Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH:13]([C:15]2([CH2:18][CH3:19])[CH2:17][CH2:16]2)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br-:20].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:18]([C:15](=[CH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:16][CH2:17][Br:20])[CH3:19]
Reactant: [Br-]
Reactant: CCC1(C(O)CCc2ccc(OC)c(OC)c2)CC1
Agent: [Li+]
Agent: [Zn+2]
Product: CCC(=CCCc1ccc(OC)c(OC)c1)CCBr

Procedure:
3-Ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-(CH3O)2C6H3, R is C2H5 ] was prepared from 16 g. of 2-(3,4-dimethoxyphenyl)ethyl 1-ethylcyclopropyl carbinol (Preparation B4), 16.8 g. of phosphours tribromide, 16.8 g. of lithium bromide and 17.6 g. of zinc bromide according to the procedure given above in Preparation C1. The product was used directly in the succeeding step (Preparation D4) without isolation.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:16])=[C:6]([CH:12]([OH:15])[C:13]#[N:14])[CH:7]=[C:8]([CH2:10][CH3:11])[CH:9]=1)[CH3:2].[CH3:17][OH:18].[ClH:19]>C(OCC)C.O1CCOCC1>[ClH:19].[CH2:1]([O:3][C:4]1[C:5]([F:16])=[C:6]([CH:12]([OH:15])[C:13](=[NH:14])[O:18][CH3:17])[CH:7]=[C:8]([CH2:10][CH3:11])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(CC)cc(C(O)C#N)c1F
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOc1cc(CC)cc(C(O)C(=N)OC)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 118E (630 mg, 2.93 mmol) in anhydrous diethyl ether (10 mL) at 0° C. was added MeOH (1.2 mL) and 4.0 N HCl in dioxane (2.9 mL). The mixture was stirred at 0° C. for 30 min and then at rt over night. Solvent was removed to give methyl 2-(3-ethoxy-5-ethyl-2-fluorophenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (5.0 mL) was added H2O (8.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude was purified by column chromatography to give 118F (632 mg, 89% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (t, J=7.69 Hz, 3H) 1.43 (t, J=7.03 Hz, 3H) 2.58 (q, J=7.76 Hz, 2H) 3.76 (s, 3H) 4.04-4.13 (m, 2H) 5.37 (s, 1H) 6.68-6.81 (m, 2H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH2:23][N:24]([CH3:28])[CH:25]([CH3:27])[CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[CH3:28][N:24]1[CH:25]([CH3:27])[CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:32]5[CH2:44][CH2:43][N:35]6[C:36]7[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=7[CH:42]=[C:34]6[C:33]5=[O:45])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:29]=[C:22]2[CH2:23]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(C)N(C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CC1Cn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2CN1C
Temperature: 30 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To a solution of 250f (75 mg, 0.123 mmol) in THF/i-propanol/water (4/2/2 mL) was added lithium hydroxide (15 mg, 0.62 mmol). The mixture was stirred at 30° C. for 1 h. After the reaction was complete, the mixture was evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 250 as a white solid (40 mg, 57%). MS-ESI: [M+H]+ 569.3. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.0 Hz, 1H), 7.96 (bs, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J=5.0 Hz, 1H), 6.91 (s, 1H), 5.71 (s, 1H), 5.03 (t, J=3.5 Hz, 1H), 4.65-4.62 (m, 1H), 4.52-4.50 (m, 1H), 4.35-4.33 (m, 1H), 4.17-4.05 (m, 3H), 3.91-3.88 (m, 2H), 3.73-3.71 (m, 1H), 3.71 (s, 3H), 3.55-3.52 (m, 1H), 2.90-2.87 (m, 1H), 2.64-2.58 (m, 4H), 2.43 (s, 3H), 1.93-1.90 (m, 2H), 1.81-1.80 (m, 2H), 1.24 (d, J=6.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]([O:14][C:15](=[O:29])[CH:16]([C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][C:18](=O)[CH3:19])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:17]=[C:18]([CH3:19])[N:1]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:29])[CH3:13]
Reactant: COC(=O)c1cccc(N)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(C(=O)OC)c2)c1-c1ccccc1

Procedure:
Methyl 3-aminobenzoate (10 mmol, 1.4 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was purified over silica gel and crystallized upon standing, 1H-NMR (CDCl3, ppm): 1.15 t (3H), 2.08 s (3H), 3.88 s (3H), 4.05 q (2H), 6.56 s (1H), 7.15-7.33 bm (7H), 7.79-7.97 bm (2H).
