Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([OH:18])=O)[CH:3]=1.S(Cl)([Cl:21])=O.CN(C)C=O.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([Cl:21])=[O:18])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccccn1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Temperature: 80 °C

Procedure:
To a mixture of 4,5-dichloro-6-(4-chlorophenyl)picolinic acid (3.00 g, 9.9 mmol) in toluene (25 mL) was added thionyl chloride (1.08 mL, 14.9 mmol) and dimethylformamide (0.04 mL, 0.5 mmol). Reaction mixture was heated at 80° C. for 2.5 h. HPLC analysis of an aliquot of the reaction mixture treated with methanol and dimethylaminopyridine indicated starting material remaining Reaction mixture was allowed to cool to rt and additional thionyl chloride (0.5 mL, 6.9 mmol) and dimethylformamide (0.04 mL, 0.5 mmol) were added. Reaction was heated at 80° C. for 2 h. Reaction was allowed to cool to room temperature and concentrated under reduced pressure to provide a white solid. Toluene (40 mL) was added to dissolve the solid and concentrated under reduced pressure and then this process was performed a second time. 4,5-Dichloro-6-(4-chlorophenyl)picolinoyl chloride was isolated as a white solid (3.05 g, 96% yield). 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.79-7.72 (m, 2H), 7.53-7.46 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 168.66, 157.63, 146.48, 145.44, 136.35, 135.10, 134.28, 131.04, 128.63, 124.90. MS Calcd. for C12H5Cl4NO: 320.91. Found: 257, 222, 207, 186, 151.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](Br)[CH:12]=2)[NH:7][N:6]=1)=[O:4].[CH:15](O[Na])=[O:16]>CN(C=O)C.CCOC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:15]=[O:16])[CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]c2ccc(Br)cc12
Reactant: O=CO[Na]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1n[nH]c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.7 %

Procedure:
A mixture of 5-bromo-1H-indazole-3-carboxylic acid methyl ester (1 g, 3.92 mmol), HCOONa (400 mg, 5.88 mmol), and PdCl2(PPh3)2 (138 mg, 0.2 mmol) in DMF (10 mL) was put under vacuum, and charged with CO. This process was repeated three times, and the mixture was kept at 110° C. for 6 hr. The reaction mixture was cooled to rt, diluted with EtOAc and water, and extracted. The organic phase was dried and concentrated. Purification via flash chromatography afforded 5-formyl-1H-indazole-3-carboxylic acid methyl ester (430 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1C=C[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].BrN1C(=[O:22])CCC1=O.C([O:27][CH2:28][CH3:29])(=O)C.O>CS(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:28](=[O:27])[C:29](=[O:22])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCn1ccc2c(Br)cccc21
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Temperature: 60 °C
Yield: 92 %

Procedure:
To a solution of 4-bromo-1-pentyl-1H-indole (25.0 g, 93.9 mmol) in anhydrous dimethylsulfoxide (350 mL) was added N-bromosuccinimide (50.2 g, 282 mmol) in portions over 30 min. The reaction mixture was heated at 60° C. for 3 h, upon which time the internal temperature increased to 120° C. After cooling down to ambient temperature, the reaction mixture was poured onto ethyl acetate/water (1/1, 600 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers was washed with water (3×500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to yield the title compound (25.7 g, 92%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.38 (t, 1H), 7.21 (t, 1H), 6.82 (d, 1H), 3.68 (t, 2H), 1.72-1.59 (m, 2H), 1.39-1.25 (m, 4H), 0.86 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 180.9, 157.2, 152.6, 138.4, 128.3, 121.7, 116.3, 108.9, 40.4, 28.9, 26.9, 22.3, 13.9.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>O1CCOCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:15][N:16]3[CH2:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)CCc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Reaction time: 24 h
Yield: 32.1 %

Procedure:
A solution of t-butyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoate (1.04 g) in dioxane (6 ml) was treated with triethylamine (0.65 ml) and trimethylsilyl trifluoromethanesulphonate (0.8 ml). The solution was stirred for 24 hours and then was diluted with water to give a viscous oil. The liquids were decanted and the oil was triturated successively with water and hexane. The resultant solid was recrystallized from ethyl acetate/hexane to give 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.3 g, 32%) as an ivory powder; mp 181-182°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])=O)[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.O.NN.C(O)COCCO.[OH-].[K+]>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:2][CH2:3]1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OCC3CC3)c2)n1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCOc1ccccc1CCCc1coc(-c2ccc(OC)c(OCC3CC3)c2)n1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A 0.5 g quantity of 3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one obtained in Example 102 and 0.18 ml of hydrazine monohydrate were added to diethylene glycol. A 0.14 g quantity of potassium hydroxide was added thereto, and the mixture was stirred at 150° C. for 1 hour. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. Drying was performed with anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 0.1 g of colorless oily 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-4-[3-(2-ethoxyphenyl)propyl]oxazole.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:18]C)=[C:14]([CH:17]=1)[C:15]#[N:16].B(Br)(Br)Br.CCOC(C)=O.O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: COc1ccc(-c2nc3ccccc3o2)cc1C#N
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(-c2nc3ccccc3o2)ccc1O
Reaction time: 4 h

