Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C([O-])(O)=O.[Na+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>CC#N.C1COCC1>[N+:34]([C:31]1[CH:32]=[CH:33][C:28]([O:27][C:25]([NH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:26])=[CH:29][CH:30]=1)([O-:36])=[O:35]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CN)CC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (0.65 g, 2.54 mmol) in MeCN (20 mL) and THF (5 mL) was added powdered NaHCO3 (0.43 g, 5.08 mmol) followed by a solution of p-nitrophenyl chloroformate (0.51 g, 5.08 mmol) in MeCN (20 mL) dropwise over 10 min. The mixture was stirred at rt for 2 h, filtered through a pad of Celite and concentrated to leave a white solid. This material was purified by chromatography on a 40-g silica cartridge eluted with a gradient from 0-100% EtOAc in hexanes to afford (S)-tert-butyl 1-(p-nitrophenoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (0.67 g, 67%) as an off-white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16].[OH-].[K+].O>CC1CCCCC1.CCOC(C)=O>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH:16]=[CH:6][C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc[nH]1
Reactant: CC(=O)c1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CC1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(C=Cc1ccc[nH]1)c1ccccc1Br
Temperature: 45 °C
Yield: 75 %

Procedure:
A mixture of 20.0 g of (0.21 moles) 2-pyrrolecarboxaldehyde, 71.4 mL of (0.52 moles) o-bromoacetophenone, 72 mL of 1N potassium hydroxide and 800 mL of water was placed in a flask under nitrogen and heated to 45° C. for 72 hr. The reaction was cooled in an ice bath until a solid formed. The solid was taken up in methylcyclohexane/EtOAc, dried over 4A sieves and allowed to cool. The resulting solid was recrystallized from methylcyclohexane/EtOAc to give 43.5 g of 1-(2-bromophenyl)-3-(1H-pyrrol-2-yl)-2-propen-1-one as a yellow solid (75%), mp 76°-78° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[C:13]([CH3:14])=[C:12]([C:15](OCC)=[O:16])[S:11][CH:10]=1)#[N:8]>O1CCCC1>[OH:16][CH2:15][C:12]1[S:11][CH:10]=[C:9]([C:7]#[N:8])[C:13]=1[CH3:14]
Reactant: CCOC(=O)c1scc(C#N)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C#N)csc1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.5 %

Procedure:
2.44 g (64 mmol) of lithium aluminum hydride were added portionwise at 0° C. to a solution of 25.1 g (129 mmol) of ethyl 3-cyano-4-methylthiophene-5-carboxylate in 400 ml of tetrahydrofuran. The mixture was stirred for 5 hours at room temperature, excess reducing agent was destroyed by adding 0.5 N hydrochloric acid, and the reaction mixture was concentrated under a water pump vacuum, diluted with water and extracted three times with ethyl acetate. The combined organic phases were then washed in each case once with 0.5 N hydrochloric acid and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under a water pump vacuum at room temperature. The residue was purified by column chromatography (eluant dichloromethane/methanol 95:5), and 16.1 g (83%) of the desired compound were obtained as a slightly yellow oil.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[OH:28][C:29]1[CH:30]=[C:31]([C:35]#[CH:36])[CH:32]=[CH:33][CH:34]=1>>[OH:28][C:29]1[CH:30]=[C:31]([C:35]#[C:36][C:13]2[CH:14]=[C:15]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]4[N:19]=[CH:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)[O:10]3)=[CH:11][CH:12]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#Cc1cccc(O)c1
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3cccc(O)c3)ccc12

Procedure:
7-(3-hydroxyphenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 28% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 3-hydroxyphenylacetylene. The title compound was isolated as a yellow solid and as a 80/20 mixture of Z/E oxime isomers.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:17][CH:16]=[CH2:15])=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
A mixture of 4-bromo-1-nitro-2-(trifluoromethyl)benzene (1.0 g, 3.7 mmol), allyl tri-n-butyltin (1.4 mL, 4.4 mmol), lithium chloride (470 mg, 11 mmol), and palladium tetrakis (210 mg, 0.18 mmol) in toluene (30 mL) was heated to reflux for 16 hours under nitrogen. TLC showed complete reaction at that point. The reaction was diluted with ethyl acetate, adsorbed onto silica gel, and purified by silica gel chromatography to afford the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[CH3:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[CH:6]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cnc1N
Yield: 88.2 %

