Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25](O)=O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O>[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[NH:1][C:2]2[C:3]([C:4]([NH2:6])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2nc(-c3cnccn3)[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
A solution of 1.68 g (7.5 mmol) of 2,3-diaminobenzamide and 3.04 g (30 mmol) of triethylamine in 50 ml of dimethylformamide was stirred at room temperature for 1 hour. 0.93 g (7.5 mmol) of pyrazine-2-carboxylic acid and 1.01 g (7.5 mmol) of N-hydroxybenzotriazole (HOBt) were added. After stirring at room temp. for 15 minutes, the mixture was cooled to 0° C. 1.44 g (7.5 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) were added, and the mixture was stirred at room temp. for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The aqueous phase was extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate. The residue obtained after concentration in vacuo was taken up in 50 ml of glacial acetic acid and refluxed for 30 minutes. The reaction mixture was concentrated in vacuo, and the residue was stirred in diethyl ether. The precipitate was removed by filtration and dried at 40° C. in vacuo. 1.11 g of brown crystals were obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:29][NH2:30].CCCCCCC>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:29][NH2:30])=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1onc(-c2ccccc2)c1C(=O)NN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (5.00 g, 24.6 mmol) in THF (50 mL) was added in one portion 1,1′-carbonyl-diimidazole (4.39 g, 27.1 mmol). After stirring for 15 min at ambient temperature the solution was warmed to 70° C. and stirred for 30 min at this temperature. After the solution was cooled to 0° C. hydrazine monohydrate (2.4 mL, 49.0 mmol) was added over a period of 2 min while the temperature raised to 15° C. The resulting suspension was stirred for 30 min at 0° C. After addition of 20 mL heptane the suspension was stirred for 15 min at 0° C. and filtered off. Washing with water and drying afforded the title compound (4.52 g, 85%) as a white solid. MS: m/e=218.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Pd]
Product: Nc1ccc(CCN2CCN(c3ccc(N)cc3)CC2)cc1

Procedure:
1-(4-Nitrophenyl)-4-(4-nitrophenethyl)piperazine (3.35 g) in methylated spirit (400 ml) was hydrogenated at 45° and 60 psi over 10% Pd/C (about 300 mg) for 3 hours. The catalyst was then removed by filtration and the filtrate evaporated to dryness, giving an off-white residual solid which was crystallized from ethyl acetate (charcoal); yield of the title compound 2.1 g, m.p. 156°-8°.
Reaction SMILES: C[O:2][C:3]([C:5]1[C@H:9]([CH2:10][Si:11]([CH3:19])([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:7][CH:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:27][C:24]([Si:21]([CH3:23])([CH3:22])[O:20][C@@H:8]1[C@@H:9]([CH2:10][Si:11]([CH3:19])([CH3:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:3][OH:2])=[CH:6][CH2:7]1)([CH3:25])[CH3:26]
Reactant: COC(=O)C1=CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C[Si](C)(C)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC=C(CO)[C@@H]1C[Si](C)(C)c1ccccc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of 43 (15 g, 37.13 mmol) in hexanes (100 mL) was added diisobutylaluminum hydride (113 mL, 113.4 mmol, 1 N in hexanes) at −78° C. slowly over a period of 30 minutes keeping the temperature below −60° C. The resulting mixture was stirred for 2 hours at the same temperature to complete the reaction. The reaction mixture was quenched by addition of sodium hydroxide (2 N, 200 mL). The organic layer was separated and washed with water, brine, and dried over magnesium sulfate. The organic layer was concentrated in vacuo to dryness to give the crude title compound (13 g, 100% yield).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:25]1[CH:26](C)[O:27][C:28](=[O:31])[C:29]=1[F:30])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:30][C:29]1[C:28](=[O:31])[O:27][CH2:26][C:25]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: CC1OC(=O)C(F)=C1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(F)C(=O)OC1)C2=O

