Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[NH2:39][C:40]1[CH:41]=[C:42]([OH:55])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:39][C:40]1[CH:45]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:43]=[C:42]([OH:55])[CH:41]=1
Reactant: CC1(C)OB(c2cc(N)cc(O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 64.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.53 g, 0.89 mmol) was treated with 3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.52 g, 2.22 mmol), sodium carbonate (0.24 g, 2.22 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.22 g, 0.27 mmol) and 22 ml 1,2-dimethoxyethane and 5 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 15% dichloromethane-2-propanol) to obtain 0.36 g (62% yield) of the title compound.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:37]([O:39][CH3:40])=[O:38])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([S:33][CH2:34][CH3:35])=[CH:29][C:28]3=[O:36])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23]2[CH:24]=[C:25]([C:37]([O:39][CH3:40])=[O:38])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([S:33]([CH2:34][CH3:35])=[O:6])=[CH:29][C:28]3=[O:36])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: CCSc1cc(=O)c2cc(C(=O)OC)cc(C(C)Nc3cc(F)cc(F)c3)c2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)c1cc(=O)c2cc(C(=O)OC)cc(C(C)Nc3cc(F)cc(F)c3)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
3-chlorobenzoperoxoic acid (326 mg, 1.13 mmol) was added in one portion to a stirred suspension of methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-(ethylthio)-4-oxo-4H-chromene-6-carboxylate (475 mg, 1.13 mmol) in DCM (5 mL) cooled with an water/ice bath. The resulting mixture was stirred at RT for 1 h. The suspension was cooled to −15° C. and filtered, the solid was washed with cold DCM (5 mL). The filtrate was then washed with an aq. sol. of sodium thiosulfate pentahydrate in water (10 mL), and with a mixture of a sat. sol. of NaHCO3 and water (1:1, 15 mL). The organic layer was decanted, dried over MgSO4 and evaporated to afford the crude product methyl 8-(1-(3,5-difluorophenylamino)ethyl)-2-(ethylsulfinyl)-4-oxo-4H-chromene-6-carboxylate (500 mg, 100%) as a reddish foam. Mass Spectrum: M+H+ 436.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(N(C(C)C)CC)(C)C.Cl.Cl.[O:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1>CN(C)C=O>[Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:39][CH:36]2[CH2:35][CH2:34][N:33]([CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[CH2:38][CH2:37]2)[CH:7]=1
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 70 °C
Yield: 80.8 %

