Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH3:2].C(O[C:9](=O)[CH3:10])(=O)C.[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N+:20]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([O-:32])(=[O:31])=[O:30])=[CH:26][CH:27]=2)[C:22]([CH3:41])([CH2:33][CH2:34][CH2:35][CH2:36][S:37]([OH:40])(=[O:39])=[O:38])[C:21]=1[CH3:42])([OH:14])=[O:13]>N1C=CC=CC=1>[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:26][CH:27]=2)[C:22]([CH3:41])([CH2:33][CH2:34][CH2:35][CH2:36][S:37]([OH:40])(=[O:38])=[O:39])/[C:21]/1=[CH:42]\[CH:15]=[CH:16]\[CH:17]=[CH:18]\[C:19]1[C:9]([CH3:10])([CH2:33][CH2:34][CH2:35][CH2:36][S:37]([OH:40])(=[O:39])=[O:38])[C:27]2[C:28](=[CH:23][CH:24]=[C:25]([S:29]([O-:32])(=[O:31])=[O:30])[CH:26]=2)[N+:20]=1[CH2:1][CH3:2])([OH:14])=[O:13]
Reactant: CC1=[N+](CCCCCC(=O)O)c2ccc(S(=O)(=O)[O-])cc2C1(C)CCCCS(=O)(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CC[N+]1=C(/C=C/C=C/C=C2/N(CCCCCC(=O)O)c3ccc(S(=O)(=O)O)cc3C2(C)CCCCS(=O)(=O)O)C(C)(CCCCS(=O)(=O)O)c2cc(S(=O)(=O)[O-])ccc21
Reaction time: 0.33 h

Procedure:
2-[(1E,3E)-4-Anilinobuta-1,3-dienyl]-1-ethyl-3-methyl-3-(4-sulphobutyl) 3H-indolium-5-sulphonate (71 mg) was dissolved in a mixture of pyridine (45): acetic acid (45): acetic anhydride (10) (5 ml), at 90° C. To this solution was added crude 1-(5-carboxypentyl)-2,3-dimethyl-3-(4-sulphobutyl)-3H-indolium-5-sulphonate, portionwise at 20 minute intervals, until UV/Vis is analysis indicated complete conversion of half-dye components (λmax=524, 430 nm) to Cy5 dye product (λmax=653 nm). The solvent was then evaporated under vacuum and the residue purified by HPLC (RPC18. Water/methanol/triethylamine, then water/acetonitrile/TFA).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:11]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>N1C=CC=CC=1>[CH3:29][S:30]([NH:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:11]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[NH:9][N:8]=2)=[CH:4][CH:3]=1)(=[O:32])=[O:31]
Reactant: Nc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 3-(4-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (107 mg, 0.29 mmol, prepared in Example 43) in pyridine (2 ml) was added methanesulfonyl chloride (47 mg, 0.41 mmol, 1.4 eq.), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was admixed with water, and filtered to give precipitates which were dried and purified by flash column chromatography to afford 3-(4-methanesulfonylaminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (84 mg, 65%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([NH:13][C:14](=[O:34])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][C@H:22]3[CH3:33])=[N:17][CH:16]=2)=[C:4]([Cl:35])[CH:3]=1.O1CCCC1.[B:41](OC)([O:44]C)[O:42]C.Cl>O.C(O)C>[Cl:35][C:4]1[C:5]([NH:13][C:14](=[O:34])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][C@H:22]3[CH3:33])=[N:17][CH:16]=2)=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([B:41]([OH:44])[OH:42])[CH:3]=1
Reactant: C[C@@H]1CN(C(=O)C(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C[C@@H]1CN(C(=O)C(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(B(O)O)cc2Cl)cn1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57 %

Procedure:
Under an atmosphere of nitrogen, a mixture of N-(4-bromo-2-chloro-5-trifluoromethoxy-phenyl)-6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide (20.0 g, 34.6 mmol) and tetrahydrofuran (200 mL) was cooled to 0° C. and then 1.3 M isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (79.9 mL, 104 mmol) was added dropwise at 0-10° C. After 2.5 h, boric acid, trimethyl ester (12.0 mL, 106 mmol) was added dropwise, and then 1 N HCl (105 mL) was added and the reaction mixture was stirred overnight. The reaction mixture was extracted with EtOAc (250 mL); the organic layer was washed with water, sat. aq. NaHCO3, dried over MgSO4, and evaporated to give crude product (22.8 g). To the crude product was added ethanol (230 mL) and then slowly water (57.5 mL). The resulting mixture was stirred for 10 days and filtered to give the title intermediate as a crystalline solid (10.7 g, 57% yield).
