Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([N:10]1[C:14]([CH3:15])=[C:13]([O:16][C:17]2[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[C:12]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:11]1)[CH:8]=C.[OH2:31].[BH4-].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:27]([C:12]1[C:13]([O:16][C:17]2[CH:18]=[C:19]([C:25]#[N:26])[CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])=[C:14]([CH3:15])[N:10]([CH2:7][CH2:8][OH:31])[N:11]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: C=CCn1nc(C(C)(C)C)c(Oc2cc(C#N)cc(C#N)c2)c1C
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1c(Oc2cc(C#N)cc(C#N)c2)c(C(C)(C)C)nn1CCO
Reaction time: 3 h

Procedure:
Sodium periodate (1.00 g, 4.60 mmol), osmium tetroxide (1.5% solution in tert-butanol, 190 mg, 0.02 mmol) and the pyrazole from Example 156 (600 mg, 1.86 mmol) were dissolved in acetone (9 ml) and water (3 ml) under nitrogen at room temperature, and the reaction was stirred for 5 hours. The acetone was removed under reduced pressure and the residue was extracted with ethyl acetate (30 ml). The organic phase was washed with water (2×30 ml) then brine (30 ml), dried over magnesium sulphate and concentrated under reduced pressure. The crude aldehyde was then dissolved in methanol (15 ml) and sodium borohydride (84 mg, 2.22 mmol) was added portionwise at room temperature under nitrogen. The reaction was stirred for 3 hours and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (10 ml) and water (10 ml) and the organic phase was washed with water (2×10 ml) then brine (10 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was purified by flash chromatography on silica gel eluting with a solvent gradient of pentane changing to ethyl acetate:pentane (50:50, by volume) to provide the title compound (250 mg) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([N:6]([CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([CH:18]=O)[CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.C(=O)(OC)OC.C[O-].[Na+].CO.Cl>CN(C=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:13]([CH3:15])[CH3:14])[CH2:7][CH2:8][C:9]([C:10]([O:12][CH3:20])=[O:11])=[CH:18][C:4]=2[CH:3]=1
Reactant: CC(C)N(CCCC(=O)O)c1ccc(Br)cc1C=O
Reactant: O=C([O-])[O-]
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CI
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
In DMF (4.5 ml) was dissolved 4-(4-bromo-2-formylisopropylanilino)butyric acid (0.9 g). To the solution was added potassium carbonate (0.49 g), followed by addition of methyl iodide (0.2 ml) and stirring at room temperature 1 hour. To the mixture was added dimethyl carbonate (9 ml), followed by addition of a 28% sodium methoxide/methanol solution (1.27 g) and stirring at 50° C. for 1 hour. After cooled to room temperature, the mixture was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=20/1→6/1) to give methyl 7-bromo-1-isopropyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g).
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:41])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH:38]3[CH2:40][CH2:39]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:52][CH2:51][CH2:50]1>>[CH:38]1([C:34]2[CH:35]=[C:36]([CH3:37])[C:31]([N:28]3[CH2:27][CH2:26][N:25]([C:23]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][S:17]5(=[O:22])=[O:21])=[CH:15][C:10]=4[C:9]([N:8]4[CH2:52][CH2:51][CH2:50][CH2:6]4)=[O:41])=[O:24])[CH2:30][CH2:29]3)=[N:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Reactant: C1CCNC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2C(=O)N2CCCC2)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzamide (90 mg) described in Example 805 and pyrrolidine (13 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (59 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6](N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)=[CH:5][C:4]=1[NH:24][C:25]1[CH:30]=[C:29]([C:31]2[C:32]([CH3:36])=[N:33][O:34][CH:35]=2)[CH:28]=[C:27]([CH3:37])[N:26]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][C:27]1[N:26]=[C:25]([NH:24][C:4]2[C:3]([C:1]#[N:2])=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:30]=[C:29]([C:31]2[C:32]([CH3:36])=[N:33][O:34][CH:35]=2)[CH:28]=1
