Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7]([OH:26])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:6][CH2:5][O:4]1)[CH3:2].[CH3:27]I>>[CH2:1]([CH:3]1[CH2:8][C:7]([O:26][CH3:27])([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:20][CH:21]=3)[CH:10]=2)[CH2:6][CH2:5][O:4]1)[CH3:2]
Reactant: CI
Reactant: CCC1CC(O)(c2cccc(Sc3ccc(C(C)(C)C)cc3)c2)CCO1
Product: CCC1CC(OC)(c2cccc(Sc3ccc(C(C)(C)C)cc3)c2)CCO1
Yield: 43 %

Procedure:
Using a similar procedure to that described in Example 3, (2RS,4SR)-2-ethyl-4-hydroxy-4-[3-(4-tert-butylphenylthio)phenyl]tetrahydropyran was reacted with methyl iodide to give (2RS,4SR)-2-ethyl-4-methoxy-4-[3-(4-tert-butylphenylthio)phenyl]tetrahydropyran in 43% yield as an oil.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([OH:37])[CH2:21][C:22]([CH3:36])([CH3:35])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.[C:44](Cl)(=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:37][C:44](=[O:62])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:21][C:22]([CH3:35])([CH3:36])[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1ccc(COC(=O)C(C)(C)CC(O)COC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(C)(C)C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a mixture of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate (20.6 g, 40 mmol), Pyridine (31.6 g, 400 mmol) in CH2Cl2 (500 mL) at 0° C., was added dropwise a solution of stearoyl chloride (18.2 g, 60 mmol) in CH2Cl2 (100 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was extracted with a 10% aqueous solution of NaHCO3 (300 mL) and the aqueous phase was washed with CH2Cl2 (200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1→5% MeOH in CH2Cl2), to give 27.2 g of 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-stearoyloxy-2,2-dimethylvalerate.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:57][OH:58])[CH:55]=[O:56])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:57][OH:58])[CH2:55][OH:56])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)O[C@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCc4ccccc4)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of (2R,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 25j (1.04 g, 1.3 mmol) in methanol (20 mL) was added sodium borohydride (98 mg, 2.6 mmol) slowly at 0° C. The mixture was stirred at 0° C. for 5 min. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with water (30 mL×2) and saturated aqueous sodium chloride (30 mL×2) in turn, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 25k as yellow oil (1.04 g, 100%). This material was not further purified.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][OH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:14](OCC)=[CH2:15]>O1CCCC1.C([O-])(=O)C.[Hg+]>[CH:14]([O:13][CH2:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[CH2:15]
Reactant: C=COCC
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: CC(=O)[O-]
Agent: [Hg+]
Solvent: C1CCOC1
Product: C=COCCC12CC3CC(CC(C3)C1)C2

Procedure:
36 g (0.2 mol) of 1-admantaneethanol and 72 g (1.0 mol) ethyl vinyl ether were put into a round bottom flask to be dissolved in 100 mL tetrahydrofuran (THF), followed by adding 5 mol % of mercury acetate. Thereafter, the reaction product was reacted for approximately 12 hours under a reflux condition.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[C:3]([N:5]=[C:6]=[O:7])=[O:4].[CH:10]([NH:12][C:13]1[S:14][C:15]([Br:39])=[C:16]([C:18](=[N:36][O:37][CH3:38])[C:19]([NH:21][CH:22]2[C:34](=[O:35])[N:24]3[C:25]([C:31]([O-:33])=[O:32])=[C:26]([CH2:29][OH:30])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1)=[O:11].[Na+].O.Cl>CC(C)=O.CN(C)C=O>[CH:10]([NH:12][C:13]1[S:14][C:15]([Br:39])=[C:16]([C:18](=[N:36][O:37][CH3:38])[C:19]([NH:21][CH:22]2[C:34](=[O:35])[N:24]3[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH2:29][O:30][C:6](=[O:7])[NH:5][C:3](=[O:4])[C:2]([Cl:9])([Cl:8])[Cl:1])[CH2:27][S:28][C@H:23]23)=[O:20])[N:17]=1)=[O:11]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)NC(=O)C(Cl)(Cl)Cl)CS[C@H]12)c1nc(NC=O)sc1Br
Reaction time: 3.5 h
Yield: 76.5 %

