Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][C:6]1([CH2:23][CH2:24][CH3:25])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH:8]([CH3:22])[O:7]1)=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=3[F:21])C.[OH-].[Na+]>C1COCC1.CO>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([F:21])=[C:13]2[C:18]=1[C:10]1[CH2:9][CH:8]([CH3:22])[O:7][C:6]([CH2:5][C:4]([OH:26])=[O:3])([CH2:23][CH2:24][CH3:25])[C:11]=1[NH:12]2)#[N:20]
Reactant: CCCC1(CC(=O)OCC)OC(C)Cc2c1[nH]c1c(F)ccc(C#N)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC1(CC(=O)O)OC(C)Cc2c1[nH]c1c(F)ccc(C#N)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of (5-cyano-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic Acid Ethyl Ester (156 mg, 0.435 mmol) in THF/MeOH (1.5 mL/1.5 mL) was added 1 N NaOH (0.871 mL, 0.871 mmol). The reaction mixture was stirred at ambient temperature overnight. The most of THF/MeOH was removed under reduced pressure and the resulting mixture was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give 125 mg (87%) of title compound as a white solid. LCMS retention time: 2.775 minutes, [M+H]+ calculated for C18H20FN2O3 331.36, found 331.10, [M−1]+ calculated for C18H18FN2O 329.36, found 329.10.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].C(O)C.Cl.[NH2:17][OH:18]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](=[N:17][OH:18])[CH3:8]
Reactant: NO
Reactant: CC(=O)COc1cccc(C)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(COc1cccc(C)c1)=NO

Procedure:
1-(3-Methylphenoxy)propan-2-one (24.9 g.) and ethanol (100 ml.) were added to a solution of hydroxylamine hydrochloride (25 g.) and fused sodium acetate (25 g.) in water (110 ml.). The resulting solution was refluxed for 31/2 hours and evaporated to near dryness under reduced pressure. The residue was partitioned between water and ether. The ether extract was washed with water, dried over anhydrous potassium carbonate and evaporated. The residue was distilled to give a fraction, b.p. 159°-163°/12 mm. Redistillation gave 1-(3-methylphenoxy)propan-2-one oxime, b.p. 165°-167°/13 mm.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[NH:19][C:18]([CH3:20])=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:5]2[C:14]([C:15]3[NH:19][C:18]([CH3:20])=[N:17][N:16]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(-c2nnc(C)[nH]2)c(C2CCC2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Temperature: 50 °C
Yield: 113.8 %

Procedure:
To a solution of methyl 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate (compound 78.3, 240 mg, 0.842 mmol) in methanol (5 mL) was added aqueous NaOH (6 mL, 1 M). The resulting mixture was heated to 50° C. for 6 hours then cooled to ambient temperature and acidified to pH 2 with aqueous 1 M HCl and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a white solid (260 mg, quantitative). m/z (ES+) 272 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:33])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)C(C)(C)C)=[CH:13][CH:12]=3)=[CH:8][C:7](=[O:24])[C:6]=2[C:25]=1[NH:26]C(=O)C(C)(C)C.Cl>O1CCOCC1>[NH2:26][C:25]1[C:6]2[C:7](=[O:24])[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[O:10][C:5]=2[C:4]([F:33])=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)cc(F)c3o2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1
Yield: 64.6 %

Procedure:
1.42 g of Compound 11 was dissolved in 84 ml of dioxane, 36 ml of concentrated hydrochloric acid was added and the mixture was heated at reflux for 3 hours. The reaction solution was cooled on ice and the precipitated crystals were collected by filtration to give 579 mg (57%) of Compound 12.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([CH2:20][CH2:21][N:22]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([Cl:36])[CH:28]=2)[S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:18][CH:17]=[CH:16]1>>[N:15]1([CH2:20][CH2:21][N:22]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH:4]=3)=[O:32])=[C:29]([Cl:36])[CH:28]=2)[S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:18][CH:17]=[CH:16]1
Reactant: CS(=O)(=O)N(CCn1cccc1)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)N(CCn1cccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
64 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 529 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cu][C:23]#[N:24].O>CN(C)C=O>[CH2:15]([O:14][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:7][C:2]=1[C:23]#[N:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCOCCc1ccc(OCc2ccccc2)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COCOCCc1ccc(OCc2ccccc2)c(C#N)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 104.5 %