Reaction SMILES: [Na].O[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.ClC[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.Cl.[CH2:24]([OH:26])C>>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[C:4]1[C:5]([O:26][CH3:24])=[C:6]([CH:9]=[CH:10][CH:3]=1)[CH:7]=[O:8]
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCO
Agent: Cl
Agent: [Na]
Product: COc1c(C=O)cccc1-c1ccc2ccccc2n1

Procedure:
To a solution of sodium metal (0.9 g, 39.13 g.a.) in absolute ethanol (50 mL) is added dropwise under nitrogen a solution of 4-hydroxybenzaldehyde (5 g, 40.94 mmole) in absolute ethanol (50 mL). The mixture is gently refluxed for 1 hour and then treated dropwise with a solution of 2-chloromethylquinoline (free base, 7.24 g, 40.76 mmole), freshly prepared from the HCl salt) in ethanol (50 mL). The mixture is refluxed for 24 hours, the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic layer is washed with 5% NaOH (pH 8), water, brine to neutral and dried (MgSO4). Removal of the solvent yields the title compound as a yellow solid (9.81 g). The crude material is further purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate 9:1 to remove less polar impurities and 8:2 to elute the product). Yield: 7.37 g (71.5%), m.p. 82°-83° C.
Reaction SMILES: C(OC(N1CC(F)C[C@H]1C=C([C:16]1[CH2:22][C@H:21]2N([C:19](=O)[C@@H:20]2[C@H:23]([OH:25])C)[C:17]=1[C:27](OCC=C)=O)C)=O)C=C.N1CC[O:36]CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(O)C.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>[CH3:19][C:20]([C:23]([OH:36])=[O:25])=[CH:21][CH2:22][CH2:16][CH2:17][CH3:27]
Reactant: C=CCOC(=O)C1=C(C(C)=C[C@@H]2CC(F)CN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C1COCCN1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCC=C(C)C(=O)O

Procedure:
To a solution of allyl (5R,6S)-3-[2-{(2S)-1-allyloxycarbonyl-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.7 g), morpholine (694 μl), and triphenylphosphine (199 mg) in tetrahydrofuran (30 ml) and ethanol (10 ml) was added tetrakis(triphenylphosphine)palladium(0) (263 mg) at room temperature. After stirring for an hour, the precipitate was filtered, washed in turn with dichloromethane (3 times) and acetone (twice), and dried under reduced pressure to give (5R,6S)-3-[2-{(2S)-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1hydroxyethyl]-7-oxo-1-azabicyclo 3.2.0]hept-2-ene-2carboxylic acid (248 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].C(Cl)(=O)C(Cl)=O.[NH4+:29].[OH-]>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][C:11]([NH2:29])=[O:13])=[CH:5][C:4]=1[C:19]([F:22])([F:20])[F:21])#[N:2]
Reactant: CC(C)(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)CN(CC(N)=O)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2-dimethylpropyl)glycine (1.13 g, 3.58 mmol) in CH2Cl2 (10 mL) at 0° C. was added oxalyl chloride (0.33 mL, 3.76 mmol), followed by DMF (0.01 mL, 0.2 mmol). The resulting solution was stirred 5 min in the cooling bath, 20 min at rt and 1 h at reflux under N2. After cooling to rt, the solution was slowly poured into NH4OH (10 mL of a 30 wt % solution) at 0° C., stirred 30 min, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (×2), combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was recrystallized from IPA/hexanes, affording 0.642 g of the title compound as a colorless, amorphous solid. The mother liquor was concentrated and purified by flash chromatography (EtOAc/hexanes), affording an additional 0.241 g of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.9 Hz, 1H), 7.07 (d, J=2.5 Hz, 1H), 6.85 (dd, J=8.9, 2.6 Hz, 1H), 5.70 (bs, 1H), 5.59 (bs, 1H), 4.12 (s, 2H), 3.38 (s, 2H), 1.