Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[N:26][CH:27]=1.O>CN(C)C=O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)=[CH:27][N:26]=2)=[CH:33][CH:32]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(Cl)cc3)nc2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 18 mg (0.44 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 5-Chloromethyl-2-(4-chloro-phenyl)-pyridine (GB 1147068) were added and stirred continued over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, methanol/water 1:1 and diisopropylether. The residue was dried at 40° C. to give 133 mg (73%) of the title compound as light brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](Cl)=[N:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([O:8][C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[NH2:1])=[N:28][CH:29]=[N:30]2)=[CH:25][C:24]=1[O:34][CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 1.25 h
Yield: 74 %

Procedure:
To a stirred solution of 3-aminophenol (1.41 g, 12.93 mmol) in dry tetrahydrofuran (70 mL) at room temperature, was added cesium carbonate (6.32 g, 19.39 mmol). After stirring for a further 75 mins, added 7-(benzyloxy)-4-chloro-6-methoxyquinazoline from the previous step (3.89 g, 12.93 mmol) in one portion and the reaction mixture was heated at 75° C. for 24 h. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was partitioned between water (200 mL) and a mixture of dichloromethane (160 mL) and 2-propanol (60 mL). The mixture was filtered through a celite plug and the organic layer was separated and dried over MgSO4 and concentrated under reduced pressure. Trituration with diethyl ether, followed by filtration and drying under reduced pressure, afforded 3-(7-(benzyloxy)-6-methoxyquinazolin-4-yloxy)aniline as a cream solid (3.57 g, 74%) which was taken into the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 7.21-7.55 (m, 8H), 6.57-6.63 (m, 3H), 5.33 (s, 2H), 4.03 (s, 3H), 3.73 (brs, 2H); LC-MS (ESI) m/z 374 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=3[N:9]=[C:10]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Oc1cc([N+](=O)[O-])ccc1NC2=O
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(s1)Oc1cc([N+](=O)[O-])ccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2-methyl-8-nitrothieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2-methyl-4-(4-methylpiperazin-1-yl)-8-nitrothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[N:19]=[CH:18][CH:17]=[N:16][C:15]=3[C:14]([C:21]([OH:23])=[O:22])=[CH:13][CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.OS(O)(=O)=O.[CH3:29][CH2:30]O>>[CH2:29]([O:22][C:21]([C:14]1[C:15]2[N:16]=[CH:17][CH:18]=[N:19][C:20]=2[C:11]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)=[CH:12][CH:13]=1)=[O:23])[CH3:30]
Reactant: COc1cc(OC)cc(-c2ccc(C(=O)O)c3nccnc23)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12

Procedure:
A mixture of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 1.2) (10 g), H2SO4 conc. (3 mL) and EtOH (500 mL) was stirred at reflux for 7 h, allowed to cool and concentrated. The residue was diluted in EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated to afford 10.1 g of the title compound as a beige solid. Title compound: ESI-MS: 339.2 [M−H]−; tR=4.72 min (System 1).
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:21]([OH:23])=O)[N:19]=1)=[O:13].[NH2:31][CH:32]1[C:49](=[O:50])[N:34]2[C:35]([C:46]([OH:48])=[O:47])=[C:36]([CH2:39][S:40][C:41]3[S:42][CH:43]=[N:44][N:45]=3)[CH2:37][S:38][C@H:33]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:21]([NH:31][CH:32]2[C:49](=[O:50])[N:34]3[C:35]([C:46]([OH:48])=[O:47])=[C:36]([CH2:39][S:40][C:41]4[S:42][CH:43]=[N:44][N:45]=4)[CH2:37][S:38][C@H:33]23)=[O:23])[N:19]=1)=[O:13]
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
Vilsmeier reagent prepared from N,N-dimethyl formamide (0.2 g.) and phosphoryl chloride (0.42 g.) in a conventional manner was added to ethyl acetate (10 ml.), and then 2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid (syn isomer, 0.75 g.) was added to the solution under ice-cooling and stirred at the same temperature for 30 minutes. The solution was added to a solution of 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (0.83 g.) and trimethylsilylacetamide (2.62 g.) in ethyl acetate (30 ml.) at -30° C., and stirred at the same temperature for 1.5 hours. After adding ethyl acetate (100 ml.) and water to the resultant solution, the ethyl acetate layer was separated. Water (100 ml.) was added to the ethyl acetate solution adjusted to pH 7.5 with saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and the ethyl acetate (150 ml.) was added thereto, and adjusted to pH 1.5 with hydrochloric acid. The ethyl acetate layer was separated, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with diethyl ether to give 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethyoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:13]([NH2:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([NH:16][CH:13]([CH3:15])[CH3:14])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)N
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc(NC(C)C)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 27 %

