Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](B(O)O)=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.Br[C:17]1[N:18]=[C:19]([CH2:36][CH3:37])[C:20]([NH:25][C@@H:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C@@H:27]2[OH:35])=[N:21][C:22]=1[CH2:23][CH3:24]>>[CH2:36]([C:19]1[C:20]([NH:25][C@@H:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C@@H:27]2[OH:35])=[N:21][C:22]([CH2:23][CH3:24])=[C:17]([C:4]2[C:3]([O:2][CH3:1])=[CH:12][C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[N:18]=1)[CH3:37]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: COc1cc2c(cc1B(O)O)CCCC2
Product: CCc1nc(-c2cc3c(cc2OC)CCCC3)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Yield: 67 %

Procedure:
Following the general procedure of Example 1 Step 3 and making non-critical variations but substituting 6-methoxy-2,3-dihydro-1H-inden-5-ylboronic acid (Preparation 2) with 3-methoxy-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid (Preparation 1), and substituting 5-bromo-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine with (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]indan-2-ol (303 mg, 0.84 mmol) and gave 550 mg of a crude orange oil. The crude was purified on a Biotage MPLC column (90 g column, 18% ethyl acetate in heptane) to give 249 mg (67%) of (1R,2S)-1-{[3,6-diethyl-5-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol as a glassy paste. Rf 0.20 (25% ethyl acetate in heptane). OAMS supporting ions at: ESI+444.3. HRMS (ESI) calcd for C28H33N3O2+H1 444.2651, found 444.2635.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[CH3:33][NH2:34]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26]([NH:34][CH3:33])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CN
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(Cl)ncn3)ccc12
Solvent: C1CCOC1
Product: CNc1cc(Cc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)ncn1

Procedure:
A solution of 40 mg (0.087 mMol) 6-(6-chloro-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide and 750 μl methylamine (2 M in THF; 1.5 mMol) in 1.5 ml THF is stirred in a sealed vessel for 20 h at rt and 3.5 h at 65° C. Concentration and chromatography (Combi Flash; EtOAc→EtOAc/EtOH 9:1) gives the title compound: MS: [M+1]+=455; TLC(EtOAc/EtOH 9:1): Rf=0.27.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].Cl.[F:11][C:12]([F:22])([F:21])[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1>>[F:22][C:12]([F:11])([F:21])[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:16][CH2:15]1
Reactant: NC1CCN(CC(F)(F)F)CC1
Reactant: COC(=O)C(Br)CCBr
Agent: Cl
Product: COC(=O)C1CCN1C1CCN(CC(F)(F)F)CC1
Yield: 8 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with 1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride 18G yielded methyl 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)azetidine-2-carboxylate as a light brown solid (8%). MS ISP (m/e): 281.1 (100) [(M+H)]+.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH2:8][CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:10][SiH:11]([Cl:13])[Cl:12]>>[C:1]([CH:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[Si:11]([Cl:13])([Cl:12])[Cl:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CCCC1
Reactant: Cl[SiH](Cl)Cl
Product: CC(C)(C)C1CCCC1[Si](Cl)(Cl)Cl
Yield: 60 %

Procedure:
A one-liter autoclave equipped with a stirrer was charged in a nitrogen atmosphere with 50 grams (0.40 mol) of 1-tert-butylcyclopentene, 108 grams (0.80 mol) of trichlorosilane and 20 grams (82 mmol) of 1,1'-azobis(cyclohexane-1-carbonitrle) and the mixture was reacted at a temperature of 130° C. for 3 days. The resulting reaction mixture was purified by distillation thereby obtaining 62 grams (0.24 mol) of 2-tert-butylcyclopentyltrichlorosilane. The structure of the resulting product was identified by 1H-NMR.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[N:29]#[C:30]Br>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:26][CH3:27])=[CH:9][C:10]3[C:11]4[N:18]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:30]([NH2:29])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: N#CBr
Reactant: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N)n(Cc3ccccn3)c12
Yield: 32 %

