Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:20].Br[CH:22]([CH2:28][CH2:29][CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:22]([CH2:28][CH2:29][CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][CH2:15]2)=[O:11])=[CH:4][C:3]=1[Cl:20]
Reactant: COc1nc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: CCCCC(Br)C(=O)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCC(C(=O)OCC)N1CCC(CNC(=O)c2cc(Cl)c(N)nc2OC)CC1
Temperature: 70 °C
Yield: 94.2 %

Procedure:
To a solution of 6-amino-5-chloro-2-(methyloxy)-N-(4-piperidinylmethyl)-3-pyridinecarboxamide (step 1 in example 13, 4.0 g, 13 mmol) in dimethylformamide (70 ml) was added ethyl 2-bromohexanoate (3.1 g, 14 mmol), sodium iodide (2.0 g, 13 mmol) and triethyl amine (2.2 ml) at room temperature. The mixture was heated at 70° C. overnight. After cooled to room temperature, the mixture was poured into water (80 ml) and extracted with diethyl ether (200 ml×2), washed with water (100 ml×2), brine (100 ml). The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:1) to give 5.4 g (93%) of the title compound as a clear colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:14](=[O:16])[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:17])=[CH:30][CH:29]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.9 %

Procedure:
A mixture of 0.64 g (2.4 mmol) of [4-(4-fluoro-benzyl)piperidin-1-yl]-oxo-acetic acid, 0.34 ml (2.4 mmol) of triethylamine, 0.35 g (2 mmol) of 4-bromo-aniline (Aldrich), 0.91 g (2.4 mmol) of HBTU and 10 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated. Then 30 ml of 8% sodium hydrogencarbonate solution and 30 ml of chloroform is added to the mixture. The organic layer is separated and the water phase is extracted three times with 20 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated. The residue is treated with diethylether and the crystals are filtered off to yield 0.36 g (43%) of the title compound. Melting Point: 156-158° C. (diethylether)
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][CH:10]=[CH:11][C:12]3[NH:13][C:14]4[CH2:15][N:16](C(OCC5C=CC=CC=5)=O)[CH2:17][C:5]([C:6]=4[C:7]=32)=[N:4][NH:3]1.[H][H]>CO.[Pd]>[CH2:17]1[NH:16][CH2:15][C:14]2[NH:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:2](=[O:1])[NH:3][N:4]=[C:5]1[C:6]=2[C:7]=34
Reactant: [H][H]
Reactant: O=C1NN=C2CN(C(=O)OCc3ccccc3)Cc3[nH]c4cccc1c4c32
Agent: [Pd]
Solvent: CO
Product: O=C1NN=C2CNCc3[nH]c4cccc1c4c32

Procedure:
A mixture of Compound 20 (34 mg, 0.1 mmol) and palladium (10%) on carbon (10 mg) in 10 mL of methanol was stirred at RT under a balloon of hydrogen for 5 h. The mixture was then filtered through a pad of celite. The catalyst cake was washed with methanol. The filtrate was concentrated. The resulting residue was purified by HPLC to give the target product as formic acid salt (white solid) (13 mg, 50%). 1H NMR (DMSO-d6) δ 11.7 (s, 1H), 9.86 (s, 1H), 7.40-7.45 (m, 2H), 7.09 (t, 1H, J=8.0 Hz), 3.94 (s, 2H), 3.41 (s, 2H). MS (ESI) m/e [M+1]+ 227.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:26][CH2:27][OH:28])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 65 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
To a solution of 5 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine in 40 ml of dimethylformamide are added 2.5 g of 2-bromoethanol and 2.8 g of potassium carbonate. After stirring at 65° C. for 12 hours, the resulting mixture is poured into ice-cold water and the precipitate is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried and then concentrated. The residue is recrystallized from a mixed solvent of hexane and toluene to give 4.6 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridine as pale yellow crystals, melting at 135°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:15])[C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1)[NH2:5].[C:16](N1C=CC=CC1=O)([N:18]1C=CC=CC1=O)=[S:17].N>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]([NH2:18])=[S:17])[CH:6]=[C:7]([F:15])[C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ncn(-c2c(F)cc(N)cc2F)n1
Agent: N
Solvent: ClCCl
Product: Cc1ncn(-c2c(F)cc(NC(N)=S)cc2F)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