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3](OC)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:13]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([Cl:13])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: COc1ncc(Br)cc1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ncc(Br)cc1Br
Temperature: 0 °C
Yield: 66.2 %

Procedure:
3,5-Dibromo-2-methoxy-pyridine (427) (1.5 g, 5.62 mmol) was dissolved in anhydrous DMF (14 mL) and chilled to 0° C. While stirring, POCl3 (2.1 mL, 22.48 mmol) was added drop wise over a period of 5 minutes. The mixture was stirred at 0° C. for 1 h. The mixture was then heated to 100° C. under N2, for 16 h. TLC indicated complete reaction at this point. Ice-chips (10 g) were added to the cooled solution and the mixture was stirred for 20 minutes. The mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and brine (2×50 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by column chromatography gave the desired product (428) as an off white solid upon concentration (1.01 g, 3.722 mmol, 66.2% yield). 1H NMR (400 MHz, CDCl3): δ 8.07 (d, 1H, J=2 Hz), 8.38 (d, 1H, J=1.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21]C(OCC2C=CC=CC=2)=O)[C:16]1=[O:32])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:33])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]1=[O:32])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(N)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
To a solution of (S)-2-(3-benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid tert-butyl ester (4 g, 8.92 mmol) in a mixture of MeOH (40 mL) and EtOAc (10 mL) was added 10% Pd/C (500 mg). The mixture was degassed and stirred at room temperature for 4 hours under an atmosphere of hydrogen (balloon pressure). The reaction mixture was filtered through a short pad of celite which was then flushed with MeOH. The combined filtrates were evaporated under reduced pressure to afford the title compound as a white solid (2.6 g, 92%); 1H NMR (400 MHz, CDCl3) δ 1.48 (9H, s), 3.32 (1H, dd), 3.52 (1H, dd), 3.95 (2H, br s), 5.55 (1H, dd), 6.00 (1H, t), 6.55 (1H, d), 6.72 (1H, d), 7.18-7.35 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]([S@@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5](/[CH:6]=[N:18]/[S@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: Cc1cc(C=O)cc(C)c1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(/C=N/[S@@](=O)C(C)(C)C)cc(C)c1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 4-chloro-3,5-dimethyl-benzaldehyde (2 g, 11.86 mmol) and (S)-2-methylpropane-2-sulfinamide (1.58 g, 13.05 mmol) in toluene (35 mL) was treated with titanium(IV) isopropoxide (5.27 mL, 17.79 mmol). The mixture was stirred at 50° C. for 24 hours. It was then quenched with 10% sodium bicarbonate solution (50 mL) and extracted twice with EtOAc. The organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by chromatography on silica gel (cyclohexane/EtOAc).
