Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][NH:8][C:9]1[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=1)[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[C:21](=O)([O:37]N1C(=O)CCC1=O)[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2>C1COCC1.O>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:1][C@@H:2]([CH2:6][CH2:7][NH:8][C:9]3[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=3)[C:3]([OH:5])=[O:4])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: N[C@@H](CCNc1ncc(C=O)s1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cnc(NCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)s1
Reaction time: 1.5 h
Yield: 23.1 %

Procedure:
To a solution of the crude material from Example 50 (6.76 g, 9.86 mmol) in a mixture of THF (74.0 ml) and water (24.7 ml) is added sequentially sodium bicarbonate (4.97 g, 59.2 mmol), and (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (3.33 g, 9.86 mmol) and the reaction is stirred at room temp. for 1.5 h. The solvent is removed in vacuo and the residue is partitioned between water (25 mL) and EtOAc (25 mL). The organic layer is discarded, and the aqueous layer treated with 1N HCl until pH 3 is achieved. The aqueous layer is extracted with CH2Cl2 (3×25 mL), the organic layers are combined, washed with brine, dried over MgSO4, filtered and evaporated to dryness to give 1.03 g (20.8%) of the title compound as a pale orange solid. LC/MS (Condition A): ret. T=3.59 min, (M+H)+ 452.14. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.75 (1 H, br. s.), 9.65 (1 H, s), 8.98 (1 H, br. s.), 8.06 (1 H, s), 7.91 (2 H, d, J=7.53 Hz), 7.68-7.83 (3 H, m), 7.39-7.47 (3 H, m), 7.30-7.39 (3 H, m), 4.19-4.39 (3 H, m), 3.97-4.10 (1 H, m), 3.41 (2 H, d, J=4.52 Hz), 2.10 (1 H, dd, J=13.55, 4.77 Hz), 1.90 (1 H, dd, J=13.55, 9.79 Hz).
Reaction SMILES: CN1CCN(C2C=CC(NC3C4[N:17]([N:29]=[CH:30]N=4)[C:18]([C:21]4[CH:22]=C(C(N)=O)SC=4)=[CH:19]N=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:45][CH:44]=2)=[N:35][CH:34]=1.C(C1N(C2CCCCO2)N=CC=1B1OC(C)(C)C(C)(C)O1)C.C(C1C(B2OC(C)(C)C(C)(C)O2)=CN(C2CCCCO2)N=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:21]([C:18]1[NH:17][N:29]=[CH:30][C:19]=1[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[CH:45][CH:44]=2)=[N:35][CH:34]=1)[CH3:22]
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Reactant: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCc1c(B2OC(C)(C)C(C)(C)O2)cnn1C1CCCCO1
Agent: CCc1nn(C2CCCCO2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: C1COCCO1
Product: CCc1[nH]ncc1-c1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine (0.032 g, 0.085 mmol), 5-ethyl-1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and 3-ethyl-1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.52 mg, 0.17 mmol), and Pd(PPh3)4 (0.025 mg, 0.021 mmol) in 1.5M Na2CO3 (aq) (0.45 mL, 0.6 mmol) and dioxane (2 mL). The reaction mixture is purified by silica gel column chromatography eluting with 1:1 petroleum ether:ethyl acetate followed by 1:4 petroleum ether:ethyl acetate to yield the title compound (45 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[N:29]1([CH2:28][CH2:27][CH2:26][NH:25][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: NCCCN1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCCCN3CCOCC3)cc2n1
Yield: 76 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using N-(3-aminopropyl)morpholine instead of aminomethylcyclopropane, to the title compound (102 mg, 76%) which was obtained as an off-white foam. MS: m/e=446.3 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]2[CH2:23][CH:22]([OH:24])[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[C:25]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:20]2[CH2:23][CH:22]([O:24][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:21]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.581 mL of triethylamine and 0.185 mL of methanesulfonyl chloride were added to chloroform (15 mL) solution of 500 mg of N-(diphenylmethyl)-3-hydroxyazetidine, and stirred at room temperature for 3 hours. Aqueous sodium carbonate solution was added to the reaction liquid, extracted with chloroform, dried with sodium sulfate, and evaporated under reduced pressure to obtain crude N-(diphenylmethyl)-3-(methanesulfonyloxy)azetidine. 