Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH:29]=1>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCCOc2ccc(C(=O)NCCCCc3cccnc3)cc2)ccc(C(C)=O)c1O
Yield: 93 %

Procedure:
The reaction of 0.635 g of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]benzoic acid with 0.28 g of 3-pyridine butanamine according to Example 40 gave 0.80 g, mp 133°-134°, (93% yield) of 4-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: O.[F:2][C:3]([F:16])([F:15])[C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10].[H][H]>[C].[Pd].C1(C)C=CC=CC=1>[F:2][C:3]([F:15])([F:16])[C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCc1cccc(C(F)(F)F)c1
Yield: 97.8 %

Procedure:
Palladium carbon (10%, 6 gm) was added to water (20 ml) and then added 3-(trifluoromethyl)cinnamic acid (100 gm) and toluene (1000 ml). The resulting contents were hydrogenated with hydrogen gas at a pressure of 4 kg at 45 to 50° C. for 2 hour 30 minutes. The reaction mass was then filtered through celite bed and the layers were separated. The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 98.7 gm of 3-[3-(trifluoromethyl)phenyl]propionic acid.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[O-:27][CH2:28][CH3:29].[Na+]>C(O)C>[CH2:28]([O:27][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH2:4]1)[CH3:29]
Reactant: CC[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CCO
Product: CCOCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 55 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol) with sodium ethoxide (1.6 mmol) in ethanol (10 ml) at a temperature 60° C. for 6 hours and by purifying the compound by silica gel column chromatography in 55% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[S:34]>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:33](=[S:34])[NH:32][C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[F:24])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2SCCC1(CO)CO
Reactant: Fc1ccc(N=C=S)c(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2SCCC1(CO)COC(=S)Nc1ccc(F)cc1F

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]thiepin-5-one (720 mg, 3.02 mmol) in 38 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.46 ml, 3.32 mmol) and 2,4-difluorophenyl isothiocyanate (985 μl, 7.55 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 ethyl acetate/hexane). The product was obtained in a yield of 170 mg (14%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]([F:17])([F:18])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:20][CH2:21][CH2:22][OH:23])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: OCCCBr
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCOc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 81.7 %

Procedure:
Using 3.5 g (13.8 mmol) of 4-trifluoromethoxy-4'-hydroxybiphenyl, 45 ml of acetonitrile, 2.01 g (14.5 mmol) of 3-bromo-1-propanol and 3.81 g (27.5 mmol) of anhydrous potassium carbonate, synthetic treatment was carried out in the same manner as in Example 2. The obtained gray powder was recrystallized from benzene/n-hexane to obtain 3.52 g (yield: 82%) of 4-trifluoromethoxy-4'-(3-hydroxypropoxy)biphenyl (21) as a colorless powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:11]([CH2:12][C:13]=1[C:14]1[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[N:18]=1)[CH2:10][N:9]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:8]2)=[O:5])C.[OH-].[Na+].Cl.N1C=CN=C1.[CH3:46][C:47]([Si:50](Cl)([CH3:52])[CH3:51])([CH3:49])[CH3:48].[NH4+].[Cl-].C([O-])([O-])=O.[K+].[K+]>CCO.CCOC(C)=O.C1COCC1.O.CO>[C:34]([O:33][C:31]([N:9]1[CH2:8][CH:7]2[N:23]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:11]([CH2:12][C:13]([C:14]3[S:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][O:22][Si:50]([C:47]([CH3:49])([CH3:48])[CH3:46])([CH3:52])[CH3:51])[N:18]=3)=[C:6]2[C:4]([OH:3])=[O:5])[CH2:10]1)=[O:32])([CH3:35])([CH3:37])[CH3:36]
Reactant: CCOC(=O)C1=C(c2nc(CCCO)cs2)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO[Si](C)(C)C(C)(C)C)cs3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A mixture of compound C2 (5.46 g, 10.2 mmol) in EtOH (120 mL) and aq. 1M NaOH (120 mL) was stirred at 80° C. for 90 min. The mixture was allowed to cool to rt, and was then diluted with EtOAc. This mixture was acidified with aq. 1M HCl until a pH between 3 and 4 was obtained. The layers were separated, then the aq. phase was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude product was dissolved in DMF (120 mL). Imidazole (2.77 g, 40.6 mmol) and TBDMS-Cl (3.83 g, 25.4 mmol) were added. The mixture was stirred overnight. Aq. sat. NH4Cl (500 mL) was added and the resulting suspension was extracted with heptane (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated to yield a yellow oil. This crude product was dissolved in THF (75 mL), MeOH (25 mL) and H2O (25 mL), and K2CO3 (702 mg) was added. The mixture was stirred at rt for 2.5 h and was concentrated to half under reduced pressure. The residue was then diluted with Et2O to produce a clear yellow sol. This yellow sol. was washed with aq. sat. NH4Cl (500 mL). The aq. phase was extracted with Et2O (2×), and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:1→MeOH/EtOAc 1:9) yielded the title compound (2.90 g, 46%). LC-MS: tR=1.15 and 1.19 min, ES+: 624.47.
Reaction SMILES: Cl.Br[C:3]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(O)(O)=O.COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:4]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1
Reactant: Brc1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(O)O
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: c1ccc(Nc2ccc(Oc3ncccc3-c3cccnc3)cc2)nc1
Temperature: 145 °C