Procedure:
Prepared as described in example C.32 (step 4) from commercially available 2-amino-5-bromo-3-methyl-pyridine (4.5 g, 24.1 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (5.03 g, 26.5 mmol). Obtained as an off-white solid (5.36 g, 88%). MS (ISP) 252.9 [(M+H)+]; mp 159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10](C4C=CC=CC=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[F:29]C1C=CC=C2C=1NC(=O)C2=O.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10]([F:29])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Product: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(F)cccc12
Yield: 10 %

Procedure:
This compound was synthesized according to the procedure described above for Compound 2, reacting 7-fluoroisatin (1.00 g, 6.06 mmol) with 3-(4-chlorophenyl)-2-oxopropyl acetate, Intermediate 2 (1.72 g, 7.57 mmol). The crude acid was purified as described above for Compound 3, then recrystallized from ethanol/benzene to give pure product as an off-white powder Compound 13 (0.206 g, 10% yield): 1H NMR (400 MHz, DMSO-D6) δ 4.34 (s, 2H) 7.37 (m, 5H) 7.55 (m, 1H) 8.34 (d, J=8.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>C(#N)C>[Br:1][C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: NCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Brc1cn2ccnc2c(NCc2ccncc2)n1
Temperature: 25 °C

Procedure:
A solution of 6,8-Dibromo-imidazo[1,2-a]pyrazine 3 (1.0 equiv.), 4-aminomethylpyridine (1.0 equiv.) and potassium carbonate (3.0 equiv.) is dissolved in 20 ml 3:1 acetonitrile: dimethylacetamide and is stirred at 100° C. for 16 hours. The mixture is cooled to RT and partitioned between ethyl acetate (EtOAc) and saturated NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-pyridin-4-ylmethyl-amine 4.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CC1CCNCC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperidine-1-carboxylate (0.0645 g, 0.131 mmol) in methylene chloride (3 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then added with saturated aqueous sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-7-(piperidin-4-ylmethyl)benzofuran-3(2H)-one (0.0395 g, 77%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Mg].[Cl-].[Mg+2].[Cl-].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].[Cl-].[NH4+]>O1CCCC1.[Cu]Br.O>[Cl:13][C:14]1[CH:15]=[C:16]([C:17](=[O:18])[CH2:2][CH2:3][CH:4]2[O:8][CH2:7][CH2:6][O:5]2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: BrCCC1OCCO1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCC1OCCO1)c1cccc(Cl)c1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (40 ml) was added dropwise within 15 minutes under argon and while stirring at a maximum 30° C. to a suspension of Rieke magnesium, prepared from 44.9 g of magnesium chloride, in 1500 ml of absolute tetrahydrofuran. The suspension was stirred at room temperature (about 23° C.) for 15 minutes, cooled to 0° C. and, after the addition of 43.5 g of copper(I) bromide, stirred at 5° C. for 15 minutes. After cooling to -70° C. 33 ml of 3-chlorobenzoyl chloride were added dropwise within 10 minutes. The reaction mixture was stirred at -70° C. for 15 minutes and at room temperature for 2 hours and subsequently hydrolyzed with 1000 ml of saturated ammonium chloride solution while cooling at a maximum 20° C. After the addition of 500 ml of water the mixture was extracted three times with 1000 ml of ethyl acetate each time. The combined organic extracts were washed with 1000 ml of saturated sodium chloride solution, dried over MgSO4 and freed from solvent. 59.2 g of oil were chromatographed on 1500 g of silica gel with ethyl acetate/hexane (1:3) as the eluent. 20.9 g (34%) of 3'-chloro-3-(1,3-dioxolan-2-yl)propiophenone were isolated as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:17][C:18]#[N:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:17][C:18]#[N:19])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N#CCCl
Reactant: Oc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCOc1cc(Br)cnc1Cl
Temperature: 80 °C
Yield: 60.9 %