Procedure:
From 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-(2-pyridinylmethyl)-3,4-quinolinediamine (for a preparation see Intermediate 17) (35 mg) and cyanogen bromide (10 mg) to give the title compound as beige solid (12 mg, 32%). LCMS (formate) Rt 0.61 min, MH+ 401
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([O:28]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:6]3=[N:32][NH:33][C:26](=[O:28])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1Nc2cc(F)cc3c(=O)[nH]nc(c23)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
A mixture of ethyl 7-fluoro-3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (200 mg, 0.486 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain a white solid, which was then dried in vacuum at 50° C. to obtain the title compound (25.4 mg, yield 14%). LC-MS (ESI) m/z: 380 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 4.52-4.53 (d, J=6.8 Hz, 1H), 5.02-5.04 (m, 1H), 6.73 (s, 1H), 6.82-6.85 (m, 1H), 6.99-7.09 (m, 4H), 7.18-7.22 (m, 2H), 7.69 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Reaction time: 16 h

Procedure:
Hydrogenate 2-nitro-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (1.0 g, 0.0032 mol) with 50 psi of H2 and 100 mg of 10% Pd/C in ethanol. After 16 hours, filter the mixture through celite and concentrate under reduced pressure to give 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)(C)C>[CH2:29]([NH:36][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)=[O:17])=[CH:13][CH:14]=2)[N:5]=[CH:4][N:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Reactant: NCc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3cc(NCc4ccccc4)ncn3)cc2)cc1
Temperature: 70 °C
Reaction time: 21 h

Procedure:
Under N2-atmosphere, a suspension of N-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(4-tert-butylphenyl)-urea (397 mg, 1.00 mmol) and benzylamine (327 μM) in isopropanol (3 ml) is stirred for 21 h at 70° C. Then the reaction mixture is concentrated in vacuo, the residue re-dissolved in saturated NaHCO3 solution and AcOEt, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. The crude product is dissolved in CH2Cl2 and after addition of SiO2 again concentrated. The resulting powder is put on top of a SiO2-column and eluted with AcOEt/hexane 3:1, yielding the title compound: m.p.: 118-120° C.; 1H-NMR (DMSO-d6): 8.73 (s, HN), 8.62 (s, HN), 8.13 (s, 1H), 7.84 (s, HN), 7.46 (d, 2H), 7.35 (d, 2H), 7.30 (m, 4H), 7.28 (m, 2H), 7.24 (m, 1H), 7.03 (d, 2H), 5.78 (s, 1H), 4.49 (s, 2H), 1.26 (Me3C).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[NH:11][C:12]#[N:13].[Na].[CH2:15](Br)[CH:16]=[CH2:17]>C(O)C>[CH2:17]([N:11]([C:12]#[N:13])[C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[CH:9]=[CH:10][C:2]=1[Cl:1])[CH:16]=[CH2:15]
Reactant: N#CNc1c(Cl)ccc2nsnc12
Reactant: C=CCBr
Agent: [Na]
Solvent: CCO
Product: C=CCN(C#N)c1c(Cl)ccc2nsnc12
Reaction time: 3 h

Procedure:
The starting material is obtained as follows: 5 g 5-chloro-N-cyano-2,1,3-benzothiadiazol-4-amine are added to a solution of 0.55 g sodium in 60 ml ethanol and the mixture is reacted with 3 g allyl bromide. The mixture is agitated 3 hours under refluxing and the solvent evaporated under vacuum. The residue is extracted with methylene chloride. N-allyl-5-chloro-N-cyano-2,1,3-benzothiadiazol-4-amine (M.P. 62°-63°) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#[N:11].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([F:22])[CH:16]=1.C[Al](C)C.C1(C)C=CC=CC=1>CC1C=CC=CC=1C>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:10](=[NH:11])[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])([CH3:13])[CH3:12])=[C:17]([F:22])[CH:16]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(C)(C#N)c1c(Cl)cccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CC(C)(C(=N)Nc1ccc(Br)cc1F)c1c(Cl)cccc1Cl
Temperature: 100 °C
Yield: 46.6 %