Step R (3): Dichloromethane (50 mL) was added to a flask charged with 3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (1.75 g, 8.33 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (2.90 g, 8.33 mmol). The resulting mixture was stirred for 24 h at rt and concentrated in vacuo. A solution of ammonia (2.0 M in methanol, 50 mL, 100 mmol) was added to the crude solid. The heterogeneous mixture was stirred at rt for 2 h, then evaporated to dryness under reduced pressure using a rotary evaporator. The solid residue was triturated with 40 mL of anhydrous ethanol and chilled to 0° C. for 1 h. The solid was collected by vacuum filtration and dried under high vacuum to afford 1-(3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (1.76 g, 6.54 mmol, 79% yield) as a gray powdery solid. LC-MS (M+H)+ 270.0. 1H NMR (500 MHz, DMSO-d6) d ppm 10.16 (1 H, br. s.), 8.77 (1 H, s), 7.64 (2 H, d, J=10.4 Hz), 2.35 (3 H, s).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>O1CCCC1.O>[F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][N:5]([S:47]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)(=[O:49])=[O:48])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)N2CCOCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (324 mg) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 121 mg) at room temperature, and the mixture was stirred for 10 min. 15-Crown-5 (664 mg) was added, morpholine-4-sulfonyl chloride (250 mg) was added and the mixture was further stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a colorless oil (yield 370 mg, 78%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:11])[CH:9]=[CH2:10].[OH-].[K+].[CH3:14]I>O1CCCC1>[CH3:14][O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:11])[CH:9]=[CH2:10]
Reactant: CI
Reactant: C=CC(=O)NCCOCCO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC(=O)NCCOCCOC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
N-[2-(2-hydroxyethoxy)ethyl]acrylamide (35.87 g), potassium hydroxide (15.2 g), tetrahydrofuran (100 g) and methyl iodide (33.58 g) were introduced into a 1 L eggplant type flask equipped with a reflux condenser and a magnetic rotor. A reaction was carried out at 45° C. for 2 hours and then for 2 hours at 60° C. as the mixture was being stirred. The salt that separated out was removed by filtration and the low boiling point components were removed by means of a rotary vacuum evaporator. Purification was performed by distillation under reduced pressure and N-[2-(2-methoxyethoxy)ethyl]acrylamide was obtained as a yellow transparent, viscous liquid.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][OH:15])[O:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:11]1[O:12][CH:13]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[N:10]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2coc(CO)n2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2coc(COS(C)(=O)=O)n2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl)-methanol (230 mg, 1.24 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.23 mL, 1.64 mmol) followed by DMAP (15 mg, 0.12 mmol) and Ms-Cl (0.13 mL, 1.61 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-(2-methyl-[1,3]dioxolan-2-yl)oxazol-2-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)oxazole as a colorless oil. To a solution of the crude azide in THF (9 mL) were added polymer-supported Ph3P (1.4 eq.) and water (3 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.22 min; [M+H]+=185.00.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F:20][C:21]1[C:22](I)=[CH:23][C:24](=[O:40])[N:25]([CH2:27][CH2:28][C@@:29]([CH3:39])([S:35]([CH3:38])(=[O:37])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:26]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[F:20][C:21]1[C:22]([C:14]2[CH:15]=[CH:16][C:11]([S:10][CH3:9])=[CH:12][CH:13]=2)=[CH:23][C:24](=[O:40])[N:25]([CH2:27][CH2:28][C@@:29]([CH3:39])([S:35]([CH3:38])(=[O:36])=[O:37])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:26]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(SC)cc2)cc1=O)S(C)(=O)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1,4-Dioxane (10 ml) and 3 M aq K3PO4 (1.12 mL, 3.3 mmol) was added to a flask containing [4-(methylthio)phenyl]boronic acid (0.283 g, 1.68 mmol), Pd(dppf)Cl2 (82 mg, 0.112 mmol) and ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate, T2, (500 mg, 1.12 mmol) that was previously flushed with nitrogen. The mixture was heated to 60° C. and stirred at this temperature for 1 h. The reaction mixture was diluted with EtOAc and washed with water. The organics were dried (MgSO4), filtered, and concentrated. The crude product was purified via flash chromatography on a 40 g silica column and an eluent of EtOAc in n-heptane (0-100%) to afford the title compound as a gum (492 mg, 99%). MS (LCMS) m/z 442.