Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[O:11])[CH2:7][C:6]=2[CH:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:63][CH2:62][CH:61]([O:64][CH2:65][C:66](O)=[O:67])[CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:69]([F:72])([F:71])[F:70])([O-:50])=[O:49]>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:66](=[O:67])[CH2:65][O:64][CH:61]4[CH2:62][CH2:63][CH:58]([NH:57][C:54]5[CH:55]=[CH:56][C:51]([N+:48]([O-:50])=[O:49])=[C:52]([C:69]([F:71])([F:70])[F:72])[CH:53]=5)[CH2:59][CH2:60]4)[CH2:16][CH2:17]3)=[O:11])[CH2:7][C:6]=2[CH:18]=1
Reactant: O=C(C1Cc2cc(F)ccc2O1)N1CCNCC1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(C(=O)C2Cc3cc(F)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
In a 50 ml round-bottomed flask containing a solution of (5-fluoro-2,3-dihydro-benzofuran-2-yl)-piperazin-1-yl-methanone (76 mg, 0.30 mmol, 1.1 eq) in 30 ml of dichloromethane was added EDAC.HCl (76 mg, 0.40 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine (56 mg, 0.55 mmol, 2.0 eq), and [4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acid (100 mg, 0.28 mmol). The solution was stirred overnight at room temperature before diluting with 30 ml of water. The crude product was then extracted from the mixture using 3×30 ml of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using ethyl acetate/dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 72 mg of the desired amide as a yellow solid (44%); 1H NMR (300 MHz, CDCl3): δ 8.04 (d, J=6.6 Hz, 1H), 6.95 (d, J=5.4, 1H), 6.83 (m, 2H), 6.66 (m, 2H), 5.43 (m, 1H), 4.25 (s, 1H), 3.75-3.95 (m, 4H), 3.27-3.80 (m, 8H), 2.12-2.22 (m, 4H), 1.50 (dd, J=7.8 Hz, 16.8 Hz, 2H), 1.31 (dd, J=7.8 Hz, 16.8 Hz, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1)=[C:16]=[S:17]>>[OH:4][CH2:3][CH:2]([NH:1][C:16]([NH:15][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1)=[S:17])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(C(F)(F)F)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-(trifluoromethyl)phenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.54 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.66 (d, J=8.7 Hz, 2H), 7.43 (d, J=6.3 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.2 Hz, 2H), 6.88-6.69 (m, 4H), 6.61-6.50 (m, 2H), 5.27-5.07 (m, 1H), 3.48-3.40 (m, 1H), 3.40-3.24 (m, 1H); ESIMS m/z 552 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1>>[C:3]([C:2]([NH:1][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:19][CH:20]=1)=[O:25])([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)#[N:4]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)cc(Cl)c2n1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(Cl)c2n1)NC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 15, and 4-biphenyl carbonyl chloride, the title compound was isolated as a white solid (32 mg). MS (ES): M/Z [M+H]=450. NMR: (400 MHz, DMSO-d6): 1.78 (s, 3H), 5.45 (d, J=13.3 Hz, 1H), 5.55 (d, J=13.3 Hz, 1H), 7.43 (m, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.70-7.78 (m, 3H), 7.81 (d, J=8.4 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.18 (d, J=1.6 Hz, 1H) and 8.83 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](O)=O)=[N:4][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:6][N:7]=1.[CH3:22][C:23]1[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=1.C(OP(C#N)(OCC)=O)C.C(N(CC)CC)C>COCCOC>[CH2:17]([S:14]([N:11]1[CH2:12][CH:13]=[C:8]([C:5]2[N:4]=[C:3]([C:19]3[NH:29][C:26]4[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][C:25]=4[N:30]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: Cc1ccc(N)c(N)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nc4cc(C)ccc4[nH]3)n2)CC1
Temperature: 170 °C
Yield: 36.7 %

Procedure:
A mixture of 3-amino-6-(1-ethylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylic acid (100 mg, 0.320 mmol), 4-methylbenzene-1,2-diamine (39.12 mg, 0.320 mmol), diethoxyphosphorylformonitrile (47.83 uL, 0.320 mmol) and triethylamine (44.63 uL, 0.320 mmol) in DME (1 mL) were heated in a microwave at 170° C. for 90 min. After this time the reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound (46.8 mg, 21% Yield). 1H NMR (400.0 MHz, DMSO) d 8.34 (s, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.46 (s, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.78 (s, 1H), 4.00 (d, J=2.8 Hz, 2H), 3.50 (t, J=5.7 Hz, 2H), 3.16 (q, J=7.4 Hz, 2H), 2.78 (s, 2H), 2.46 (s, 3H) and 1.25 (t, J=7.4 Hz, 3H) ppm; MS (ES+) 399
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[N:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[N:16]3)[S:12][CH:13]=2)OCC[O:5]1.Cl.[OH-].[Na+]>C1COCC1>[N+:20]([C:18]1[CH:17]=[N:16][N:15]([CH2:14][C:11]2[S:12][CH:13]=[C:9]([C:4](=[O:5])[CH3:3])[N:10]=2)[N:19]=1)([O-:22])=[O:21]
Reactant: CC1(c2csc(Cn3ncc([N+](=O)[O-])n3)n2)OCCO1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1csc(Cn2ncc([N+](=O)[O-])n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-4-nitro-2H-[1,2,3]triazole (2.360 g, 7.94 mmol) in THF (40.0 mL) was treated with 1N HCl (21.4 mL, 21.4 mmol) and the reaction mixture was stirred at rt overnight. The reaction mixture was neutralized with 1N NaOH. The aq. layer was extracted twice with EA (20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow solid: TLC:rf (6:4 hept-EA)=0.29. LC-MS-conditions 02: tR=0.81 min, [M+H]+=254.35.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>CO.[Pd]>[C:20]1([C:14]2([CH2:13][NH:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[CH:2][N:11]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1nc(NCC2(c3ccccc3)CCCCC2)c2ccccc2n1