Procedure:
A dry 10 mL, one neck round bottom flask was charged with 5-bromo-2-chloropyridin-3-ol (0.0518 g, 0.249 mmol), cesium carbonate (0.0972 g, 0.298 mmol), a stirbar and 2 mL dry DMF. The stirring slurry was treated with 2-chloroacetonitrile (0.0709 ml, 1.12 mmol) and fitted with an inert atmosphere inlet. The reaction was heated to 80° C. using an oil bath for 3 h, and cooled. The slurry was filtered through a 0.22 μm PTFE filter, and concentrated in vacuo. The residue was purified in one injection using a YMC pack diol-120-NP column (PN DN12S05-2520 wt, 250×20 mm, spherical particle, 5 μm particle size, 120 Å pore size, flow=20 mL/min: A=hexanes; B=THF; 15% B isocratic). A fraction that eluted from 10.0 to 11.8 minutes was isolated. The solvent was removed in vacuo to afford 2-(5-bromo-2-chloropyridin-3-yloxy)acetonitrile (0.0375 g, 61.0% yield). 1H NMR (300 MHz, chloroform-d) δ ppm 4.88 (s, 2H) 7.52 (d, J=1.97 Hz, 1H) 8.25 (d, J=1.97 Hz, 1H). 13C NMR (75 MHz, chloroform-d) δ ppm 54.71 (s, 1 C) 113.51 (s, 1 C) 118.90 (s, 1 C) 125.53 (s, 1 C) 140.63 (s, 1 C) 144.40 (s, 1 C) 148.93 (s, 1 C).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[Cl:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[Cl:29][C:30]1[CH:31]=[N:32][N:33]([C:6]2[CH:5]=[CH:4][C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)=[C:2]([F:1])[CH:7]=2)[CH:34]=1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: Clc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1cn(-c2ccc(-n3cc(Cl)cn3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 14.7 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (488 mg, 1.0 mmol), 4-chloro-1H-pyrazole (103 mg, 1.0 mmol), Cu2O (14.3 mg, 0.1 mmol), salicylaldoxime (54.9 mg, 0.4 mmol), and Cs2CO3 (652 mg, 2.0 mmol) in CH3CN (10 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography eluting with AcOEt followed by purification by preparative HPLC. Recrystallization from MeOH/H2O gave the title compound (68.1 mg, 15% yield) as a pale yellow powder: mp 190-192° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.92 (3H, s), 6.43 (1H, t, J=9.0 Hz), 7.23 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.35 (1H, d, J=1.9 Hz), 7.36-7.48 (5H, m), 7.57 (1H, dd, J=2.6, 12.4 Hz), 7.68 (1H, s), 7.79 (1H, d, J=1.9 Hz), 7.82 (1H, d, J=2.3 Hz), 7.92 (1H, d, J=0.8 Hz). LC-MS (ESI) m/z 463 [M+H]+. Anal. Calcd for C23H16ClFN6O2: C, 59.68; H, 3.48; N, 18.16. Found: C, 59.81; H, 3.50; N, 18.14.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:4][CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)[NH:4][CH2:3]1
Reactant: CC1CN=C(c2ccc(C(F)(F)F)cc2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CNC(c2ccc(C(F)(F)F)cc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A 100-mL round-bottomed flask was charged with 4-methyl-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (4.89 g, 16.9 mmol) and MeOH (30 mL). After cooling down to 0° C., sodium borohydride (1.93 g, 50.7 mmol) was added and the mixture was stirred at RT for 45 min. Then, the solvent was removed and the residue redissolved in EtOAc, washed with sat NaHCO3, water and dried over Na2SO4. The mixture was used crude in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:59]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]2[C:66]([O:92][CH3:93])=[CH:67][C:68]3[C:74](=[O:75])[N:73]4[CH:76]=[C:77](/[CH:79]=[CH:80]/[CH3:81])[CH2:78][C@H:72]4[C:71](=O)[N:70](COCC[Si](C)(C)C)[C:69]=3[CH:91]=2)=[CH:58][C:6]2[N:7](COCC[Si](C)(C)C)[C:8](=O)[C@@H:9]3[CH2:15][C:14](/[CH:16]=[CH:17]/[CH2:18][NH:19][C:20](=[O:48])[C@@H:21]([NH:23][C:24](=[O:47])[C@@H:25]([NH:29][C:30](=[O:46])[O:31][CH2:32][CH:33]4[C:45]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:39]5[C:34]4=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:26]([CH3:28])[CH3:27])[CH3:22])=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1.[Li+].[B-](CC)(CC)CC>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[C:59]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]2[C:66]([O:92][CH3:93])=[CH:67][C:68]3[C:74](=[O:75])[N:73]4[CH:76]=[C:77](/[CH:79]=[CH:80]/[CH3:81])[CH2:78][C@H:72]4[CH:71]=[N:70][C:69]=3[CH:91]=2)=[CH:58][C:6]2[N:7]=[CH:8][C@@H:9]3[CH2:15][C:14](/[CH:16]=[CH:17]/[CH2:18][NH:19][C:20](=[O:48])[C@@H:21]([NH:23][C:24](=[O:47])[C@@H:25]([NH:29][C:30](=[O:46])[O:31][CH2:32][CH:33]4[C:45]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:39]5[C:34]4=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:26]([CH3:28])[CH3:27])[CH3:22])=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC6c7ccccc7-c7ccccc76)C(C)C)C[C@H]4C(=O)N5COCC[Si](C)(C)C)cc3N(COCC[Si](C)(C)C)C(=O)[C@@H]2C1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC6c7ccccc7-c7ccccc76)C(C)C)C[C@H]4C=N5)cc3N=C[C@@H]2C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
SEM Fmoc amine 18c (0.212 g, 0.162 mmol, 1.0 eq.) was solubilised in THF (9.2 mL) and cooled to −78° C. under a nitrogen atmosphere. Super hydride solution (0.330 mL, 0.330 mmol, 2.04 eq.) was added drop wise over 4 minutes. After 45 minutes an aliquot was diluted with water and MeOH for LCMS After stirring for a further 10 mins, the reaction mixture was diluted with water (27 mL) and the cold bath removed. The organic layer was extracted with EtOAc (2×27 mL) and the combined organic extracts washed with brine (27 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was dissolved in MeOH (11.05 mL), DCM (5.53 mL) and water (1.85 mL) and enough silica gel was added to form a thick suspension which was left stirring for 5 days. The suspension was filtered and washed with DCM/MeOH 9:1 (−200 mL) until complete elution of product. The organic layer was washed with brine (2×70 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel; 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH) to afford the product as a yellow solid (0.060 g, 36%). LC/MS (2.802 min (ES+)), m/z: 1016.15 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:33]([F:36])([F:35])[F:34])=[N:10][C:11]2[C:16]([C:17]=1Cl)=[CH:15][C:14]([C:19]([C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH3:78][N:79](C)C(=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N.[Zn]>[CH2:1]([C:8]1[C:9]([C:33]([F:36])([F:35])[F:34])=[N:10][C:11]2[C:16]([C:17]=1[C:78]#[N:79])=[CH:15][C:14]([C:19]([OH:20])([C:27]1[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: Cn1cncc1C(O)(c1ccc2nc(C(F)(F)F)c(Cc3ccccc3)c(Cl)c2c1)c1ccccn1
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(O)(c1ccc2nc(C(F)(F)F)c(Cc3ccccc3)c(C#N)c2c1)c1ccccn1
Temperature: 120 °C