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.17-1.27 (m, 3 H) 1.74 (s, 3 H) 2.38-2.61 (m, 5 H) 3.09 (s, 3 H) 3.88-4.02 (m, 1 H) 4.17-4.32 (m, 3 H) 6.57 (d, J=7.61 Hz, 1 H) 7.21-7.34 (m, 3 H) 7.37-7.48 (m, 2 H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)O)[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.O>[N:21]([CH:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:9]=[CH:8][N:7]=1)[CH:3]([CH2:19][CH3:20])[CH2:1][CH3:2])=[N+:22]=[N-:23]
Reactant: CCC(CC)C(O)c1ncnn1Cc1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)C(N=[N+]=[N-])c1ncnn1Cc1ccc(F)cc1
Yield: 67 %

Procedure:
To a stirred solution of 2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol (0.459 g, 1.42 mmol) in DMF (10 mL) was added sodium azide (0.277 g, 4.26 mmol) and the mixture was heated to reflux for 3 h. After cooling, the reaction mixture was diluted with H2O and extracted with EtOAc twice. The organic extracts were dried (MgSO4), filtered, concentrated in vacuo and purified by column chromatography (SiO2, EtOAc/hexane, 1:9) to yield a clear oil in 67% yield.
Reaction SMILES: [C:1](O)(=[O:4])[C:2]#[CH:3].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>O1CCCC1.CN(C)C=O>[C:1]([NH:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1)(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)O
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
To a solution of propiolic acid (27 mg, 0.387 mmol) in tetrahydrofuran (2 mL) and N,N-dimethylformamide (2 mL) was added N,N′-dicyclohexylcarbodiimide (100 mg, 0.484 mmol) under ice-cooling, and the mixture was stirred for 30 min. To the reaction mixture was added N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), and the mixture was stirred under ice-cooling for 4 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0) to give the title compound (24 mg, 21%) as a pale-orange powder.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:27]>>[ClH:27].[N:17]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[C:23]([F:26])([F:24])[F:25])[CH2:9][NH:8][CH2:16]3)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N3CCOCC3)c(C(F)(F)F)cc2C1
Agent: Cl
Product: FC(F)(F)c1cc2c(cc1N1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-morpholin-4-yl-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 273.0 ([M+H]+, 100%).
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:12](=O)[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]#[N:22])[C:15]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][CH3:11])(C)(C)C>O1CCOCC1>[NH2:8][C@H:9]([C:12]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[C:16]([C:21]#[N:22])=[C:17]([F:20])[CH:18]=[CH:19][C:14]=2[N:13]=1)[CH2:10][CH3:11]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c(C#N)c1Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Yield: 69.5 %

Procedure:
HCl in dioxane (4M, 10 mL, 0.04 mol) was added to a solution of [(S)-1-(3-cyano-4-fluoro-2-phenylaminophenylcarbamoyl)propyl]carbamic acid tert-butyl ester (0.54 g, 1.32 mmol) in dioxane (5 mL) at 20° C., and the resultant mixture stirred at 80° C. for 17 h. After cooling, the reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (3×20 mL). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2 0-20% methanol in EtOAc) to give the title compound as an oil (0.27 g, 69%) LCMS (method H): RT 2.03 min, [M+H]+ 295.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Br:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])(=[O:3])[CH3:2].[BH4-].