Procedure:
A solution of methyl 2,6-dichloroisonicotinate (1 g, 4.85 mmol), isopropyl amine (0.286 g, 4.85 mmol), Cs2CO3 (2.06 g, 6.3 mmol) in toluene (30 mL) was purged with argon for 10 min. Then, Pd(OAc)2 (0.108 g, 0.485 mmol) and BINAP (0.3 g, 0.485 mmol) were added and argon was purged again for 15 min. Reaction mass was stirred at 80° C. for 6 h. On completion, reaction mass was filtered and residue washed thoroughly with ethyl acetate. Combined filtrates were concentrated and purified by column over silica gel to obtain pure methyl 2-chloro-6-(isopropylamino)isonicotinate (0.3 g, 27.27%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[C:17]([F:29])=[CH:18][C:19]([Cl:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:28][C:19]1[CH:18]=[C:17]([F:29])[C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:27][C:20]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)SCCO1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (4.2 g, 0.035 mole) was added to a stirring slurry of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid 4.8 g, 0.030 mole) in methylene chloride (40 ml). The mixture was warmed to 35° C. for 3 hours, then left stirring overnight at room temperature. The solution was then evaporated under reduced pressure at about 35° C. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the solution chilled in ice and treated dropwise with a solution of 1-methylethyl 5-amino-2-chloro-4-fluorobenzoate (7.0 g, 0.030 mole) and triethylamine (3.5 g, 0.035 mole) in methylene chloride (50 ml). The addition was carried out over 2 hours, after which the reaction mixture was stirred at 20°-35° C. for 3 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:37])[F:38])(=[O:35])=[O:34])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)c2ccc3ccccc3c2N1
Yield: 94 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 2-(trifluoromethyl)benzene-1-sulfonyl chloride, the title compound (yield 94%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH3:33])[C:13](=[O:34])[C:12]([CH3:39])([C:35](OC)=[O:36])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1>C1COCC1.CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[C@@H:15]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[O:32][CH3:33])[C:13](=[O:34])[C:12]([CH2:35][OH:36])([CH3:39])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(Cc2ccc(OC)cc2OC)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CN2C(=O)C(C)(CO)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1

Procedure:
2M lithium borohydride (1.078 mL, 2.157 mmol) was added to a solution of (5R,6S)-methyl 5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxopiperidine-3-carboxylate (Example 88, Step A) (1.17 g, 2.157 mmol) in anhydrous THF (21.57 mL) and anhydrous ether (20 mL) at 0° C. under nitrogen. The reaction was quenched after 58 hours with the addition of sat. aq. NH4Cl and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil. Purification using a 80 g SiO2 column and eluting with 35 to 65% EtOAc/hexanes provided the title compound as a ˜30:1 mixture of isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36]([CH:38]1[O:40][CH2:39]1)Br.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:36][CH:38]1[CH2:39][O:40]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 443) (87 mg) was dissolved in N,N-dimethylformamide (4 ml) to prepare a solution, and potassium carbonate (93 mg) and epibromohydrin (0.06 ml) were added to the solution. The mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (97 mg, yield 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)=[C:4]([F:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:14]([C:13]4[CH:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=5[F:19])[NH:9][C:10](=[O:18])[NH:11][C:12]=4[CH3:17])=[O:16])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2ccc(Cl)cc2F)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(4-Chloro-2-fluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=527 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Yield: 58.3 %

Procedure:
To 70 g of diethyl 2-chloro-4,5-difluorobenzoylmalonate, 90 cc of water was added for emulsification. Then, 0.2 g of p-toluenesulfonic acid was added thereto, and the mixture was refluxed for three hours under vigorous stirring. After cooling, the reaction mixture was extracted three times with 150 cc of methylene chloride, and the extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated and then recrystallized from methylene chloride/n-hexane to obtain 32 g of the desired compound. The physical properties of obtained ethyl 2-chloro-4,5-difluorobenzoylacetate were as follows. From the results of the NMR analysis in chloroform-d1, this compound was found to be a mixture of a keto form and an enol-form. ##STR26##
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1>[C:20]([NH:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1nc(N)sc1Cc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Product: CCCc1nc(NC(C)=O)sc1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2 g (7.2 mmol) of 2-amino-5-(4-nitrobenzyl)-4-propylthiazole in 2.5 ml of acetic anhydride, in the presence of 88 mg of 4-dimethylaminopyridine (0.72 mmol), are heated at 80° C. for 1 hour. As the reaction mixture is cooled, the formation of a precipitate is observed. This is filtered off and washed with ether to give 1.6 g of the derivative 2-acetamido-5-(4-nitrobenzyl)-4-propylthiazole, which is pale yellow solid melting at 170° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([O:10]C(C)(C)C)=[O:9].Cl>>[O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:8]([OH:10])=[O:9]
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1CCCS1(=O)=O
Agent: Cl
Product: CC(C)C[C@@H](C(=O)O)N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl(2S)-2-(1,1-dioxidoisothiazolidin-2-yl)-4-methylpentanoate (0.656 g, 2.251 mmol) from Step B was combined with HCl (4 N in dioxane, 5 mL, 20.00 mmol). The reaction mixture was stirred at room temperature for 24 hours, then the solvent removed in vacuo to furnish (2S)-2-(1,1-dioxidoisothiazolidin-2-yl)-4-methylpentanoic acid: MS (DCI+) m/z 253 (M+NH4)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][CH2:10]Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:8][O:9][CH2:10][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCl
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.7 %