Reaction SMILES: [NH2:1][CH:2]1[C:28](=[O:29])[N:4]2[C:5]([C:25]([OH:27])=[O:26])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:55]([NH:57][C:58]1[S:59][CH:60]=[C:61]([C:63](=[N:67][O:68][CH3:69])[C:64](O)=[O:65])[N:62]=1)=[O:56]>C(OCC)(=O)C.CN(C)C=O>[CH:55]([NH:57][C:58]1[S:59][CH:60]=[C:61]([C:63](=[N:67][O:68][CH3:69])[C:64]([NH:1][CH:2]2[C:28](=[O:29])[N:4]3[C:5]([C:25]([OH:27])=[O:26])=[C:6]([CH2:9][S:10][C:11]4[S:12][C:13]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:14][N:15]=4)[CH2:7][S:8][C@H:3]23)=[O:65])[N:62]=1)=[O:56]
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: CC(C)(C)OC(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CNC(=O)OC(C)(C)C)s3)CS[C@H]12)c1csc(NC=O)n1
Yield: 62.6 %

Procedure:
A solution of 7-amino-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (4.6 g), trimethylsilylacetamide (7.86 g) and bis(trimethylsilyl)acetamide (4.0 g) in ethyl acetate (50 ml) and a solution of dimethylformamide (0.804 g), phosphoryl chloride (1.69 g) and 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 12.3 g) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 4.2 g).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:18]([Cl:19])=[C:17]([Cl:20])[C:10]2[S:11][C:12]([C:14](=[O:16])[CH3:15])=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl.C(OCC)C>C(O)C>[C:14]([C:12]1[S:11][C:10]2[C:17]([Cl:20])=[C:18]([Cl:19])[C:7]([O:6][CH2:5][C:4]([OH:21])=[O:3])=[CH:8][C:9]=2[CH:13]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(=O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To 5.1 g of ethyl[(6,7-dichloro-2-acetylbenzo[b]thien-5-yl)oxy]acetate in 200 ml of 95% ethanol is added 150 ml of a 6N sodium hydroxide solution and the mixture is refluxed at 100° for 45 mins. The solvent is removed in vacuo to give a white slurry to which is added 250 ml of a 6N hydrochloric acid and 200 ml ethyl ether. The mixture is stirred for 2 hrs, filtered and the filter cake is distributed between 6N hydrochloric acid and ethyl ether. The organic layers are separated and the aqueous layers are extracted with ethyl ether. The combined organic extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated to give a solid. Recrystallization from acetone-hexane gives 2.2 g of [(2-acetyl-6,7-dichlorobenzo[b]thien-5-yl)oxy]acetic acid, mp 203°-205°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]1([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[N:11]1([C:17]([NH2:19])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]2[CH:29]=[C:25]([C:26]([OH:28])=[O:27])[CH:24]=[N:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: NC(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cncc(-c2ccc(F)cc2)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
1.2 g of Pd[P(Ph)3]4 and 7.6 g of p-fluorobenzeneboronic acid are added to a solution of 14.3 g of 5-bromonicotinic acid morpholinamide in 100 g of THF. A solution of 8.0 g of Na2CO3 in 25 g of water is subsequently added dropwise with stirring at 65° C. After 16 hours, the reaction mixture is cooled and evaporated in a rotary evaporator. The residue is taken up in dichloromethane, activated carbon is added, and the mixture is filtered. Repeated extraction of the filtrate with water and evaporation in a rotary evaporator gives a residue of 15.7 g, which, according to HPLC, comprises 89% of 5-(4-fluorophenyl)pyridine-3-carboxylic acid morpholinamide (net yield 93% of theory). Recrystallisation from ethyl acetate gives 8.0 g of 5-(4-fluorophenyl)pyridine-3-carboxylic acid morpholinamide having an HPLC purity of 99.6% (53.3% of theory).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[N:19]=1)=[O:12])=O)(C)(C)C>O1CCOCC1.CO>[ClH:1].[ClH:1].[NH2:9][CH2:10][C:11]([NH:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[N:21]=[C:22]([N:25]=[C:26]([NH2:28])[NH2:27])[S:23][CH:24]=2)[N:19]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Reaction time: 24 h

Procedure:
A solution of hydrogen chloride in dioxane (4N, 5 ml) was added slowly to a suspension of 4-(2-t-butoxycarbonylaminoacetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole-(1.0 g) in methanol (5 ml) with cooling on an ice-water bath. The mixture was stirred for 24 hours with cooling on an ice-water bath. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-(2-aminoacetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (0.58 g).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[N:8]=1.[I:17]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.CCCCCC>[Cl:6][C:7]1[C:12]([I:17])=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[N:8]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(I)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
