Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[F:15])[CH:10]=[O:11].[N+:16]([O-])([OH:18])=[O:17]>>[F:6][C:7]1[CH:8]=[C:9]([C:12]([N+:16]([O-:18])=[O:17])=[CH:13][C:14]=1[F:15])[CH:10]=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Product: O=Cc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 520 cm3 of sulphuric acid, stirred and cooled to 0° C., 60 cm3 of fuming nitric acid are added in the course of 30 minutes. 100 g of 3,4-difluorobenzaldehyde are added in the course of 30 minutes at approximately 0° C. to the solution obtained. The temperature is allowed to rise to approximately 20° C. and the mixture is stirred for a further 3 hours at this temperature. After cooling to approximately 5° C., the reaction mixture is introduced in the course of 30 minutes with vigorous stirring into 1,200 g of crushed ice. The temperature is allowed to rise to approximately 20° C. and the mixture is extracted with twice 600 cm3 of toluene. The combined organic extracts are washed with 3 times 1,000 cm3 of water and concentrated under reduced pressure (20 kPa) to 50° C. 113 g of 3,4 -difluoro-6-nitrobenzaldehyde are obtained in the form of a brown oil, which is used in the subsequent syntheses without further treatment. A purified sample of 3,4-difluoro-6-nitrobenzaldehyde gives the following characteristics:
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:26]1[S:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:29][N:30]=1)[NH:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:16])=[CH:10][CH:9]=1.CN(C=O)C.CCN=C=NCCCN(C)C.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:53][S:54]([NH:57][C:33](=[O:35])[CH2:32][CH2:31][C:28]1[S:27][C:26]([CH:4]([NH:5][C:6](=[O:25])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[O:16])=[CH:12][CH:13]=2)[CH2:3][CH:2]([CH3:36])[CH3:1])=[N:30][CH:29]=1)(=[O:56])=[O:55]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)O)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)NS(C)(=O)=O)s2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A mixture of 3-[2-(3-methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid (Example 13) (91 mg, 0.2 mmol), DMF (5 ml), EDCI (48 mg, 0.2 mmol) and DMAP (26 mg, 0.2 mmol) was stirred at room temperature. After 10 min. methane sulfonamide (51 mg, 0.5 mmol) was added. After stirring 16 h the solution was diluted with EtOAc and washed with 1N HCl (2×). The organic layer was dried over Na2SO4; filtered; and concentrated under reduced pressure. The resulting solid was purified by Flash 12 chromatography eluting with 10% AcOH in EtOAc to give 30 mg of the title compound as a white amorphous solid. MS [M−1]+584.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:4]([Cl:23])[CH:3]=1.C([Mg]Cl)C.[CH2:28]([O:30][C:31](C#N)=[O:32])[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31]([C:2]1[S:6][C:5]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:4]([Cl:23])[CH:3]=1)=[O:32])[CH3:29]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)cc3Cl)c(C)nn12
Reactant: CCOC(=O)C#N
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Cl)c(-c2c(C)nn3c(C(CC)CC)cc(C)nc23)s1
Temperature: 0 °C
Yield: 18.7 %

Procedure:
Chill to 0° C. a mixture of 3-(5-bromo-3-chloro-thiophene-2-yl)-7-(1-ethyl-propyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (0.62 g, 1.5 mmol) in anhydrous THF (5 mL) under an inert atmosphere and add ethyl magnesium chloride (2 M THF solution, 0.83 mL, 1.65 mmol). Stir the reaction 5 min, warm to room temperature, and stir an additional 15 min before lowering the reaction temperature to 0° C. Add ethylcyanoformate (0.16 mL, 1.58 mmol) diluted in anhydrous THF (1 mL). Warm the reaction to room temperature and stir 1 h. Quench the reaction with saturated sodium bicarbonate (20 mL) and extract with ether (2×75 mL). Combine the organic portions, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify using flash chromatography, eluting with 100% hexane/0% (20% ethyl acetate/hexane) to 0% hexane/100% (20% ethyl acetate/hexane) in a step gradient of 10% increments. Dry the resulting material under vacuum to provide a white solid (0.114 g, 19%). ES/MS m/z (35Cl) 406.3 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].C(C(C)=O)C.[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:21][CH2:20][C:19]([F:26])([F:18])[C:22]([F:25])([F:24])[F:23])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCC(C)=O
Product: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C
Temperature: 75 °C
Reaction time: 108 h
Yield: 74.4 %