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (150 mg, 0.590 mmol), 4-fluoro-2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (148 mg, 0.590 mmol), xantphos (34.1 mg, 0.059 mmol), water (0.032 mL, 1.77 mmol) in toluene (20 mL) was degassed by nitrogen followed by addition of palladium acetate (6.6 mg, 0.029 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCC>O1CCCC1>[Br:20][CH:8]([C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)c1cc(Cl)cc(-c2ccc(C#N)cc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(Br)c1cc(Cl)cc(-c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (±)-3′-chloro-5′-(1-hydroxyethyl)biphenyl-4-carbonitrile (171 mg, 0.664 mmol) and carbon tetrabromide (264 mg, 0.796 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triphenylphosphine (209 mg, 0.796 mmol). The resulting solution was stirred at room temperature for 45 min. The reaction was diluted with ca. 2 volumes of pentane and filtered to remove the undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (3%→8% ethyl acetate/hexanes) to give 201 mg (94%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.74 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.50 (s, 1H), 7.47 (s, 2H), 5.18 (q, J=6.7 Hz, 1H), 2.06 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 146.1, 143.8, 141.5, 135.4, 132.8, 127.9, 127.3, 127.1, 124.2, 118.6, 112.1, 47.4, 26.8.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[C:6]2[C:16](=[O:19])[CH2:17][CH2:18][C:5]=2[N:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:3]1=[O:30].O=C1N(C2C=CC=C(C(F)(F)F)C=2)C2CCC(=O)C=2[C@@H](C2C=CC(C#N)=CC=2)N1>>[CH3:1][N:2]1[C@H:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[C:6]2[C:16](=[O:19])[CH2:17][CH2:18][C:5]=2[N:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=2)[C:3]1=[O:30]
Reactant: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Agent: N#Cc1ccc([C@H]2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)[C@H]1c1ccc(C#N)cc1

Procedure:
The title compound is prepared in analogy to 4-(3-methyl-2,5-dioxo-1-(3-(trifluoromethyl)-phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 2), using (R)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1A, 40 mg, 0.10 mmol) as starting material. Yield: 20 mg; ESI mass spectrum [M+H]+=412; Retention time HPLC: 0.59 min (X012_801).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[C:10]([O:16][OH:17])([CH2:13][CH2:14][CH3:15])([CH3:12])[CH3:11].C1(O)C=CC=CC=1>>[C:10]([O:16][O:17][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3])([CH2:13][CH2:14][CH3:15])([CH3:12])[CH3:11]
Reactant: C=C(C)c1ccccc1
Reactant: CCCC(C)(C)OO
Solvent: Oc1ccccc1
Product: CCCC(C)(C)OOC(C)(C)c1ccccc1
Yield: 87.8 %

Procedure:
Into the 200 ml jacketed reactor described in Example II were added 15.6 grams (0.13 m) alpha-methylstyrene, 15.0 grams (0.104 m) 82% t-hexyl hydroperoxide and 4.0 grams (0.043 m) phenol. The mixture was stirred to obtain a clear solution and the temperature was adjusted to 20° C. To this solution was added 1.5 grams (0.0095 m) of t-cumyl chloride from the addition funnel over 5 minutes while holding the temperature at 21°-22° C. The reaction self-exothermed to 25° C. over 10 minutes and then was stirred an additional 1/2 hour at 25° C. The reaction was then stirred 80 minutes at 35° C. and 90 minutes at 40° C. at which point the reaction was complete. The reaction was terminated by adding 25 mls of water, stirring 5 minutes, adding 5 mls of 50% NaOH, stirring another 5 minutes and separating the aqueous caustic layer. The organic layer was successively washed with 25 mls of 15% NaOH, saturated NaHCO3 solution, water, 15% NaHSO3 solution, saturated NaHCO3 solution and water. After drying with anhydrous sodium sulfate the crude product weighed 26.7 grams and contained 80.6% cumyl t-hexyl peroxide for a corrected yield of 21.5 grams and a 87.8% yield. The pure cumyl t-hexyl peroxide was isolated by fractional distillation under vacuum.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>ClC1C=CC=CC=1Cl.[Cu]>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Ic1ccccn1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: c1ccc(N2c3ccccc3Sc3ccccc32)nc1
Yield: 70 %