Procedure:
To a stirred solution of the obtained 4′-benzyloxy-3′-bromophenethyl alcohol (782 mg) in dichloromethane (8 ml) were added N,N-diisopropylethylamine (665 μl) and chloromethyl methyl ether (232 μl) under ice-cooling, and the mixture was stirred for 6 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. After the extract was washed with brine, removal of the solvent under reduced pressure gave benzyl 2-bromo-4-(2-methoxymethoxyethyl)phenyl ether (804 mg). To a solution of benzyl 2-bromo-4-(2-methoxymethoxyethyl)phenyl ether (804 mg) in N,N-dimethylformamide (5 ml) was added copper(I) cyanide (458 mg) and the mixture was stirred for 2 days at 120° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave 2-benzyloxy-5-(2-methoxymethoxyethyl)benzonitrile (711 mg).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:15]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]1[CH2:11][NH:12][CH2:13][CH2:14]2.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([N:12]1[CH2:13][CH2:14][C:15]2([O:9][CH:10]2[CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C23CCNCC2O3)cc1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: c1ccc(CN2CCC3(c4ccccc4)OC3C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
22.5 Ml of benzyl bromide was added dropwise to a stirred solution of 32.3 g of 3,4-epoxy-4-phenylpiperidine and 38.1 ml of triethylamine in 254 ml of benzene. A precipitate appeared during the addition. The whole reaction mixture was then stirred at room temperature for three hours. The residual solid was removed by filtration and the solvent evaporated to give 53.4 g of 1-benzyl-3,4-epoxy-4-phenyl-piperidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:12]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][C:10]([F:23])=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[N:12]=1
Reactant: CC1(C)CCC(=O)N1c1nc(-c2ccc(C#N)cc2)cs1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)N1c1nc(-c2ccc(C#N)cc2)c(F)s1
Reaction time: 16 h
Yield: 32 %

Procedure:
4-[2-(2,2-Dimethyl-5-oxopyrrolidin-1-yl)-1,3-thiazol-4-yl]benzonitrile (0.50 g, 1.7 mmol), prepared in step 2 of Example 88, was dissolved in acetonitrile (16 mL) and the Selectfluor® reagent (0.65 g, 1.9 mmol) was added. The mixture was stirred for 16 h, diluted with ethyl acetate, washed with H2O, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone/hexane) afforded the title compound (0.17 g, 32%) as colorless crystals. HRMS: calcd for C16H14FN3OS+H+, 316.09144; found (ESI-FT/MS, [M+H]1+), 316.0916; Analytical HPLC purity 100% at 210-370 nm, 10.6 min; 98.4% at 296 nm, 10.6 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3Cl)[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:17]>CS(C)=O.O>[C:16]([O:20][C:21](=[O:44])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31]([C:34]2[S:42][C:41]3[C:36](=[N:37][CH:38]=[CH:39][C:40]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=3[F:9])[CH:35]=2)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1ccc(O)c(F)c1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of 4-amino-2-fluorophenol (4) (1.933 g, 15.21 mmol) in DMSO (30 mL) was added potassium tert-butoxide (2.017 g, 17.97 mmol). After 30 min, intermediate 11 (6 g, 13.83 mmol) was added and the reaction mixture was heated at 100° C. for 45 min. The reaction mixture was then cooled down, poured in water (250 mL) at 40-45° C. and the resultant suspension was stirred for 30 min. The precipitate was collected by filtration, washed with water (2×30 mL) and dried overnight. The dry solid was triturated with Et2O (50 mL), to afford intermediate 13 (4.18 g, 58% yield) as a brown solid. MS (m/z): 525.2 (M+H).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27]>>[C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[N:19][C:20]([NH:26][NH2:27])=[CH:21][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCC(O)COc1cc(O)ccc1-c1ccc(Cl)nn1
Reactant: NN
Solvent: O
Product: CC(C)(C)NCC(O)COc1cc(O)ccc1-c1ccc(NN)nn1

Procedure:
3-[2-(3-t-Butylamino-2-hydroxypropoxy)-4-hydroxyphenyl]-6-chloropyridazine was reacted with hydrazine hydrate under similar conditions to those described in Example 7b(iii) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Clc1ccnc(Cl)n1
Product: O=[N+]([O-])c1cccc(-c2ccnc(Cl)n2)c1
Reaction time: 2 h
Yield: 60 %