Reactant: Cc1cc(-c2conc2C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2conc2C)cc(Nc2cccnc2C#N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl (1S,2R)-2-(6-cyano-5-(6-methyl-4-(3-methylisoxazol-4-yl)pyridin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate (50 mg, 0.099 mmol) in DCM (1 ml) was added TFA (1.0 ml, 13 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give 54(1R,2S)-2-aminocyclohexylamino)-3-(6-methyl-4-(3-methylisoxazol-4-yl)pyridin-2-ylamino)picolinonitrile. MS ESI calc'd. for C22H26N7O [M+H]+ 404. found 404.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:19]2[N:20]=[C:21]([CH2:31][O:32][CH3:33])[C:22]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:18]2[CH:17]=[CH:16][CH:15]=1.[H-].[Na+].Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.O>CN(C)C=O.C(OCC)(=O)C>[CH:38]1([CH2:37][N:23]([C:22]2[C:21]([CH2:31][O:32][CH3:33])=[N:20][N:19]3[C:14]([C:4]4[C:5]([O:12][CH3:13])=[CH:6][C:7]([CH2:9][O:10][CH3:11])=[CH:8][C:3]=4[O:2][CH3:1])=[CH:15][CH:16]=[CH:17][C:18]=23)[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH2:40][CH2:39]1
Reactant: BrCC1CC1
Reactant: COCc1cc(OC)c(-c2cccc3c(NC(=O)OC(C)(C)C)c(COC)nn23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc(OC)c(-c2cccc3c(N(CC4CC4)C(=O)OC(C)(C)C)c(COC)nn23)c(OC)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (170 mg) dissolved in N,N-dimethylformamide (4 mL) was added sodium hydride (60% in oil; 22 mg) and (bromomethyl)cyclopropane (0.043 mL), and the reaction mixture was stirred for 30 minutes at 40° C. Water was added to the obtained reaction mixture, extraction was performed with ethyl acetate and the organic extract was washed with brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].[CH3:11][Si:12]([CH3:15])([CH3:14])Cl.C(O)(=O)C>CCOCC.CCCCCC.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:11]
Reactant: C#CCOC1CCCCO1
Reactant: C[Si](C)(C)Cl
Solvent: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: C[Si](C)(C)C#CCOC1CCCCO1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To a stirred -20° C. solution of 125 g (0.89 mol.) of 3-tetrahydropyranyloxy-1-propyne (Example 56) in 450 ml of ether, under a nitrogen atmosphere, is added dropwise, over one hour, a solution of 45 ml (0.89 mol.) of 2.0 N n-butylithium in hexane. After 150 ml of dry ether is added and the mixture stirred at -20° C. for 30 minutes, a solution of 98 g (0.89 mol.) of trimethylchlorosilane in 73 ml of ether is added dropwise. Stirring is continued for 30 minutes at -20° C. and at ambient temperature for 18 hours. The reaction mixture is again cooled to -20° C., and a solution of 90 ml of acetic acid in 300 ml of ether is added dropwise, followed by 90 ml of water. It is then diluted with 500 ml of water, and extracted 3 times with 300 ml of 5% sodium bicarbonate solution. The organic phase is separated, washed with 500 ml of a saturated brine solution, dried over sodium sulfate, and evaporated at 40° C. under vacuum (12 mm.). The crude product is fractionally distilled, bp 120°-125° C. (18 mm.), to yield 120 g of an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[CH:32][S:33][CH:34]=1)CCC>C1(C)C=CC=CC=1.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>[F:23][C:15]1[CH:14]=[C:13]([C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[N:31]=[CH:32][S:33][CH:34]=4)=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1-c1ccc(S(C)(=O)=O)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccc(-c3cscn3)cc2)c1-c1ccc(S(C)(=O)=O)c(F)c1
Yield: 90.1 %

Procedure:
A mixture of 3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole (219 mg, 0.53 mmol), tributyl(1,3-thiazol-4-yl)tin (200 mg, 0.53 mmol) and tetrakis(triphenylphosphine)palladium (62 mg, 0.053 mmol) in toluene (5 ml) was refluxed for 26 h. The mixture was evaporated and the obtained residue was chromatographed on a column of silica gel (40 g) as eluting with ethyl acetate/hexane (1/2) to give 198 mg of a white solid, which was recrystallized from ethyl acetate/hexane to afford 128 mg (58%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.B.C1COCC1>C1COCC1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
4-Bromo-2-methyl-benzoic acid (9.88 g, 45.9 mmol) was dissolved in THF (100 ml), and the solution was cooled to 0° C. To this solution, a solution of 1M BH3.THF (91.89 ml, 91.89 mmol) was added at 0° C., and the solution was vigorously stirred for 3 hours at room temperature. The reaction mixture was diluted with cold water (20 mL), washed with a saturated solution of NaHCO3, then extracted with ether 3 times (300 mL). The combined organic ether was washed with brine (250 mL), dried over MgSO4, and concentrated in Vacuo. The residue was purified via flash column chromatography (25% to 55% EtOAc in Hexane) to give white solid (8.24 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ: 2.32 (2 H, s) 4.64 (1 H, d, J=5.81 Hz) 7.20-7.26 (2 H, m) 7.30-7.36 (1 H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:12]3[N:11]=[C:10]([CH3:23])[C:9]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:48]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:16]=[C:12]3[N:11]=[C:10]([CH3:23])[C:9]=2[CH:24]([OH:48])[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COC(=O)Cc1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(O)c1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of methyl 2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (106 mg, 0.269 mmol) in anhydrous THF (5 ml) at −78° C. was added dropwise KHMDS (0.808 mL, 0.404 mmol) in toluene. Reaction mixture was stirred at −78° C. for 30 min and to this was added dropwise 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (106 mg, 0.404 mmol) in THF (2 mL) and the contents were stirred at −78° C. for 30 min and allowed slowly to warm to room temperature, then quenched with a drop of saturated ammonium chloride solution. Evaporated to remove the solvent. Purified by prep HPLC to afford methyl 2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (56 mg, 0.134 mmol, 49.8% yield) as white solid. 1H-NMR (500 MHz, CDCl3) δ 1.15 (6 H, s), 1.69-1.75 (4 H, m), 2.62 (3 H, s), 3.77-3.79 (2 H, m), 3.81-3.83 (2 H, m), 3.85 (3 H, s), 5.49 (1 H, s), 7.56-7.60 (3 H, m), 8.20-8.22 (2 H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.Br[N:13]1[C:17](=O)[CH2:16][CH2:15][C:14]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrCC1C=C2C(=CC=1)N=CC=N2>C(N)CCC.CCCCC.ClC1C=CC=CC=1>[CH2:14]([NH:13][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2)[CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nccnc2c1
Agent: BrCc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCN
Solvent: Clc1ccccc1
Solvent: CCCCC
Product: CCCCNCc1ccc2nccnc2c1
Temperature: 85 °C

Procedure:
In a 50 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolved together with N-bromosuccinimide (2.32 g, 13.0 mmol) and benzoyl-peroxide (0.15 g, 0.62 mmol) in 31. g of chlorobenzene. The solution was stirred with heating at 85° C. for 2.0 hours to yield a reddish solution. The solution was cooled down to room temperature and one volume of pentane was added to facilitate the removal of succinimides. The precipitate was washed with pentane and the extracts were combined with the chlorobenzene solution. The yellow solution was vacuum dried to give a yellow residue mainly composed of 6-bromomethyl-quinoxaline. The yellow solid was dissolved in 19.0 g of n-butylamine to give a yellow solution that was stirred at room temperature for ˜5 minutes. Analysis of a sample showed that the 6-bromomethyl-quinoxaline was consumed to give exclusively 6-n-butylaminomethyl-quinoxaline as a deep yellow oil (1.71 g, 92% over all yield). MS (70 ev): 215 M+, 172 (M+—CH3—CH2—CH2),143 (M+—CH3—CH2—CH2—CH2).