Procedure:
A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g), methyl ethyl ketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.29 g) and hexamethylphosphoric acid triamide (2.07 g) was heated at 70-80° C. with stirring for 4.5 days. Then, the insoluble matter was filtered off and the filtrate was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract layer was dried over magnesium sulfate, then the solvent was distilled off, and the residue was applied to a silica gel column (50 g). Elution with chloroform-methanol (10:1) and recrystallization form ethyl acetate-hexane gave 2.4 g of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as colorless needles. Melting point 148-149° C.
Reaction SMILES: [N-:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[K+].[CH2:7]([O:9][CH2:10][CH2:11]Br)[CH3:8]>C1COCC1>[CH2:7]([O:9][CH2:10][CH2:11][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:8]
Reactant: c1c[n-]cn1
Reactant: CCOCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCCn1ccnc1

Procedure:
A Schlenk tube is charged with 5.5 g (52 mmol) of potassium imidazolide in 50 ml of THF. While stirring, 7.7 g (50 mmol) of 2-bromoethyl ethyl ether are added and the suspension is stirred for 4 hours, then warmed gently. After cooling, the reaction mixture is filtered and the solvent is removed. Distillation in a high vacuum gives 7a as a colorless liquid. The purity was checked by GC-MS. Only one fraction was observed here.
Reaction SMILES: S1C=CC=C1CC([NH:9][CH:10]1[C:38](=[O:39])[N:12]2[C:13]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:14]([CH:18]=[N:19][O:20][CH3:21])[C@@H:15]([CH3:17])[S:16][C@H:11]12)=O.P(Cl)(Cl)Cl.OP([O-])([O-])=O.[K+].[K+].OP(O)(O)=O>C(Cl)Cl.CO.N1C=CC=CC=1>[NH2:9][CH:10]1[C:38](=[O:39])[N:12]2[C:13]([C:22]([O:24][CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:23])=[C:14]([CH:18]=[N:19][O:20][CH3:21])[C@@H:15]([CH3:17])[S:16][C@H:11]12
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S[C@@H]1C
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2S[C@@H]1C
Reaction time: 1 h
Yield: 66 %

Procedure:
A 5 ml portion of pyridine was added to a solution of 2.8 g of diphenylmethy 7-(2-thienylacetamido)-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate in 60 ml of CH2Cl2, and 3.05 g of PCl3 was then added to the mixture at -10° C. under a stream of nitrogen, followed by stirring at the same temperature for 1 hour. After adding 50 ml of MeOH in once, the mixture was stirred at from -15° to -10° C. for 30 minutes and further at room temperature for 2 hours. Following addition of 100 ml of 0.5M K2HPO4 solution, the reaction solution was adjusted to pH 2.0 with 25% H3PO4, and stirred for 30 minutes to separate out the CH2Cl2 layer. The CH2Cl2 layer was washed with saturated aqueous NaCl solution, and dried over MgSO4 , followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (35:1) were collected to distill off the solvent under reduce pressure, thus yielding 1.44 g (66%) of diphenylmethyl 7-amino-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH2:25][CH3:26])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH2:25][CH3:26])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=4)(=[O:36])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Agent: Cl
Product: CCC1(C)C(=O)N(C2CCN(S(=O)(=O)c3cccc(C)c3)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B9*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH:19]=[CH:20][C:21]=2[CH:22]=[O:23])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>CCOC(C)=O>[C:4]([O:8][C:9]([N:11]1[CH2:12][CH:13]([O:15][C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH:19]=[CH:20][C:21]=2[C:22]([OH:42])=[O:23])[CH2:14]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C=O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C(=O)O)C1
Reaction time: 15 h
Yield: 37.2 %

