Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]1[C:22]2[NH:21][C:20](=[O:23])[CH2:19][O:18][C:17]=2[C:16]([C:24](=[O:27])[CH2:25]Cl)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C>[N:1]([CH2:25][C:24]([C:16]1[C:17]2[O:18][CH2:19][C:20](=[O:23])[NH:21][C:22]=2[C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:15]=1)=[O:27])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1COc2c(C(=O)CCl)ccc(OCc3ccccc3)c2N1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Reaction time: 2 h

Procedure:
Sodium azide (1.176 g) was added to a suspension of 5-(benzyloxy)-8-(2-chloroacetyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (example 11, step e) (4.8 g) in DMF (50 mL) and stirred for 2 h. The mixture was poured onto ice/water and the resulting solid collected by filtration, washed with water and dried under vacuum at 40° C. to afford the subtitled compound as a light brown solid. Yield 4.6 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:30])=[N+:11]([O-])[C:12]([CH:15]([O:25][C:26](=[O:28])[CH3:27])[CH2:16][N:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18](=[O:20])[CH3:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[C:26]([O:28][CH2:30][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=[C:12]([CH:15]([O:25][C:26](=[O:28])[CH3:27])[CH2:16][N:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18](=[O:20])[CH3:19])[N:11]=1)(=[O:25])[CH3:27]
Reactant: CC(=O)OC(CN(C(C)=O)C(C)(C)C)c1ccc(OCc2ccccc2)c(C)[n+]1[O-]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1nc(C(CN(C(C)=O)C(C)(C)C)OC(C)=O)ccc1OCc1ccccc1

Procedure:
3-Benzyloxy-2-methyl-6-[1-acetoxy-2-(N-tert-butylacetamido)ethyl]pyridine N-oxide is heated in acetic anhydride according to the method of Example 21 to produce 2-acetoxymethyl-3-benzyloxy-6-[1-acetoxy-2-(N-tert-butylacetamido)ethyl]pyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[C:9](=[O:16])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:10].C([O-])([O-])=O.[K+].[K+].CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[C:12]([O:11][C:9]([NH:10][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: Clc1ccc(Br)cc1
Reactant: CC(C)(C)OC(N)=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 78.2 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), 4-bromo-1-chlorobenzene (192 mg, 1.00 mmol), tert-butyl carbamate (142 mg, 1.21 mmol), K2CO3 (280 mg, 2.03 mmol), briefly evacuated and backfilled with argon. N,N′-Dimethylethylenediamine (11 μL, 0.10 mmol, 10 mol %) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting pale blue suspension was allowed to reach room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with ethyl acetate (10 mL). The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 9:1; 15 mL fractions). Fractions 12-22 provided 178 mg (78% yield) of the product as white crystals.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=2)[C@H:7]([NH2:24])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.O>ClCCl.C([O-])(O)=O.[Na+].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)c1
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2ccc3c(c2)[C@H](Nc2cccnc2)C[C@H](C)N3C(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.45 %