Procedure:
To a solution of 5-(1,3-benzoxazol-2-yl)-2-methoxy benzonitrile (270 mg, 1.1 mmol) in CH2Cl2 (5 mL) at 0° C., was added BBr3 (1.0M solution in CH2Cl2, 430 μL, 4.4 mmol) dropwise. The reaction was stirred at it for 4 h. EtOAc (150 mL) was added, as well as H2O (30 mL). The organic layer was washed with brine (2×20 mL), dried (MgSO4), concentrated and the crude product was recrystallized in EtOAc to afford 5-(1,3-benzoxazol-2-yl)-2-hydroxy benzonitrile. MS (ESI) 237 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH:9]=[C:8]([C:18]([O:20]C)=[O:19])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].O.O[Li].O>C1COCC1>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[CH:9]=[C:8]([C:18]([OH:20])=[O:19])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cn[nH]c2)cc2c1cnn2C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3cn[nH]c3)cc21
Temperature: 80 °C
Yield: 75.7 %

Procedure:
To a stirred solution of methyl 1-isopropyl-6-(1H-pyrazol-4-yl)-1H-indazole-4-carboxylate (750 mg, 2.64 mmol) in THF:H2O (30 mL) was added LiOH.H2O (330 mg, 7.85 mmol) and the resulting mixture was refluxed at 80° C. for 8 h. THF was distilled off under reduced pressure and the aqueous layer was acidified with 10% HCl (to pH ˜5) at 0° C. The precipitated solid was collected by filtration and dried to afford the title compound 1-isopropyl-6-(1H-pyrazol-4-yl)-1H-indazole-4-carboxylic acid as an off-white solid (540 mg, 76%). LCMS (ES+) m/z=271.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12](OC)[CH:11]=1.[CH3:26][NH2:27].CS(C)=O.Cl>O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([NH:27][CH3:26])[CH:11]=1
Reactant: COc1ccccc1OCCNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: CN
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(C(=O)NCCOc2ccccc2OC)ccc1[N+](=O)[O-]
Yield: 89 %

Procedure:
A mixture comprising N-[2-(2-methoxyphenoxy)ethyl]-3-methoxy-4-nitrobenzamide (4.0 g, 11.6 mmol), aqueous methylamine (40%, 10 mL) and DMSO (2 mL) in a sealed tube was heated at 110° C. for 4 hours, cooled and then poured into water (25 mL). The dilution was treated with 3M aqueous hydrochloric acid to give an orange solid. The solid was isolated by filtration to provide N-[2-(2-methoxyphenoxy)ethyl]-3-methylamino-4-nitrobenzamide (3.56 g, 89% yield); MS (PB-PCI) C17H19N3O5 m/e calc 345.35; found 346 (MH+).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[CH:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][CH:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCC/C=C\CN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCC/C=C\CN1C(=O)CCCC1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.8 %

Procedure:
Sodium borohydride (16 mg, 0.42 mmol), followed by MeOH (0.25 mL), was added to a solution of (Z)-7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-enoic acid methyl ester (16 mg, 0.042 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 2.5 h at rt, the reaction was quenched with aqueous HCl (1.0 M) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→50% EtOAc/CH2Cl2, gradient) afforded 10 mg (62%) of the title compound.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=O.C(Cl)(=O)C([Cl:12])=O>C(OCC)C.CCCCCC>[Cl-:12].[Cl:12][CH:1]=[N+:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=CN1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: ClC=[N+]1CCOCC1
Product: [Cl-]
Temperature: 25 °C
Yield: 183 %

