Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]1[C:16](=[O:17])[CH:15]=[C:14]([Br:18])[NH:13]1.[F:19][C:20]([F:35])([C:31]([F:34])([F:33])[F:32])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[S:23](F)(=[O:25])=[O:24]>O1CCCC1.O>[CH3:11][N:12]1[C:16]([O:17][S:23]([C:22]([F:27])([F:28])[C:21]([F:29])([F:30])[C:20]([F:19])([F:35])[C:31]([F:34])([F:33])[F:32])(=[O:25])=[O:24])=[CH:15][C:14]([Br:18])=[N:13]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cn1[nH]c(Br)cc1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(Br)cc1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1M, 0.70 mL, 0.70 mmol) was added at −78° C. under nitrogen to a stirred solution of 1-methyl-3-bromo-5-pyrazolone from Step 1 (0.10 g, 0.565 mmol) in dry tetrahydrofuran (2 mL). After 10 min, nonafluorobutanesulfonyl fluoride (0.13 mL, 0.70 mmol) was added dropwise. The resulting gel was warmed to room temperature and stirred for 1 hour. The solution was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The extracts were dried (Na2SO4) and concentrated. Flash column chromatography on silica, eluting with 10% ethyl acetate-isohexane, gave 1-methyl-3-bromo-5-(nonafluorobutanesulfonyloxy)pyrazole (0.204 g, 79%) as a colourless oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[NH:21]1[CH:25]=[N:24][C:23]([SH:26])=[N:22]1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][S:26][C:23]3[N:24]=[CH:25][NH:21][N:22]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Sc1nc[nH]n1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CSc2nc[nH]n2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1H-1,2,4-triazole-3-thiol. m/e+ 336 for C18H18N5S (M+H)+; 1H NMR (400 MHz, CDCl3) δ␣ 8.10 (s, 1H), 7.90 (s, 1H), 7.57 (m, 3H), 7.21 (d, J=7.7 Hz, 2H), 7.11 (dd, J=1.1, 9.1 Hz, 1H), 4.78 (s, 2H), 2.36 (s, 3H), 2.33 (s, 3H) 0.90 (bs, 1H) ppm.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].[CH2:18]([NH:20]CC)[CH3:19].C(N)C>C1COCC1>[CH2:18]([NH:20][C:8]1[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:19]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Cl
Agent: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous K2CO3 (19 g, 144.5 mmol) is suspended in a solution of 3-chloro-4-nitro-pyridine-1-oxide (10 g, 57.8 mmol) in anhydrous acetonitrle (100 mL). Excess diethyl amine (2.0 M) in THF is added to the above suspension with ice-bath cooling. After complete addition of ethylamine, the reaction mixture is allowed to warm to room temperature and stir overnight. The reaction mixture is filtered to remove K2CO3 and the filtrate is evaporated under reduced pressure to remove volatile solvents. The organic residue is subjected to chromatography eluting with 30% EtOAc-hexanes to afford 3-ethylamino-4-nitro-pyridine-1-oxide as an orange solid (8.2 g); 1H NMR (300 MHz, CDCl3): δ 8.0 1 (d, J=7.5 Hz, 1H), 7.91(s, 1H), 7.8 (brs, NH), 7.44 (d, J=7.2 Hz, 1H), 3.30 (t, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), m/z 184 [M+1]
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:12][N:13]([CH3:17])[CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)#[N:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:25][C:20]1[CH:19]=[C:18]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:28]#[N:29])=[CH:8][CH:9]=3)[CH2:14][N:13]([CH3:17])[CH2:12]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CN1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cc(-c3ccccc3C#N)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 63 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (100 mg, 0.23 mmol) which was prepared in Step G of Example 11, 2-cyanophenylboronic acid (51 mg, 0.35 mmol) and cesium carbonate (225 mg, 0.69 mmol) in water (1 mL) and N,N-dimethylformamide (2 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (8 mg, 0.01 mmol) was added. The mixture was degassed again and then heated to 90° C. for 3 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by preparative thin-layer chromatography (1:4 hexanes/ethyl acetate) to give 2-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile (57 mg, 63%) as a brown solid: ESI MS m/z 393, 395 [M+H]+.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[C:2]1[C:9]([OH:11])=[O:10].[C:12](=O)([O-])[O-].[Na+].[Na+].CI>CN(C)C=O>[CH3:12][O:7][C:6]([C:5]1[S:1][C:2]([C:9]([OH:11])=[O:10])=[CH:3][CH:4]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C(=O)O)s1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C(=O)O)s1