Procedure:
To a stirred solution of methyl 3-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (for a preparation see Intermediate 98) (50.0 mg, 0.148 mmol) in dichloromethane (DCM) (2 mL) were added triethyalamine (0.062 mL, 0.443 mmol) and copper (II) acetate (40.2 mg, 0.221 mmol) followed after 10 min by 3-pyridinylboronic acid (36.7 mg, 0.299 mmol). The resulting mixture was stirred at room temperature for 3 h. Further 3-pyridinylboronic acid (9.2 mg, 0.075 mmol) was added and the mixture was stirred at room temperature for a further 6 days after which time the solvent had evaporated in vacuo. After standing for 19 days, further dichloromethane (DCM) (2 mL) was added followed by further 3-pyridinylboronic acid (18.8 mg, 0.153 mmol) and copper (II) acetate (45.0 mg, 0.248 mmol). The mixture was stirred at room temperature for a further 24 h, then left to stand for 36 h before further triethyalamine (0.062 mL, 0.443 mmol) and 3-pyridinylboronic acid (18.2 mg, 0.148 mmol) were added. The mixture was stirred at room temperature for a further 6 hours before additional 3-pyridinylboronic acid (18.5 mg, 0.151 mmol) was added. After stirring for a further 65 h a 3:1 mixture of water/0.880 ammonia (1 mL) was added and the mixture was stirred for 15 min then was diluted with a saturated NaHCO3 aqueous solution (6 mL). The aqueous phase was extracted with dichloromethane (3×6 mL). The combined organic phases were dried using a phase separator and the solvent was evaporated under a stream of nitrogen. Purification of the residue by MDAP (modifier: ammonium bicarbonate) gave methyl 3-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (10.1 mg, 0.024 mmol, 16.45% yield) as a clear gum.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:48][CH:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.C(Cl)Cl.C(OCC)C.CO>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:53][CH2:54][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:56][CH2:57]3)=[CH:48][CH:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CCN(C4COC4)CC3)cc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCN(C5COC5)CC4)cc3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 130 °C
Yield: 61.4 %

Procedure:
Following Example 121b, 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (217 mg, 0.45 mmol), 214b (158 mg, 0.375 mmol), 1M sodium carbonate solution (1.5 mL, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol) and 1,2-dimethoxyethane (3.5 mL) were heated at 130° C. for 15 minutes in the microwave reactor. Work-up and flash column chromatography (silica, 60:35:5 methylene chloride/diethyl ether/methanol) give a 62% yield (160 mg) of 214c as brown oil: MS (ESI+) m/z 696.1 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCN(C)C)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: CN(C)CCOc1cccc2cc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)oc12
Agent: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: CN(C)CCOc1cccc2cc(C(=O)Nc3ccccc3N)oc12

Procedure:
was prepared from (2-{[7-(2-Dimethylamino-ethoxy)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (16) in an analogous manner to that described for the preparation of (1) example 1, step 5; white solid, mp. 108–118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:14][C:15](C)([O-])[CH3:16].[K+].BrC(C)C.O>CS(C)=O.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH:15]([CH3:16])[CH3:14])[CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)cc1OC(C)C
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
A solution of 10.0 g (54.9 mmol) methyl 4-methoxysalicylate in 35 ml of dimethyl sulfoxide is treated dropwise with 7.4 g (65.9 mmol) of potassium t-butoxide in 75 ml of dimethylsulfoxide. The resulting pale yellow solution is stirred at 25° C. under nitrogen for 70 minutes. Then 19.7 g (159.8 mmol) of 2-bromopropane is added and the resulting mixture is stirred at 25° C. for 70 hours. The reaction mixture is poured onto 400 ml of H2O and the resulting solution is extracted with diethyl ether (3×125 ml). The combined extracts are washed with aqueous saturated NaCl, dried (Na2SO4) and concentrated in vacuo to give 8.5 g of the crude product as a yellow oil. Flash chromatography (SiO2, 18×65 cm, 15% ethyl acetate-hexane) gives 7.45 g (12.31 g theoretical, 61%) of analytically pure methyl 4-methoxy-2-(1-methylethoxy)benzoate as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][C@@H:8]1[CH2:16][N:15]2[C@H:10]([CH2:11][C:12](=O)[CH2:13][C:14]2=[O:17])[CH2:9]1>C(O)C>[CH3:6][O:7][C@@H:8]1[CH2:16][N:15]2[C@@H:10]([CH2:11][C:12]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:13][C:14]2=[O:17])[CH2:9]1
Reactant: C1CCNC1
Reactant: CO[C@H]1C[C@H]2CC(=O)CC(=O)N2C1
Solvent: CCO
Product: CO[C@H]1C[C@@H]2CC(N3CCCC3)=CC(=O)N2C1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
3.07 ml (36.8 mmol) of pyrrolidine were added to a solution of 3.38 g (18.4 mmol) of (2S,8aS)-2-methoxy-1,2,3,5,6,7,8,8a-octahydroindolizine-5,7-dione [obtained as described in Preparative Example 10(iii)′ above] in 34 ml of ethanol, and the resulting mixture was left to stand for 30 minutes at room temperature. At the end of this time, the solvent and any excess pyrrolidine were distilled off under reduced pressure to afford 4.26 g (yield: 98%) of the title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[CH2:13][N:14]([CH2:16][CH3:17])[CH3:15])[CH2:7][CH2:6][CH2:5]2>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]([CH2:16][CH3:17])[CH3:15])[CH2:7][CH2:6][CH2:5]2
Reactant: CCN(C)CC(=O)N1CCCc2cc(Br)ccc21
Solvent: C1CCOC1
Solvent: CO
Product: CCN(C)CCN1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.9 %