Procedure:
A pressure tube containing (3-benzyl-4-chloro-2-(trifluoromethyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol•TFA (86 mg, 0.12 mmol, Example 97), Pd2(dba)3 (10 mg, 0.011 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (X-Phos, 10 mg, 0.021 mmol), zinc cyanide (12 mg, 0.10 mmol) and zinc nanopowder (2.3 mg, 0.035 mmol) in N,N-dimethylacetamide (1 mL) was sparged with nitrogen for 8 minutes, and then heated at 120° C. for 2 hours. The mixture was allowed to cool to room temperature, EtOAc and saturated NH4Cl aqueous solution were added. The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 8.98 (s, 1H), 8.62 (d, J=4.04 Hz, 1H), 8.47 (d, J=2.02 Hz, 1H), 8.32 (d, J=9.09 Hz, 1H), 8.17 (dd, J=2.02, 9.09 Hz, 1H), 7.93 (dt, J=2.02, 7.58, 1H), 7.83 (d, J=8.08 Hz, 1H), 7.40-7.45 (m, 1H), 7.24-7.31 (m, 2H), 7.18-7.24 (m, 1H), 7.15 (d, J=1.52, 1H), 7.05 (d, J=7.58 Hz, 2H), 4.64 (s, 2H), 3.63 (s, 3H); MS m/e 500.3 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][OH:8].[CH:9]1([NH:12][C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=3)[CH:15]=2)[CH2:11][CH2:10]1>>[CH:9]1([NH:12][C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([NH:21][C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:8][CH2:7][C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:27][CH:28]=3)[CH:15]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: OCc1ncccn1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ncccn2)cc1
Yield: 58 %

Procedure:
The title compound was prepared from 2-pyrimidinemethanol and N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide according to the method used to prepared Example 8, to give the title compound as a solid (149 mg, 58%); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.67 (m, 2H), 2.24 (s, 3H), 2.84 (m, 1H), 5.37 (s, 2H), 7.09 (d, 2H), 7.31 (d, 1H), 7.47 (m, 1H), 7.61 (m, 1H), 7.78 (d, 1H), 7.93 (d, 2H), 8.35 (m, 1H), 8.83 (m, 2H), 9.80 (s, 1H); Mass Spectrum: M+H+ 403.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].[CH2:10](I)[CH2:11][CH2:12][CH3:13]>CN(C=O)C>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7])[CH2:11][CH2:12][CH3:13]
Reactant: O=C1CCCCN1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CCCCC1=O

Procedure:
2-Piperidinone is deprotonated with NaH in DMF solution and butylated with n-butyl iodide to give the title compound.