Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:46]=[CH:45][C:39](/[CH:40]=[CH:41]/B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](/[CH:41]=[CH:40]/[C:39]3[CH:45]=[CH:46][C:36]([Cl:35])=[CH:37][CH:38]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(/C=C/c2ccc(Cl)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), (E)-4-chlorostyrylboronic acid (54.6 mg, 0.299 mmol) and PdCl2(PPh3)2 (42.0 mg, 0.060 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-((E)-4-chlorostyryl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was diluted with dichloromethane (3.0 mL) and treated with TFA (3 mL) for 1.5 hours to remove the protecting groups. The volatiles were subsequently evaporated from the reaction mixture, and the residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with 20-60% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (42 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=15.66 Hz, 1H), 1.98-2.22 (m, 1H), 3.50-3.73 (m, 2H), 3.79-4.08 (m, 3H), 4.32-4.51 (m, 2H), 4.55 (br s, 1H), 7.17 (d, J=5.05 Hz, 1H), 7.50 (d, J=8.59 Hz, 2H), 7.55-7.73 (m, 2H), 7.92 (d, J=4.55 Hz, 3H), 8.22 (d, J=16.17 Hz, 1H), 8.53 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20ClFN4O2, 403. found, 403.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]O)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:18])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][Cl:18])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc2cc(Cl)ccc2n1CCCO
Solvent: ClC(Cl)Cl
Product: Cc1nc2cc(Cl)ccc2n1CCCCl
Reaction time: 3 h

Procedure:
To a stirred mixture of 6.5 parts of 5-chloro-2-methyl-1H-benzimidazole-1-propanol and 120 parts of trichloromethane are added dropwise 12 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and evaporated. Water is added to the residue and the mixture is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 5-chloro-1-(3-chloropropyl)-2-methyl-1H-benzimidazole.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([O:13][C:14](=O)[O:15]C(C)(C)C)([CH3:12])([CH3:11])[CH3:10]>O1CCOCC1.O>[NH:1]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC(C)[C@H](N)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 10 g (0.086 mol) of valine and 3.4 g (0.086 mol) of NaDH in 250 ml of dioxan: H2O (2:1) mixture was slowly added 20.5 g (0.094 mol) of ditertbutylcarbonate at 0° C. with vigorous stirring. The reaction mixture was then stirred for another hour at room temperature, dioxan was removed under reduced pressure, and BOC-Val-OH was obtained by acidifying the mixture to a pH of 2-3. The raw product consisting of 18 g of viscous oil was obtained after evaporating the solvent from the ethyl acetate extracts.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.C([Sn]([C:45]#[N:46])(CCCC)CCCC)CCC>ClCCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:45]#[N:46])[CH2:13]1
Reactant: O=S(=O)(Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1)C(F)(F)F
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: N#Cc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Temperature: 80 °C
Yield: 7.6 %

Procedure:
A mixture of trifluoromethanesulfonic acid 3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenyl ester (51 mg, 0.11 mmol), tributyltin cyanide (142 mg, 0.45 mmol) and tetrakis(triphenylphosphine)palladium (189 mg, 0.164 mmol) in 1,2-dichloroethane (15 ml) was heated in a microwave reactor at 80° C. for 80 h. The solid precipitate was filtered off and the mixture was evaporated to dryness. The residue was redissolved in DCM, filtered and washed two times with 1 M HCl. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness. The crude product was purified by flash chromatography first using gradient of DCM and MeOH and then using gradient of heptane and EtOAc as eluent to give 2.8 mg of the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2I)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn]([C:37]1[CH2:41][CH2:40][CH2:39][CH:38]=1)(CCCC)CCCC)CCC>CN(C=O)C.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>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:37]2[CH2:41][CH2:40][CH2:39][CH:38]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(cc(I)n2S(=O)(=O)c2ccccc2)c1OC
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(cc(C3=CCCC3)n2S(=O)(=O)c2ccccc2)c1OC
Temperature: 90 °C
Yield: 65 %