Yield: 26.3 %

Procedure:
Thiophene-2,5-dicarboxylic acid (1.72 g, 10 mmol) and sodium carbonate (3.18 g, 30 mmol) suspended in dimethylformamide (25 mL) were stirred with methyl iodide (623 μL) at room temperature overnight. The sodium salt of the desired product was extracted with water, and 12 M hydrochloric acid was added to the combined aqueous layer. The desired product was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and purified by silica gel column chromatography to give 0.49 g of the desired product as a colorless solid (yield 28%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[C:20]([F:23])([F:22])[F:21])(=O)=O.[CH3:24][C:25]1[C:30]([CH3:31])=[C:29](O)[CH:28]=[CH:27][C:26]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36]>>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:29]3[CH:28]=[CH:27][C:26]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([CH3:24])[C:30]=3[CH3:31])=[C:8]([C:20]([F:23])([F:22])[F:21])[S:9][CH:10]=2)=[CH:13][CH:14]=1)[CH3:19]
Reactant: CCc1ccc(-c2csc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: CCc1ccc(-c2csc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 183 by coupling of [4-(4-ethylphenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate and ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((4-(4-ethyl-phenyl)-2-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl) propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.35 (d, J=7.1 Hz, 2H), 7.19 (d, J=7.1 Hz, 2H), 6.94 (d, J=6.7 Hz, 1H), 6.62 (d, J=6.7 Hz, 1H), 4.92 (s, 2H), 2.93 (t, J=7.3 Hz, 2H), 2.65 (q, J=7.5 Hz, 2H), 2.60 (t, J=7.2 Hz, 2H), 2.23 (s, 3H), 2.10 (s, 3H), 1.25 (t, J=8.5 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:19])=[O:28])=[CH:14][CH:13]=1
Reactant: CSc1ccc(OCc2ncc([N+](=O)[O-])n2C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c([N+](=O)[O-])cnc1COc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27.9 Grams (0.1 mol) of 1-methyl-2-(4-methylthiophenyloxymethyl)-5-nitro-imidazole are dissolved in 200 ml of chloroform, and the solution is added dropwise while stirring at 25° C. to a solution of 17.25 g (0.1 mol) of m-chloroperbenzoic acid in 70 ml of chloroform. The reaction mixture is stirred for 1 hour at 25° C., the solution is shaken with dilute sodium carbonate solution, the chloroform phase is separated, dried over sodium sulfate and evaporated. The residue is recrystallized from ethanol with the addition of charcoal.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([SH:10])[N:4]=1.[CH3:11]I>CO>[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([S:10][CH3:11])[N:4]=1
Reactant: CI
Reactant: Cc1cc(O)nc(S)n1
Agent: [Na]
Solvent: CO
Product: CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
To a solution of sodium (1.25 g, 54 mmol, 1.1 equivalents) dissolved in anhydrous methanol (100 mL) was added 4-hydroxy-6-methyl-pyrimidine-2-thiol (7.00 g, 49.2 mmol). The mixture was warmed to ~40° C. and methyl iodide (13.06 mL, 49.2 mmol) was added. The mixture was heated under reflux for 3 hours and then cooled to ambient temperature and allowed to stand overnight. The crystals were filtered, washed with methanol and dried to give 7.10 g (75%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 2.17 (s, 3H), 2.48 (s, 3H), 5.60 (bs, 1H). MS (DCl/NH3) m/e 157 (M+H)+, 174 (M+H+NH3)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13].[C:14]([OH:17])(=[O:16])[CH3:15]>C1COCC1>[C:14]([OH:17])(=[O:16])[CH3:15].[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: ClCCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: ClCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of NaH (1.11 g; 46.3 mmol) in dry THF, imidazole (3 g; 44.1 mmol) dissolved in 15 ml dry THF is added drop-wise at RT. After completion of the addition the mixture is refluxed for 1 h. After cooling to RT 1-bromo-4-chloro-butane (15.2 ml; 132 mmol) is added and the reaction is stirred for 16 h at RT. The mixture is acidified with acetic acid, filtered and evaporated. The residue is taken-up in hydrochloric acid (10%, 80 ml) and extracted with EtOAc (2×20 ml). The aqueous layer is adjusted to pH 8 with carbonate buffer and the product is extracted with Et2O. After addition of 1 eq AcOH the organic layer is dried over MgSO4 and concentrated in vacuo to give the compound (6.78 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[CH:12][N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=2)=[O:28])[N:13]2[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]2