Procedure:
2-(2,6-Dichlorophenyl)-2-methylpropanenitrile (20 g, 93 mmol) and 4-bromo-2-fluoroaniline (28.4 g, 149 mmol) were dissolved in anhydrous o-xylene (200 mL) and heated to 100° C. under N2. Trimethylaluminum (2 M) in toluene (140 mL, 280 mmol) was added drop-wise (˜0.9 mL per minute) over 2.5 hours while the reaction mixture was stirred at 100° C. After addition, the reaction mixture was stirred at 100° C. for 30 minutes, and then cooled to −5° C. The reaction mixture was very carefully quenched with potassium sodium tartrate (20 g in 100 mL water) (Caution: gas and heat formation). The reaction mixture was filtered through Celite 545. The filtrate was washed with 1N HCl (4×70 mL). The aqueous was neutralized with 2N NaOH and extracted with EtOAc (4×100 mL). The organics were combined, washed with brine, dried with Na2SO4, and concentrated on a rotary evaporator to afford 24 g of crude product. The crude product was recrystallized with 72 mL of MTBE and 240 mL of hexane to give N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (17.5 g, 43.3 mmol, 46.4% yield) as a white solid (purity: 99%). 1H-NMR (MeOD, 400 MHz) δ 7.42 (d, 2H, J=8.0 Hz), 7.30 (m, 2H), 7.16 (t, 1H, J=8.0 Hz), 6.93 (t, 1H, J=8.0 Hz), 2.11 (s, 6H); 13C-NMR (DMSO-d6, 100 MHz) δ 166.5, 156.1, 153.7, 140.6, 138.5, 135.9, 131.4, 128.6, 128.0, 125.7, 119.5, 112.9, 50.0, 29.2; MS m/e 403.09 (M+H+); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 2.32 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:18][CH2:19][CH3:20])[CH2:7][C@@H:6]([C:8]([O:10]CC)=[O:9])[C@@H:5]1[C:13]([O:15]CC)=[O:14])[CH3:2].CO.[OH-].[K+]>O1CCCC1>[CH2:19]([O:18][C:4]1([O:3][CH2:1][CH3:2])[CH2:7][C@@H:6]([C:8]([OH:10])=[O:9])[C@@H:5]1[C:13]([OH:15])=[O:14])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CC(OCC)(OCC)[C@H]1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC1(OCC)C[C@@H](C(=O)O)[C@@H]1C(=O)O
Reaction time: 72 h

Procedure:
A solution of trans-3,3-diethoxy-1,2-cyclobutanedicarboxylic acid, diethyl ester (100 g) in 1400 ml of tetrahydrofuran under argon was treated with 1400 ml of methanol and 1400 ml of 1N potassium hydroxide solution. The resulting mixture was allowed to stand for 3 days at room temperature and then was evaporated in vacuo to an aqueous solution. The pH was adjusted to 2.3 with 3N hydrochloric acid and the solution was saturated with sodium chloride. The resulting suspension was extracted with ethyl acetate (3×1000 ml). The combined extracts were washed with 250 ml of water and 250 ml of brine, dried over sodium sulfate, and evaporated to afford the product as solid, 78.8 g, m.p. 118°-120° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1ccc(-n2nccc2-c2ccnc(Cl)c2)cc1
Reactant: NCc1ccccc1
Product: Fc1ccc(-n2nccc2-c2ccnc(NCc3ccccc3)c2)cc1
Temperature: 180 °C
Yield: 89 %

