Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12)[CH3:2].S(Cl)([Cl:26])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[C:7]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[N:8][N:9]2[CH:14]=[C:13]([Cl:26])[CH:12]=[N:11][C:10]=12)[CH3:2]
Reactant: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn2cccnc12
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)Cc1c(-c2ccc(Cl)cc2)nn2cc(Cl)cnc12
Temperature: 0 °C
Yield: 37.1 %

Procedure:
A solution of 3.2 g (0.01 mole) of 2(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine-3-acetic acid ethyl ester in 30 ml of methylene chloride was stirred under nitrogen and cooled to 0° C. in an ice bath. The cooled reaction solution was treated with 1.4 g (0.84 ml) (0.01 mole) of sulfuryl chloride and the reaction was allowed to warm to room temperature. The reaction mixture was concentrated in vacuo and the residue dissolved in 20 ml of methylene chloride, and washed successively with water, saturated sodium carbonate solution, and water, and then concentrated in vacuo to obtain 3.5 of residue. The crude residue was placed on on a 100 g silica gel column and chromatographed with a methanol:benzene gradient (0-4%). Concentration of combined fractions yielded a solid which was recrystallized from benzene (300 mg). A second crop obtained after adding ligroin amounted to 1.1 g of mixed product. The combined residues recrystallized from ethanol to yield 1.3 g (37%) of long pale yellow needles, mp 139°-140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:11][N:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=1.[C:45]([O:51][CH2:52]Cl)(=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[N:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][C:37]=1[CH3:38])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:52][O:51][C:45](=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47])=[O:16])=[CH:11][N:10]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=2)[N:9]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccc(C(F)(F)F)cc3)cc2/C=C/C(=O)OCOC(=O)C(C)(C)C)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A mixture of (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoic acid (0.303 g), chloromethyl pivalate (0.075 g), potassium carbonate (0.138 g) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the obtained crystal from hexane-ethyl acetate gave [(2,2-dimethylpropanoyl)oxy]methyl (2E)-3-{3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}-2-propenoate as a colorless powder (0.271 g, yield 75%). melting point: 131-132° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH:11]=[C:12]([CH3:20])[CH2:13][P:14]([O:18][CH3:19])([O:16][CH3:17])=[O:15])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C([OH:25])(C)C.C(OCC)(=O)C>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6].S(=O)(=O)(O)O>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH:11]=[C:12]([CH3:20])[CH2:13][P:14]([O:16][CH3:17])([O:18][CH3:19])=[O:15])[C:9]([OH:25])=[O:10])=[O:21])([CH3:3])([CH3:4])[CH3:2]
Reactant: COP(=O)(CC(C)=C[C@H](CO)NC(=O)OC(C)(C)C)OC
Reactant: CC(C)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COP(=O)(CC(C)=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 0.323 g of 8 in 10 ml of acetone there is added 0.77 ml ofa solution that is 3.25 molar in chromium trioxide and 5.29 molar in sulphuric acid. The mixture is stirred at room temperature for 40 minutes and then there are added 2 ml of isopropanol followed by 50 ml of ethyl acetate. 0.1 g of activated carbon is then added to the mixture. After 10 minutes, the mixture is filtered and washed with 50 ml of ethyl acetate. The filtrate is extracted three times with 50 ml of 10% sodium hydrogen carbonate solution each time. The aqueous phase is extracted twice with 40ml of ethyl acetate each time, acidified to pH 1 using 2N hydrochloric acid, and then extracted three times with 70 ml of ethyl acetate each time. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. Chromatography on 8 g of silica gel using chloroform/methanol/acetic acid 18:1:1 as eluant yields 65 mg of 9. 1H-NMR (300 MHz, DMSO-d6): 1.37 (s, (CH3)3CO); 1.82 (d, J=2, CH3 --C(4)); 2.63 (d, J=22, 2H--C(5)); 3.61 (d, J=11, (CH3O)2PO); 4.62 (t, J=8, H--C(2)); 5.25 (m, H--C(3)); 7.18 (d, J=8, NH); 11.7-12.5 (CO2H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1.[CH3:16][Zn]C.CO>O1CCOCC1.C(OCC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd]Br>[F:15][C:4]1[CH:3]=[C:2]([CH3:16])[C:7]([F:8])=[CH:6][C:5]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C)c1cc(F)c(Br)cc1F
Reactant: C[Zn]C
Agent: Br[Pd]Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C(C)c1cc(F)c(C)cc1F
Temperature: 25 °C
Yield: 144 %