Procedure:
Under an ice bath, about 200 g of phenol and about 256 g of chloromethyl methyl ether were mixed and stirred in about 2 L of methylene chloride (MC), and about 740 ml of diisopropylethylamine (DIPEA) was gradually dropped. Next, the ice bath was removed and a temperature was increased, and then a synthesis reaction (see Equation 1 below) was performed while stirring for about 12 hours at room temperature. Next, distilled water was added in a reaction mixed liquid to complete the synthesis reaction and to extract an organic phase. Next, the organic phase was washed using about 0.5 N of HCl aqueous solution, distilled water, about 1 N of NaOH aqueous solution, and distilled water in the stated order, and then dried using magnesium sulphate. Next, the organic phase was filtered and concentrated to obtain about 240 g (a yield: about 81.7%) of methoxymethoxybenzene, and a structure of the methoxymethoxybenzene was observed by 1H-NMR (see FIG. 1):
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)=O>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)=[CH:33][CH:34]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccc(Cl)cc3)cs2)C1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 63 mg (0.269 mmol) of 2-bromo-1-(4-chlorophenyl)ethanone were reacted according to the General Method 3. Yield: 15 mg (12% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[OH:20].S(=O)(=O)(O)O.[CH2:26](O)[CH3:27]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([O:18][CH2:26][CH3:27])=[O:17])=[CH:11][C:10]=1[OH:20]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)c(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(-c2ccc(F)cc2F)c(O)c1

Procedure:
A solution of 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propionic acid (4.5 g.) in absolute ethanol (50 ml.) containing concentrated sulphuric acid (2 ml.) was refluxed overnight (16 hours). After distillation of ethanol the residue was poured onto ice-water and the product was isolated in ether. The extracts were washed with dilute sodium bicarbonate dried and evaporated. The solid residue thus obtained was purified by two crystallisations from light petrol (b.p. 62°-68° C.), to give ethyl 2-(2',4'-difluoro-2-hydroxy-4-biphenylyl)propionate, m.p. 72°-73° C.
Reaction SMILES: C1C2C(=CC=CC=2)[C@H](N)[C@@H]1O.[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2.[OH-].[K+]>C(O)(C)C.C1C=CC=CC=1.Cl[Ru]Cl>[NH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]2
Reactant: Nc1cccc2c1CC(=O)CC2
Agent: Cl[Ru]Cl
Agent: N[C@H]1c2ccccc2C[C@H]1O
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)O
Product: Nc1cccc2c1C[C@H](O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
A stirred solution benzeneruthenium(II) chloride dimmer (1.55 g) and (1S, 2R)-(−)-cis-1-amino-2-indanol (1.85 g) in degassed isopropanol (500 ml) was heated at 80° C. for 20 minutes under argon, and then cooled to room temperature. The mixture was added to the solution of 8-amino-3,4-dihydro-1H-naphthalen-2-one (25.0 g) in isopropanol (700 ml) at room temperature followed by the prepared solution of potassium hydroxide (1.74 g) in 300 ml of isopropanol (pre-prepared at 45° C. to dissolve and then cooled to room temperature). After stirred at 45° C. for 30 minutes, the mixture was cooled to room temperature and was passed through silica gel pad and washed with ethylacetate. The filtrate was concentrated under reduced pressure, and the obtained solid was dissolved in dichloromethane and treated with activated charcoal for 10 minutes. After filtered through a silica gel pad, the mixture was concentrated under reduced pressure. The obtained product was recrystallized from dichloromethane to afford red crystal of (R)-8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (14 g, 56% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=O)[C:16]3[C:11](=[CH:12][C:13]([OH:21])=[C:14]([CH2:19][CH3:20])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:16]3[CH:15]=[C:14]([CH2:19][CH3:20])[C:13]([OH:21])=[CH:12][C:11]=3[OH:10])=[N:23][NH:24][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCc1cc2c(=O)c(-c3ccc(Br)cc3)coc2cc1O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1cc(-c2n[nH]cc2-c2ccc(Br)cc2)c(O)cc1O
Yield: 71 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(4-Bromo-phenyl)-6-ethyl-7-hydroxy-chromen-4-one (0.13 g, 0.38 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The crude solid product was columned to give 4-[4-(4-bromo-phenyl)-1H-pyrazol-3-yl]-6-ethyl-benzene-1,3-diol as a white solid (0.0969 g, 71%); Rf 0.44 Cf SM 0.79 ethyl acetate/hexane (75/25).