Procedure:
A mixture of 2-chloro-4-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]pyridine (Example 46; 0.56 g, 0.002 mol) and benzylamine (20 mL) was heated at 180° C. overnight (about eighteen hours). The excess benzylamine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 0.63 g (89% yield) of product as a white solid: mp: 125-127° C.; Anal. Calc'd. for C22H17FN4: C, 73.24; H, 4.98; N, 16.27. Found: C, 72.89; H, 4.69; N, 15.82.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(O[CH:13](OCC)[N:14]([CH3:16])[CH3:15])C>CN(C=O)C>[CH3:13][N:14]([CH3:16])/[CH:15]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(OCC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
Acetophenone (1.18 mL) and N,N-dimethylformamide diethyl acetal (1.71 mL) were dissolved in DMF (4 mL) and the resulting mixture was stirred at 120° C. for 20 h. The solvent was removed in vacuo and the residue was crystallized in Et2O. The mother liquors were cooled to 0° C. and precipitation occurred. The solid was filtered off and combined with the first batch to afford (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (1.02 g of yellow solid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:11]=[N:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16](=[O:22])[NH:17]3)=[C:4]([O:30]C)[CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:25])([F:24])[F:26])[CH:11]2[NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16](=[O:22])[NH:17]3)=[C:4]([OH:30])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(C)(C)CC(O)(C=Nc1cccc2c1CC(=O)N2)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c2CC(=O)N3)c2cc(Br)cc(O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
235.9 mg of 4-{[4-(4bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}-1,3-dihydroindol-2-one is mixed at 0° C. with 6.42 ml of a 1 M solution of BBr3 in dichloromethane and stirred for four hours at room temperature. At 0° C., saturated sodium bicarbonate solution is carefully added in drops. After 3× extraction with ethyl acetate, the organic phases are dried on sodium sulfate. The desiccant is suctioned off, and the solvent is spun off. The residue is chromatographed on a Flashmaster. 125.4 mg (54%) of the desired compound is isolated.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[S:11]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12]1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>ClCCl>[CH2:23]([O:22][C:20](=[O:21])[NH:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][S:11][CH:12]=1)[CH3:24]
Reactant: NCCc1ccsc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NCCc1ccsc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
Add diisopropylethylamine (54.0 g, 418.0 mmol) to a suspension of 2-thiophene-3-yl-ethylamine hydrochloride in dichloromethane (400 mL) and stir the mixture for 40 min at RT. Cool the mixture to 0° C. and add dropwise ethyl chloroformate (22.7 g, 209.0 mmol) over 15 min. After the addition is complete, stir the reaction for 1 h at 0° C. Wash with 10% sodium bisulfate (500 mL). Extract the aqueous portion with dichloromethane (2×100 mL) and dry the combined organic portions over Na2SO4, filter and concentrate in vacuo. Purify the resulting residue by silica gel chromatography, using an eluent of 100% dichloromethane to give 22.6 g (60%) of the title compound. MS/ES m/z 200.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[Br:11].C(N1C=CN=C1)(N1[CH:18]=[CH:17]N=C1)=O.C(O)C>C(#N)C>[CH2:17]([O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[C:3]([Br:11])[CH:4]=[N:5][CH:6]=1)[CH3:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cncc(Br)c1Br
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)c1cncc(Br)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A suspension of 4,5-dibromonicotinic acid (10 g, 36 mmol) in acetonitrile (160 mL) under nitrogen was treated with 1,1′-carbonyldiimidazole (8.65 g, 53.4 mmol) in portions over 10 min. The resulting mixture was stirred for 3 h at room temperature. Ethanol (24 mL) was added and the mixture was heated to 55° C. for 16 h. The solution was then filtered and the filtrate evaporated in vacuo. The residual oil was dissolved in ethyl acetate and the solution was washed with water followed by brine. The organic fraction was then dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to afford 9 g (82%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.70 (s, 1H), 8.74 (s, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20].O>N1C=CC=CC=1>[F:23][C:22]([F:25])([F:24])[S:19]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)(=[O:20])=[O:18]
Reactant: Oc1cccc2ncccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Oc1cccc2ncccc12)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 5-hydroxy-quinoline (8 g, 55 mmol) and K2CO3 (15.2 g, 110 mmol) in anhydrous pyridine (60 mL) under nitrogen was cooled to −20° C. Tf2O (13.97 mL, 83 mmol) was added drop-wise via syringe. The reaction mixture was stirred 1 hour at −20° C. then warmed to 0° C. for 1 hour then stirred at ambient temperature for 48 hours. The reaction mixture was then poured into H2O (200 mL) and extracted in CH2Cl2 (2×200 mL). The aqueous layer was acidified with 1 N HCl (100 mL) and back extracted with CH2Cl2 (2×200 mL). The organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (40% EtOAc/Hexanes) affording 13.97 g (90%) of the product as a pink oil: MS EI m/e 277 (M+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:5]1[CH:6]=[CH:7][C:8]([C:16](O)=[O:17])=[N:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[NH2:26][C@@H:27]([CH2:31][CH:32]1[CH2:34][CH2:33]1)[C:28]([NH2:30])=[O:29]>>[C:28]([C@@H:27]([NH:26][C:16]([C:8]1[CH:7]=[CH:6][C:5]([N:4]([CH2:19][C:20]([F:21])([F:22])[F:23])[CH2:3][C:2]([F:24])([F:1])[F:25])=[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:9]=1)=[O:17])[CH2:31][CH:32]1[CH2:34][CH2:33]1)(=[O:29])[NH2:30]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-[bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=483.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-:14].[Na+]>CCN(C1C=CC=CC=1)CC>[NH2:14][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=[C:10]([CH3:13])[N:9]=1
Reactant: Cc1ccc(-c2ccccc2)cn1
Reactant: [NH2-]
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Product: Cc1ccc(-c2ccccc2)c(N)n1