Procedure:
To a solution of trans-dibromobis(triphenylphosphine)-palladium(II) [trans-Pd(PPh3)2Br2] (0.048 g, 5.6 mol %) in 1,4-dioxane (30 mL), a solution of compound (30a) (3.0 g, 10.7 mmol) in dry 1,4-dioxane (4 mL) was added under argon gas flow. To this mixture, dimethyl zinc (2M-solution in toluene, 11.0 mL, 22.0 mmol) was slowly added dropwise and the reaction mixture was heated to reflux for 4 hours. After cooling the reaction mixture to room temperature, methanol (4.0 mL) was added to the reaction mixture and the obtained mixture was diluted with diethyl ether. The organic layer was washed with a 1M aqueous solution (34 mL) of hydrochloric acid and dried (over magnesium sulfate). The solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 3.3 g (83%) of compound (31a) as colorless liquid matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:19])[CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:18])[N:11]=[CH:10][CH:9]=2)=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2F)ccnc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nccc(-c2ccc(Cl)cc2F)c1C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
To a solution of methyl 4-(4-chloro-2-fluorophenyl)-2-methylnicotinate (40 mg, 0.143 mmol) in MeOH (2 mL) and water (3 mL) was added NaOH (11.44 mg, 0.286 mmol) and the reaction mixture was stirred at RT for 14 h. The reaction mixture was concentrated under reduced pressure and acidified with 1.5N HCl the extracted with ethyl acetate (5 mL). The organic layer was washed with saturated NaHCO3 (2×10 mL) and water (10 mL); dried over Na2SO4 and concentrated under reduced pressure to afford crude 4-(4-chloro-2-fluorophenyl)-2-methylnicotinic acid (30 mg, 0.113 mmol, 79% yield) as brown solid. This was taken into the next step without further purification. LC/MS, (ESI) m/z 266.1 [(M+H)+, calcd for C13H10ClFNO2. 266.0]; LC/MS retention time (method D): tR=0.64 min.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:40][CH:41]([CH3:45])[CH2:42][CH2:43][NH2:44]>CN(C)C=O>[F:1][C:2]1[C:3]([C:8]([NH:44][CH2:43][CH2:42][CH:41]([CH3:45])[CH3:40])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCN
Reactant: O=C(O)c1ncccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)CCNC(=O)c1ncccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of 3-fluoro-pyridine-2-carboxylic acid (0.50 g, 3.54 mmol) in dimethylformamide (6 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3.41 g, 10.63 mmol) and N-methylmorpholine (1.56 ml, 14.2 mmol) at 0° C. followed by the addition of 3-methyl-butyl-amine (0.61 ml, 5.32 mmol). The reaction mixture is stirred at RT for 2 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×50 ml). The combined organic layers are washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 50% EtOAc/hexane) affording 3-fluoro-N-(3-methyl-butyl)-pyridine-2-carboxylic acid amide (0.31 g, 1.47 mmol, 42%).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][C@H:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[O:35])[CH2:30]2)[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO.O1CCCC1.C(OCC)(=O)C>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([CH2:27][S:28][C@H:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=3)=[O:35])[CH2:30]2)[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CS[C@H]2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[{(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio}methyl]pyrrolidine (1.94 g) in a mixture of methanol (20 ml) and tetrahydrofuran (20 ml) was added conc. hydrochloric acid (0.48 ml) at ambient temperature and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (50 ml) and the solution was washed three times with saturated aqueous sodium hydrogen carbonate (50 ml) and saturated aqueous sodium chloride (20 ml) successively, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (5:1 v/v) to give (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[{(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio}-methyl]pyrrolidine (1.10 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N+:24]([O-:27])=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21]1[CH:22]=[CH:23][N+:24]([O-:27])=[CH:25][CH:26]=1)[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2cc[n+]([O-])cc2)cc1
Product: COc1ccc(S(=O)(=O)N(C(C)=O)c2ccccc2/C=C/c2cc[n+]([O-])cc2)cc1

Procedure:
Using 1.54 g of the compound obtained in Example 20, the reaction was conducted in the presence of acetic anhydride at 140° C. for 10 minutes and, then, after-treated. The crystal crop was recrystallized from ethanol to provide 0.62 g of the title compound (white granules). m.p. 235-237° C. (decomp.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].S([O-])([O-])=O.[Na+].[Na+].[C:22](=O)([O-])O.[Na+].IC>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[S:12]([CH3:22])(=[O:14])=[O:13]
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CI
Solvent: O
Product: CC(=O)Cc1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 75 °C