Reactant: COc1c(C)cn2ccccc12
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n2ccccc12
Yield: 89.8 %

Procedure:
1.8 ml (12.92 mmol) of triethylamine are added, at ambient temperature under an inert atmosphere, to 1.7 g (10.77 mmol) of 1-methoxy-2-methylindolizine in 15 ml of dichloroethane, followed, dropwise, by 2.2 g (11.85 mmol) of 4-nitrobenzoic acid chloride. The reaction medium is stirred for 30 minutes at ambient temperature, hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is washed with diethyl ether. 3 g of an orange solid are obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:15]([O-:18])(O)=[O:16].[Na+]>O.O1CCOCC1>[NH:1]([C:15]([O:18][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
H-Glu(OtBu)-OH (Rf(BuOH/AcOH/H2O 4:1:1 v/v/v): 0.52, [α]D=+9.3° C.=1.05 H2O, mp: 181° C. (dec.); lit24: [α]D=+9.8° C.=2 H2O, mp: 182° C.) (2.0 g, 9.85 mmol), NaHCO3 (1.86 g, 22.2 mmol, 2.25 eq.) were dissolved in H2O (40 mL) and Boc2O25 (2.36 g, 10.8 mmol, 1.10 eq.) dissolved in dioxane (20 mL) was added. The reaction mixture became turbid and gas evolution started. After 3 hrs of stirring at room temperature, the reaction mixture was partially evaporated in vacuo. The aqueous solution was acidified with 10% citric acid and the precipitating oil was taken up into EtOAc (three extractions 20 mL). The EtOAc layer was subsequently washed with H2O (five times 30 mL), saturated NaCl (three times 30 mL) and dried on Na2SO4. The residue obtained after evaporation in vacuo was an oil which crystallized slowly. Yield: 2.91 g (98%), Rf(BuOH/AcOH/H2O 4:1:1 v/v/v): 0.87, Rf(CH2Cl2/MeOH 9:1 v/v): 0.17, [α]D=−10.3° C.=0.93 MeOH, mp: 98-99° C. (lit26: [α]D=−10.9° C.=1 MeOH, mp:101-102° C.), 1H NMR (CDCl3): δ=1.44 (s, 18H, Boc/OtBu (2×9H)); 1.99/2.18 (dm, 2H, β-CH2); 2.38 (m, 2H, γ-CH2); 4.34 (m, 1H, α-CH); 5.23 (d, 1H, NH).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[H-].[Na+].[F:41][C:42]([F:58])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:43](=[O:51])[CH2:44]P(=O)(OC)OC>ClCCl.C1COCC1>[F:41][C:42]([F:58])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:43](=[O:51])/[CH:44]=[CH:2]/[C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: N#CCCCCCCN1C(=O)OC[C@@H]1CO
Reactant: COP(=O)(CC(=O)C(F)(F)c1ccccc1)OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CCCCCCCN1C(=O)OC[C@@H]1/C=C/C(=O)C(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of alcohol 2-3 (480 mg) in dichloromethane (10 mL) was added Dess-Martin periodanane (1 g) and the mixture was stirred at room temperature for 1 h and concentrated. The residue was co-evaporated with toluene several times, resuspended in ethyl acetate and was allowed to sit at 5° C. overnight. The mixture was filtered and the filtrate was concentrated to give the crude aldehyde 7-[(4S)4-formyl-2-oxo-1,3-oxazolidin-3-yl]heptanenitrile (2-5) which was used directly. To a suspension of NaH (168 mg) in THF was added dimethyl 3,3-difluoro-2-oxo-3-phenylpropylphosphonate (1.1 g) dropwise at 0° C. and the mixture was stirred at the temperature for 30 min. To the mixture was added crude aldehyde 2-5 in THF via a cannula and the mixture was stirred at room temperature for 5 h and quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate and the organic layer was dried and concentrated. The residue was purified by flash chromatography to give the desired product 2-4. 1H NMR (400 MHz, acetone-d6): δ 7.70–7.55 (m, 5H), 7.08 (dd, 1H), 6.95 (d, 1H), 4.70 (m, 1H), 4.52 (t, 1H), 3.30 (m, 1H), 3.00 (m, 1H), 2.48 (t, 2H), 1.70–1.25 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.Br[C:16]1[CH:17]=[C:18]([C:21]#[N:22])[O:19][CH:20]=1>>[CH3:11][CH:9]1[O:8][C:7]([CH3:13])([CH3:12])[C:6]2[CH:14]=[C:2]([C:16]3[CH:17]=[C:18]([C:21]#[N:22])[O:19][CH:20]=3)[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reactant: N#Cc1cc(Br)co1
