Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]3=[O:30])=[CH:19][C:18]=2[N:31]2[CH2:35][CH2:34][CH2:33][S:32]2(=[O:37])=[O:36])=[O:16])[CH2:11][CH2:10]1.[CH3:38]I>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C@H:27]([CH2:28][O:29][CH3:38])[CH2:26][O:25][C:24]3=[O:30])=[CH:19][C:18]=2[N:31]2[CH2:35][CH2:34][CH2:33][S:32]2(=[O:36])=[O:37])=[O:16])[CH2:13][CH2:14]1
Reactant: CI
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 69.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-3-(1,1-dioxoisothiazolidin-2-yl)phenyl}-4-hydroxymethyloxazolidin-2-one (687 mg) described in Example 332 and methyl iodide (221 mg), the title compound (488 mg) was obtained.
Reaction SMILES: [CH2:1]([Sn:5]([Cl:8])([Cl:7])[Cl:6])[CH2:2][CH2:3][CH3:4].[Na].[F:10][C:11]([F:16])([F:15])[C:12]([OH:14])=[O:13]>>[F:10][C:11]([F:16])([F:15])[C:12]([O-:14])=[O:13].[CH2:1]([Sn+:5]([Cl:7])[Cl:6])[CH2:2][CH2:3][CH3:4].[CH2:1]([Sn:5]([Cl:8])([Cl:7])[Cl:6])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Agent: CCCC[Sn](Cl)(Cl)Cl
Agent: [Na]
Product: CCCC[Sn+](Cl)Cl
Product: O=C([O-])C(F)(F)F
Reaction time: 8 h

Procedure:
A reaction mixture of monobutyltin trichloride (200 g., 0.7 moles) and the sodium salt of trifluoroacetic acid (10 g., 0.07 moles) were heated at 70° C. for 3 hours and allowed to stand overnight at room temperature. The sodium chloride by-product and unreacted sodium salt were filtered. A liquid coating composition of about 12 wt.% monobutyldichlorotin trifluoroacetate and 88 wt% monobutyltin trichloride was produced in situ.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.[CH3:13][N:14](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:15].[B-](F)(F)(F)F.Cl.CNC.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:13][N:14]([CH3:15])[C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1nn(C)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (500 mg, 2.92 mmol) in DMF (5 ml) under inert gas atmosphere was treated with TBTU (1030 mg, 3.2 mmol), dimethylamine hydrochloride (262 mg, 3.2 mmol) and N,N-diisopropylethylamine (2.0 ml, 11.7 mmol) and stirring was continued for 4 h. All volatiles were removed and the crude product was extracted with water and ethyl acetate. The organic phase was washed with sodium bicarbonate and the aqueous phases were back-extracted with ethyl acetate and dichloromethane. The combined organic phases were dried and the solvent was evaporated. The product was obtained after purification by silica gel chromatography using a dichloromethane/methanol gradient as white solid (230 mg, 40%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20](B(O)O)[CH:21]=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>[CH3:7][O:6][C:4]([C:3]1[C:2]([C:18]2[CH:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])=[CH:11][CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=1)=[O:5]
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(Cl)ccc1OC
Yield: 55 %

Procedure:
This compound was prepared in a manner similar to that of methyl-(5′-fluoro-2′-methoxy-4-nitro-2-biphenyl)carboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (1.25 g, 4.8 mmol, 1.0 equivuiv), tetrakis(triphenylphosphine)palladium (Aldrich: 0.16 g, 0.14 mmol, 2.9 mol %), and 5-chloro-2-methoxyphenylboronic acid (1.30 g, 6.9 mmol, 1.5 equivuiv) to afford 0.85 g (55%) of methyl-5′-chloro-2′-methoxy-4-nitro-2-biphenylcarboxylate as a yellow-orange solid. Data for methyl-5′-chloro-2′-methoxy-4-nitro-2-biphenylcarboxylate: 1H NMR (400 MHz, CDCl3): 8.73 (d, J=2.4, 1H); 8.38 (dd, J=8.5, 2.5, 1H); 7.49 (d, J=8.5, 1H); 7.36 (dd, J=8.7, 2.5, 1H); 7.23 (d, J=2.5, 1H); 6.85 (d, J=8.7, 1H); 3.76 (s, 3H); 3.70 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:12][CH2:11][CH2:10][O:5]1
Reactant: O=Cc1ccccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccccc1C1OCCO1
Yield: 98.6 %