Procedure:
A mixture of N-(4-(3-Bromopyridin-2-yloxy)phenyl)pyridin-2-amine hydrochloride (0.257 g, 0.68 mmol), 3-pyridineboronic acid (0.115 g, 0.94 mmol), sodium carbonate anhydrous (0.358 g, 3.4 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (0.045 g, 0.064 mmol) in 6:3:2 DME:H2O:EtOH was sealed under argon in a microwave tube and heated at 145° C. for 15 min in the microwave (Emrys by Personal Chemistry). The reaction was filtered and the filtrate was partitioned between EtOAc/brine. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography [Isco, (40 gram)] eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 341.1 [M+1]. IC50 (uM) 0.002612.
Reaction SMILES: [NH2:1][CH:2]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:3].[CH:12](CC(OC(=O)CC=O)=O)=[O:13]>>[CH:12]([NH:1][CH:2]([P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[CH3:3])=[O:13]
Reactant: CCOP(=O)(OCC)C(C)N
Reactant: O=CCC(=O)OC(=O)CC=O
Product: CCOP(=O)(OCC)C(C)NC=O
Temperature: 120 °C

Procedure:
A mixture of 3.6 g of diethyl α-aminoethyl-phosphonate prepared by the process of Chalmers et al, J.A.C.S., Vol 75 (1953), p. 5278 and 2 g of formylacetic acid anhydride stood overnight at room temperature and was then heated at 120° C. under a pressure of 0.5 to 1 mm Hg for 15 to 20 minutes. The residue was distilled to obtain pure diethyl 1-(N-formylamino)-ethyl-phosphonate with a boiling point of 148°~150° at 0.5 mm Hg which was used as is for the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH:19]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[C:13]1([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([CH2:3][OH:2])=[CH:19][C:9]=3[CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc2oc(-c3ccccc3)cc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 2-phenyl-benzofuran-5-carboxylic acid methyl ester 27 (0.7 g, 2.8 mmol) in THF (15 ml) was added dropwise a solution of lithium aluminum hydride (1M in THF) (3.6 ml, 3.6 mmol) at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 2 hrs. The mixture was cooled to 0° C., diluted with ether and sodium sulfate decahydrate was added. After filtration the solids were washed with ether, and the organic layer was washed and dried. Evaporation of the solvent and purification by chromatography yielded (2-phenyl-benzofuran-5-yl)-methanol (0.55 g). A mixture of (2-phenyl-benzofuran-5-yl)-methanol (0.5 g, 2.23 mmol), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.55 g, 2.68 mmol), triethylamine (0.74 ml, 5.35 mmol) and THF (15 ml) was heated at 50° C. for 6 hrs. Additional (R) 2-isocyanato-3-phenyl-propionic acid methyl ester 5 (0.15 g) was added, and the mixture was stirred at 50° C. overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. After extraction and evaporation of the solvent, the residue was purified by chromatography to give about 0.76 g of (R)-3-phenyl-2-(2-phenyl-benzofuran-5-ylmethoxycarbonylamino)-propionic acid methyl ester 28.