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[Cl:38]>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:27][C:26]=3[Cl:38])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=C1CCC(c2ccc(OCCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)c(Cl)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH2:3]1.[O-]CC.[Na+].[CH3:21][C:22]([CH:24]=[CH2:25])=[O:23].Cl>C(O)C>[O:23]=[C:22]1[CH2:24][CH2:25][C:3]2[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2]=2[CH2:21]1
Reactant: C=CC(C)=O
Reactant: O=C1Cc2ccccc2Oc2ccccc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC2=C(C1)c1ccccc1Oc1ccccc12

Procedure:
To a solution of 42 g of the compound 10-keto-10,11-dihydro-dibenzo(b,f)-oxepine in 200 ml of dry ethanol a solution of sodiumethoxide (7 g of sodium in 500 ml of ethanol) is added dropwise. After stirring the mixture for 30 minutes 16.2 ml of methylvinylketon in 50 ml of ethanol are added, whereupon the solution is refluxed for 1 hour. The solution is cooled then and poured into 2 N HCl. After extracting into ether, washing the ether layer with water (till neutral) and drying the etherial phase, the solvent is evaporated.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:42]=[C:43]([N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1)[CH2:44][NH:45][C:46](=[O:60])[C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1.Cl>CN(C=O)C.O>[F:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([N:64]1[CH2:65][CH2:66][N:61]([C:43](=[O:42])[CH2:44][NH:45][C:46](=[O:60])[C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[CH:51][CH:52]=2)[CH2:62][CH2:63]1)=[O:15]
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2F)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
DIPEA (68 mg, 0.09 mL, 0.53 mmol) was added drop wise to 2,5-difluoro-benzoic acid (33 mg, 0.21 mmol) in DMF (5 mL). EDCI (40 mg, 0.21 mmol) and HOBT (28 mg, 0.21 mmol) were added consecutively and, after 10 minutes, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenylamino-benzamide in its HCl salt form (60 mg, 0.17 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 39 mg (46% yield) of N-{2-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 96.62%. 1H-NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (d, 2H), 7.4 (t, 3H), 7.3 (t, 2H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (dd, 2H), 3.6 (m, 4H), 3.5 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=3)=[O:38])[CH:35]=2)[N:30]([C:47]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:29]=1.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C=O>[F:46][C:41]1[CH:40]=[C:39]([CH:44]=[C:43]([F:45])[CH:42]=1)[C:37]([C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:47]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[N:29]=[C:28]2[NH:27][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)=[CH:10][C:11]=1[N+:18]([O-:20])=[O:19])=[O:38]
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(C(=O)c3cc(F)cc(F)c3)cc12
Reactant: CN1CCN(c2ccc(C(=O)O)c([N+](=O)[O-])c2)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(C(=O)c5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a suspension of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acid hydrochloride (1.5 g, 4.97 mmol) in dry tetrahydrofuran (80 mL) were added oxalyl chloride (1.4 mL, 19.9 mmol) and N,N-dimethylformamide (1-2 drops). The mixture was stirred at room temperature overnight and then evaporated to dryness. The resulting crude acyl chloride was taken-up with toluene and evaporated again then dissolved in dry tetrahydrofuran (180 mL). A solution of (3-amino-1-trityl-1H-indazol-5-yl)-(3,5-difluoro-phenyl)-methanone (1.83 g. 3.55 mmol) and N,N-diisopropylethylamine (2.5 mL, 14.22 mmol) in dry tetrahydrofuran (15 mL) was added to the reaction mixture. The mixture was stirred at room temperature overnight and then at 75° C. for 2 hours. The volatiles were evaporated and the residue taken up with dichloromethane and washed with brine. The organic phase was dried over sodium sulfate and evaporated to dryness. Purification of the crude by chromatography over silica gel (DCM/MeOH) afforded 2.51 g of the title compound as yellow powder (92% yield).