Procedure:
A mixture of 2-bromobenzaldehyde (100 g; 0.54 mol), ethylene glycol (67.03 g; 1.08 mol), p-toluenesulphonic acid (0.5 g) and toluene was heated to and maintained at reflux temperature for 6 hours. During this period, water/ethylene glycol (23 ml) was removed by azeotropic distillation. The mixture was cooled and ether (1 l) was added. The ether solution was washed with saturated sodium bicarbonate solution (200 ml) water (3×150 ml) and saturated brine (1×150 ml). After drying and filtration, evaporation of the ether solution gave 2-(2-bromophenyl)-1,3-dioxolane (121.96 g, 98.6% yield) as an oil.
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14]CC)[O:11][CH2:12]C)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2].[C:17]1([CH3:27])[C:18](S(O)(=O)=O)=CC=C[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([N:4]([CH2:9][CH:10]1[O:14][CH2:22][C:17]([CH3:18])([CH3:27])[CH2:12][O:11]1)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(CC1OCC(C)(C)CO1)C(=O)CCl

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), 2,2-dimethylpropandiol-1,3 (4.1 grams) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-isopropyl-N-(5,5-dimethyl-1,3-dioxan-2-ylmethyl)-α-chloroacetamide having a boiling point of 175° C. at 1 mm of Hg pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH3:11])[CH:5]=1.[C:13](=[O:16])(O)[O-].[Na+].[CH2:18](Cl)[CH:19]=C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][C:13](=[O:16])[CH:18]=[CH2:19])[CH:5]=1
Reactant: C=CCCl
Reactant: O=C([O-])O
Reactant: CNc1cccc(C(=O)OC)c1
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)CNc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred mixture of 3-methylaminobenzoic acid methyl ester (3.11 g, 18.8 mmol) and sodium bicarbonate (3.16 g, 37.6 mmol) in DCM (20.0 mL) at 0° C. was added 2-propenyl chloride (2.29 mL, 28.2 mmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.12 g, 100% yield), which was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:20][CH2:19][S:18][C:17]([NH:21]C(=O)C4C=CC([N+]([O-])=O)=CC=4)=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:33])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:20][CH2:19][S:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:33])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(NC1=NC2(CCS1)c1cc(I)ccc1Oc1ncc(Br)cc12)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC1=NC2(CCS1)c1cc(I)ccc1Oc1ncc(Br)cc12

Procedure:
A suspension of N-(3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]thiazin]-2′-yl)-4-nitrobenzamide (0.906 g, 1.422 mmol) and lithium hydroxide hydrate (0.179 g, 4.27 mmol) in MeOH (28.4 ml) was heated to reflux for 3 hours. The solvent was removed under reduced pressure to afford 3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]thiazin]-2′-amine as a pink solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][CH:12]=O.C[Si]([C:18]#[N:19])(C)C.[NH3:20]>C(Cl)Cl.CO.[Zn+2].[I-].[I-]>[NH2:20][CH:12]([CH2:11][C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:18]#[N:19]
Reactant: O=CCC1=Cc2ccccc2CC1
Reactant: N
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CO
Solvent: ClCCl
Product: N#CC(N)CC1=Cc2ccccc2CC1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a solution of 3.44 g (20 mmol) of the aldehyde obtained in Step 2 in 100 ml of CH2Cl2 there are added, in succession, at 20° C., 0.25 g of ZnI2 and then, slowly, 2.18 g (22 mmol) of trimethylsilyl cyanide. After stirring for 20 hours at 20° C., the mixture is concentrated in vacuo. The residue obtained is treated with 200 ml of a solution of NH3 in CH3OH (7N); the mixture is stirred for 4 hours in a stoppered receptacle and then concentrated in vacuo. The residue is taken up in 1N HCl and the suspension is washed with 50 ml of Et2O; the aqueous phase is rendered alkaline with 6N NaOH and extracted with CH2Cl2 (3×50 ml). The combined organic phases are washed with saturated NaCl solution, dried and concentrated to yield the expected compound in the form of an oil, which is used directly for the following reaction.
Reaction SMILES: O=[C:2]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].Cl.[NH2:13][OH:14]>C(O)C>[N:9]1[CH:10]=[CH:11][C:6]([C:2]2[CH:3]=[C:4]([NH2:5])[O:14][N:13]=2)=[CH:7][CH:8]=1
Reactant: N#CCC(=O)c1ccncc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Nc1cc(-c2ccncc2)no1
Temperature: 70 °C
Yield: 68.9 %