Procedure:
To 539 mg (1.22 mmol) the iodo intermediate from step 2 in 5 mL dry DMF was added 43 mg (0.061 mmol, 5 mol %) of PdCl2(PPh3)2, followed by 870 mg (2.44 mmol, 2 eq) tributylstannylcyclopentene. The reaction was heated to 90° C. for 4 h, concentrated, dissolved in EtOAc and filtered through celite. The EtOAc layer was washed with H2O, aqueous NaCl solution, dried (MgSO4), and concentrated. The product was purified by silica gel chromatography (5-15% EtOAc/hexane) to yield 302 mgs of 1-benzenesulfonyl-2-cyclopent-1-enyl-4,5-dimethoxy-1H-indole (65%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([N:9](C=O)[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.ClCCl.CS(O)(=O)=O>CO>[CH:19]1[C:20]([N:23]2[C:24](=[O:29])[CH2:25][O:26][CH2:27][CH2:28]2)=[CH:21][CH:22]=[C:17]([N:13]2[C:14](=[O:16])[O:15][C@@H:11]([CH2:10][NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[CH2:12]2)[CH:18]=1
Reactant: O=CN(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1

Procedure:
In four neck round bottom flask charge 5-chloro-N-formyl-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (120 g), dichloromethane(2400 ml) and 70% methanesulphonic acid (120 ml) at 25-30° C. Obtained reaction mixture is heated to reflux for 4 to 5 h. After completion of reaction, concentrate reaction mass under reduced pressure to obtain residue. Added Dichloromethane (120 ml) and slowly added Methanol (600 ml) to the residue. The precipitated solid is filtered off and washed by methanol (240 ml)
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.CCOC(C)=O>C1COCC1.O>[C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCCCCCCSc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(SCCCCCCCCCC(=O)O)cc1
Reaction time: 24 h
Yield: 106 %

Procedure:
4-(9-Methoxycarbonyl nonylsulfanyl) benzoic acid tert-butyl ester (2.46 g, 6.2 mmol) was dissolved in THF (25 ml). 1 N NaOH (6.2 ml, 6.2 mmol) was added and the mixture was stirred under N2 for 1 d. 1 N HCl (6.5 ml) diluted with water (100 ml) was added, and then AcOEt (100 ml) was added. The organic phase was dried over MgSO4 and concentrated under vacuum to yield a white solid (2.5 g).
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])C)=O)(OC(C)(C)C)=O.[CH:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.Cl.O.N1C=C[CH:30]=[CH:29][CH:28]=1>>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([CH:17]=[CH2:16])=[CH:19][CH:20]=1.[O:8]1[CH2:1][CH2:30][CH2:29][CH2:28][CH:9]1[O:11][C:12]1[CH:14]=[CH:23][C:18]([CH:17]=[CH2:16])=[CH:19][CH:15]=1
Reactant: C#Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Di-t-butyl dicarbonate in an amount of 1.6 g was added to a solution containing poly(p-hydroxystyrene) [weight-average molecular weight: 11,000] in 40 ml of pyridine while stirring at room temperature. Therein, the reaction was run for 3 hours at room temperature, and the resultant solution was poured into a solution containing 20 g of conc. hydrochloric acid in 1 liter of ion-exchanged water. A powdery matter thus precipitated was filtered off, washed with water, and dried to give a p-hydroxystyrene/p-(t-butyloxycarbonyloxy)styrene (50/50) copolymer.
Reaction SMILES: CC([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=C.OO.[OH:19]S(O)(=O)=O.[O-]S([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[OH:19][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: C=C(C)c1ccc(OC(C)C(=O)OC)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(O)cc1
Temperature: 10 °C
Reaction time: 0.03 h
Yield: 94 %

Procedure:
An 86.0 g-portion of methyl 2-(4-(1-methylethenyl)phenoxy)propanoate was dissolved in 360 ml glacial acetic acid. An equimolar portion of 30% aqueous H2O2 was added. The solution was cooled to 10° C. and 7.6 mol % of 98% H2SO4 was added. The solution was allowed to slowly warm to 35° C. over 11 minutes at which point the ice bath was put back on. The temperature peaked at 84° C. two minutes later. The reaction mixture was allowed to cool slowly to 36° C. over 25 minutes. A 26 g-portion of 20% aqueous Na2SO3 was added, followed by 900 ml water. The mixture was extracted with four 200 ml-portions of CH2Cl2. The combined organic layers were washed with two 200 ml-portions and one 400 ml-portion of 5% aqueous NaHCO3. The organic layer was dried with Na 2 SO4. Removal of solvent gave 74.8 of 94% pure methyl 2-(4-hydroxyphenoxy)propanoate, corresponding to a 92% yield. Distillation under reduced pressure gave 59.3 g of methyl 2-(4-hydroxyphenoxy)propanoate (b.p. 154°-155° C./4 torr) corresponding to a 77% yield.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([CH2:12][CH2:4][CH:3]=[CH2:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccccc1
Reactant: C1CCOC1
Product: C=CCCc1ccccc1
Yield: 94 %