Product: CC1Nc2ccc(-c3coc(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared using the coupling procedure for Example 13 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-cyanofuran. A light brown solid: mp 116-118° C.; 1H-NMR (DMSO-d6) δ 8.43 (s, 1H), 8.06 (s, 1H), 7.38 (d, 1H, J=1.98 Hz), 7.25 (dd, 1H, J=7.93, 1.98 Hz) 6.58 (d, 1H, J=7.93 Hz), 6.37 (s, 1H), 4.77 (q, 1H, J=5.55 Hz), 1.50 (s, 3H), 1.46 (s, 3H), 1.27 (d, 3H, J=5.55 Hz); MS (ES) m/z 269 ([M+H]+); Anal. Calc. For C16H16N2O2: C, 71.62; H, 6.01, N, 10.44. Found: C, 71.55; H, 6.26, N, 10.17.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:29])=[CH:26][C:25]=1[CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>C(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:33]1([CH2:32][CH2:31][NH:30][C:28]([C:27]2[CH:38]=[CH:39][C:24]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)=[CH:6][CH:7]=3)=[C:25]([CH3:40])[CH:26]=2)=[O:29])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)ccc1Br
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: CCO
Product: Cc1cc(C(=O)NCCN2CCCC2)ccc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 33), 4-bromo-3-methyl-N-(2-pyrrolidin-1-yl-ethyl)benzamide (0.31 g, Example 63a)), 2M aqueous sodium carbonate (0.57 ml) and tetrakis(triphenylphosphine)palladium(0) (0.012 g) in ethanol(5 ml) with heating at reflux for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil. (0.14 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]([O:21]C)=[C:6]([C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH:7]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]([OH:21])=[C:6]([C:8](=[O:20])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(CC(=O)c2cc(Br)c(OC)cc2OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(=O)c2cc(Br)c(OC)cc2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of methyl 4-(2-(5-bromo-2,4-dimethoxyphenyl)-2-oxoethyl)benzoate (1.1 g, 2.8 mmol) in DCM (100 mL) was added AlCl3 (7.4 g, 56 mmol) and the mixture was stirred at room temperature for 1 h. Then the mixture was poured into ice-water (100 mL), extracted with DCM (20 mL×4). The organic phase was washed with brine (30 mL), dried with Na2SO4, filtered and the filtrate was concentrated in vacuo to give brown oil, which was purified by prep-TLC (PE/EA=3/1) to afford Intermediate J (750 mg, 71%) as a light yellow solid. MS (ESI): m/z 379.0 [M+1]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([NH:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23])=[O:19])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b) and (2S)-2-amino-N,3,3-trimethyl-butanamide, (CAN 89226-12-0) as starting materials, MS (EI): m/e=390.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2.ClC(OC(Cl)=O)C.C(Cl)Cl>C(Cl)CCl>[CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CNCCN1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 88 °C
Yield: 62.7 %

Procedure:
A solution of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (1.65 g, 6.17 mmol) in ClCH2CH2Cl (20 mL) was cooled to 0° C. (ice/water bath) then treated with alpha chloroethylchoroformate (1.009 mL, 9.26 mmol) dropwise. The resulting suspension was heated at 88° C. for 1.5 hours then concentrated to dryness. The residue was dissolved in MeOH (50 mL) and heated at reflux for 2 hours. The dark mixture was concentrated and partitioned between saturated sodium bicarbonate solution (50 mL) and CH2Cl2 (200 mL). The mixture was transferred to a separatory funnel and extracted. After extraction, the organic layer was separated, dried (Na2SO4), filtered, and concentrated to give a brown residue. This residue was subjected to flash chromatography on silica gel using 5:95 (2M NH3 in MeOH):CH2Cl2 as the eluent to give a yellow residue (980 mg, 62.7%). 1H-NMR (CDCl3) δ 7.97 (d, J=2.7 Hz, 1H), 7.87 (d, J=2.7, 9.3 Hz, 1H), 6.68 (d, J=9.3 Hz, 1H), 3.86-3.82 (m, 2H), 3.55 (t, J=6.6 Hz, 2H), 3.04-3.01 (m, 2H), 2.87 (t, J=6.6 Hz, 2H), 2.49 (s, 3H), 1.32 (brs, 1H).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[CH2:10]([NH:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: N#Cc1ccc(Cl)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCCCCCNc1ccc(C#N)cc1
Yield: 91.9 %

Procedure:
According to the general procedure B, 4-Chlorobenzonitrile (69 mg, 0.50 mmol) reacted with n-hexylamine (80 μl, 0.60 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 70° C. for 8 h to give the title compound as a solid (79 mg, 78%). On the other hand, the reaction of 4-chlorobenzonitrile (69 mg, 0.50 mmol) with n-hexylamine (61 mg, 0.60) using K3PO4 and DME also occurred in 92% yield to afford the title compound (93 mg) at 100° C. for 13 h. 1H-NMR (300 MHz, CDCl3): δ 7.39 (d, 2H, J=8.4 Hz), 6.54 (d, 2H, J=8.7 Hz), 4.34 (bs, 1H, —NH—), 3.13 (t, 2H, J=6.9 and 7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 151.43, 133.47, 120.60, 111.56, 97.69, 43.03, 31.37, 28.89, 26.55, 22.43, 13.88. GC/MS(EI): m/z 202 (M+).