Procedure:
A solution of trichloroacetyl isocyanate (1.32 g.) in dry acetone (5 ml.) was added dropwise to a solution of sodium 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate (1.9 g.) in dry dimethylformamide at -30° C. and stirred at -40° to -20° C. for 3.5 hrs. Water (20 ml.) was added dropwise to the reaction mixture below -20° C. and the mixture was poured into water (180 ml.). The mixture was adjusted to pH 2 with 6N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diethyl ether and dried to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 1.9 g.).
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.FC1C=CC(S(F)(F)(F)(F)F)=CC=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](S(F)(F)(F)(F)F)=[CH:37][CH:36]=1.FS(F)(F)(F)(F)C1C=CC(O)=CC=1>CO>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:19])([F:18])([F:17])([F:16])[F:6])=[CH:9][CH:10]=2)=[CH:37][CH:36]=1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: COc1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Agent: Fc1ccc(S(F)(F)(F)(F)F)cc1
Agent: Oc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: CO
Product: COc1ccc(-c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Reaction time: 312 h

Procedure:
In Methanol: Diazonium salt 1 (22.5 mg, 0.0314 mmol) was dissolved in methanol (0.82 mL). After 13 d stirring at room temp. a portion of the solution was diluted with CDCl3 and analyzed by NMR, which indicated the formation of 1-fluoro-4-(pentafluorosulfanyl)benzene 30, (Umemoto, et al., Beilstein J. Org. Chem. 2012, 8, 461-471) 1-methoxy-4-(pentafluorosulfanyl)-benzene, (Beier, et al., Org. Lett. 2011, 13, 1466-1469) and 4-(pentafluorosulfanyl)phenol (Beier, et al., Org. Lett. 2011, 13, 1466-1469).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:24][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[C:18]([CH3:23])[CH:17]=[CH:16]3)C1C=CC=CC=1>C(Cl)Cl>[CH3:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][C@@H:10]([CH2:9][OH:8])[O:24][C:14]3=2)[N:19]=1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(COCc1ccccc1)O3
Solvent: ClCCl
Product: Cc1ccc2c3c(ccc2n1)OC[C@@H](CO)O3
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of (2R)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino [2,3-f]quinoline (0.74 g, 2.3 mmol) in CH2Cl2 (16 mL) being cooled in an ice-bath, FeCl3 (1.9 g, 12 mmol) was added. After 1 h, the ice-bath was removed and the reaction mixture was stirred for another 17 h. CHCl3 (30 mL) and 1N NaOH (50 mL) were added to result in a suspension which was then filtered. The filtered solid was washed with CH3OH (50 mL). The combined organic layers were concentrated in vacuo. Purification on SiO2, eluted with (10:1) CHCl3:iPrOH gave 0.45 g (84%) of the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:20][C:21]1[O:25][CH:24]=[N:23][CH:22]=1)(C(OCC)=O)[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:10]([OH:12])=[O:11])[CH2:20][C:21]1[O:25][CH:24]=[N:23][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1cnco1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC(Cc1cnco1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.5 %