Reaction SMILES: CI.[C:3]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[CH:4].[N-:23]=[N+:24]=[N-:25].[Na+].[C:27](O)(C)(C)C>C(OCC)(=O)C.N.[Cu]I.O>[CH3:27][N:23]1[CH:4]=[C:3]([C:5]2[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=2)[CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[N:25]=[N:24]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)O
Reactant: C#Cc1cccc(CCOCCC(=O)OC(C)(C)C)c1
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)nn1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Methyl iodide (0.20 mL) was added in one portion to a mixture of tert-butyl 3-(3-ethynylphenethoxy)propanoate [Example 4, Step ii)] (682 mg), sodium azide (194 mg), tert-butanol (0.750 mL), water (3 mL) and copper (I) iodide (47 mg) and sealed into a microwave tube. The reaction was heated to 70° C., over a period of 2 h in the microwave reactor. The reaction mixture was diluted with ethyl acetate and 35% ammonia was added. The mixture was stirred for 30 min and separated. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20-100% ethyl acetate in isohexane then elution gradient 0-10% methanol in ethyl acetate to afford the subtitled compound (500 mg). 1H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 7.70 (s, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.19 (d, J=7.7 Hz, 1H), 4.15 (s, 3H), 3.73-3.66 (m, 4H), 2.92 (t, J=7.0 Hz, 2H), 2.49 (t, J=6.4 Hz, 2H), 1.43 (s, 9H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32](O)=[O:33]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:32](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:25][CH:24]=2)=[O:9])=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: O=C(O)c1ccccn1
Agent: Cl
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC(=O)c2ccccn2)cc1

Procedure:
mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)benzoic acid via Procedure G to yield tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate. Tert-butyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCl in Dioxane to remove the Boc protecting group and form the HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 50 mg of the crude HCl salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to picolinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 443.3 (M)+.
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[P:19](=[O:23])([OH:22])([OH:21])[OH:20].C(#N)C.C1(C)C=CC=CC=1>O>[P:19]([O-:23])([O-:22])([OH:21])=[O:20].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: O=P(O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=P([O-])([O-])O

Procedure:
Tetra-n-butylammonium hydroxide (40% aq. w/w, about 150 g) was added dropwise to a solution of phosphoric acid (85% aq, w/w, 18 g, 0.155 mmol) in water (150 mL) until the pH reached 7. Water was then evaporated in vacuo to give a syrup which was co-evaporated with dry acetonitrile (2×400 mL) followed by dry toluene (2×400 mL). The resulting white solid (75 g) was dried in vacuo and stored over phosphorus pentoxide under vacuum until used.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH:34]=[O:35])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([OH:6])=[O:35])[CH2:26]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccccc2C=O)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
A solution of sodium chlorite (1.85 g; 20.43 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.6 g; 13.37 mmol; 3.6 eq.) in water (10 mL) was added dropwise to a mixture of 2-methyl-2-butene (3.71 mL) and 3-(2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.03 g; 3.71 mmol; 1 eq.) in 1,4-dioxane (10 mL). and the reaction mixture was stirred at room temperature for 2 hours. The dioxane was evaporated in vacuo, the mixture diluted with water and the pH made acidic with 0.1M HCl. The precipitate was filtered off, washed with water and dried to afford the title compound (1.02 g, 94%) as a white solid. UPLC/MS: (MS−) 292.4 ([M−H]−).