Procedure:
A stirred solution of 1-bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (D53) (0.30 g, 1.04 mmole) in dimethylformamide (5 ml) at room temperature under argon was treated with diisopropylethylamine (0.59 ml, 3.3 mmole) and 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (D40) (0.28 g, 1.1 mmole) and heated at 70° C. for 1 hr. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated under vacuum to leave an orange solid which was purified by chromatography on silica gel eluting with 0-20% methanol/ethyl acetate to afford the title compound as a bright yellow solid (0.38 g, 81%). MH+=452, 454.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[C:33]2[N:32]=[C:31]3[N:34]([C:38]4[C:39]([CH3:47])=[N:40][C:41]([O:45][CH3:46])=[N:42][C:43]=4[CH3:44])[CH2:35][CH2:36][CH2:37][N:30]3[C:29]=2[C:28]([CH2:48][OH:49])=[CH:27][CH:26]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH:48]=[O:49])=[C:29]2[C:33]=1[N:32]=[C:31]1[N:34]([C:38]3[C:39]([CH3:47])=[N:40][C:41]([O:45][CH3:46])=[N:42][C:43]=3[CH3:44])[CH2:35][CH2:36][CH2:37][N:30]21
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(OC)ccc(CO)c23)c(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1nc(C)c(N2CCCn3c2nc2c(OC)ccc(C=O)c23)c(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
Dess-Martin reagent (1.31 g, 3.09 mmol) was added to a stirred solution of [9-methoxy-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (761 mg, 2.06 mmol) in dimethyl sulfoxide (0.50 mL) and acetonitrile (8.2 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-5% methanol/ethyl acetate gradient mixture. The eluate was concentrated in vacuo to give the title compound as a brown solid (467 mg).
Reaction SMILES: [I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N+:10]([CH3:16])=[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:8]=[C:7]2SC.[I-].[CH3:26][C:27]1[S:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[N+:31]=1[CH3:32].C(N(CC)CC)C>CN(C)C=O>[I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:16])[C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[N:8][C:7]2=[CH:26][C:27]1[S:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[N+:31]=1[CH3:32]
Reactant: COc1cc2c(SC)nc(-c3ccccc3)[n+](C)c2cc1OC
Reactant: Cc1sc2ccccc2[n+]1C
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)N(C)C(c1ccccc1)=NC2=Cc1sc2ccccc2[n+]1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
500 mg (1.10 mmol) 6,7-Dimethoxy-1-methyl-4-methylsulfanyl-2-phenyl-quinazolin-1-ium iodide and 320 mg (1.10 mmol) 2,3-Dimethyl-benzothiazol-3-ium iodide were dissolved in 200 ml dimethylformamide and 445 mg (0.61 ml, 4.40 mmol) triethylamine were added. The solution was stirred for 1 h at 80° C., filtrated and the residue is washed with water and methanol.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:26]2[N:27]=[C:28]([NH:31]C=O)[S:29][CH:30]=2)[C:9]([NH:11][CH:12]2[C:24](=[O:25])[N:14]3[C:15]([C:21]([OH:23])=[O:22])=[C:16](C=C)[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl.O.C(=O)(O)[O-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[CH:1]1([O:6][N:7]=[C:8]([C:26]2[N:27]=[C:28]([NH2:31])[S:29][CH:30]=2)[C:9]([NH:11][CH:12]2[C:24](=[O:25])[N:14]3[C:15]([C:21]([OH:23])=[O:22])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.9 %

Procedure:
A mixture of 7-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem 4-carboxylic acid (syn isomer)(3.1 g) in methanol (22 ml), tetrahydrofuran (10 ml) and conc. hydrochloric acid (1.3 g) was stirred for 2.5 hours at ambient temperature. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were filtered off, washed with water and dried over phosphorus pentoxide in vacuo to give 7-[2-(2-cyclopenten-1-yloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4carboxylic acid (syn isomer)(2.7 g).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([CH2:26]Cl)=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CS(C)=O>[C:10]([O:14][C:15]([N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([CH2:26][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Reactant: CC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)C(Cc1cn(C(=O)OC(C)(C)C)c2ncccc12)C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To acetylacetone (0.563 g, 5.62 mmol) in dimethyl sulfoxide (29.0 mL) was added sodium hydride (0.225 g, 60% in mineral oil, 5.62 mmol). After 20 minutes, 3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (512, 1.00 g, 3.75 mmol) was added to the reaction. The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give a colorless oil (513, 0.59 g, 48.0%). MS (ESI) [M+H+]+=331.4.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][CH2:15][CH:16]([OH:20])[CH2:17][O:18][CH3:19]>ClCCl>[CH3:13][O:14][CH2:15][CH:16]([O:20][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:17][O:18][CH3:19]
Reactant: COCC(O)COC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(COC)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
Triethylamine (5 ml, 0.036 mol) followed by slow addition of methanesulphonyl chloride (2.72 ml, 0.035 mol) was added to a solution of 1,3-dimethoxy-2-hydroxypropane (3.84 g, 0.032 mol) in dichloromethane (70 ml) cooled at 5° C. The mixture was then stirred at ambient temperature for 24 hours. The mixture was then absorbed onto silica gel and purified by chromatography eluting with dichloromethane/isohexane (1:1) to give the title compound (3.74 g, 59%). NMR: 3.15 (s, 3H), 3.28 (s, 6H), 3.52 (d, 4H), 4.78 (q, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[CH:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[C:25]([C:27]5[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=5)=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc3cc(-c4nc5cc(Cl)ccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in dimethylformamide (3 mL) was added methyl 4-formylbenzoate (143 mg, 0.872 mmol) and oxone (313 mg, 0.509 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered, and after washing with water and ethyl acetate, drying yield the title compound (239 mg, 67% yield) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.[BH3-]C#N.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CCO.CC(O)=O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Nc1ccc(Cl)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
A mixture of 1 g (7.84 mmol) of 4-chloroaniline, 0.91 g (15.68 mmol) of acetone, 0.99 g (15.68 mmol) of NaCNBH3, 4 g of MgSO4 in 99 mL anhydrous EtOH and 1 mL AcOH was stirred at room temperature overnight, filtered and the solvent was removed. The residue was dissolved in 50 mL EtOAc, washed with 50 mL H2O, dried (Na2SO4) and evaporated. The residue was purified on silica gel using hexane/EtOAc as eluent to yield 0.86 g colorless oil. MS: 170.08 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:12])[CH:4]=1)(=[O:10])=[O:9]
Reactant: NCCCCO
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Product: Cc1cc(S(=O)(=O)NCCCCO)ccc1Br