Procedure:
A solution of 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-(ethyl(methyl)amino)ethanone (1.05 g, 3.37 mmol) in THF (10 mL) was cooled to 0° C. then treated with BH3 in THF (1M) (33.7 mL, 33.7 mmol). The clear solution was allowed to warm to room temperature and stirred at this temperature for 3 days. The mixture was cooled to 0° C. and treated with methanol (5 mL) dropwise with caution. After stirring for 15 minutes, the mixture was concentrated to dryness then dissolved in methanol (25 mL) and concentrated again. The residue was dissolved in 25 mL methanol and heated at reflux for 5 hours then stirred at room temperature overnight. The reaction was concentrated to dryness to give a light yellow residue. This residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/95% CH2Cl2 to give a colourless residue (0.89 g, 89%). 1H-NMR (CDCl3) δ 7.09 (dd, J=1.8, 6.6 Hz, 1H), 7.02-7.01 (m, 1H), 6.44 (d, J=6.6 Hz, 1H), 3.36 (t, J=5.7 Hz, 2H), 3.29 (t, J=4.2 Hz, 2H), 2.70 (t, J=4.8 Hz, 2H), 2.53-2.43 (m, 4H), 2.28 (s, 3H), 1.94-1.88 (m, 2H), 1.06 (t, J=5.4 Hz, 3H). MS (ESI): 397.1 and 399.1 (M+1, 100%).
Reaction SMILES: [C:1]([C:3]1(C(O)=O)[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:4]1([CH3:13])[CH3:12])#[N:2].[Li+].[Cl-].C([O-])(O)=O.[Na+].O>CS(C)=O.[Cl-].[Na+].O>[CH3:12][C:4]1([CH3:13])[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]1[C:1]#[N:2]
Reactant: CC1(C)C(c2ccccc2)C1(C#N)C(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(C#N)C1c1ccccc1
Yield: 72.2 %