Procedure:
Under dry nitrogen, a solution of N-formyl morpholine (50.6 gm) 440 mmol) in anhydrous diethyl ether (300 ml), stirring rapidly in an ice bath is treated dropwise with a solution of oxalyl chloride (50.8 gm, 400 mmol) in hexane (30 ml). After warming to room temperature for 30 minutes, the solid product is filtered off under dry nitrogen and dried in vacuum to give 91.5% (62.2 gm, 366 mmol) of N-(chloromethylene)-morpholinium chloride.
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#[N:2].[BrH:11]>CC(C)=O.C(OCC)(=O)C.C(O)(=O)C>[NH2:2][C:1]1[NH:6][C:5]([Br:11])=[C:4]([C:7]#[N:8])[C:3]=1[C:9]#[N:10]
Reactant: Br
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: N#Cc1c(N)[nH]c(Br)c1C#N
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Tetracyanoethylene (10.02 g, 78.23 mmol) was dissolved in the mixed solvent of acetone (60 mL) and ethyl acetate (120 mL), to which hydrogen bromide (33 wt %, 60 mL) dissolved in acetic acid was added at 0˜5° C. The yellow solid compound observed after one hour-stirring was isolated by filtering. After washing the compound with cold distilled water (100 mL), the mixture was dried in the air to give the target compound (11.02 g, 52.22 mmol, 66.8%).
Reaction SMILES: O[C:2]1([C:15]2[C:16](=[O:31])[NH:17][C:18](=[O:30])[N:19]([CH:29]=2)[C@@H:20]2[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]2[OH:22])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:13]1[C:14]2[CH:2]([C:15]3[C:16](=[O:31])[NH:17][C:18](=[O:30])[N:19]([CH:29]=3)[C@@H:20]3[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:21]3[OH:22])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C1(O)c2ccccc2-c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 33.6 %

Procedure:
The product of step (ii) (3.37 g) was dissolved in dichloromethane (100 ml) and triethylsilane (1.39 ml) and treated with trifluoroacetic acid (6.23 ml). The mixture was stirred at room temperature for 36 hours. The solvent was evaporated under reduced pressure and the residue azeotroped three times with toluene. The remaining residue was purified by flash chromatography on silica-gel eluting with 15% methanol in ethyl acetate to give 5-(9H-fluoren-9-yl)uridine as white powder (1.09 g).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.C1COC2C=CC(NC3N=C(NC4C=CC5OCCOC=5C=4)C(Br)=CN=3)=CC=2[O:36]1.OC1C=CC(B(O)O)=CC=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:29]4[CH:34]=[CH:33][C:32]([OH:36])=[CH:31][CH:30]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Reactant: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Agent: OB(O)c1ccc(O)cc1
Product: Oc1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine, N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine and 4-hydroxyphenylboronic acid were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-(4-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.53 (s, 1H), 8.92 (s, 1H), 7.78 (s, 1H), 7.74 (bs, 1H), 7.24 (bs, 1H), 7.22 (d, 2H, J=8.7 Hz), 7.12-7.09 (m, 2H), 6.97 (dt, 1H, J=2.4 and 8.7 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.72 (d, 1H, J=8.1 Hz), 6.62 (d, 1H, J=9.0 Hz), 4.19 (s, 4H), 4.17 (s, 4H); LCMS: ret. time: 23.51 min.; purity: 95%; MS (m/e): 471 (MH+).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][C@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][NH:7]1.C(N(CC)CC)C.C([O:31][C:32](=O)[C:33](OCC)=[O:34])C>C(Cl)(Cl)Cl>[CH3:3][N:4]1[C:32](=[O:31])[C:33](=[O:34])[N:7]2[CH2:8][C@@H:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[C:15]([C@@H:6]2[CH2:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CNC[C@@H]1NC[C@H](c2ccccc2)c2ccccc21
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1C[C@H]2c3ccccc3[C@H](c3ccccc3)CN2C(=O)C1=O
Yield: 77.4 %

Procedure:
To a stirred solution of cis-1,2,3,4-tetrahydro-1-methylaminomethyl-4-phenylisoquinoline dihydrochloride (30.6 g, 0.094 m) in chloroform (500 ml) maintained under nitrogen at ambient temperature was added triethylamine (42.6 g, 0.42 m) and then in one portion diethyloxalate (30.1 g, 0.206 m) and the mixture heated to reflux for 4 hours. The mixture was cooled and washed with 10% HCl (3×150 ml) and water (150 ml), then dried over MgSO4. The solvent was evaporated to give 22.3 g of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline-3,4-dione as a pale yellow solid. An analytical sample, recrystallized from isopropanol, had m.p. 193°-194°.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[F:15][C:16]1[CH:17]=[C:18]([S:22]([Cl:25])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>[N+](C1C=CC=CC=1)([O-])=O.FC(S([O-])(=O)=O)(F)F.[Ag+]>[ClH:25].[ClH:25].[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=2)(=[O:24])=[O:23])=[CH:6]1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN(C)CCn1ccc2cccnc21
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=[N+]([O-])c1ccccc1
Product: CN(C)CCn1cc(S(=O)(=O)c2cccc(F)c2)c2cccnc21
Product: Cl
Temperature: 100 °C

