Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:35][CH2:36][C:37](O)=[O:38])(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:73]>CN(C=O)C.O1CCOCC1>[ClH:73].[NH2:35][CH2:36][C:37]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:38]
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(C(=O)CN)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2) (73 mg, 0.2 mmol) and BOC-glycine (35 mg, 0.2 mmol) in DMF (1.0 mL) at room temperature was treated with diisopropylethylamine (35 μL, 0.2 mmol) followed by HATU (84 mg, 0.22 mmol). The reaction mixture was stirred for 2 h then partitioned between EtOAc (10 mL) and a saturated aqueous NaHCO3 solution (10 mL). The organic component was isolated and further washed with brine (10 mL) then dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 40% EtOAc/hexane as eluant to afford BOC-containing coupled product as a foam (85 mg, 81%). LC/MS 7.46 min, [M+1]+ 524. The BOC-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in dioxane and stirred for 2 h then evaporated to a solid which was filtered and washed with diethyl ether to afford product as a colorless solid (42 mg, 49% based on trihydrochloride salt). LC/MS 4.66 min, [M+1]+ 424.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)=[N:5]/[O:6][CH3:7].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][Br:23])[CH:16]=1)=[N:5]/[O:6][CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CO/N=C(/C(=O)OC)c1ccccc1Oc1cccc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
To a solution of (E)-methyl-2-[2-(3-methylphenoxy)phenyl]-2-methoxyiminoacetate (4.60 g) in benzene (120 ml), N-bromosuccinimide (2.88 g) and benzoyl peroxide (0.37 g) were added, and the resultant mixture was refluxed for 1 hour, followed by cooling to room temperature. Insoluble materials were removed by filtration and, after removal of the solvent, the residue was purified by silica gel column chromatography to give (E)-methyl-2-[2-(3-bromomethylphenoxy)phenyl]-2-methoxyiminoacetate (4.60 g).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH2:15])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20].O.[C:24](Cl)(=[O:26])[CH3:25]>CC(N(C)C)=O>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH:15][C:24](=[O:26])[CH3:25])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20]
Reactant: CC(=O)Cl
Reactant: CNC(=O)CCNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)CCNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Yield: 58.8 %

Procedure:
99.5 g. (0.15 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-β -alanine methylamide . 1.1 H2O (IVf), m.p. 250°-252° C. (decomposition) in 190 ml. of dimethylacetamide yield, after reaction with 40.0 ml. of acetyl chloride analogously to Example 1, 60.4 g. (58.8%) of the desired compound. A sample for analysis is purified in alcohol by way of the dimethylammonium salt; m.p. 288°-289° C. (under decomposition).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:21][CH2:20][C:19]2([CH3:25])[C:22]([CH3:24])([CH3:23])[CH:15]1[CH2:16][C:17]1[CH:29]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:27]=[CH:26][C:18]=12)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:7]([O:11][C:12]([N:14]1[CH2:21][CH2:20][C:19]2([CH3:25])[C:22]([CH3:23])([CH3:24])[CH:15]1[CH2:16][C:17]1[CH:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=[CH:26][C:18]=12)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3CC1C2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(-c4ccccc4)cc3CC1C2(C)C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Aqueous 2 M Na2CO3 solution (5 mL) is added to a mixture of 6,11,11-trimethyl-9-trifluoromethanesulfonyloxy-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (1.00 g) and phenylboronic acid (0.34 g) in N,N-dimethylformamide (5 mL) in argon atmosphere. The resulting mixture is flushed with argon and then 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.18 g) is added. The mixture is heated to 100° C. and stirred at this temperature for 4 h. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and the solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1→1:1) to give the product as a colorless oil.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])=[S:5].[CH3:17]O>>[ClH:1].[ClH:1].[CH3:2][NH:3][C:4](=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[S:5][CH3:17]
Reactant: CNC(=S)NCCSCc1[nH]cnc1C
Reactant: CO
Agent: Cl
Product: CNC(=NCCSCc1[nH]cnc1C)SC

Procedure:
Dry hydrogen chloride gas was passed into a solution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (73.2 g) in methanol (600 ml) and the mixture was refluxed for 5 hours. Concentration and re-evaporation with isopropyl alcohol afforded a crystalline solid which was recrystallised from isopropyl alcohol-ether to give N,S-dimethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]isothiourea dihydrochloride (96.2 g) m.p. 191°-192°. (isopropyl alcohol-ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[S:23][CH:24]=[C:25]([C:27](OCC)=[O:28])[N:26]=2)=[C:9]1[C:32]([O:34][CH2:35][CH3:36])=[O:33].[OH-].[NH4+:38]>O1CCOCC1>[C:27]([C:25]1[N:26]=[C:22]([CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[S:23][CH:24]=1)(=[O:28])[NH2:38]
Reactant: CCOC(=O)C1=C(COCc2nc(C(=O)OCC)cs2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCc2nc(C(N)=O)cs2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 43 h

Procedure:
A mixture of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-ethoxycarbonylthiazole (0.54 g), dioxane (20 ml) and 0.880 aqueous ammonium hydroxide solution (20 ml) was stirred at room temperature for 43 hours and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (Na2SO4) and evaporated. The residual oil was purified by chromatography on silica (t.l.c. grade, 10 g) using dichloromethane plus 0-3% v/v methanol as eluant. Appropriate fractions were combined and evaporated and the residual oil triturated with diethyl ether. The resulting solid was collected, washed with diethyl ether and dried to give the title compound (0.30 g) as a monohydrate, m.p. 160°-164° C. decomp.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I:15]I>O>[F:1][C:2]1[N:3]=[C:4]([I:15])[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: Oc1ccc(F)nc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(F)nc1I
Temperature: 25 °C
Yield: 26.8 %

Procedure:
A 125 mL pressure flask was charged with 2-fluoro-5-hydroxypyridine (5.0374 g, 45 mmol), 50 mL water, a stirbar, and sodium carbonate (4 ml, 89 mmol). The slurry was stirred and heated using a heat gun until homogenous. The solution was cooled to room temperature, and treated with iodine (2 ml, 45 mmol). The flask was sealed, and the reaction was stirred overnight at room temperature. The slurry was filtered through a 0.22 μm PTFE membrane, and the precipitate was washed with water (3×30 mL). The precipitate was dried at <1 mm Hg and 60° C. for 12 h, and then heated into 20 mL dry DCE. The cloudy solution was filtered hot, and allowed to cool. The filtrate was acidified to pH 3 with 2 M HCl, during which a precipitate had formed. The precipitate was isolated using a 0.22 μm PTFE membrane, washed with water (3×30 mL), and dried under a stream of nitrogen overnight. The solids were washed with hexanes (3×50 mL), DCM (3×50 mL), and then dried under a stream of nitrogen for 1 h to afford 6-fluoro-2-iodopyridin-3-ol (2.88 g, 27% yield). 1H NMR (400 MHz, acetone) δ ppm 6.93 (ddd, J=8.56, 3.57, 0.29 Hz, 1H) 7.38 (ddd, J=8.58, 6.58, 0.39 Hz, 1H) 9.39 (br. s., 1H). 19F NMR (377 MHz, acetone) δ ppm −78.17 (s, 1 F). 13C NMR (101 MHz, acetone) δ ppm 103.81 (d, J=15.17 Hz, 1 C) 110.35 (d, J=39.45 Hz, 1 C) 127.81 (d, J=7.37 Hz, 1 C) 154.14 (d, J=4.33 Hz, 1 C) 156.76 (d, J=234.95 Hz, 1 C). HPLC-MS: 1.39 min (>99%@215 nm; >99% @254 nm; m/z=239.9, calculated for C5H3FINO+H+=239.9).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)/[C:21](=[N:25]/[OH:26])/[CH2:20][CH2:19][CH2:18]2)=[CH2:14].[C:27]1([C:33]2[O:37][N:36]=[C:35]([C:38](OC)=O)[C:34]=2[C:42]([F:45])([F:44])[F:43])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.CCCCCCC.ClCCl.C1(C)C=CC=CC=1>[C:27]1([C:33]2[O:37][N:36]=[C:35]([C:38]3[O:26][N:25]=[C:21]4[C:22]5[C:17]([CH2:18][CH2:19][C:20]=34)=[CH:16][C:15]([CH:13]=[CH2:14])=[CH:24][CH:23]=5)[C:34]=2[C:42]([F:45])([F:44])[F:43])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCCC
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 37.4 %

Procedure:
To a stirred solution of diisopropylamine (2.80 mL, 19.62 mmol) in anhydrous THF (15 mL) was added n-butyllithium (7.85 mL, 19.62 mmol) (2.5 M in hexanes) dropwise at 0° C. under a nitrogen atmosphere. The yellow cloudy solution was stirred at the same temperature for 20 min before a solution of 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 1.705 g, 9.11 mmol) in anhydrous THF (7 mL) was added dropwise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 50 min. A solution of methyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (Intermediate 5, 1.9 g, 7.01 mmol) in anhydrous THF (5 mL) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 70 min., quenched with saturated aqueous ammonium chloride