Procedure:
To a CH2Cl2 (6 mL) solution of the title compound of Step A (0.236 g, 0.560 mmol) was added m-CPBA (77 wt %, 0.189 g, 0.840 mmol). After 15 h, 10% Na2S2O5 was added and the solution allowed to stir until the aqueous was KI paper negative and extracted with CH2Cl2 (2×). The combined organic layers were dried and treated with MeOH (10 mL) and 1N NaOH (10 mL). After 15 h, the reaction was partially concentrated to remove the MeOH and acidified with 1M HCl (220 mL) then extracted with EtOAc (2×). The combined organic layers were dried and concentrated. Silica gel chromatography (0-30% EtOAc in hexanes) gave 0.091 g (37% yield) of the title compound. (MS (ESI): mass calcd. for C22H22F3NO5, 437.15; m/z found, 382.1 [M-56]+, 460.1 [M+Na]+. 1H NMR (CDCl3): 7.73 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.87 (dd, J=8.2, 1.9 Hz, 1H), 6.52 (d, J=1.0 Hz, 1H), 4.97-4.88 (m, 1H), 4.30 (dd, J=9.8, 6.4 Hz, 2H), 4.05 (dd, J=9.9, 3.7 Hz, 2H), 1.45 (s, 9H)) and 0.091 g (39% yield) of 3-(4-Hydroxy-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (MS (ESI): mass calcd. for C21H22F3NO4, 409.15; m/z found, 354.1 [M-56]+, 432.1 [M+Na]+. 1H NMR (CDCl3): 8.19 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.12 (dd, J=8.0, 1.3 Hz, 1H), 6.63 (s, 1H), 5.11-5.00 (m, 1H), 4.36 (dd, J=10.1, 6.4 Hz, 2H), 4.12 (dd, J=10.6, 3.6 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:28]4[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][CH3:24])[CH2:27]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CNC1CCCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Reaction time: 12 h
Yield: 32.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (2.95 g), 3-methylaminopiperidine dihydrochloride (6.69 g) and triethylamine (10 g) in acetonitrile (50 ml) was refluxed with stirring for 12 hours. The reaction mixture was concentrated in vacuum, and the residue was extracted with chloroform. The extract was washed with a saturated NaCl solution and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol:ammoniumhydroxide=15:5:1) to give 1.28 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid, which was recrystallized from acetonitrile-water, colorless needles. m.p. 134°-135° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:22])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCCCCOc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
n-Octyloxybenzene (301 g, 1.46 mol), succinic anhydride (146.8 g, 1.468 mol) and carbon disulfide (1.3 l) were agitated at room temperature, followed by portion-wise feeding anhydrous aluminum chloride (392 g, 2.94 mol), further agitating the mixture at 50° C. for 4 hours after the reaction became quiet, cooling the mixture down to room temperature, adding it to ice (2 Kg), distilling off carbon disulfide, collecting solids, adding toluene (1 l), distilling off water on heating, filtering while hot, and distilling off toluene under reduced pressure to obtain oily β-(p-octyloxybenzoyl)-propionic acid (238 g, yield 53%).
Reaction SMILES: O[CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([CH2:24][CH2:25][CH3:26])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47].CCOC(C)=O>C(Cl)Cl>[Br:47][CH2:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([CH2:24][CH2:25][CH3:26])[CH:4]=1
Reactant: CCCc1cc(CO)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1cc(CBr)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 36 %

Procedure:
To a solution of 839 mg of the crude product from Step N in CH2Cl2 (20 mL) were added triphenylphosphine (525 mg, 2 mmol) and carbon tetrabromide (663 mg, 2 mmol) at 0° C. The solution was stirred at 0° C. for 1 hour and at rt for 15 hours. The solution was poured into EtOAc (100 mL). After the precipitate was removed, the filtrate was washed with H2O and brine, and dried over anhydrous MgSO4. Concentration afforded 302 mg of the title compound as a white solid.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[O:15])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)C=CC(=O)O)cc1
Yield: 37.4 %