Procedure:
A stirred solution of 2-Chloro-5-(2-oxo-propyl)-benzenesulphonyl chloride (prepared as described in Example 174a) (20.0 g, 74.9 mmol) in dioxane (300 ml) at room temperature is treated with a solution of sodium sulphite (18.9 g, 150 mmol) and sodium hydrogen carbonate (12.6 g, 150 mmol) in water (200 ml). The reaction mixture is heated to 75° C. for 10 minutes and then allowed to cool to room temperature. The solvent is removed in vacuo and the residue dissolved in DMF (200 ml). The solution is stirred at room temperature and treated with iodomethane (21.2 g, 150 mmol). After stirring for 20 minutes, the reaction mixture is diluted with water (1000 ml) and extracted with ethyl acetate (3×250 ml). The combined organic layers are washed with water (2×200 ml), brine (100 ml), dried over MgSO4 and concentrated in vacuo to yield the titled compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[C:12]1([S-:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH2:7][S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: [S-]c1ccccc1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cccc(CSc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
A solution of 3-nitrobenzyl chloride (10.0 g) in ethanol (120 mL) was cooled to 0° C., treated with sodium thiophenolate (9.1 g, 90%) in 3 portions, while the temperature was slowly increased to room temperature the mixture was stirred for 18 hours. The reaction mixture was then concentrated in vacuo, treated with diethyl ether (350 mL), washed with water (2×150 mL) and brine (100 mL), dried with sodium sulfate and evaporated to dryness. The title compound (14.6 g) was thus obtained and used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH3:26][S:27]([O:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])=[CH:5][CH:4]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.1 %

Procedure:
To a mixture containing tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate (101; 4.5 g, 20.2 mmol) and DIPEA (16.0 g, 121 mmol) in THF (45 mL) was added MsCl (6.93 g, 60.5 mmol) over a period of 30 min at 0° C. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was then washed with water (2×5 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (10:1 petroleum ether/ethyl acetate) to afford (6-(tert-butoxycarbonylamino)pyridin-3-yl)methyl methanesulfonate 102 (3.0 g, 61%).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([O:13][C@H:14]1[C@@H:20]2[C@@H:18]([O:19]2)[CH2:17][C@:16]([OH:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:15]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C1COCC1.[Cu]I>[C:5]([O:13][C@@H:14]1[CH2:15][C@@:16]([OH:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:17][C@@H:18]([CH:1]=[CH2:2])[C@@H:20]1[OH:19])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@]1(O)C[C@@H]2O[C@@H]2[C@H](OC(=O)c2ccccc2)C1
Reactant: C=C[Mg]Br
Agent: [Cu]I
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C[C@@H]1C[C@](O)(C(=O)OC)C[C@@H](OC(=O)c2ccccc2)[C@H]1O
Reaction time: 1 h

Procedure:
Vinylmagnesium bromide can be added to a −78° C. suspension of CuI in THF. After stirring for 1 hour, a solution of Example 17D and BF3.Et2O in THF can be added. After stirring for 2 hours at −78° C., the reaction mixture can be quenched with saturated NH4Cl. The reaction mixture can be extracted several times with dichloromethane and the combined dichloromethane layers are washed with brine, dried (MgSO4), filtered and concentrated. The concentrate can be purified by flash column chromatography to afford the desired product.
Reaction SMILES: Cl[C:2]1([CH2:7][Cl:8])[O:5][C:4](=O)[CH2:3]1.Cl.[NH2:10][C:11]([NH2:13])=[NH:12].Cl>O>[NH2:13][C:11]1[N:12]=[C:2]([CH2:7][Cl:8])[CH:3]=[C:4]([OH:5])[N:10]=1
Reactant: O=C1CC(Cl)(CCl)O1
Reactant: N=C(N)N
Agent: Cl
Solvent: O
Product: Nc1nc(O)cc(CCl)n1
Temperature: 120 °C

Procedure:
620 parts of 4-chloro-4-chloromethyloxetan-2-one and 440 parts of guanidine hydrochloride were charged to a reaction flask and the mixture was stirred and heated under nitrogen purge as the bath temperature was gradually raised to 120° C. When the bath temperature approached 100° C., reaction commenced accompanied by evolution of hydrogen chloride. When the initial reaction subsided after a few minutes the bath temperature was raised to 130° C. and held until the reaction ceased as indicated by cessation of gassing (about 1 hour). The reaction mixture was allowed to cool about 60° C. and 1750 parts of water was added to the syrup. The solution was extracted with 500 parts of ethyl acetate and the extract was discarded. The aqueous phase was treated with decolourising charcoal, filtered and the pH was adjusted to pH 8 by the addition of saturated aqueous sodium bicarbonate solution. The precipitated solid was filtered, washed with water and dried to constant weight at 80° C. in a vacuum oven to give 2-amino-4-chloromethyl-6-hydroxypyrimidine, m.p. 195°-197° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[N+:6]([O-])[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:3]1[C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[CH:4]=1
Reactant: COC(=O)c1ccc(Cl)c(Cl)[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Yield: 83 %