Procedure:
2,4 dichloropyrimidine was coupled to 3-nitrophenyl boronic acid following procedure A. The workup and purification protocol was modified as follows: The THF was removed from the reaction mixture by rotary evaporation and the residue taken up in ethyl acetate. The solution was washed with water followed by sat. NaCl and the organic layer concentrated by rotary evaporation until the product started to precipitate, at which point the flask was placed in an ice bath for two hours. The product was collected by filtration in a Buchner funnel. The yield was 60%. Product was >95% pure by LC-MS and showed the expected M+H+ of 236.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][Cl:29])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[ClH:29].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)[C@H:13]([CH:18]([CH3:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@H](NS(=O)(=O)c1ccc(OC)cc1)C(C)C
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C(C)C)N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2(R)-[[4-methoxybenzenesulfonyl]amino]-3-methylbutanoate (1662 g, 5.52 mol) in dimethylformamide (10.9 L) is added 3-picolyl chloride hydrochloride (947.3 g, 5.77 mol) followed by powdered potassium carbonate (2409.9 g, 17.36 mol). The reaction mixture is stirred at room temperature for 2 days. At that time, additional quantities of 3-picolyl chloride hydrochloride (95 g) and powdered potassium carbonate (241 g) are added, and the reaction is stirred for 3 more days. The solids are then filtered away, the crude product is poured into water (22 L), and the pH is adjusted to pH=8 with 6N sodium hydroxide. This solution is extracted well with toluene (4×10 L), the combined organic layers are washed with water (2×12 L), and then with 6N hydrochloric acid (3×1600 mL). This aqueous layer is then re-adjusted to pH=8 with 6N sodium hydroxide, extracted with toluene (4×10 L), dried (Na2SO4), and the solvent is evaporated. The oil obtained is re-dissolved in ethyl acetate (12 L), cooled to 5° C., and to this is added methanolic HCl (834 mL). After stirring for 2 hours, the precipitated product is collected by filtration to give methyl 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoate hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:29]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[F:55][C:51]1[CH:52]=[CH:53][CH:54]=[C:24]([NH:23][C:10](=[O:11])[CH2:9][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:40])[F:41])[N:30]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:29]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC(=O)O)c2cccc(F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cccc2NC(=O)C[C@H](c2ccc(S(C)(=O)=O)cc2)c2cccc(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (34 mg, 0.1 mmol) and the product from step 4 of Example 99 (50 mg, 0.1 mmol) were dissolved in pyridine (1 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 (0.01 mL, 0.12 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (1 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-Boc)+=684.
Reaction SMILES: [NH3:1].CC(O)C.[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[C:20]([C:21]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23](SC)[N:22]=3)=[CH:19][C:18]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:33][CH2:32]3)=[CH:17][N:16]=2)=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[C:20]([C:21]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:1])[N:22]=3)=[CH:19][C:18]([CH2:30][N:31]3[CH2:32][CH2:33][N:34]([S:37]([CH3:40])(=[O:38])=[O:39])[CH2:35][CH2:36]3)=[CH:17][N:16]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: CC(C)O
Product: COc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 90 °C
Yield: 56.3 %

Procedure:
2 M NH3 in 2-propanol (2.00 mL, 92 mmol) was added to N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-amine (221 mg, 0.428 mmol) and the mixture was sealed and heated at 90° C. overnight. After cooling, the reaction mixture was concentrated, adsorbed onto a plug of silica gel and chromatographed through a RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (DCM to 10% MeOH in DCM) followed by washing of the isolated solid with MeOH to give 4-(2-(6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (117 mg, 0.241 mmol, 56.3% yield) as a yellow solid. LCMS (API-ES) m/z 486 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.76 (br. s., 1H) 8.71 (br. s., 1H) 8.55 (br. s., 1H) 8.03-8.28 (m, 2H) 7.87 (br. s., 1H) 7.73 (br. s., 1H) 6.82 (d, J=7.63 Hz, 1H) 3.84 (br. s., 3H) 3.48 (br. s., 2H) 3.11 (br. s., 4H) 2.87 (br. s., 3H) 2.52-2.58 (m, 3H) 2.44 (br. s., 4H).
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C1COCC1>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:5][C:6]#[N:7])=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 60% suspension of NaH in mineral oil (2.16 g, 54.1 mmol) was suspended in THF (50 ml) and cooled to 0° C. under nitrogen. Diethyl-cyanomethyl phosphonate (8.74 ml, 54.1 mmol) was added dropwise and the whole stirred at 0° C. for 30 min. 4-bromobenzaldehyde (10 g, 54.1 mmol) was then added dropwise as a solution in 20 ml THF, and the mixture allowed to warm to room temperature overnight. The reaction was quenched with water, extracted with EtOAc (3×50 ml), dried (MgSO4) and then filtered and evaporated to a yellow oil. This oil was taken up in a 9:1 mixture of pentane:EtOAc from which the title product crystallised (5.8 g, 52%); 1HNMR (400 MHz, CDCl3) δ: 5.82 (d, 1H), 7.21-7.28 (m, 3H), 7.50 (d, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[I-].[Na+].[C:8]([O:16][CH2:17][C@@H:18]1[O:23][C@@H:22]([O:24][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH2:26]Br)[CH2:21][CH2:20][CH2:19]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[C:8]([O:16][CH2:17][C@@H:18]1[O:23][C@@H:22]([O:24][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH2:26][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:21][CH2:20][CH2:19]1)(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: O=C(OC[C@H]1CCC[C@H](OC(CBr)c2ccc(Cl)cc2Cl)O1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1)c1ccccc1
Temperature: 130 °C
Reaction time: 6.5 h
Yield: 48.2 %