Procedure:
To 3-oxo-3-pyridin-4-yl-propionitrile (2.0 g, 13.7 mmol) in 20 mL of ethanol was added hydroxylamine hydrochloride (0.75 g, 10.8 mmol) and the resulting solution was heated at 70° C. overnight. The resulting white precipitate was collected and the solution was concentrated and dried in vacuum to afford the title compound (1.2 g, 54%) as a yellow solid. FIA MS: MH+162.2, M−160.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:11][C:12](N)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]=O.[BH3-][C:36]#[N:37].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:11][C:12]([N:37]([CH3:36])[CH3:33])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: CCCCCCCCCCCCCCCCc1nc(N)nc(C)c1OCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCc1nc(N(C)C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 230 mg (0.52 mmol) of 5-(benzyloxy)-4-hexadecyl-6-methylpyrimidin-2-amine in 4 mL of methanol were added 4 mL of 35% aq. formaldehyde followed by 263 mg (4.18 mmol) of NaCNBH3. The reaction mixture was stirred at 23° C. for 3 h. The reaction mixture was quenched with acetic acid until bubbling ceased then poured into 20 mL of water and extracted with two 40-mL portions of ethyl acetate. The combined organic layer was washed with one 40-mL portion of saturated aq. NaHCO3 and one 40-mL portion of brine. The organic solution was dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (8×3 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as colorless oil: yield 100 mg (41%); silica gel TLC Rf 0.75 (4:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 0.86 (t, 3H, J=6.8 Hz), 1.23-1.28 (br m, 26H), 1.68 (quint, 2H, J=6.8 Hz), 2.31 (s, 3H), 2.61 (dd, 2H, J=7.6, 7.6 Hz), 3.14 (s, 6H), 4.69 (s, 2H) and 7.40-7.46 (m, 5H); 13C NMR (CDCl3) δ 14.05, 19.29, 22.64, 27.72, 27.84, 29.31, 29.50, 29.55, 29.62, 29.64, 29.64, 29.64, 29.66, 29.66, 29.66, 31.59, 31.70, 31.89, 37.21, 37.21, 75.67, 127.90, 128.16, 128.16, 128.54, 128.54, 137.17, 141.27, 158.60, 159.01 and 163.62; mass spectrum (APCI), m/z 468.3950 (M+H)+ (C30H50N3O requires 468.3954).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:18][CH:17]([C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)=[O:20])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@H](O)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CNC1)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of 3-((S)-3-hydroxypyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester (460 mg, 1.7 mmol) in dichloromethane (12 mL) The resulting reaction mixture was stirred at RT for 2 h. The solvents were reduced in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM to afford Azetidin-3-yl-((S)-3-hydroxypyrrolidin-1-yl)methanone as colourless oil (243 mg, 84%). 1H NMR (400 MHz, DMSO, d6): δ 4.28-4.18 (1 H, m), 3.72-3.17 (10 H, m), 2.11-2.10 (1 H, m), 1.81-1.80 (2 H, m)
Reaction SMILES: [CH2:1]([N:3]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:4]1[C:5]([CH3:26])=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][C:68]1[C:69](=[O:77])[NH:70][C:71]([CH3:76])=[C:72]([F:75])[C:73]=1[CH3:74]>CN(C=O)C>[CH2:1]([N:3]([CH:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[C:4]1[C:5]([CH3:26])=[C:6]([C:7]([NH:66][CH2:67][C:68]2[C:69](=[O:77])[NH:70][C:71]([CH3:76])=[C:72]([F:75])[C:73]=2[CH3:74])=[O:9])[CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:17][CH:18]=2)[CH:12]=1)[CH3:2]
Reactant: Cc1[nH]c(=O)c(CN)c(C)c1F
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)O)c1C)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)c(F)c(C)[nH]c2=O)c1C)C1CCOCC1
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
A stirred solution of 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzoic acid (100 mg, 0.22 mmol) in anhydrous DMF (4.0 ml) at 0° C. under a balloon of nitrogen, was treated with HATU (99 mg, 0.26 mmol) and DIPEA (75 μl, 0.43 mmol) dropwise. The resulting solution was stirred for 10 minutes and then treated with 3-(aminomethyl)-5-fluoro-4,6-dimethyl-1,2-dihydropyridin-2-one (50%, 81 mg, 0.24 mmol). The resulting suspension was stirred at 0° C. for 30 minutes and then stirred at room temperature for 18 hours. The reaction mixture was partitioned between water (20 ml) and CH2Cl2 (15 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×15 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (40 ml), water (2×25 ml), brine (20 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-6% MeOH/CH2Cl2) and then dissolved in a mixture of EtOAc (40 ml) and CH2Cl2 (10 ml), and washed with water (6×30 ml), brine (2×30 ml), dried (MgSO4), filtered and concentrated in-vacuo. The solid was thoroughly dried in-vacuo at 40° C. for 40 hours to give 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((5-fluoro-4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide (93 mg, 73%) as a powdery white solid. LC-MS 100%, 2.76 min (7 minute LC-MS method), m/z=591.2; 1H NMR (500 MHz, Chloroform-d) δ 11.79 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.4 Hz, 3H), 7.08 (t, J=6.0 Hz, 1H), 4.56 (d, J=6.0 Hz, 2H), 3.95 (d, J=11.2 Hz, 2H), 3.76-3.66 (m, 4H), 3.51 (s, 2H), 3.31 (td, J=11.3, 2.7 Hz, 2H), 3.10 (q, J=7.0 Hz, 2H), 3.00 (tt, J=9.6, 4.6 Hz, 1H), 2.45 (s, 4H), 2.43 (d, J=1.8 Hz, 3H), 2.34 (s, 3H), 2.13 (d, J=2.7 Hz, 3H), 1.74-1.62 (m, 4H), 0.89 (t, J=7.0 Hz, 3H). One proton assumed to be coincident with a solvent peak.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14](O)[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:32])CC>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14]([F:32])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CCC1F
Temperature: 25 °C