433 mg of 1-(4-nitrophenyl)piperazine and 433 mg of potassium carbonate were added to DMSO (10 mL) solution of the compound obtained in the above reaction, and heated at 100° C. for 3 hours. Water was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. The organic layer was dried with sodium sulfate, concentrated under reduced pressure, and the crude product was purified through column chromatography (ethyl acetate/hexane=2/1). A catalytic amount of trifluoroborane ether solution was added to acetic anhydride (6 mL) solution of the obtained diphenylmethyl compound, and heated at 90° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, sodium hydrogencarbonate was added to the residue, and extracted with chloroform. The organic layer was dried with sodium sulfate, and then concentrated under reduced pressure. The crude product was purified through column chromatography (methanol/chloroform=1/10), and then solidified from ethyl acetate/hexane to obtain 160 mg of the entitled compound as a yellow solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=O)C.Cl[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]3)=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[NH4+]>C(O)CCC.O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([N:53]5[CH2:54][CH2:55][N:56]([CH3:59])[CH2:57][CH2:58]5)=[CH:49][N:48]=4)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)[C:6]=1[CH2:5][OH:4])[N:30]=[CH:29]2)([CH3:34])([CH3:32])[CH3:33]
Reactant: CN1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCCCO
Product: CN1CCN(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (221 mg, 0.45 mmol), 6-chloro-4-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (100 mg, 0.30 mmol), potassium phosphate (159 mg, 0.75 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (14.2 mg, 0.03 mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (8.59 mg, 0.01 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×50 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 14% methanol in dichloromethane) and recrystallized from dichloromethane and isopropyl acetate to give 6-tert-butyl-2-(3-{5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one (45 mg, 24%) as a light yellow solid: mp 260-264° C.; 1H NMR (300 MHz, DMSO-d6) δ: ppm 1.38 (s, 9H) 2.20 (s, 3H) 2.33-2.46 (m, 4H) 2.98-3.19 (m, 4H) 3.77 (s, 3H) 4.27-4.69 (m, 3H) 7.24-8.07 (m, 8H) 8.32-8.74 (m, 2H) 9.23 (s, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O-:19])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].O>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O:19][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C#CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C#CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 61.4 %

Procedure:
To a solution of sodium 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (1.1 g) was added iodomethyl pivalate (0.744 g) under ice-cooling and the resultant mixture was stirred at the same temperature for 10 minutes. After the reaction mixture was added to a stirred mixture of water and ethyl acetate, the separated organic solution was washed in turn with water, saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The solution was evaporated in vacuo to give pivaloyloxymethyl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (0.82 g).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)N.C(O[CH:17](OCC)[CH2:18][CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])C.C(OCC)(=O)C>C(O)(=O)C>[O:31]=[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29](=[O:30])[N:21]1[CH2:20][CH2:19][C:18]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([NH2:13])=[O:12])[CH:8]=2)[NH:2][CH:17]=1
Reactant: NNc1ccc(CC(N)=O)cc1
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A mixture of the crude 2-(4-hydrazinophenyl)acetamide hydrochloride (16.19 g) (contains 0.05 mol) and 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanal diethyl acetal (14.5 g) was heated under reflux in 25% aqueous acetic acid (1 l) for 30 min. The cooled mixture was poured into ethyl acetate (750 ml) the organic phase was separated and the aqueous phase was washed with ethyl acetate (250 ml). The combined organic extracts were washed with water (500 ml), dried (Na2SO4) and evaporated under reduced pressure. Water (500 ml) was added to the oily residue which solidified on stirring. The solid was collected by filtration, washed with water and dried. Crystallisation from ethyl acetate-methanol gave the title compound as pale yellow granules (11.9 g) m.p. 191°-3° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([Cl:17])[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:18][PH:19]([CH3:21])=[O:20].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:17][C:15]1[N:16]=[C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([P:19]([CH3:21])([CH3:18])=[O:20])=[CH:3][CH:4]=3)=[CH:13][CH:12]=[CH:11][N:10]2[N:14]=1