Procedure:
To start with, 2.35 g (11.8 mmol) of phenothiazine (product of Tokyo Kasei Kogyo Co., Ltd.), 3.63 g (17.7 mmol) of 2-iodopyridine (product of Tokyo Kasei Kogyo Co., Ltd.), 6.5 g of potassium carbonate, 1.5 g of copper powder, and 0.31 g of 18-crown-6-ether were mixed with the use of 20 ml of o-dichlorobenzene as a solvent, followed by reflux under a nitrogen atmosphere for 16 hours. After that, copper and inorganic salt were removed and then column purification using a toluene solvent was performed to give a ligand ppt (10-(2-pyridyl)phenothiazine) (opaque white powder; yield: 70%). A summary of the synthesis scheme is shown in the following (a-1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][OH:13])[CH2:9][N:8]3[CH:14]=[C:15]([C:17]([NH2:19])=[O:18])[N:16]=[C:7]3[C:6]=2[CH:20]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:23]=1>>[OH:31][C:27]([C:24]1[CH:23]=[C:22]([CH3:21])[O:26][N:25]=1)([CH3:28])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][OH:13])[CH2:9][N:8]3[CH:14]=[C:15]([C:17]([NH2:19])=[O:18])[N:16]=[C:7]3[C:6]=2[CH:20]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(CO)C2
Product: Cc1cc(C(C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CC(CO)O3)no1
Yield: 40 %

Procedure:
Similar to as described in General Procedure G, racemic 10-bromo-6-(hydroxymethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with racemic 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as a yellow solid (mixture of diasteromers, 98 mg, 40%).
Reaction SMILES: [F:1][C:2]1[O:6][C:5]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:4]=2[CH:3]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:5]3[O:6][C:2]([F:1])=[CH:3][C:4]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:23]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1cc2oc(F)cc2cc1-c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2oc(F)cc2cc1-c1ccc(NC(=O)c2c(F)cccc2F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To a solution of 5-(2-fluoro-6-methylbenzo[b]furan-5-yl)-2-pyridylamine (231) (23 mg, 0.095 mmol) in 3 ml DCM was added 2,6-difluorobenzoyl chloride (36 μl, 3 eq) followed by addition of DIEA (149 μl). The resulting solution was stirred overnight at r.t. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 3 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 2 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished (2,6-difluorophenyl)-N-[5-(2-fluoro-6-methylbenzo[b]furan-5-yl)(2-pyridyl)]carboxamide (223) (24.9 mg, yield: 68.6%, purity>95%) as white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=[O:21])[CH2:14]2>>[OH:21][C:15]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:16]2[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]2)[CH2:14]1
Reactant: Brc1ccncc1
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Product: OC1(c2ccncc2)CN2CCC1CC2
Yield: 56.8 %

Procedure:
By the procedure described in Description 1, n-butyl lithium (1.6M in hexanes, 19.5 ml, 31.2 mmol), 4-bromopyridine (5.37 g, 34.0 mmol) and 3-quinuclidinone (3.90 g, 31.2 mmol) gave 3.62 g of the title compound as a tan powder. The dihydrochloride salt was prepared; m.p. 225°-235° C.; Found: C, 50.50; H, 6.39; N, 9.76. C12G20N2, Cl2O.0.5H2O requires C, 50.36; H, 6.69; N, 9.79; δ(360 MHz, D2O) 8.854 (2H, d, J=6.8 Hz, py-H), 8.207 (2H, d, J=6.8 Hz, py-H), 4.016 (1H, d, J=14.2 Hz, H-2ax), 3.696 (1H, d, J=14.2 Hz, H-2eq), 3.52-3.30 (4H, m, H2 -6 and H2 -7), 2.70-1.60 (5H, m, H-4, H2 -5 and H2 -8); m/e 204 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.C(N(CC)CC)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CN(C=O)C>[F:10][C:4]1[CH:3]=[C:2](/[CH:20]=[CH:19]/[C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: C=CC(=O)OCC
Reactant: Oc1c(F)cc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc(F)c(O)c(F)c1
Temperature: 110 °C
Reaction time: 21 h
Yield: 68.1 %