Procedure:
A solution of 3-phenyl-6-methyl pyridine (0.815 g, 4.82 mmol), and sodium amide (752 mg, 19.3 mmol) in diethylaniline (10 mL) was heated at 180° C. for 72 hours. The reaction was cooled and quenched with ice (100 g), and the mixture extracted with EtOAc. The organic extract was washed with brine (50 mL), dried (MgSO4), silica gel (100 g) was added and the solvent evaporated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:17])[C:12](OCC)=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:12]([OH:13])[C:11]([OH:17])=[N:10]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(Cl)c(Cl)cc1N
Product: Oc1nc2cc(Cl)c(Cl)cc2nc1O

Procedure:
4,5-dichloro-o-phenylenediamine and diethyl oxalate were reacted by the procedure of Cheeseman [J.C.S., (1962), p. 1174] to obtain 6,7-dichloroquinoxaline-2,3-diol which was reacted with phosphorus oxychloride/phosphorus pentachloride to form 2,3,6,7-tetrachloroquinoxaline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[CH:13]=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH:21]1([CH2:26][NH:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C=O)C>[CH:21]1([CH2:26][N:27]([CH2:28][CH3:29])[C:2]2[N:7]=[C:6]3[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]3=[CH:4][C:3]=2[CH:13]=[O:14])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCNCC1CCCC1
Reactant: Cc1nn(C)c2nc(Cl)c(C=O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
A suspension of 6-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (5 g, 0.023 mol) and potassium carbonate (9.9 g, 0.0717 mol) in DMF (75 mL) was stirred for 20 min at RT. Cyclopentylmethyl ethyl amine (4.25 g, 33.0 mmol) was then added and the reaction was refluxed for 8 h. After cooling the reaction to RT, water (500 mL) was added to the reaction mixture and extracted with ethyl acetate (3×400 mL) and the combined organic layers were dried and concentrated. The residue was purified by silica gel (100-200 mesh) column chromatography. Elution with 10% ethyl acetate in hexanes gave the pure product as a colorless, gummy mass (yield: 76%).