Reactant: C[PH](C)=O
Reactant: Clc1nc2c(-c3ccc(Br)cc3)cccn2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CP(C)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Temperature: 90 °C

Procedure:
198 a) 8-(4-Bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 4.5 mmol) and 4-bromobenzeneboronic acid (1.0 g, 5.0 mmol) in a manner analogous to Example 2c. Product isolated as an off-white solid (1.0 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.5 Hz, 1H), 7.88 (d, J=7.1 Hz, 2H), 7.70 (d, J=7.0 Hz, 1H), 7.65 (d, J=7.1 Hz, 2H), 7.16 (t, J=7.5 Hz, 1H). MS=310, 312 (MH)+. 198 b) To an oven dried tube was added 8-(4-bromo-phenyl)-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.90 g, 2.9 mmol), methylphosphinoylmethane (0.24 g, 3.1 mmol)(prepared as described in WO2005/009348), palladium acetate (13.5 mg, 0.0601 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (36.0 mg, 0.0622 mmol), cesium carbonate (1422.0 mg, 4.3644 mmol) and 1,4-dioxane (9 mL). The tube was evacuated, carefully, and backflushed with nitrogen. The tube was sealed and heated at 90° C. for 24 hours then cooled to room temperature, diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→7% dichloromethane:methanol). 2-Chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine was isolated as a white solid (0.303 g, 34%). MP=220-223° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.55 (d, J=6.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 2H), 7.94-7.86 (m, 2H), 7.77 (t, J=7.4 Hz, 1H), 7.21 (t, J=6.9 Hz, 1H), 1.80 (s, 3H), 1.77 (s, 3H). MS=306, 308 (MH)+. 198 c) {8-[4-(Dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3271 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (28.0 mg, 0.0512 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan solid (0.097 g, 64%). MP=243-246° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.2 Hz, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.92-7.84 (m, 2H), 7.63-7.50 (m, 1H), 7.34 (s, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.02-6.96 (m, 2H), 6.84 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.30-3.25 (m, 4H), 2.63-2.58 (m, 4H), 2.37 (s, 3H), 1.80 (s, 3H), 1.77 (s, 3H). MS=461 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.IC.[C:21]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:21][O:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(-n2ccc(OC)cc2=O)cc1

Procedure:
A solution of Example 296A (2.3 g, 10 mmol) in acetone (300 mL) was treated with iodomethane (5 mL) and K2CO3 (15 g), heated to reflux for 18 hours, and filtered. The filtrate was concentrated and he concentrate purified by flash column chromatography on silical gel with 4:1 hexanes/ethyl acetate to provide the desired product. MS (ESI) m/e 260 (M+H)+.
Reaction SMILES: C([NH2:4])(=O)C.[C:5]([C:9]1[CH:49]=[CH:48][C:12]([C:13]([NH:15][C@H:16]([C:44]([O:46][CH3:47])=[O:45])[CH2:17][C:18]2[CH:43]=[CH:42][C:21]([C:22]([O:24][CH2:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=3)=O)=O)=[CH:20][CH:19]=2)=[O:14])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CC(=O)OCC>[C:5]([C:9]1[CH:49]=[CH:48][C:12]([C:13]([NH:15][C@@H:16]([CH2:17][C:18]2[CH:43]=[CH:42][C:21]([C:22]3[O:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)[N:4]=3)=[CH:20][CH:19]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:14])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(N)=O
Reactant: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2coc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To borontrifluoride diethyl etherate (33.3 μl, 0.27 mmol) was added a mixture of acetamide (763 mg, 12.9 mmol) and (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (159 mg, 0.26 mmol). The reaction mixture was stirred at 140° C. for 1 h. The reaction mixture was allowed to cool to RT, diluted with EA (15 mL) and extracted with NaHCO3 (3×15 mL) and brine (15 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was recrystallised from Et2O (5 mL), filtered and rinsed with Et2O. The filtrate was concentrated to afford 55 mg (16%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoate as an orange oil. LCMS-ESI (m/z) calculated for C37H44N2O5: 596.8. found 597.0 [M+H]+, tR=3.11 min. (Method 4).