Procedure:
To a solution of 1-cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid (13.6 g, 63 mmol) in DMSO (125 mL) was added LiCl (10.72 g, 252 mmol) followed by NaHCO3 (7.96 g, 94.5 mmol) and water (4.55 g, 252 mmol). Gas evolution was observed, and within 30 minutes enough solids were dissolved to allow the milky mixture to stir. The reaction mixture was stirred at 170° C. for 18 hours, then cooled and poured into a mixture of water and brine (7/1, 800 mL) and extracted with ethyl ether. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to give 7.79 g (76% yield) of 2,2-dimethyl-3-phenyl-cyclopropanecarbonitrile (3/1, cis/trans mixture).
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:13](O)=O)([CH2:5]3)[CH2:3]1)[CH2:9]2.CS(Cl)(=O)=O.[NH3:21].Cl>N1C=CC=CC=1>[CH3:1][C:2]12[CH2:12][CH:6]3[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:13]#[N:21])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: N
Reactant: CC12CC3CC(C)(C1)CC(C(=O)O)(C3)C2
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC12CC3CC(C)(C1)CC(C#N)(C3)C2
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A solution of 3,5-dimethyl-1-adamantanecarboxylic acid (2.51 g, 12.1 mmol) in dry pyridine (40 mL) at 0° C. was treated dropwise with methanesulphonyl chloride (1.4 g, 12.2 nmmol), stirred for 2 h, saturated with ammonia gas, stirred for 5 min and the excess ammonia removed in vacuo. The resulting suspension at 0° C. was treated with methanesulphonyl chloride (11.8 g, 102 mmol), stirred overnight at room temperature, poured into cold 1-M HCl (200 mL) and extracted with EtOAc (3×40 mL). The organic phase was washed with dilute HCl (50 mL), water (50 mL), dried (MgSO4), concentrated in vacuo and the residue purified by chromatography [SiO2; CH2Cl2] to give the product (1.97 g, 86%) as a pale brown oil: IR νmax (liquid film)/cm−1 2922, 2849, 2235, 1455, 1359 and 1098; NMR δH (400 MHz, CDCl3) 0.87 (6H, s), 1.19 (2H, s), 1.3-1.45 (4H, m), 1.55-1.75 (4H, m), 1.8-1.9 (2H, m) and 2.1-2.15 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10](N)[CH:11]=[N:12][C:13]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[Br:17]C1C=C(N)C=NC=1OC.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:17][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[N:12][CH:11]=1
Reactant: COc1ncc(N)cc1Br
Reactant: COc1ncc(N)cc1-c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ncc(Br)cc1-c1cccc(Cl)c1
Temperature: 110 °C
Yield: 84 %

Procedure:
5-(3-Chlorophenyl)-6-methoxypyridin-3-amine. A 10 mL microwave vial was charged with 5-bromo-6-methoxypyridin-3-amine (2.00 g, 10 mmol) (3-chlorophenyl)boronic acid (1.87 g, 12 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride DCM complex (365 mg, 0.45 mmol), ACN (6 mL) and saturated aq. sodium bicarbonate (3 mL). The vial was sealed, purged with nitrogen and heated at 110° C. for 15 min. The layers were separated and the aq. phase extracted with EtOAc. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-50%, EtOAc/hexanes) afforded the title compound (1.95 g, 84%) which was taken on directly to the next step.
Reaction SMILES: [NH2:1]/[C:2](=[N:8]\[O:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]>N1C=CC=CC=1>[F:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[CH2:11][C:10]1[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:1]=1
Reactant: CCOC(=O)/C(N)=N/OC(=O)Cc1cc(F)ccc1F
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(Cc2cc(F)ccc2F)n1
Temperature: 120 °C
Yield: 70.6 %

Procedure:
(Z)-ethyl 2-amino-2-(2-(2,5-difluorophenyl)acetoxyimino)acetate (0.455 g; 1.59 mmol) was dissolved in pyridine (10 mL). The solution was heated at 120° C. for 2 h and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent: 0 to 20% of ethyl acetate in dichloromethane) to give 0.301 g (71%) of ethyl 5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:39][CH3:40]>C(#N)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:39][CH3:40])[CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=3)[CH:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)N1CCC(NCc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCC(N(CC)Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(ethoxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methylamino]piperidine (400 mg) in acetonitrile (5 mL) was added potassium carbonate (13 mg) and iodoethane (145 mg). The mixture was placed in sealed vessel and stirred at 80° C. for 2 hours. After removing the solvent in vacuo, ethyl acetate was added, washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was subjected to a column of silica gel using chloroform-methanol (30:1) as an eluent. Fractions containing the product were collected and evaporated to give the title compound as yellow syrup.
Reaction SMILES: [C:1]([C@H:4]([N:6]1[C:11](=[O:12])[C@@H:10]([NH2:13])[C@@H:9]([OH:14])[CH2:8][O:7]1)[CH3:5])([OH:3])=[O:2].C([O-])(O)=O.[Na+].[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC#N>O>[C:1]([C@H:4]([N:6]1[C:11](=[O:12])[C@@H:10]([NH:13][C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:9]([OH:14])[CH2:8][O:7]1)[CH3:5])([OH:3])=[O:2]
Reactant: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](N)C1=O
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: 5 °C
Yield: 91.1 %