[Na+].O>CCOCC>[Br:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an ice bath, about 10 mmols of 3-acetyl-4-nitro-bromobenzene was put into a 100 mL two-neck round flask, dissolved in about 30 mL solvent ether, and sodium borohydride was gradually added. The solution was stirred at room temperature for about 2 hours. After confirming reaction completion using TLC, reaction was completed by using about 5 mL water. The precipitate was filtered, and the filtered solution was washed twice with sodium chloride solution (about 30 mL). Then the washed solution was dried with sodium sulfate anhydride, and distilled under reduced pressure. Then, 1-(5-bromo-2-nitrophenyl)ethanol was obtained in a form of about 71% yellow oil using silica gel column chromatography (Hexane/EtOAc=2/1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1)(=[O:3])[CH3:2].C1COCC1.[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1)[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a mixture of methyl 5-acetylpyridine-2-carboxylate (1.00 g), THF (24 mL), and methanol (12 mL) was added sodium borohydride (110 mg), followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and then to the obtained residue was added a saturated aqueous sodium chloride solution. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and then dried under reduced pressure to obtain methyl 5-(1-hydroxyethyl)pyridine-2-carboxylate (897 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.Br[C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[CH:19][CH:18]=1.C(O[Na])(C)(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[O:21][C:20]1[CH:28]=[CH:29][C:17]([N:13]2[CH2:14][CH2:15][CH:10]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:9])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: CN(c1ccc(Cl)cc1)C1CCNCC1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(c1ccc(Cl)cc1)C1CCN(c2ccc(OC3CCCCO3)cc2)CC1
Yield: 29.6 %

Procedure:
4-(N-(4-chlorophenyl)-N-methylamino)-piperidine (2.52 g, 11.22 mmol), 2-(4-bromophenoxy) tetrahydropyran (2.89 g, 11.22 mmol), palladium acetate (50 mg, 0.22 mmol), (S)-(−)-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (212 mg, 0.34 mmol) and tert-butoxy sodium (1.51 g, 15.71 mmol) were refluxed with heating in toluene (30 ml) under nitrogen atmosphere for 3 hours. Ethyl acetate and water were added into the reaction solution and stirred, then the resulting precipitate was removed by filtration through Celite, thereafter the filtrate was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, and then filtered. After the resulting filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=20/1) to afford 1-(4-(tetrahydropyran-2-yloxy)phenyl)-4-(N-(4-chlorophenyl)-N-methylamino)piperidine (1.33 g, yield 30%) as a light yellow powder.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([NH:20][CH2:21][C:22]([OH:24])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Cl-].[Mg+2].[Cl-].[C:28]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:29]C([O-])=O.[K+]>C1COCC1>[C:16]([O:15][C:13]([NH:20][CH2:21][C:22](=[O:24])[CH2:29][C:28]([O:34][CH2:35][CH3:36])=[O:33])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CNC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
Referenced: J. Med. Chem. 2008, 51 (3), 487-501. At RT, 1,1′-carbonyldiimidazole (13.88 g, 86 mmol) was added to a solution of N-Boc-glycine (Sigma-Aldrich Chemical Company, Inc.) (10.00 g, 57.1 mmol) in THF (200 mL) and the mixture was stirred for 3 h. Magnesium chloride (10.87 g, 114 mmol) and potassium ethyl malonate (Sigma-Aldrich Chemical Company, Inc.) (19.43 g, 114 mmol) were added and the resulting suspension was heated in an oil bath at 50° C. for 18 h. The reaction mixture was concentrated under reduced pressure. The off-white residue was treated with EtOAc (300 mL), then washed sequentially with 5% sodium bisulfate (2×25 mL), saturated NaHCO3 (2×50 mL), and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by chromatography through a Thomson Single Step pre-packed silica gel column (160 g, eluted with a gradient of 0-75% EtOAc in hexanes) to provide ethyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (10.33 g, 42.1 mmol, 74% yield) as a colorless viscous oil after drying under vacuum overnight. 1H NMR (400 MHz, CDCl3) δ ppm 5.16 (1H, d, J=5.7 Hz), 4.21 (2H, m), 4.08-4.16 (2H, m), 3.48 (2H, s), 1.45 (9H, s), 1.29 (3H, m). m/z (ESI, +ve) 268.0 (M+Na)+.