Procedure:
In 200 ml of dichloromethane were dissolved 5.4 g of anisol and 4.98 g of maleic anhydride, and 9.95 g of anhydrous aluminum chloride was added gradually under ice-cooling with stirring. Then, the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced presource, and poured into a mixture of 10 ml of conc. hydrochloric acid and 150 g of ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The ethyl acetate was removed from the solution by evaporation under reduced pressure, and the residue was recrystallized from a mixture of hexane and diethyl ether to give 3.85 g of 3-(4-methoxybenzoyl)acrylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH:22]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:21]=1/[CH:22]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C(F)(F)F)ccc1Cl)C2=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of 6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 13 (0.120 mg, 0.485 mmol) in toluene (10 mL) was added 2-chloro-5-(trifluoromethyl)benzaldehyde 75 (0.101 mg, 0.485 mmol). PTSA (0.184 mg, 0.971 mmol) was added to the reaction mass, reaction stirred at 100° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 157 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 15% ethyl acetate in hexane to afford yellow coloured solid (E)-2-(2-chloro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 157.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][CH2:14][CH:15](O)[CH2:16][F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:15]([CH2:16][F:17])[CH2:14][F:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: OC(CF)CF
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FCC(CF)Oc1ccc2ncnc(Cl)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
4-Chloro-6-hydroxy-quinazoline (500 mg; 2.78 mmol), 800 mg (8.33 mmol) of 1,3-difluoro-2-propanol and 2.18 g (8.33 mmol) of triphenyl phosphine were dissolved in 30 ml of THF and 3.62 g (8.33 mmol) was added thereto at room temperature. The reaction solution was stirred at room temperature for 3 hours more, a saturated aqueous solution of sodium hydrogen carbonate was added and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=1:2) to give 530 mg (yield: 74%) of 4-chloro-6-(2-fluoro-1-fluoromethyl-ethoxy)-quinazoline as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:5]1([N:4]2[CH2:3][CH2:2][O:1][C:19]2=[O:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCNc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCCN1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under N2, a solution of N-(2-hydroxyethyl)aniline (500 mg, 3.65 mmol) and triethylamine (1 mL, 7.29 mmol) in THF (2 mL) was added slowly to a solution of triphosgene (360 mg, 1.21 mmol) in THF (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for one hour. The reaction was then quenched with a saturated solution of sodium bicarbonate (4 mL) and extracted with methylene chloride (3×4 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (5%-35% EtOAc/CH2Cl2) gave 3-phenyl-1,3-oxazolidin-2-one. LCMS (ES) m/z 164.2 (M+H)+.
Reaction SMILES: C(=O)=O.C(Cl)(Cl)(Cl)Cl.[BH4-].[Na+].[C:11]([O:14][CH2:15][CH2:16][N:17]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]1[C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:13])[CH3:12]>CO.O.C(O)(=O)C>[C:11]([O:14][CH2:15][CH2:16][N:17]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]1[CH:23]([OH:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:13])[CH3:12]
Reactant: CCOC(=O)C(=O)c1cc(Cl)cn1CCOC(C)=O
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(O)c1cc(Cl)cn1CCOC(C)=O
Reaction time: 1 h

Procedure:
A solution of water (25 ml) in methanol (300 ml) is cooled in a dry ice:carbon tetrachloride:acetone bath to -30° and 23.7 g of sodium borohydride is added thereto. When the violent reaction has subsided, there is added, in a dropwise manner, 40 g. (0.139 moles) of ethyl 1-(2-acetoxyethyl)-4-chloropyrrole-2-glyoxalate dissolved in methanol (400 ml.) at a rate such that the temperature does not exceed -20° C. The reaction is maintained at this temperature for two hours when there is added a solution of 21.5 ml. of acetic acid in 320 ml water. The solution is stirred for a further 1 hour at -30° during which time a white precipitate forms. This solid is collected by filtration and dissolved in dichloromethane. The organic solution was washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. There is obtained 33.15 g. of a solid product which is homogeneous by thin layer chromatography. Recrystallization from dichloromethane-hexane yields ethyl 1-(2-acetoxyethyl)-4-chloropyrrole-2-glycolate, m.p. 60°-61° C. (Formula 6 where Y is Cl).
Reaction SMILES: [NH:1]([C:18]([O:20][CH:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([O:29][CH3:30])[C:23]([CH3:32])([CH3:31])[CH2:22]1)=[O:19])[NH:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)=[O:4].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[N:2]([C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)=[O:4])=[N:1][C:18]([O:20][CH:21]1[CH2:22][C:23]([CH3:31])([CH3:32])[N:24]([O:29][CH3:30])[C:25]([CH3:28])([CH3:27])[CH2:26]1)=[O:19]
Reactant: CON1C(C)(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(OC)C(C)(C)C2)CC1(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CON1C(C)(C)CC(OC(=O)N=NC(=O)OC2CC(C)(C)N(OC)C(C)(C)C2)CC1(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 113.9 %

Procedure:
To a solution of 8.2 g of bis(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl) hydrazine-1,2-dicarboxylate, as prepared in Example 1, in 100 mL of methylene chloride is added 6.3 g of iodobenzene diacetate in one portion at room temperature. After stirring at room temperature for 50 minutes, the solution is washed with a 10% solution of sodium carbonate and then with brine, and dried over anhydrous magnesium sulfate. The dried solution is then evaporated to leave 9.3 g of the desired product. Recrystallization of the crude product from acetonitrile affords 6.5 g of the title compound; mp 145°-147° C.