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-3-methylphenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([O:30]C)=[O:29])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([OH:30])=[O:29])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
In methanol (40 ml) and THF (60 ml) was dissolved methyl 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g). To the solution was-added 1N sodium hydroxide solution (5 ml), and the mixture was stirred at room temperature overnight. To the mixture was added 1N sodium hydroxide solution (2.5 ml), and the mixture was stirred at room temperature overnight and concentrated. The residue was neutralized with 1N hydrochloric acid, precipitated crystals were filtered and washed with water to give 1-methoxycarbonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.29 g) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([N:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH:16]=O)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1C=CC=CC=1.B>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[N:1]1([CH2:16][C@@H:15]2[CH2:18][CH2:19][CH2:20][N:14]2[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: C1COCCN1
Agent: B
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN1CCOCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
Part A. Morpholine (7.1 g, 7.1 mL, 82 mmol) was added to a stirring solution of N-BOC-(S)-prolinal (3.3 g, 17 mmol) in methylene chloride (83 mL) followed by zinc chloride (0.5 M in THF, 100 mL, 50 mmol). After stirring at ambient temperature for 5 h, borane-pyridine (ca. 8 M, 2 mL, 16 mmol) was added. After stirring at ambient temperature overnight, the reaction was evaporated in vacuo. Methanol was added to the residue and the solids were filtered. Evaporation of the filtrate afforded 13 g of crude product. Purification over silica gel afforded 3.9 g (87%) of 1,1-dimethylethyl (S)-2-(4-morpholinylmethyl)-1-pyrrolidinecarboxylate: 1H-NMR (CDCl3) δ 3.90 (1H, m), 3.69 (4H, m), 3.34 (2H, m), 2.57 (2H, m), 3.40 (2H, m), 2.18 (1H, m), 1.90 (4H, m), 1.74 (1H, m), 1.47 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([CH3:20])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]1.S(=O)(=O)(O)O.[N+:26]([O-])([O-:28])=[O:27].[K+]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[C@:9]1([CH3:20])[CH2:14][C@@H:13]([C:15]([F:18])([F:16])[F:17])[O:12][C:11]([NH2:19])=[N:10]1
Reactant: O=[N+]([O-])[O-]
Reactant: C[C@@]1(c2cccc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: C[C@@]1(c2cc([N+](=O)[O-])cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 0.25 h

Procedure:
To a solution of (4S,6S)-4-(2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.06 g, 3.41 mmol) in sulfuric acid (13.64 ml, 256 mmol) cooled in an ice bath was added potassium nitrate (0.448 g, 4.44 mmol) in one portion. After stirred for 15 min, ice bath was removed, and the mixture was stirred at room temperature for 40 min. The reaction mixture was poured into ice water containing sodium carbonate (40 g). The resulted suspension was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated and dried in vacuum to afford the crude (4S,6S)-4-(2-chloro-3-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine as a light yellow solid, which was used in next step without purification. MS m/z=356 [M+H]+. Calculated for C12H10ClF4N3O3: 355.6.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Temperature: 25 °C