solution (15 mL) and water (15 mL) and extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated to yield a brown foamy solid. To the solid was added anhydrous toluene (40 mL) and p-toluenesulfonic acid monohydrate (2.67 g, 14.01 mmol) and the contents were heated at 110° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and the liquid was separated from the solid by decantation and washed with saturated aqueous sodium bicarbonate solution (5 mL). The left solid was stirred with dichloromethane (70 mL) and water (50 mL) for 1 hr with occasional sonication. The solid was filtered off and washed with dichloromethane (2×5 mL). The filtrate was basified with aqueous ammonia solution (2 mL). The aqueous layer was separated, combined with previous sodium bicarbonate solution wash, and extracted with dichloromethane (2×20 mL). The combined organic solutions were dried over sodium sulfate and concentrated under reduced pressure. Silica gel chromatography (10 to 100% dichloromethane in heptane) afforded 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (1.07 g, 2.62 mmol, 37.4% yield) as a yellow solid. LC/MS M+1=409.4.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C(Cl)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([OH:42])[CH:29]([NH2:41])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:41][CH:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=2)[CH:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[OH:42])=[O:11])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: CCCCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a solution of 4-n-butylbenzoic acid (153 mg, 0.86 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.15 ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 30 min. The reaction solution was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 ml) were added (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the title compound (172 mg, 64%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: C1COCCN1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromo-1-methyl-2-nitrobenzene (225 mg, 1.04 mmol), morpholine (125 μL, 1.25 mmol), and cesium carbonate (474.4 mg, 1.46 mmol) in toluene, palladium diacetate (31.2 mg, 0.139 mmol) and 2-(di-t-butylphosphino)biphenyl (125 mg, 0.403 mmol) are added and stirred at 100° C. for 5 hours. After cooling, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted with ethyl acetate twice. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified with silica gel column chromatography (n-hexane:ethyl acetate=5:1) to afford 4-(4-methyl-3-nitrophenyl)-morpholine as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:15][NH:16][CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH3:17])[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1nc2ccccc2n2cnnc12
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)c1nc2ccccc2n2cnnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
A slurry of 2.0 g. (0.01 mole) of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 2) in N,N-dimethylformamide (30 ml.) was saturated with dimethylamine gas and stirred at room temperature overnight. The mixture was poured over ice and the precipitate was removed by filtration. Recrystallization from ethanol gave 640 mg. (44% yield) of 4-dimethylamino-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 184°-186° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1.N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC.O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: OB(O)c1ccccc1Br
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: COCCOC
Solvent: O
Product: COc1cc(OC)cc(-c2ccccc2Br)c1
Temperature: 85 °C
Yield: 48.7 %

Procedure:
To a 250-mL round bottom flask equipped with a magnetic stir bar was added water (41 mL) and 1,2-dimethoxyethane (41 mL). The solution was sparged with nitrogen for 20 minutes, and then potassium carbonate (11.1 g, 81.0 mmol, 3 equiv), 2-bromophenylboronic acid (6.35 g, 31.6 mmol, 0.98 equiv) and 1-bromo-3,5-dimethoxybenzene (7.00 g, 32.2 mmol, 1 equiv) were added. The flask was purged with N2 for 10 minutes before finally adding palladium(II) acetate (145 mg, 0.645 mmol, 0.02 equiv) and triphenylphosphine (677 mg, 2.58 mmol, 0.08 equiv). The reaction mixture was heated to 85° C. under a positive pressure of nitrogen for 16 hours. After cooling to room temperature, the phases were partitioned. The organic phase was collected and the aqueous phase was washed with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotary evaporator. The crude yellow oil was purified by column chromatography on the Isco (120-g column; gradient: 2 column volumes heptane, ramp up to 94:6 heptane:ethyl acetate over 8 column volumes, hold at 94:6 for 6 column volumes) to afford the title compound as a colorless oil (4.51 g, 94 area % by HPLC, 48% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.68-7.62 (m, 1H), 7.40-7.31 (m, 2H), 7.24-7.15 (m, 1H), 6.55 (d, J=2.3 Hz, 2H), 6.50 (t, J=2.3 Hz, 1H), 3.83 (s, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 159.8, 142.6, 142.1, 132.8, 130.7, 128.5, 127.0, 122.1, 107.4, 99.6, 55.