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]2[N:47]=[C:46]([C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)[CH:45]=[CH:44][N:43]=2)[C:37]([CH3:40])=[N:38][CH:39]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:33][C:34]3[CH:39]=[N:38][C:37]([CH3:40])=[C:36]([NH:41][C:42]4[N:47]=[C:46]([C:48]5[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=5)[CH:45]=[CH:44][N:43]=4)[CH:35]=3)=[O:15])=[CH:16][CH:17]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ncc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a flask was added 4-((4-methylpiperazin-1-yl)methyl)benzoic acid (3.2 g), dicyclohexylcarbodiimide (3.0 g), N-(5-amino-2-methylpyridin-3-yl)-4-(3-pyridyl)pyrimidin-2-amine (3.0 g) and CH2Cl2 (100 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtrated and the filtrate was washed with water (100 mL×2), dried, filtrated, concentrated, and purified through column chromatography to give 4-[(4-methylpiperazin-1-yl)methyl]-N-{6-methyl-5-[(4-(pyrid-3-yl)pyrimid-2-yl)amino]pyrid-3-yl}benzamide (4.0 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([CH2:25][CH2:26][CH2:27][CH3:28])[O:7][CH2:8][C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:39]([C@H:8]([O:7][C@H:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH2:27][CH3:28])[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCCC(OCC(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCC[C@H](O[C@@H](Cc1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Temperature: 0 °C

Procedure:
Benzhydryl 4-(2-furyl)-3-oxaoctanoate (2.0 g, 5.28 mmol) was dissolved in 20 mL freshly distilled THF and cooled to -80°±5° C. under dry argon. Sodium bis(trimethylsilyl)-amide (1.0M in THF, 5.6 mL, 5.6 mmol) was slowly added keeping the temperature at -80°±5° C. After 15 m, freshly distilled and filtered (through basic alumina) benzyl bromide (0.7 mL, 5.81 mmol) in HMPA (4 mL) was added dropwise maintaining the reaction temperature at -75°±5 ° C. After 15 m, the reaction was allowed to warm to 0° C. for 1 h before quenching with water and extraction with ether. The combined ether extracts were washed with saturated NH4Cl, 5% NaHCO3, brine,dried over MgSO4, and purified by flash silica gel chromatography to give 771.3 mg (31%): [α]25D - 65.5°; 1H NMR (300 MHz, CDCl3) δ 0.81 (t, 3H, J=7 Hz), 1.22 (m, 4H), 1.80 (m, 2H), 2.91 (m, 2H), 4.12 (dd, 1H, J=9 Hz), 4.30 (t, 1H, J=7 Hz), 5.86 (m, 1H), 6.19 (m, 1H), 6.69
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH3:26])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>N1C=CC=CC=1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH3:26])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)cc1C
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(OC(=O)C(C)C)cc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 36 %