Procedure:
1.5 g of diethyl 2-(tert-butoxyformamido)-2-[(5-oxazolyl)methyl]malonate were dissolved in 1.5 ml of water and 1.5 ml of ethanol. 337 mg of sodium hydroxide were added and the mixture was stirred overnight at room temperature. The mixture was then acidified to pH 5 with acetic acid and the solvent was removed by evaporation. The residue was dissolved in 5 ml of toluene and 0.64 ml of triethylamine was added. The mixture was heated at reflux for 2 hours and then the solvents were evaporated. Ethyl acetate was added and the solution was washed with saturated aqueous citric acid solution. The organic layer was dried over magnesium sulphate to give 1.224 g of crude N-(tert-butoxycarbonyl)-3(5-oxazolyl)-DL-alanine, 1H NMR (250 MHZ, d6-DMSO) δ: 1.4 (s,9H), 3.0-3.3 (m,2H), 6.95 (s,1H), 7.25 (m, 1H), 8.3 (s,1H).
Reaction SMILES: C([O:3][C:4]1[C:5](=O)[CH:6]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH:9]=1)C.[CH3:18][NH:19][NH2:20]>C(O)(=O)C>[CH3:18][N:19]1[C:5]2[C:4](=[O:3])[CH2:9][CH2:8][CH2:7][C:6]=2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:20]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)C1CCC=C(OCC)C1=O
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(C)c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.1 %

Procedure:
30 g (0.125 mol) of ethyl (3-ethoxy-2-oxocyclohex-3-en-1-yl)(oxo)acetate were dissolved in 150 mL of glacial acetic acid and 6.5 mL of methylhydrazine (0.125 mol) were added. The mixture was stirred at room temperature for 6 hours. The solvent was then evaporated and the crude redissolved in water, made basic with 30% NH4OH and extracted with dichlormethane. The organic layer was then dried over Na2SO4 and concentrated. The residue was crystallized from diethyl ether to give 19.2 g (68% yield) of title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].O=CCCCNC(C1CCCCC1)=O>>[O:1]=[CH:2][CH2:3][NH:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6]
Reactant: O=C(NCCO)c1ccc2ccccc2c1
Agent: O=CCCCNC(=O)C1CCCCC1
Product: O=CCNC(=O)c1ccc2ccccc2c1
Yield: 39 %

Procedure:
Naphthalene-2-carboxylic acid (2-oxo-ethyl)-amide (32B) is prepared from 32A as described for 20B.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH:7]([NH:10][C:11](=[O:17])[C@@H:12]([NH2:16])[CH:13]([CH3:15])[CH3:14])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[C:4](=[O:22])[N:3]1[CH:23]([CH3:25])[CH3:24].[F:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35](O)=[O:36])[CH:30]=[C:31]([F:33])[CH:32]=1.CN(C)CCCN=C=NCC>ClCCl>[F:26][C:27]1[CH:28]=[C:29]([CH2:34][C:35]([NH:16][C@@H:12]([CH:13]([CH3:15])[CH3:14])[C:11]([NH:10][CH:7]2[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[C:4](=[O:22])[N:3]([CH:23]([CH3:25])[CH3:24])[N:2]([CH3:1])[C:8]2=[O:9])=[O:17])=[O:36])[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: CC(C)[C@H](N)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)N(C(C)C)C(=O)c2ccccc21
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-3-methyl-5(R,S)-[[(2S)-2-amino-3-methyl-1-oxobutyl]amino]-2-(1-methylethyl)-1H-2,3-benzodiazepin-1,4-dione (IIA, 1.44 mL, 0.28 mmol, 0.2 M solution in dichloromethane) in dichloromethane (2 mL) was added the solution of 3,5-difluorophenyl acetic acid (X, 2.16 mL, 0.43 mmol, 0.2 M solution in dichloromethane) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide polymer (0.72 g, 1.00 mmol) (Desai, et al., Tet. Lett, 1993, 34(48), 7685-7688). The resulting mixture was shaken on the shaker for 18 h and the resin was filtered off and washed with dichloromethane (2×1 mL). The combined solvent was collected and evaporated and product was analyzed by HPLC using the column YMC S7 C18 (3.0×50 mm) with a flow rate of 5.0 mL/min and gradient time of 2.0 min., starting with solvent A (10% MeOH—90% H2O—0.1% TFA), and ending with solvent B (90% MeOH—10% H2O—0.1% TFA). (70% yield).
Reaction SMILES: [CH3:1][CH:2]([C:4]1C=CC=C(C(C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33]([C:36]1C=C[CH:39]=[C:38](C(C)C)[C:37]=1CC(Cl)=O)(C)[CH3:34].C(Cl)(=O)CCCCCCCCCCC>>[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)(=[O:15])[CH2:13][CH2:5][CH2:4][CH2:2][CH2:1][CH2:34][CH2:33][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Agent: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetyl chloride was replaced with dodecanoyl chloride; 1H NMR (DMSO-26): δ 7.09 (s, 3H), 3.65 (heptet, 2H), 2.05 (t, 2H), 1.48-1.15 (m, 18H); 1.10 (d, 6H), 0.86 (t, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:14])=[O:13].B(F)(F)F.[C:19](=O)(O)[O-].[Na+]>>[CH3:19][O:13][C:12]([C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:9]=2[CH:10]=[CH:11][C:2]=1[OH:1])=[O:14]
Reactant: O=C(O)c1c(O)ccc2ncccc12
Reactant: O=C([O-])O
Agent: FB(F)F
Agent: [Na+]
Product: COC(=O)c1c(O)ccc2ncccc12

