step 24c was added. The reaction was stirred for 1 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by FCC on silica gel eluting methylene chloride:ethyl acetate (60:50) to give 3-{5-(tert-butyl-dimethyl-silanyloxymethyl)-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acrylic acid methyl ester (0.24 g, 20%) as an oil. MS found: (M+H)+=547.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1>>[CH3:13][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:15][CH:16]=3)=[O:21])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Cc1cc(=O)[nH]c2cc(N)ccc12
Product: Cc1cc(=O)[nH]c2cc(NC(=O)c3ccc(-c4ccccc4)cc3)ccc12

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-4-methyl-1-H-quinolin-2-one (50 mg, 0.29 mmol) and 4-biphenylcarboxylic acid (68 mg, 0.34 mmol) as a cream solid. 1H NMR (250 MHz, DMSO) δ (ppm): 11.60 (br, 1H), 10.55 (br, 1H), 8.09 (d, 2H), 8.02 (s, 1H), 7.86 (d, 2H), 7.77 (d, 2H), 7.69 (d, 1H), 7.55 (dd, 1H), 7.52 (t, 2H), 7.43 (t, 1H), 6.29 (s, 1H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH3:23]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:22][CH3:23])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: CCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Yield: 58.4 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.11 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 25 mg of lithium hydride and 584 mg of ethyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 577 mg of 2-[(4-chlorophenyl)imino]-2,3-dihydro-3-ethyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (58%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 61 mg of 2-[N-(4-chlorophenyl)-N-ethylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (6%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[NH4+:14].[Cl-].N>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[NH4+:14].[NH4+:14].[NH4+:14]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
930 g of citric acid was dissolved in 2 l of deionized water and a salmiac solution containing 25 wt.-% of NH3 was added until a pH of 6.8 was reached (approximately one liter of the salmiac solution was used for the purpose).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)C>[Pd].[C].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1
Reaction time: 2 h
Yield: 78.8 %

Procedure:
A mixture of tert-butyl (2E)-3-[4-(benzyloxy)phenyl]acrylate (13.3 g, 42.8 mmol), 10% Pd carbon (1.3 g), ethanol (100 mL) and tetrahydrofuran (30 mL) was stirred under a hydrogen atmosphere for 2 hrs. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (7.5 g, yield 79%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([F:19])=[C:6]([Cl:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Br:17])[CH:10]=1.Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[Cl:18][C:6]1[C:5]([F:19])=[N:4][C:3]([NH:26][CH2:25][C:24]([O:23][CH3:22])=[O:27])=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Br:17])[CH:10]=1
Reactant: COC(=O)CN
Reactant: COc1ccc(Oc2c(Cl)c(F)nc(F)c2Cl)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(Br)c2)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
To a solution of 3,5-dichloro-2,6-difluoro-4-(3-bromo-4-methoxyphenoxy)pyridine (250 mg) and glycine methyl ester hydrochloric acid (150 mg) in DMF (2.0 mL) was added potassium carbonate powder (250 mg) in one portion. The resulting mixture was stirred at ambient temperature for 20 hours. The reaction mixture was diluted with brine and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL×3), dried (Na2SO4) and concentrated. Chromatography with ethyl acetate-hexanes (0-50% gradient elution) provided the title compound as a white solid (253 mg).