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:37])=[C:24]([C@@:26]2([CH:34]([F:36])[F:35])[C@H:32]3[C@H:30]([CH2:31]3)[O:29][C:28]([NH2:33])=[N:27]2)[CH:25]=1.[Cl:38][C:39]1[CH:40]=[C:41]([O:48][CH3:49])[C:42]([C:45](O)=[O:46])=[N:43][CH:44]=1>C([O-])(O)=O.[Na+]>[NH2:33][C:28]1[O:29][C@H:30]2[C@@H:32]([C@:26]([C:24]3[CH:25]=[C:20]([NH:19][C:45](=[O:46])[C:42]4[C:41]([O:48][CH3:49])=[CH:40][C:39]([Cl:38])=[CH:44][N:43]=4)[CH:21]=[CH:22][C:23]=3[F:37])([CH:34]([F:35])[F:36])[N:27]=1)[CH2:31]2
Reactant: NC1=N[C@](c2cc(N)ccc2F)(C(F)F)[C@@H]2C[C@@H]2O1
Reactant: COc1cc(Cl)cnc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@@]2(C(F)F)N=C(N)O[C@@H]3C[C@@H]32)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
A solution of 1-propanephosphonic acid cyclic anhydride (50 wt % in EtOAc, 0.352 ml, 0.553 mmol) was added to a solution of (1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16g-B, 0.075 g, 0.277 mmol) and 5-chloro-3-methoxypicolinic acid (0.062 g, 0.332 mmol) in EtOAC (2 mL) at room temperature. The reaction mixture was stirred at rt for 12 h, diluted with aqueous saturated NaHCO3 solution and extracted with EtOAC. The organic phase dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using (0-100% EtOAc/heptane) to give the title compound (0.082 g, 0.186 mmol, 67.3% yield). MS m/z=441.1 [M+H]+
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([NH:23][NH2:24])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[C:2]1([C:1](=[N:24][NH:23][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1cccnc1
Reactant: O=C(c1ccccc1)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NN=C(c1ccccc1)c1ccncc1)c1cccnc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A mixture of 9.16 gm (0.05 mole) of 4-benzoyl pyridine, 6.86 gm (0.05 mole) of nicotinic acid hydrazide, 100 ml of ethanol and 4.4 ml of concentrated hydrochloric acid was refluxed 16 hr. The reaction mixture was cooled to room temperature. An equal volume of water was added containing 5.4 gm (0.05 mole) of sodium carbonate. The mixture was placed in the refrigerator. The product which separated was collected, washed with water and dried to give 8.21 gm (54%) of the title compound having a melting point of 74.0° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([CH:7]=[N:8][OH:9])[CH2:4][O:3]1.[Cl:11]N1C(=O)CCC1=O.CCOCC.O>CN(C=O)C>[OH:9][N:8]=[C:7]([Cl:11])[C@@H:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)OC[C@@H](C=NO)O1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](C(Cl)=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde oxime (10.3 g, 71.0 mmol) in 40 mL DMF was added 1-chloropyrrolidine-2,5-dione (10.4 g, 78.1 mmol) and the reaction was stirred overnight at ambient temperature. The reaction mixture was poured into ether (1400 mL) and water (500 mL). The ether layer was extracted with water (5×500 mL), dried over MgSO4, filtered and concentrated to (S)-N-hydroxy-2,2-dimethyl-1,3-dioxolane-4-carbimidoyl chloride (10.0 g, 55.7 mmol, 78.5% yield) as white solid.
Reaction SMILES: [N:1]([CH3:4])=[C:2]=[O:3].[F:5][C:6]1[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[O:31][CH3:32])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][S:20]([CH3:23])(=[NH:22])=[O:21])[CH:14]=2)=[N:10][CH:11]=1.C(N(CC)CC)C>CN(C=O)C.[Cl-].[Na+]>[F:5][C:6]1[C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[O:31][CH3:32])=[N:8][C:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:19][S:20]([CH3:23])(=[O:21])=[N:22][C:2]([NH:1][CH3:4])=[O:3])=[N:10][CH:11]=1
Reactant: COc1cc(F)ccc1-c1nc(Nc2cccc(CS(C)(=N)=O)c2)ncc1F
Reactant: CN=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)N=S(C)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.7 %

Procedure:
Isocyanatomethane (7.3 μL; 0.12 mmol) was added to a solution of (rac)-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}pyrimidin-2-amine (50 mg; 0.12 mmol) in DMF (2.0 mL) and triethylamine (17.2 μL; 0.12 mmol) at RT. The batch was stirred for 17 hours at RT. The batch was diluted with saturated aqueous sodium chloride solution and extracted with ethyl acetate (2×). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/EtOH 95:5) to give the desired product (24 mg; 0.05 mmol).