Procedure:
Example 1 was repeated except that 1.0 L of tetrahydrofuran was used as a solvent in place of the mixed solvent of 250 ml of tetrahydrofuran and 750 ml of toluene, and 127.0 g (yield 94%) of 4-phenyl-1-butene was obtained. The analysis of the product by gas chromatography indicated the purity of 98.0%.
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[Cl:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:10]=1[NH2:11].C(N(CC)CC)C.[Cl:24][C:25]1[C:26]2[N:27]([N:34]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[N:36]=2)[C:28]([CH3:33])=[N:29][C:30]=1[O:31][CH3:32].CS(C)=O>C(#N)C>[Cl:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:10]=1[NH:11][S:37]([C:35]1[N:36]=[C:26]2[N:27]([C:28]([CH3:33])=[N:29][C:30]([O:31][CH3:32])=[C:25]2[Cl:24])[N:34]=1)(=[O:38])=[O:39]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COc1nc(C)n2nc(S(=O)(=O)Cl)nc2c1Cl
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1nc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2c1Cl

Procedure:
Anhydrous sodium iodide (11.7 g, 0.078 mol) was placed in 50 ml of dry acetonitrile and 8.5 g (0.078 mol) of trimethylsilyl chloride added with stirring. To this was added 6.3 g (0.039 mol) of 2,6-dichloroaniline and 7.9 g (0.078 mol) of triethylamine. The mixture was stirred at ambient temperature for 30 min and then the volatiles were carefully removed by evaporation under reduced pressure and the residue diluted with ether and filtered. The contents of this solution appeared to be N-trimethylsilyl-2,6-dichloroaniline of about 97 percent purity by GLC analysis. The ether precipitation of insolubles was repeated and the ether was removed by evaporation under reduced pressure. The residue was mixed with 50 ml of dry acetonitrile, 3.9 g (0.013 mol) of 8-chloro-2-chlorosulfonyl-7-methoxy-5-methyl-1,2,4-triazolo[1,5-c]pyrimidine, and 0.2 ml (0.003 mol) of dimethylsulfoxide and the mixture stirred overnight. The resulting mixture was concentrated under reduced pressure and the solid residue was mixed with hexane and water and filtered. The residue was then dissolved in 400 ml of methylene chloride and resulting solution was twice extracted with water, dried over sodium sulfate and filtered. It was then concentrated under reduced pressure and the residue was mixed with hexane, collected by filtration, and dried to obtain 3.3 g (60 percent of theory) of the title compound as a pale yellow powder melting at 255° C.-256° C. with decomposition.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH:20]([CH3:24])[NH:19]1.[OH-].[NH4+]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH3:17][CH:18]1[NH:19][CH:20]([CH3:24])[CH2:21][N:22]([C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:23]1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: CC1CNCC(C)N1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC1CN(C2=Nc3ccccc3Oc3ccccc32)CC(C)N1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a stirred solution of 10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one (0.4 g; 1.9 mmol; Aldrich) in dry toluene (20 mL) at room temperature was added 2,6-dimethyl piperazine (0.99 g; 8.7 mmol; Aldrich) followed by the dropwise addition of TiCl4 (1M in toluene, 2.27 mL; 2.27 mmol). The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution (30%, 50 mL). The resulting mixture was extracted with dichloromethane (4×75 mL), and the combined organic phases were then dried (K2CO3) and concentrated. Purification of the product was conducted on silica gel using CHCl3 :MeOH (94:6) eluant to give 0.353 g (60%) of 11-(3,5-dimethyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine as a pale yellow solid; m.p. 112°-114° C.
Reaction SMILES: [CH2:1]([Zn]CC)C.S1CCCC1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCCl.ClCCl>[CH2:1]1[O:18][CH:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: ClCCCl
Solvent: C1CCSC1
Product: c1ccc(C2CO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of diethyl zinc (1.8 ml of 1.1M solution in toluene, 2.0 mmol) in 1,2-dichloroethane (6 ml) was added chloroiododomethane (218 μl. 3 mmol) at -15° C. and the reaction mixture was stirred for 15 minutes. Tetrahydrothiophene (240 μl , 3 mmol) and benzaldehyde (1 mmol) were added and the reaction mixture was warmed to room temperature. After stirring at that temperature for 1 hour the reaction mixture was refluxed for one hour. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (20 ml) and washed with saturated solution of NH4Cl (3×5 ml). The organic layer was dried over MgSO4. After filtration of the drying agent the solvent was removed in vacuo and the residue was chromatographed over silica (eluant petrol:dichloromethane (40:60) to give the title compound as a clear oil (92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10]([F:14])([F:13])[C:11]#[N:12].Cl.[NH2:23][OH:24].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10]([F:13])([F:14])[C:11](=[N:23][OH:24])[NH2:12]
Reactant: N#CC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NC(=NO)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 99.1 %