Procedure:
A solution of methyl 5,6-dichloropyridine-2-carboxylate-N-oxide (22.0 g, 0.100 mol) and phosphorus oxychloride (15.70 mL, 0.169 mol) was heated at 70° C. for 36 hours. The solvent was removed and the residue carefully taken up into diethyl ether and water. The organic layer was washed with saturated sodium bicarbonate solution, water, brine, dried and concentrated to give methyl 4,5,6-trichloropyridine-2-carboxylate (20.0 g, 0.083 mol). 1H NMR (CDCl3): δ 8.16 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[C:15]([C:24](=[O:34])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[CH:26]=3)=[CH:14]2)[N:7]=1)=O.C(NCC)C>CO>[NH2:5][C:6]1[N:7]=[C:8]([CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[C:15]([C:24](=[O:34])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[CH:26]=3)=[CH:14]2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)c2cn(Cc3cccc(NC(=O)C(F)(F)F)n3)c3ccccc3c2=O)cc1C
Solvent: CCNCC
Solvent: CO
Product: COc1ccc(C(=O)c2cn(Cc3cccc(N)n3)c3ccccc3c2=O)cc1C
Yield: 18.9 %

Procedure:
A solution of 212 mg (0.43 mmol) 2,2,2-Trifluoro-N-{6-[3-(4-methoxy-3-methyl-benzoyl)-4-oxo-4H-quinolin-1-ylmethyl]-pyridin-2-yl}-acetamide, excess diethylamine and 5 mL of methanol were heated at 45° C. overnight. The solid was collected by filtration and purified by reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 32.4 mg of 1-(6-Amino-pyridin-2-ylmethyl)-3-(4-methoxy-3-methyl-benzoyl)-1H-quinolin-4-one. LC-MSD, m/z for C24H21N3O3 [M+H]: 400.16 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 1.5 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH3:10])=[CH:4][CH:3]=1.Br[C:12]1[C:13]2[C:14]3[CH:27]=[CH:26][S:25][C:15]=3[C:16](=[O:24])[NH:17][C:18]=2[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]2[NH:17][C:16](=[O:24])[C:15]3[S:25][CH:26]=[CH:27][C:14]=3[C:13]=2[C:12]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH3:10])=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CNCc1ccc(Br)cc1
Product: CNCc1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 41.4 %

Procedure:
Following General Procedure E, 1-(4-bromophenyl)-N-methylmethanamine (200 mg, 1.0 mmol) was reacted to bis(pinacoato)diboron (280 mg, 1.1 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (310 mg, 1.0 mmol) to afford the desired product (145 mg, 42%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=8.1 Hz, 2H), 7.58-7.52 (m, 2H), 7.42-7.35 (m, 3H), 6.02 (d, J=5.4 Hz, 1H), 4.33 (s, 2H), 3.73 (s, 3H), 2.83 (s, 3H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@H:12]([OH:14])[CH2:11][CH:10]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[OH:14][C@H:12]1[CH2:13][NH:9][CH:10]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CC1COc1ccccc1CCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CNC(COc2ccccc2CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
3 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 200 mg of (4R)-1-t-butoxycarbonyl-4-hydroxy-2-[2-(2-phenylethyl)phenoxymethyl]pyrrolidine [prepared as described in step (b) above] in 3 ml of dioxane, and the resulting solution was stirred at room temperature for 2 hours. At the end of this time, the solution was concentrated by distillation under reduced pressure, the resulting residue was dissolved in a small amount of methylene chloride, and ethyl acetate was added to the solution. The resulting mixture was then allowed to stand an room temperature. The crystals which precipitated were collected by filtration, to give 133 mg (yield 79%) of the title compound as colorless crystals, melting at 143°-145° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[Br-].[CH3:28][C:29]1[CH:54]=[CH:53][CH:52]=[CH:51][C:30]=1[CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:9]([CH2:18][CH2:19][CH2:28][C:29]2[CH:54]=[CH:53][CH:52]=[CH:51][C:30]=2[CH3:31])=[C:8]([CH:21]([CH3:23])[CH3:22])[N:7]=1)([CH3:26])[CH3:25]
Reactant: Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccccc1CCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from methyl-2,6-diisopropyl-4(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 2-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1H NMR (300 MHz, CDCl3): δ 7.07 (m, 7 H), 6.90 (m, 1 H), 4.31 (s, 2 H), 3.39 (sept, J=6.6 Hz, 1 H), 3.15 (sept, J=6.6 Hz, 1 H), 2.43 (t, J=7.5 Hz, 2 H), 2.34 (m, 2 H), 2.17 (s, 3 H), 1.6 (m, 2 H), 1.31 (d, J=6.6 Hz, 6 H), 1.27 (d, J=6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.12; H, 8.01; N, 3.25. mp 65-70° C. Rf=0.4 (20% ethyl acetate/hexane).