Procedure:
In a 350-mL pressure-tube was added 4-bromo-2,6-difluorophenol (23.82 g, 0.11 mol), triethylamine (55 mL, 0.39 mol), ethyl acrylate (34.27 g, 0.34 mol), DMF (50 mL), palladium (II) acetate (1.29 g, 5.75 mmol), and tri-o-tolyphosphine (2.34 g, 7.6 mmol) under N2. The mixture was sealed in the glass tube and was stirred at 110° C. overnight (21 hours). The reaction was cooled to room temperature and EtOAc (150 mL) was added. The mixture was stirred for 30 minutes, filtered through celite and rinsed with EtOAc (100 mL×3). The filtrate was acidified with 2N HCl to pH ˜2. The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL×2). The organic layers were combined and washed with water ((100 mL×2), brine (100 mL) and dried over sodium sulfate. After filtration, heptane (200 mL) was added and the solution was concentrated in vacuo. The resulting precipitate was filtered, washed with heptane (50 mL×2) and dried to afford the desired product (10) (17.09 g) as a light-yellow solid. The mother liquor was concentrated to obtain additional desired product (4.29 g) as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.50 (d, J=15.9 Hz, 1H), 7.09 (d, J=8.3 Hz, 2H), 6.29 (d, J=15.9 Hz, 1H), 5.54 (br, 1H), 4.26 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: [ClH:1].O(CCCNC(C)(C)CC1C=CC([O:21][CH3:22])=CC=1)C1C=CC=CC=1.Cl.[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1C)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1>>[ClH:1].[OH:26][CH:27]([CH2:42][O:43][C:44]1[CH:49]=[C:48]([O:21][CH3:22])[CH:47]=[C:46]([Cl:1])[CH:45]=1)[CH2:28][NH:29][C:30]([CH3:41])([CH3:40])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cc(Cl)cc(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 378 (M−15, 0.1), 275 (5), 274 (34), 273 (16), 272 (100), 163 (5), 121 (17), 114 (8).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[C:6](=[N:13]O)[CH2:5]2.Cl>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH2:7][CH:6]([NH2:13])[CH2:5]2
Reactant: O=C1C(=NO)Cc2cc(F)c(F)cc21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: NC1Cc2cc(F)c(F)cc2C1
Reaction time: 24 h
Yield: 31 %