Procedure:
In 6 ml of chloroform was dissolved 300 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile. To the resulting solution were added 83 mg of hydroxylamine hydrochloride and 100 mg of triethylamine at 0°-5° C. The resulting mixture was subjected to reaction at 20°-25° C. for 3 hours. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of chloroform and 5 ml of water. The resulting solution was adjusted to pH 9.0 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 330 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide oxime.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C([N:20]([CH2:23][CH3:24])CC)C.[C-:25]#N.C#C>>[C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@:3]([CH:25]=[CH:24][C:23]#[N:20])([OH:4])[CH2:2]1
Reactant: [C-]#N
Reactant: CCN(CC)CC
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: C#C
Product: Cc1cn([C@H]2C[C@@](O)(C=CC#N)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
The title compound is obtained by following essentially the same method described in Example V. Thus starting from thymidine (360 mg, 1.5 mmol), triethylamine (210 μl, 1.5 mmol) and acetylene cyanide. (152 mg, 3 mmol), the title compound is obtained after purification on preparative TLC (5% methanol in ethyl acetate, Rf 0.45), as a slight yellow oil (140 mg, 35%) pure by TLC analysis. 1HNMR, (DMSO) 1.86 (s, 1H,-CH3 ) 6.17 (t,J=6.1 Hz, 1H, --O--CH--N) 6.18 (d, J=9 Hz, 1H, --CH=CH--CN) 7.06 (d,J=9 Hz, 1H, --CH=CH--CN) 7.89 (s,1H, N--CH=C--CH3).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[O:5][C:6]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:8]=1.Cl>C(O)C>[Cl:3][C:4]1[O:5][C:6]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:8]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
An aqueous solution of 1 N sodium hydroxide (34 ml) was dropwise added to an ethanol (50 ml) solution; of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (8.50 g), with cooling with ice. After stirring for 20 minutes with cooling and then for 30 minutes at room temperature, 2 N hydrochloric acid was added thereto, and the crystals thus precipitated were collected by filtration to obtain 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (8.00 g, 99%) This was recrystallized from ethyl acetate to give colorless prisms. mp 169-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18](N)=[CH:17][CH:16]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 35 h

Procedure:
50 g of 1-chloro-3,4-dinitrobenzene in 250 ml of ethanol is mixed with 50 ml of 4-fluoroaniline and stirred for 35 hours at 60° C. After concentration by evaporation to half the volume, water and dichloromethane are divided up. After the organic phase is washed with 1N aqueous hydrochloric acid, it is dried on sodium sulfate, filtered and concentrated by evaporation. After chromatography on silica gel, 62.33 g (5-chloro-2-nitrophenyl)-(4-fluorophenyl)amine is obtained.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCCCCCC>CC(O)COC>[CH3:10][C@@H:7]1[N:6]2[C:5]3[C:14]([C:13]([C:12]([C:17]([OH:19])=[O:18])=[CH:11]2)=[O:16])=[CH:15][C:2]([F:1])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:4]=3[O:9][CH2:8]1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Solvent: COCC(C)O
Solvent: CCCCCCC
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
3 g (10.67 mmole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4]benzoxazine-6-carboxylic acid was put in suspension in 30 mL of PGME and 4.75 mL (43 mmole) of N-methyl piperazine. The reaction mixture was heated to reflux for 23 hours until completion of the reaction. During that time, the reaction mixture became soluble. The mixture was then cooled to 90° C. and n-Heptane (10 mL) was added at this temperature. The reaction mixture was then cooled to 0° C. and the precipitation occurred around 65° C. The reaction was left at 0° C. for 3 hours, filtrated under vacuum and dried overnight to obtain 2.98 g (77.3%) of levofloxacin.