Procedure:
3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (2.0 g, 5.7 mmol) was suspended in pyridine (25 ml), isobutyryl choride (5 ml) added, and the mixture stirred for 17 hours at room temperature; the solid rapidly dissolved to give a clear solution. The pyridine was evaporated, and the residue taken up in dichloromethane and washed with aqueous sodium bicarbonate and brine, dried and evaporated. Recrystallisation from isopropyl ether gave 3-butyryl-4-(4-isobutyryloxy-2-methylphenylamino)-8-methoxyquinoline (0.87 g, 36%), m.p. 123°-125°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[S:17][CH:18]=[C:19]([Br:21])[N:20]=1>>[Br:21][C:19]1[N:20]=[C:16]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[S:17][CH:18]=1
Reactant: Brc1csc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-42 using tert-butyl 4-hydroxypiperidine-1-carboxylate and 2,4-dibromothiazole (0.1 g, 25%); MS: 363.2 (M+1).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]=[C:24]([CH3:26])[O:25][C:21]=4[CH:20]=3)=[CH:17][N:16]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:14]=2[N:15]=1>C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([O:8][CH:5]2[CH2:6][CH2:7][O:3][CH2:4]2)[C:13]2[C:18]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]=[C:24]([CH3:26])[O:25][C:21]=4[CH:20]=3)=[CH:17][N:16]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[C:14]=2[N:15]=1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCOC5)c34)cc2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a suspension of sodium hydride (1.2 equiv, 60% by weight in mineral oil) in THF (0.3 M) under nitrogen atmosphere was added tetrahydrofuran-3-ol (1.5 equiv) in THF (0.6 M) at 0° C. The resulting reaction mixture was stirred at 0° C. for 20 min. A solution of 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv) in THF (0.6 M) was added and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (0.6 M) and the organic solvents were removed under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (15% ethyl acetate in petroleum ether) to afford the title compound (83% yield). MS (ESI) m/z 501.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: CCOC(=O)C(=NOC(C)C)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOC(C)C)c1csc(N)n1
Yield: 60.3 %

Procedure:
Ethyl 4-chloro-3-oxo-2-iso-propoxyiminobutyrate (syn isomer, 41.5 g.), thiourea (13.4 g.), sodium acetate (14.4 g.), water (110 ml.) and ethanol (110 ml.) were treated in a similar manner to that of Example D-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-iso-propoxyiminoacetate (syn isomer, 27.3 g.), mp. 162° to 164° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([N:17]3[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCN(C(=O)C2CCN(c3cccc(C(F)(F)F)c3)CC2)C1

Procedure:
tert-Butyl [(3S)-1-({1-[3-(trifluoromethyl)phenyl]piperidin-4-yl}carbonyl)pyrrolidin-3-yl]carbamate (0.975 g, 2.21 mmol) was treated with trifluoroacetic acid (5 mL) and methylene chloride (5 mL) for 1 h at room temperature. The solution was concentrated to give 1.75 g of product which was used for the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[CH3:16]S(C)=O>O>[CH3:16][N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[O:11][C:10]1=[O:13]
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2o1
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)oc2c([N+](=O)[O-])cccc21
Reaction time: 16 h
Yield: 85 %

Procedure:
3.94 g (21.9 mmol) of 7-nitro-2-benzoxazolidinone (for preparation of the latter compound, see EP 0189612 and references cited therein), were dissolved in 40 ml of DMSO after which 1.72 g of 85% powdered KOH (26.2 mmol) were added. While stirring and cooling (water) 3.72 g (26.2 mmol) of Mel dissolved in 6 ml of DMSO, were added dropwise over a period of 10 minutes. Stirring was continued at room temperature for 16 hrs, during the latter period an extra amount of Mel (0.5 g) was added. After the reaction was completed, the reaction mixture was diluted with water after which extraction took place with CH2Cl2. The combined organic fractions were washed with water and brine respectively, after which the organic fraction was dried on MgSO4. After removal of the drying agent and evaporation of the solvent in vacuo, 4.1 g of a solid residue was left. Flash column chromatography (SiO2, eluent: CH2Cl2) of the latter yielded 3.6 g (85%) of pure 3-methyl-7-nitro-2-benzoxazolidinone.
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:18])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+:26]>CO>[CH3:1][N:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:9][C:8](=[O:18])[C:4]([C:5]([O-:7])=[O:6])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+:26]
Reactant: Cc1ccc(-c2cc(=O)c(C(=O)O)c(-c3ccccc3)n2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cc(=O)c(C(=O)[O-])c(-c3ccccc3)n2C)cc1
Yield: 87.7 %

Procedure:
0.64 gms of 1-methyl-2-phenyl-6-(4'-methylphenyl)-4-oxonicotinic acid, 0.09 gms of NaOH and 30 mls of methanol were mixed. Evaporation of the solvent provided 0.6 gms of sodium 1-methyl-2-phenyl-6-(4'-methylphenyl)-4-oxonicotinate as a glassy solid.