Procedure:
(R)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1, 80 mg, 0.180 mmol), pyrimidin-5-ylboronic acid (66.8 mg, 0.539 mmol), Pd(PPh3)2Cl2 (7.57 mg, 10.78 μmol) and Na2CO3 (57.1 mg, 0.539 mmol) were added to a MW vial and treated with a mixture of DME (762 μL), water (218 μL) and EtOH (109 μL). The vial sealed, evacuated/purged with argon and then the RM was subjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT, diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 70.7 mg, 0.090 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2)) to yield the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.37 min, m/z=445.0 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.81 (m, 1H) 1.82-1.93 (m, 1H) 2.68 (dd, J=10.15, 1.10 Hz, 1H) 2.97-3.11 (m, 2H) 3.17-3.27 (m, 1H) 4.17-4.25 (m, 1H) 4.87 (d, J=3.67 Hz, 1H) 6.98 (d, J=9.05 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.79-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.20 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:3]=1.FC(F)(F)C(O)=O.[NH2:35][CH2:36][CH2:37][NH:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][N:40]=1.CS(C)=O.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[N:12]1([CH2:11][C:9]2[N:10]=[C:6]3[N:7]([C:2]([NH:35][CH2:36][CH2:37][NH:38][C:39]4[N:40]=[CH:41][C:42]([C:43]#[N:44])=[CH:45][CH:46]=4)=[N:3][C:4]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)=[CH:5]3)[N:8]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: FC(F)(F)c1ccc(-c2cc3nc(CN4CCOCC4)nn3c(Cl)n2)cc1
Reactant: N#Cc1ccc(NCCN)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(C(F)(F)F)cc3)cc3nc(CN4CCOCC4)nn23)nc1

Procedure:
300 mg (0.75 mmol) of 5-chloro-2-(morpholin-4-ylmethyl)-7-[4-(trifluoromethyl)-phenyl][1,2,4]triazolo[1,5-c]pyrimidine (Example 151A) and 180 mg (0.91 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (Example 13A) are introduced into DMSO (4 ml), 0.79 ml (4.5 mmol) of DIEA is added, and the reaction solution is irradiated in a microwave reactor at 140° C. for 30 min. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated sodium bicarbonate solution, ammonium chloride solution and saturated sodium chloride solution, dried and concentrated. The residue is taken up in acetonitrile (4 ml), and the solid which precipitates is filtered off and dried. 300 mg (76% of theory) of the product are obtained as a solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([CH2:20][CH2:21][CH3:22])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>O1CCOCC1>[CH2:2]([O:4][C:5]([C:7]1([CH2:20][CH2:21][CH3:22])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCCC1(C(=O)OCC)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydrochloric acid (12N, 4.2 mL) in dioxane (6.8 mL) is added to 4-propylpiperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (2.2 g, 0.0073 mol) and stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is treated with aqueous solution of sodium bicarbonate to adjust the pH to 8-9. It is again concentrated under reduced pressure and the residue is treated with dichloromethane. After drying over sodium sulfate solvent is removed to get 4-propylpiperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Li]CCCC.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1COCC1.C(OCC)(=O)C>[C:12]([NH:6][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C/C=C/C(N)=O
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C

Procedure:
Experimental Procedure: To a suspension of (E)-but-2-enamide (1.0 equiv) in 3.5 mL THF was added n-BuLi in hexanes (2.5 M,1.2 equiv) slowly at −78° C. The reaction mixture was warmed up to room temperature and stirred for 8 h before a solution of methacryloyl chloride (2.0 equiv) in 2 mL of THF was added drop wise at −78° C. The reaction mixture was allowed to warm up to rt overnight. The crude reaction mixture was diluted with ethyl acetate, and quenched with cold NH4Cl(aq, sat), and the organic layer separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. After filtration and evaporation under reduced pressure, the residue was purified by column chromatography to yield the pure compound.