A hexane solution of n-butyl lithium (3.8 mL) was added to a tetrahydrofuran (10 mL) solution of 2,2,6,6-tetramethylpyrrolidine (0.93 mL) at −78° C. The reaction mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran (5 mL) solution of 2-chloro-6-trifluoromethylpyridine (1.0 g) was added dropwise to the reaction mixture, and the solution was further stirred at −78° C. for 30 minutes. A tetrahydrofuran (5 mL) solution of iodine (1.54 g) was added to the solution, and the temperature of the solution was increased to the room temperature. An aqueous sodium sulfite solution was added to the solution, and the solution was extracted with diethyl ether. The organic layer was sequentially washed with an aqueous sodium sulfite solution, an aqueous sodium hydrogencarbonate solution, and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluate; n-hexane:ethyl acetate=100:0 to 95:5). The title compound (750 mg) was obtained as pale yellow oil.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]CC.[Na+].[C:11](OCC)(=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.[NH2:22][NH2:23]>C(O)C.O>[CH2:15]([O:14][C:12]([C:11]1[C:2]2[CH2:3][CH2:4][CH2:5][C:1]=2[NH:23][N:22]=1)=[O:13])[CH3:16]
Reactant: NN
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1n[nH]c2c1CCC2
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
Cyclopentanone (10.0 g, 118.9 mmol) was taken up in absolute ethanol (30 cm3) and sodium ethoxide (53 cm3, 21% in ethanol, 143 mmol) was added. The resulting solution was stirred under argon for 10 minutes, then diethyl oxalate (19.1 g, 131 mmol) added. Further ethanol (10 cm3) was added and the solution heated at 75° C. for 3 hours and cooled to room temperature. Hydrazine hydrochloride (8.15 g, 119 mmol), taken up in water (20 cm3) was added and the solution heated to 75° C. overnight. Solvent was removed under reduced pressure and the resulting taken up in ethyl acetate (200 cm3) and washed with water (200 cm3), dried (Na2SO4), filtered and solvent removed under reduced pressure to give 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid ethyl ester as an off white solid (16.16 g, 90.0 mmol, 76%). δH (CD3OD): 4.34 (q, 2H, J=7.1, OCH2CH3), 2.78 (t like, 2H, J=7.0), 2.72 (br s, 2H), 2.49 (br s, 2H), 1.36 (t, 3H, J=7.1, OCH2CH3). m/z (ES): 181 [M+H]+.
Reaction SMILES: ON1C(=O)CCC1=O.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:22]([C:29]1[C:30](=[O:37])[NH:31][NH:32][C:33]=1[CH:34]([CH3:36])[CH3:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([C:29]1[C:30](=[O:37])[NH:31][N:32]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:33]=1[CH:34]([CH3:35])[CH3:36])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1
Reactant: CCOC(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Hydroxysuccinimide (1.06 g) was dissolved in tetrahydrofuran (10 g) at room temperature. Triethylamine (0.936 g) and ethyl chloroformate (1.00 g) were added to the solution successively. After stirring the reaction mixture at room temperature for 30 minutes, 4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (2.00 g) was added to the mixture at room temperature. After the reaction mixture was stirred at room temperature for 13 hours, the reaction mixture was stirred at 50° C. for 6 hours. The insoluble materials were removed, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 4-benzyl-1-ethoxycarbonyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]([O:11][CH2:12][CH3:13])(=[O:10])[CH3:9].N1C=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:5]([O:4][C:1]1[CH:15]=[C:16]([CH:13]=[C:12]([O:11][C:8](=[O:10])[CH3:9])[CH:2]=1)[CH:17]=[CH2:18])(=[O:7])[CH3:6]
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Product: C=Cc1cc(OC(C)=O)cc(OC(C)=O)c1
Yield: 87 %

Procedure:
The product mixture was solved in 10 ml of pyridine and treated with 2.33 ml (21.2 mmol) of acetic anhydride without further purification for 15 h at room temperature. The resulting solution was poured into 100 ml ethyl acetate and extracted three times against 100 ml of 1N HCl. The organic layer washed twice with 50 ml of brine and dried over MgSO4. After evaporation of the solvent chromatographic purification over silica gel using a 7:2 (v/v) mixture of n-hexane and ethyl acetate gave 8.04 g of 3,5-diacetoxystyrene as a colorless oil (36.5 mmol, 87%).