Procedure:
To a solution of the amino acid 13 (0.290 g, 1.36 mmol) and NaHCO3 (0.343 g, 4.08 mmol) in water (7 mL), a solution of phenylacetyl chloride (0.191 g, 1.24 mmol) in abs. MeCN (3 mL) was added dropwise with cooling (−5˜−6° C.) and stirring. The reaction mixture was stirred for 2 h at 0˜−2° C. and for 1 hour at room temperature and was concentrated in vacuo to a volume of circa 5 mL. The solution was cooled to ca. 5° C. and adjusted to pH 2-3 with 1M aqueous HCl. (2.8 mL). The white precipitate was filtered off, washed with water and dried in vacuo to afford 0.364 g (91%) of the product 14 as a white solid with mp 194-195° C. (decomp.) (from iso-PrOH). 1H NMR (400 MHz) in CD3OD (J, Hz): δ 1.47 (3H, d, 3J=7.3, α-MeCH), 3.62 (1H, d, 2J=−14.8, CHAPh), 3.67 (1H, d, 2J=−14.8, CHBPh), 4.06 (1H, dd, 2J=−11.4, 3J=3.7, 6-HA), 4.12-4.06 (1H, m, 5-H), 4.33 (1H, dd, 2J=−11.4, 3J=5.6, 6-HB), 4.66 (1H, d, 3J=8.0, 4-H), 4.96 (1H, q, 3J=7.3, α-CH), 7.38-7.17 (5H, m, Ph). 13C (100 MHz) in CD3OD: δ 1371, 43.63, 55.70, 57.54, 71.84, 79.10, 127.85, 129.51, 130.37, 136.63, 169.61, 172.71, 174.89. IR (KBr), cm−1: 3361, 2913, 1729, 1666, 1630, 1542, 1440, 1233. MS (CI, isobutane), m/Z: 323 (M++1). Anal. Calcd for C15H18N2O6: C, 55.9; H, 5.6; N, 8.7. Found: C, 55.7; H, 5.7; N, 8.6%.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7].[CH2:26]([OH:29])[CH2:27][CH3:28].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([O:29][CH2:26][CH2:27][CH3:28])=[O:7]
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F)C(=O)Cl
Reactant: CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
2-[2-Fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionyl chloride (0.9 g; 2.3 mmole) was dissolved in dry dichloromethane and the solution was added slowly with stirring to a cooled mixture of n-propanol (5 ml) and triethylamine (1 ml). The mixture was stirred at room temperature for a period of 4 hours and then the solvent was evaporated under vacuum and the residue was dissolved in dichloromethane. The solution was washed with water and the organic phase was dried over magnesium sulfate. The solution was filtered and the solvent was removed under vacuum to give a light brown oil (0.92 g; 95.3%). The product was crystallised from ethanol to give the title compound as a crystalline solid (0.58 g; 60.4%); mp 70°-72° C. The assigned structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:12][C:13]([CH:21]([CH3:23])[CH3:22])([CH2:18][CH2:19][CH3:20])[C:14](OC)=[O:15]>O1CCCC1>[CH2:18]([C:13]1([CH:21]([CH3:23])[CH3:22])[NH:12][C:10](=[S:11])[N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:14]1=[O:15])[CH2:19][CH3:20]
Reactant: CCCC(N)(C(=O)OC)C(C)C
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Solvent: C1CCOC1
Product: CCCC1(C(C)C)NC(=S)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of 2.0 g of 3,5-dichlorophenyl isothiocyanate in 10 ml of absolute tetrahydrofuran was added dropwise at 20° C. to a solution of 1.7 g of methyl 2-amino-2-(1-methylethyl)-pentanoate in 10 ml of absolute tetrahydrofuran and the mixture was stirred at 20° C. for a further 4 hours. Then the solvent was removed and the residue was recyrstallized from diisopropyl ether to obtain 1.6 g (46% of theory) of title compound melting at 160° C.