Procedure:
6-Hydroxy-5-quinolinecarboxylic acid [as reported by Da Re, P. et al. in Ann. Chem. (Rome) 1970, 60(3), 215-24 (C.A. 73, 25338 m)] is reacted with methanolic boron trifluoride solution for several hours. The resulting mixture is added to an aqueous solution of sodium bicarbonate to give finally a basic solution. The solution is extracted with chloroform. The chloroform extract is dried over anhydrous sodium sulfate and concentrated and the residue is crystallized from a suitable solvent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=1.[N:16]([CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[N+:17]=[N-:18]>C1C=CC=CC=1>[CH2:13]([O:12][C:10]([C:9]1[N:16]([CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:17]=[N:18][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:15])=[O:11])[CH3:14]
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: CCOC(=O)C#Cc1ccc(Br)cc1F
Solvent: c1ccccc1
Product: CCOC(=O)c1c(-c2ccc(Br)cc2F)nnn1C[Si](C)(C)C
Temperature: 90 °C
Reaction time: 4 h

Procedure:
In a 50 mL pear-shaped flask, ethyl 3-(4-bromo-2-fluorophenyl)propiolate (1.27 g, 4.68 mmol) and (azidomethyl)trimethylsilane (2.42 g, 2.78 mL, 18.7 mmol, Eq: 4) were combined with benzene (3.5 mL) to give a light yellow solution. The reaction mixture was heated to 90° C. and stirred for 4 h. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 20% EtOAc in heptane) to afford 616 mg (33%) of the desired less polar regio-isomer as a white solid. (M+H)+=400.0/402.0 m/e.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=O.[CH:22]1([NH:25][C:26]2[S:27][CH2:28][C:29](=[O:31])[N:30]=2)[CH2:24][CH2:23]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:22]1([NH:25][C:26]2[S:27]/[C:28](=[CH:1]\[C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]4[O:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)/[C:29](=[O:31])[N:30]=2)[CH2:24][CH2:23]1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1OC1CCOCC1
Reactant: O=C1CSC(NC2CC2)=N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc2c1OC1CCOCC1

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-(tetrahydro-pyran-4-yloxy)-quinoline-3-carbonitrile (example 76b), 2-cyclopropylamino-thiazol-4-one (example 37c), sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(tetrahydropyran-4-yloxy)quinoline-3-carbonitrile. LC-MS m/e 421 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.CS([O-])(=O)=O.[C:22]([O:27][CH3:28])(=[O:26])[CH:23]([CH3:25])O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:23]([CH3:25])[C:22]([O:27][CH3:28])=[O:26])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2F)cc1
Reactant: COC(=O)C(C)O
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2F)cc1