Procedure:
A stirred solution of N,N-dimethyl-N-[2-(1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl]amine (1.66 g, 8.8 mmol) in nitrobenzene is treated with 3-fluorophenylsulfonyl chloride (1.88 g, 9.7 mmol) under nitrogen, followed by silver trifluoromethylsulfonate (2.94 g, 11.4 mmol), heated to 100° C. for 22 h, cooled and filtered through a cotton plug. The filtrate is treated with water and saturated aqueous NaHCO3 and extracted with CH2Cl2. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed eluting with 2:98 concentrated NH4OH:ethanol, to afford the free amine of the title compound as a viscous oil which solidifies (1.25 g, 41%). The free amine is dissolved in warm ethanol, treated with 4M HCl in dioxane and filtered. The filtercake is dried to give the title product as a pale yellow solid, 1.07 g (29% yield), mp 191-192° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N+:3]=1[O-].COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>>[CH3:1][C:2]1[N:3]=[C:4]([C:24]#[N:25])[CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Cc1cc(C=Cc2ccccc2)cc[n+]1[O-]
Reactant: [C-]#N
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: Cc1cc(/C=C/c2ccccc2)cc(C#N)n1

Procedure:
Following, the general method described in example 2b, 2-methyl-4-styryl-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and chromatography (SiO2 with CH2Cl2) the title compound was obtained as a yellow crystalline material. MS: m/e=220 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]#[C:13][Si](C)(C)C)[C:3]=1[NH2:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]#[CH:13])[C:3]=1[NH2:18]
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)cc(Br)c1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(C(F)(F)F)cc(Br)c1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
4.26 g of 2-bromo-4-trifluoromethyl-6-trimethylsilanylethynyl-phenylamine (13 mmol) were dissolved in 40 ml THF and the solution was cooled to 0° C. Then 15.2 ml of a 1 M solution of tetrabutylammonium fluoride in THF (15 mmol) were added and the reaction mixture was stirred for 20 min at 0° C. After addition of water, the mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried with magnesium sulfate, filtered and concentrated. 1.82 g (54%) of 2-bromo-6-ethynyl-4-trifluoromethyl-phenylamine were isolated as a brown solid after purification (silica gel; cyclohexane/EtOAc 9:1). 1H NMR (CDCl3, 300 MHz): δ 3.48 (s, 1H), 5.03 (br s, 2H), 7.54 (s, 1H), 7.65 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]#[CH:16])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.C(NCC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:4][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]#[C:16][C:29]1[CH:28]=[CH:27][C:26]([NH:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[CH:31][CH:30]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: Fc1ccccc1CNc1ccc(I)cc1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC#Cc1ccc(NCc2ccccc2F)cc1)NC(=O)OC(C)(C)C
Yield: 28.1 %

Procedure:
To a stirred solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D64, 365 mg, 1.60 mmol), prepared with analogous procedure to that described hereinabove, N-[(2-fluorophenyl)methyl]-4-iodoaniline (D63, 630 mg, 1.92 mmol) and diethylamine (0.82 ml, 585 mg, 8 mmol) was added CuI (30 mg, 0.08 mmol) and PdCl2(PPh3)2 (56 mg, 0.08 mmol). After stirring at room temperature for 5 h ethyl acetate was added and the solution was extracted with sat. ammonium chloride solution. The organic layer was dried (Na2SO4), filtered and evaporated. The resulting crude material was purified by flash chromatography using a cyclohexanes, ethyl acetate gradient (5%40%) on silica gel to afford the title compound (192 mg, 28%); UPLC: 0.88 min, MS: (ES/+) m/z: 427 [MH]+, C24H27FN2O4 requires 426.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=O)=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[F:31])[CH2:17][CH2:16]1)=[O:14].[CH:32]([O-:35])([CH3:34])[CH3:33].[Na+].[OH2:37]>>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:37])=[CH:6][CH:5]=[C:4]([O:35][CH:32]([CH3:34])[CH3:33])[C:3]=1[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=2[F:31])[CH2:19][CH2:20]1)=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3c(F)ccc(S(C)(=O)=O)c3F)CC2)c(F)c1
Reactant: O
Reactant: CC(C)[O-]
Agent: [Na+]
Product: CC(C)Oc1ccc(S(C)(=O)=O)c(F)c1C(=O)N1CCN(c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
0.2 mmol of (2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone were dissolved in a solution of sodium isopropanolate (prepared by dissolving 0.2 mmol of sodium in 1 ml of isopropanol). The reaction mixture was heated to 50° C. for 2 hours, then stirred at room temperature for 48 hours. The solution was diluted with water and extracted with ethyl acetate. The product was purified by chromatography (SiO2, ethyl acetate/cyclohexane 9:1) to yield the title compound as a colorless solid. MS (m/e): 517.1 (MH+, 100%)