Procedure:
8.24 g of imidazole and 12.0 g of sodium iodide were added to a solution of 19.70 g of trans-6-benzoyloxymethyl-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran in 150 ml of dimethylformamide, and the resulting mixture was stirred on an oil bath at 130° C. for 6.5 hours. The reaction mixture was then cooled, poured into water and extracted with diethyl ether. The ethereal extract was washed with aqueous sodium chloride and dried over anhydrous sodium sulphate, after which the solvent was evaporated off. The residue was purified by column chromatography through silica gel eluted with a B 100:25:1 by volume mixture of ethyl acetate, benzene and triethylamine, to give 9.25 g of the title compound as a liquid.
Reaction SMILES: F[C:2]1[C:16]([CH:17]=[O:18])=[CH:15][C:5]2[C:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[N:7][O:8][C:4]=2[C:3]=1[F:19].[CH3:20][C@H:21]1[O:26][C@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1>>[CH3:27][C@@H:25]1[CH2:24][N:23]([C:2]2[C:16]([CH:17]=[O:18])=[CH:15][C:5]3[C:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[N:7][O:8][C:4]=3[C:3]=2[F:19])[CH2:22][C@@H:21]([CH3:20])[O:26]1
Reactant: CC(C)NC(=O)c1noc2c(F)c(F)c(C=O)cc12
Reactant: C[C@@H]1CNC[C@@H](C)O1
Product: CC(C)NC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@H](C)C3)c(C=O)cc12

Procedure:
The title compound was prepared from 6,7-difluoro-5-formyl-N-isopropylbenzo[d]isoxazole-3-carboxamide (Intermediate 242) and (2R,6R)-2,6-dimethylmorpholine.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Yield: 92.6 %

Procedure:
Acetic acid (3 ml) and zinc powder (2.4 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate (1.8 g) in anhydrous dimethylformamide (10 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was extracted by pouring into a mixture of 5% hydrochloric acid (50 ml) and ethyl acetate (40 ml). The ethyl acetate layer was washed with water and dried. After the solvent was distilled off, the residue was dissolved in ether and allowed to stand, after which the precipitating crystals were collected by filtration and dried to give 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid (1.2 g), mp 175° C. (dec.).
Reaction SMILES: N1[CH:6]=[C:5]([O:7][C:8]2[CH2:12][CH2:11][O:10][N:9]=2)[CH:4]=[N:3][CH:2]=1.Cl[C:14]1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[N:3]1[CH:2]=[CH:14][CH:6]=[C:5]([O:7][C:8]2[CH2:12][CH2:11][O:10][N:9]=2)[CH:4]=1
Reactant: c1ncc(OC2=NOCC2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: c1cncc(OC2=NOCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Racemic 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-132 was dissolved in methylene chloride (0.5 M with respect to isoxazole) after which point m-chloroperbenzoic acid (2.0 equiv) was added in 1 portion and the reaction was allowed to stir at room temperature for 1 h. After the reaction was determined to be complete by LC/MS, the solvent was evaporated. The crude mixture was then redissolved in tert-butylmethyl ether (0.5 M) after which hexane was slowly added until a solid precipitated. The solid was then collected via vacuum filtration and washed with 1:1 hexanes/tert-butylmethyl ether to provide the desired 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-133a and I-133b as a white solid. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=404.1 m/z. Activity: A