Procedure:
A mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.23 g; 0.01 mole), the methanesulfonate of S methyl lactate (18.22 g; 0.1 mole, minimum of 90% optical purity), and potassium carbonate (1.4 g; 0.01 mole) in DMSO (75 ml) was stirred at room temperature for 18 hours. After this period, the mixture was poured into water (500 ml) then extracted into ether (3×100 ml). The ether extracts were dried (MgSO4), and the solvent evaporated. The residue was purified by preparative HPLC using 8:2 hexane-ethylacetate as the eluent. The first peak to elute (after the solvent front) was collected and the solvent evaporated. This gave 2.3 g (17%) of a light yellow oil whose 1H and 19F NMR (CDCl3) were consistent with the assigned structure. This material possessed an optical rotation of +24.68° as measured at 25° C. The refractive index was 1.5466. Attempts to measure the optical purity using the optically active NMR shift reagent tris-[3-(trifluoromethylhydroxymethylene)-d-camphorateo]europium (III) were not successful. Based upon the optical purity of the starting lactate the optical purity is estimated to be between 75 and 95%.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][C:10](=O)[CH3:11])[O:3]1.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[CH:17][N:16]=1.O>O1CCOCC1>[Cl:14][C:15]1[CH:20]=[C:19]([N:21]2[C:10]([CH3:11])=[CH:9][C:4]([OH:3])=[CH:5][C:6]2=[O:8])[C:18]([CH3:22])=[CH:17][N:16]=1
Reactant: Cc1cnc(Cl)cc1N
Reactant: CC(=O)CC1=CC(=O)OC(C)(C)O1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a screw top vial with rubber septa inset was added 2,2-dimethyl-6-(2-oxo-propyl)-[1,3]dioxin-4-one, prepared as described in Organic Letters, 11(21), 4910-4913; 2009, (500 mg, 2.7 mmol) and 2-chloro-5-methyl-pyridin-4-ylamine (575 mg, 4 mmol, 1.5 eq). The mixture was dissolved in anhydrous 1,4-dioxane (10 mL). Once the mixture was homogeneous the vial was placed on a stirrer/hot plate preset to 90° C. The reaction was heated at this temperature for 3.5 h. The reaction was removed from heat and analyzed by HPLC which showed the reaction was >95% complete. The vial was placed back on the hot plate. To the heated mixture was added H2SO4 (250 μL) and the reaction was heated for 1 h. The reaction was removed from the heat and after cooling to ambient temperature, the dioxane was removed by passing a stream of air over the top of the open vial to give a brown residue. Water (˜4 mL) was added to the vial, which was stirred for 30 min. The resulting tan solid was filtered off with washing from additional water and the diethyl ether to give the desired product (531 mg, 57% based on being the sulfate salt) as a tan solid which by HPLC was ˜95% pure: MS (M+H) 250.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[C:13]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]1[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1I.[CH:52]1([O:55][C:56]2[CH:57]=[C:58](B3OC(C)(C)C(C)(C)O3)[CH:59]=[CH:60][C:61]=2[O:62][CH:63]([F:65])[F:64])[CH2:54][CH2:53]1.C1(B(O)O)C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:58]2[CH:59]=[CH:60][C:61]([O:62][CH:63]([F:65])[F:64])=[C:56]([O:55][CH:52]3[CH2:53][CH2:54]3)[CH:57]=2)=[C:13]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]1[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Reactant: CCOC(=O)c1c(Cc2ccc(OC)nc2)c(Br)n(COCc2ccccc2)c1C=O
Agent: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Agent: OB(O)c1ccccc1
Product: CCOC(=O)c1c(Cc2ccc(OC)nc2)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Yield: 95.7 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 31 except for using 322 mg (0.66 mmol) of ethyl 1-benzyloxymethyl-5-bromo-2-formyl-4-(6-methoxy-3-pyridylmethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 43-(b) in place of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 323 mg (0.96 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in Reference example 1-(a) in place of phenylboronic acid, respectively, whereby 383 mg of the title compound was obtained as a slightly yellowish oil. (Yield: 96%)