Reaction SMILES: [C:1]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:22]([N:25]([CH2:34][C@@H:35]([OH:45])[C@@H:36]([NH2:44])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:24])[CH3:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:22]([N:25]([CH2:34][C@@H:35]([OH:45])[C@@H:36]([NH:44][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:1](=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])([CH3:24])[CH3:23]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Reactant: CC(C)N(C[C@@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.9 %

Procedure:
To a stirred solution of the product of Step A (0.111 g; 0.386 mmol), the product of Example 2, Step B (0.13022 g; 0.386 mmol), benzotriazol- 1 -yloxytris (dimethylamino)phosphonium hexafluorophosphate (0.205 g; 0.46 mmol) and 1-hydroxybenzotriazole (0.052 g; 0.384 mmol) in 1 ml of anhydrous DMF was added, N,N-diisopropylethylamine (0.24 ml; 1.38 mmol). After stirring for 12 hours at room temperature the reaction was diluted to 30 ml with ethyl acetate and washed with water, 2% potassium bisulfate, 5% sodium bicarbonate and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure and purification of the residue by column chromatography (silica gel, ethyl acetate) gave 0.152 g (65% yield) of the title product melting at 109°-114° C.; Rf (C)=0.36; Rf (D)=0.37; NMR (CDCl3) 1.0 (m, 6H, val, isopropyl CH3); 1.42 (s, 9H, t-butyl CH3); 2.5-3.1 (m, 7H, asn CH2, butyl CH2 -1,-4, CH-3); 3.44 (m, 1 H, isopropyl CH); 4.21 (m, 1 H, butyl CH-2); 4.55 (s, 1 H, OH); 4.94 (m, 1H, asn CH-α); 5.4-6.2 (m, 3H, amide); 6.7-8.4 (m, 11H, aromatic); 9.25 (m, 1H, NH).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32](OC)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1.O>CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32]([C:2]5[S:3][CH:4]=[CH:5][N:6]=5)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2nccs2)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
2-Bromothiazole (0.643 mL, 7.14 mmol) in dry ether (7 mL) was added to n-butyllithium (2.5 M in Hexanes) (2.92 mL, 7.31 mmol) in dry ether (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (1.0 g, 2.339 mmol) in dry ether (15 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at −78° C. Water (60 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with dichloromethane (3×75 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as an off-white solid (984 mg). LCMS (Method F, ES-API): RT 2.64 min, m+H=480.9; 1H NMR (400 MHz, CDCl3): δ 8.06 (1H, d, J=3.0 Hz), 7.64 (1H, s), 7.48-7.43 (2H, m), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.55 (1H, s), 5.60 (1H, br s), 4.49 (1H, d, J=15.0 Hz), 4.21 (1H, br s), 3.28-3.25 (1H, m), 2.86-2.81 (3H, m), 2.49 (1H, d, J=14.5 Hz), 1.55 (9H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[O:13][C:12](=[O:22])[NH:11]2)[C:6]([F:9])=[N:7][CH:8]=1)#[CH:2].Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([F:30])[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(N(CC)CC)C.[Cu]I.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>[F:9][C:6]1[C:5]([C@@H:10]2[C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[O:13][C:12](=[O:22])[NH:11]2)=[CH:4][C:3]([C:1]#[C:2][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([F:30])[CH:25]=2)=[CH:8][N:7]=1
Reactant: C#Cc1cnc(F)c([C@H]2NC(=O)O[C@@H]2c2cccc(F)c2)c1
Reactant: Fc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cc(C#Cc3ccnc(F)c3)cnc2F)[C@@H](c2cccc(F)c2)O1
Temperature: 90 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a 15 ml sealable vial was added (4R,5R)-4-(5-ethynyl-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (20 mg, 0.067 mmol) in triethylamine (2 mL). To this suspension was added 4-bromo-2-fluoropyridine (15.24 mg, 0.087 mmol), triphenylphosphine (5.24 mg, 0.020 mmol) and copper(I) iodide (0.254 mg, 1.332 μmol). The solution was degassed with nitrogen for 20 min, then bis(triphenylphosphine)palladium(II) chloride (0.935 mg, 1.332 μmol) was quickly added and the vial was sealed, heated to 90° C., and allowed to stir overnight. The next day the suspension had turned homogeneous and the reaction was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by silica gel chromotagraphy eluting first with 100% CH2Cl2 then 1% MeOH/99% CH2Cl2 affording (4R,5R)-4-(2-fluoro-5-((2-fluoropyridin-4-yl)ethynyl)pyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one (9.1 mg, 0.021 mmol, 31.4% yield) as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 8.51 (d, J=4.0, 1H), 8.45 (s, 1H), 8.14 (dd, J=8.0, 4.0, 1H), 7.69-7.64 (m, 1H), 7.60-7.54 (m, 1H), 7.50-7.43 (m, 1H), 7.21-7.13 (m, 2H), 6.05 (brs, 1H), 5.39 (d, J=4.0, 1H), 5.04 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.01 min. Mass=396.20 (MH)+.