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][NH2:22])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:28][C:29]=1[F:30].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:21][NH:22][S:31]([C:26]2[CH:27]=[CH:28][C:29]([F:30])=[C:24]([Cl:23])[CH:25]=2)(=[O:33])=[O:32])([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(I)cc2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(F)c(Cl)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a stirred solution of 4-aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.24 mmol) in CH2Cl2 (1.0 mL) at room temperature under Ar was added a solution of 3-chloro-4-fluorophenylsulfonyl chloride (0.06 g, 0.26 mmol, 1.1 eq.) followed by pyridine (0.25 mL). The mixture was stirred at room temperature for 16 h, diluted with EtOAc (5 mL), washed with saturated aqueous NaHCO3 (5 mL) and saturated brine (5 mL) and dried over Na2SO4. Filtration and rotary evaporation yielded the crude 4-[(3-chloro-4-fluoro-benzenesulfonylamino)-methyl]-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.09 g, 0.14 mmol, ˜62%). 1HNMR (300 MHz, CDCl3): δ 8.66 (d, 1H), 7.81-7.73 (m, 3H), 7.34 (m, 1H), 7.15 (d, 1H), 7.08 (d, 1H), 3.79 (m, 2H), 3.13 (m, 3H), 2.19 (m, 3H), 1.77 (m, 2H), 1.56 (s, 9H). MS(ESI): 509 (M−Boc).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[S:16][C:15]([CH3:17])=[N:14][C:13]=1[CH3:18])=O)C.C(OCC)(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)C>[CH3:17][C:15]1[S:16][C:12]([CH2:10][OH:9])=[C:13]([CH3:18])[N:14]=1
Reactant: CCOC(=O)c1sc(C)nc1C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1nc(C)c(CO)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
To a suspension of lithium aluminum hydride (563 mg, 14.8 mmol) in diethyl ether (25 mL) at 0° C. was added ethyl-2,4-dimethylthiazole-5-carboxylate (2.5 g, 13.5 mmol) in three portions. The reaction mixture was allowed to stir at 0° C. for 10 min, then at room temperature for 24 h. Ethyl acetate (65 mL) was added very slowly dropwise at 0° C. The reaction mixture was then added slowly to an aqueous solution of potassium sodium tartrate (30% w/v; 20 mL) and stirred for 2 h. The layers were separated and the aqueous layer was re-extracted with ethyl acetate (1×30 mL). The combined organic layers were dried (MgSO4), filtered, evaporated under reduced pressure. The resulting colorless solid was dried under high vacuum to give 2,4-dimethylthiazole-5-methanol (1.7 g, 91% yield). This material was used in a subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Cc1cccc(CCl)n1
Agent: Cl
Product: Cc1cccc(Cn2cc(C#Cc3cccc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=322.4 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloromethyl-6-methyl-pyridine hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15]([O:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([C:25](=[O:27])[CH3:26])=[CH:20][C:19]=3[CH3:28])=[N:14][C:13](Cl)=[N:12][C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>O>[C:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([O:17][C:15]2[C:16]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:9]=[CH:10][C:11]=3[N:12]=[C:13]([NH:30][C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[N:14]=2)=[C:19]([CH3:28])[CH:20]=1)(=[O:27])[CH3:26]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)c1cc(C)c(Oc2nc(Cl)nc3ccn(Cc4ccccc4)c23)c(C)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
In a sealed tube was added 1-(4-(5-benzyl-2-chloro-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylphenyl)ethanone (111 mg, 0.27 mmol), 4-aminobenzonitrile (129 mg, 1.1 mmol), TFE (1.7 mL) and TFA (0.2 mL, 2.16 mmol). The reaction mixture was stirred at 90° C. for 16 h. Upon completion of the reaction, the resulting mixture was cooled, diluted with water, and washed with EtOAc. The combined organic layers were washed with NaHCO3 and brine; dried over Na2SO4; filtered; and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (9:1-100% EtOAc), to give the product as an off-white solid (68 mg, 51%).