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[C:28](=[O:31])[NH:29][CH3:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:25]=[CH:26][C:27]=1[C:28](=[O:31])[NH:29][CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Reactant: CNC(=O)c1ccc(B(O)O)cc1F
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2nccnc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 90 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
To a round bottomed flask (RBF) was added tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (2 g, 6.72 mmol), (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (1.64 g, 8.33 mmol; Combi-Blocks), potassium phosphate (3.56 g, 16.79 mmol), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.476 g, 0.672 mmol), and dioxane (20 mL):Water (2 mL). The mixture was stirred at 90° C. After 16 h, the reaction was allowed to cool to room temperature and poured into water (50 mL). The aqueous solution was extracted with ethyl acetate (EtOAc) (3×25 mL). The combined EtOAc layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 30-100% EtOAc in hexane, to provide tert-butyl 4-(3-(3-fluoro-4-(methylcarbamoyl)phenyl)pyrazin-2-yl)piperidine-1-carboxylate (2.46 g, 5.94 mmol, 88% yield), as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[OH:27][C@@H:28]([CH3:43])[CH2:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[C:38]([CH:41]=O)[CH:37]=[CH:36]2.C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:41]([C:38]3[CH:37]=[CH:36][C:35]4[C:40](=[C:31]([O:30][CH2:29][C@@H:28]([OH:27])[CH3:43])[CH:32]=[CH:33][CH:34]=4)[N:39]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: C[C@H](O)COc1cccc2ccc(C=O)nc12
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](O)COc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.1 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.16 g, 0.39 mmol) and (S)-8-(2-hydroxypropoxy)quinoline-2-carbaldehyde (0.91 g, 0.39 mmol) in ethanol (2.0 mL, 0.39 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.0 mL) and iodosobenzene diacetate (0.14 g, 0.43 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.11 g, 49%).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=O.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:10]([O:9][C:7](=[O:8])[NH:1][CH2:2][CH2:3][C:4](=[O:6])[NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BOC-Beta-Ala-OH (25 g, 0.132 mol) is dissolved in DCM (500 ml) and then treated with EDC1 (30.4 g, 0.59 mol) followed by t-butylamine (16.7 ml, 0.159 mol) to give a pale orange solution. The reaction mixture is stirred at room temperature overnight and then partitioned between 20% citric acid (400 ml) and DCM (250 ml). The organic portion is separated and washed with water (400 ml), saturated NaHCO3 (400 ml), brine (400 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH2:10]OCC2C=CC=CC=2)[CH2:8][N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2].[S:28]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1.C(C=P(CCCC)(CCCC)CCCC)#N>C(O)C.C1C=CC=CC=1.[Pd]>[C:1]([N:4]1[CH:9]([CH2:10][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][S:28]2(=[O:35])=[O:34])[CH2:8][N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1COCc1ccccc1
Reactant: O=S1(=O)CCCCN1
Agent: [Pd]
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCO
Solvent: c1ccccc1
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1CN1CCCCS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-acetyl-5-[(benzyloxy)methyl]-1-(4-fluorobenzyl)piperazin-2-one (6.5 g) and 20% Pd/C (1.4 g) in ethanol (175 mL) was shaken under an atmosphere of hydrogen (60 psi) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum. Residual ethanol was removed by co-evaporation with toluene under vacuum (3×). The resultant alcohol was used without further purification. A mixture of the alcohol (1.0 g, 3.57 mmol), 1,2-thiazinane 1,1-dioxide (0.73, 5.4 mmol), and cyanomethylenetri-n-butylphosphorane (1.3 g, 5.4 mmol; [157141-27-0]) in benzene (20 mL) was purged with nitrogen and heated in a sealed tube at 100° C. overnight. The reaction mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with a mixture of 5% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH:13]3[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[CH:11]=[N:10][C:9]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:5]=[CH:4][N:3]=1.Cl>CO>[NH:15]1[CH2:14][CH:13]([N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:10]=[CH:11]2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(N)n2)C1
Agent: Cl
Solvent: CO
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CNC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-[5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-1-yl]azetidine-1-carboxylate (C4) (2.1 g, 5.1 mmol) in methanol (10 mL) was added aqueous hydrochloric acid (5 N, 30 mL) and the reaction was stirred for 2 hours at room temperature. The solution was concentrated and the residue was diluted with water (100 mL) and ethyl acetate (100 mL). After adjusting the mixture to pH=9 with aqueous ammonia, the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the product as a solid. Yield: 1.1 g, 3.5 mmol, 69%. LCMS m/z 311.4 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.95 (br d, J=7.5 Hz, 4H), 5.51 (m, 1H), 6.38 (br d, J=5.2 Hz, 1H), 7.10 (br dd, J=8.5, 8.5 Hz, 2H), 7.44 (br dd, J=8, 5 Hz, 2H), 8.10 (br d, J=5.0 Hz, 1H), 8.21 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[I:14])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a solution of 1.00 g (2.82 mmol) (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester in 10 ml DMF were added 0.12 g (3.1 mmol) sodium hydride (60% in mineral oil) at −10° C. (The preparation of (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester has been described in US 2002/0022624 A1.) The reaction mixture was allowed to warm to room temperature. After 1 h, the mixture was cooled back to −10° C., and 0.44 ml (7.1 mmol) iodomethane were added during 5 min. The reaction mixture was allowed to warm to room temperature. After 2.5 h at room temperature, the reaction was quenched by addition of 10 ml of a saturated aqueous solution of NaHCO3 and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, hexanes/ethyl acetate=4:1) to give 1.06 g (100%) of the title compound as a colorless oil.