Procedure:
To an acetic acid solution (100 mL) containing 5,6-difluoro-1H-indene-1,2(3H)-dione 2-oxime (3.97 g, 20.2 mmol) in a Parr bottle was added 8 mL of concentrated HCl followed by 10% Pd/C (1.07 g). The solution was hydrogenated at 50 psi for 24 hours on a Parr hydrogenator. The heterogeneous solution was filtered through a bed of Celite with the celite being rinsed thoroughly with chloroform. The solvent was then removed in vacuo and the residual dark oil dissolved in water. The aqueous solution was then made basic with solid K2CO3. The organics were extracted with chloroform three times followed by drying over MgSO4. The solvent was removed in vacuo and the residual amber oil purified by column chromatography (10% MeOH/CH2Cl2) yielding 1.06 g (6.26 mmol) of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine as a brown oil. 1H NMR (400 MHz, CDCl3) delta 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J=15.8, 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz) ppm; (M+1) 170.1, 0.68 min (LC/MS method A). The oil was dissolved in diethyl ether (˜5 mL) and 4.0 mL of a 4.0 M dioxane solution of HCl (16.0 mmol) was added. The resulting precipitate was triturated with diethyl ether and collected by vacuum filtration yielding 795 mg (3.87 mmol, 19% yield) of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine hydrochloride as an off-white solid.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([NH2:13])[NH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][O:17][C:16]2[CH:20]=[C:21]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])[CH:22]=[CH:23][C:15]1=2>C(O)(=O)C>[CH2:1]([C:8]1[N:9]=[C:10]2[NH:13][C:24]([C:21]3[CH:22]=[CH:23][C:15]4[O:14][CH2:19][CH2:18][O:17][C:16]=4[CH:20]=3)=[CH:25][C:26](=[O:27])[N:11]2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(Cc2ccccc2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(c1)OCCO2
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc3c(c2)OCCO3)[nH]c2nc(Cc3ccccc3)nn12
Temperature: 110 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
A mixture of 5-benzyl-2H-1,2,4-triazol-3-amine (174 mg, 1.00 mmol, 1.00 equiv), acetic acid (3 mL), and ethyl 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopropanoate (275 mg, 1.10 mmol, 1.10 equiv) was stirred overnight at 110° C. The reaction was concentrated to dryness and purified with prep-TLC (MeOH:DCM=1:30) to afford 30.7 mg (8%) of 2-benzyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1CCOCC1.[OH-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(Cl)c1OCc1ccccc1
Reactant: C1COCCO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: O
Product: Oc1cccc(F)c1OCc1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 2-(benzyloxy)-1-chloro-3-fluorobenzene (3 g, 12.71 mmol), dioxane (6 ml), KOH (0.78 g, 14 mmol), water (6 ml), Tris(dibenzylideneacetone)dipalladium (0.12 g, 0.13 mmol) and 2-di-tertbutylphosphine-2,4,6-triisopropylbiphenyl (0.22 g, 0.51 mmol) was flushed with N2 and heated under microwave radiation at 120° C. for 7 min. HCl (1 N) was added and the solution was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and evaporated to dryness. Flash column chromatography (isooctane/EtOAc) yielded the title compound (1.86 g). MS m/z (rel. intensity, 70 eV) 218 (M+, 4), 92 (8), 91 (bp), 65 (13), 51 (9).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=O.[NH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[NH2:12].C(=O)([O-])[O-].[Cs+].[Cs+].CN1C(=O)CCC1>C(OC(=O)C)C.O>[I:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[N:12]=[CH:4]2
Reactant: NNc1ccccn1
Reactant: O=Cc1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Ic1ccc2c(cnn2-c2ccccn2)c1
Temperature: 100 °C
Yield: 4.6 %

Procedure:
2-Fluoro-5-iodobenzaldehyde (527 mg, 2.11 mmol), 2-hydrazinopyridine (237 mg, 2.17 mmol), cesium carbonate (2.06 g, 6.32 mmol) and NMP (10 ml) werer charged in a 10 ml vial which was sealed and stirred (magnetic bar) over night at 100° C. Water and ethylacetate were added and the phases was separated. The organic layer was washed three times with brine and concentrated. Purification on silica with ethylacetate:heptane 5:95 to 10:90 over 15 min, 10 ml/min, followed by evaporation afforded 31 mg (5%) of 5-iodo-1-pyridin-2-yl-1H-indazole.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14](OB([O-])[O-])=[C:15](F)F.[K+].[K+]>C(O)(C)C.O.C(N)(C)(C)C>[F:10][C:9]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:2]=1[CH:14]=[CH2:15])[NH2:6]
Reactant: [O-]B([O-])OC(F)=C(F)F
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)(C)N
Product: C=Cc1ccc(N)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
In 20 mL of isopropanol, 10 mL of water and 5 mL of t-butylamine, 4.0 g (16.7 mmol) of 4-bromo-3-(trifluoromethyl)aniline was dissolved, and 4.0 g (29.9 mmol) of potassium (trifluoro)vinylborate and 300 mg (0.37 mmol) of PdCl2(dppf)2•2(dichloromethane) complex were added thereto, and the mixture solution was stirred in an argon atmosphere at 80° C. for 20 hours. The reaction solution was concentrated and the residue was partitioned between water and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The product was purified by a silica gel column (n-hexane:ethyl acetate=6:1) to obtain 2.475 g (79%) of a target product as a pale yellow oil.