Procedure:
To a solution of (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) in dichloromethane (0.3 M solution) was added DAST at −78° C. The reaction mixture was slowly warmed up to room temperature for 15 h. After quenched with saturated sodium bicarbonate aqueous solution, ethyl acetate and water were added for work-up. The (+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-fluoropiperidine-1-carboxylate was obtained by silica column chromatography (30% EtOAc in hexanes, 40%). LCMS (m/z): 253.1[(M-Boc)H+]; LC Rt=4.08 min. The enantiomerically pure (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-fluoropiperidine-1-carboxylate and (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-fluoropiperidine-1-carboxylate were resolved by chiral HPLC (for analysis: Rt=9.4 min and 12.6 min respectively; n-heptane:isopropanol=90:10 (v:v), Chiralpak AS 250×4.6 mm at 1 mL/min. For preparative separation, n-heptane:isopropanol=90:10 (v:v), Chiralpak AS 50×500 mm. at 90 mL/min)
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>O.CN(C=O)C>[OH:1][C:2]1[C:3]([C:12]([NH:24][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:26][CH:25]=2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc([N+](=O)[O-])cc1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
8-Hydroxyquinoline-7-carboxylic acid (0.51 g) of Preparation 1 is added to 20 mL DMF. 4-Nitrobenzylamine hydrochloride (0.53 g) followed by diisopropylethylamine (0.49 mL) is then added. After 10 minutes, all solids go into solution. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g) and 1-hydroxybenzotriazole monohydrate (0.38 g) are added and the reaction stirred at room temperature overnight. The reaction is poured into 75 mL H2O. The resulting solid is filtered and dried to give the title product (0.53 g).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Cl:24])(=O)C>S(Cl)(Cl)=O>[ClH:24].[Cl:24][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccn1
Reactant: CC(=O)Cl
Solvent: O=S(Cl)Cl
Product: Cl
Product: ClC(c1ccccc1)(c1ccccc1)c1ccccn1
Temperature: 50 °C

Procedure:
To a mixture of diphenyl(pyridin-2-yl)methanol (4 g, 0.015 mol) in thionylchloride (50 mL) was added acetylchloride (15 mL, 0.195 mol) at RT and heated to 50° C. for 48 h. The reaction mixture was concentrated under vacuum and the residue was azeotroped with dry benzene (100 mL×2) to give the title compound as the hydrochloride salt (4.4 g, >95%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][C:26]3[C:27]([CH:31]=1)=[N:28][O:29][N:30]=3)=[CH:8]2)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[N:30]1[O:29][N:28]=[C:27]2[CH:31]=[C:23]([C:9]3[C:10](=[O:22])[N:11]([CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:12]4[C:7]([CH:8]=3)=[C:6]([OH:32])[C:5]([C:3]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])=[N:14][CH:13]=4)[CH:24]=[CH:25][C:26]=12
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc4nonc4c3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccc4nonc4c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
A mixture of 3-benzo[1,2,5]oxadiazol-5-yl-1-benzyl-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (33 mg, 0.077 mmol), β-alanine (687 mg, 7.7 mmol) and NaOMe solution (12 mL, 6.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After stirring the mixture for another 24 h at r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as a brown solid. MS: (+) m/z 486.26 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][O:25][C:21](=[O:24])[CH:22]=[CH:23][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:10]=2)[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cccc(Sc2cccc(-c3ccccc3)n2)c1
Reaction time: 0.33 h

Procedure:
Crude aryl bromide (14) (100 mg, 0.18 mmol), methyl acrylate (18 mg, 0.21 mmol), triethylamine (71 mg, 0.70 mmol), tri(o-toly)phosphine (5 mg, 0.016 mmol) and palladium(II) acetate (12 mg, 0.054 mmol) in acetonitrile (2 mL) was heated in a CEM Discover microwave for 45 minutes at 90° C. More tri(o-toly)phosphine (3 mg) and palladium(II) acetate (3 mg) were added and the reaction mixture retreated in the microwave for 20 minutes; palladium(II) acetate (2 mg) was then added and the process repeated for a further 25 minutes. The solvent was removed under a stream of nitrogen gas, water was added, and the organics extracted with EtOAc, washed with water, dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was partially purified by column chromatography. Yield: 51 mg, 60%; LC-MS tr 1.82 min; HPLC Purity: 70%; MS (ES+) m/z 348 (M+H)