Agent: [Pd]
Solvent: CO
Product: c1ccc(C2(CNc3ncnc4ccccc34)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A solution of (2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-amine (0.065 g; 0.18 mmol) in anhydrous methanol (2 mL) was treated with 10% palladium on carbon (200 mg) and placed under an atmosphere of hydrogen (45 psi). The reaction mixture was shaken at room temperature for 3 h. The reaction mixture was filtered through celite and evaporated. The crude residue was purified by column chromatography on silicia gel using 9:1 ethyl acetate:hexane as the eluent to give 0.052 g (1-phenyl-cyclohexylmethyl)-quinazolin-4-yl-amine as a white foam. LCMS m/z=318.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([Cl:19])[C:3]=1[NH2:4].C(N(CC)CC)C.[F:27][C:28]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31].[OH-].[Na+]>CN(C)C1C=CN=CC=1.O1CCCC1>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:10]([F:13])([F:12])[F:11])[C:14]([F:15])([F:16])[F:17])[CH:6]=[C:5]([Cl:19])[C:3]=1[NH:4][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:36]([N+:37]([O-:39])=[O:38])[C:28]=1[F:27]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1F
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1F
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
In a dried 4.5 l reactor equipped with mechanical stirrer, thermometer, reflux condenser, 1 liter dropping funnel, under inert atmosphere, was dissolved 2-bromo-6-chloro-4-(1,1,1,2,3,3,3-heptafluoro-prop-2-yl)aniline (described in WO/10127926) (177 g, 0.473 mol, 1 equiv.) in anhydrous tetrahydrufurane (800 ml) at 20° C. Triethylamine (143 g, 1.418 mol, 3 equival.) and 4-dimethylaminopyridine (0.58 g, 4.73 mmol, 0.01 equiv.) were added. To the dark red solution was added, under stirring, a solution of 2-fluoro-3-nitro-benzoyl chloride (0.993 mol, 2.1 equiv.) in tetrahydrofurane (800 ml). After the addition, the orange suspension was heated with an oil bath to reflux temperature for four days. The reaction progression was monitored by LC-MS analysis of the reaction mixture. After almost complete conversion to the corresponding imide, the reaction mixture was concentrated under reduced pressure and the residue was taken up in dichloromethane (1 l) and carefully treated, under stirring, with a saturated aqueous solution of sodium hydrogenocarbonate (500 ml). After the gas evolution had ceased, the layers were separated and the organic layer was concentrated under reduced pressure. The residue was taken up in tetrahydrofurane (1 l) and treated with 2 N aqueous sodium hydroxide (470 ml, 0.94 mol, 2 equiv.) at 20° C. in order to hydrolyze the intermediate imide. The reaction was followed by LC-MS analysis. After 30 minutes, the reaction mixture was concentrated under reduced pressure and the resulting aqueous mixture was extracted with ethyl acetate (1 l). The aqueous phase was further extracted with three portions of ethyl acetate (200 ml each) and the combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude product was dissolved in methanol (1.5 l) at 50° C. Water (600 ml, at 50° C.) was added. A suspension formed, that was stirred until cooled to 20° C., then filtered. The residue was washed three times with 300 ml of a mixture of methanol/water:5/1. After drying, the titel compound was isolated as brown crystals with a melting point of 177-180° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2(O)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:24]>O1CCOCC1>[ClH:24].[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C2=CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of tert-butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate (6.5 g, 20 mmol) in 1,4-dioxane (100 mL) at 0° C. was added 50 mL of 1M HCl (dioxane solution) and the mixture was allowed to warm to rt and stirred for 12 h. The solvent was then removed under reduced pressure. The residue was triturated with ethyl acetate to obtain 4.5 g crude 4-(3-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride as a solid which was was isolated by filtration and used without further purification. LCMS (Method P) RT 0.57 min, m/z 208 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37-2.61 (m, 2H), 3.12-3.38 (m, 3H) 3.80-3.94 (m, 3H) 3.95-4.12 (m, 2H) 7.10-7.29 (m, 1H) 7.33-7.44 (m, 1H) 7.51 (dd, J=13.05, 2.51 Hz, 1H) 9.27-9.63 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22]C(=O)C)=[N:19][CH:20]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[N:19][CH:20]=1
Reactant: CC(=O)OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
A mixture of [5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]acetate (18.00 g), 1N aqueous sodium hydroxide solution (75 ml) and methanol (100 ml) was stirred at room temperature for 3 hours, and concentrated. The residue was dissolved in ethyl acetate, which was washed with water and saturated aqueous sodium chloride solution. The organic layer was dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethanol (14.29 g, yield 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 125–126° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:27]([N:25]([CH3:26])[C:24]1[C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:30]([O:32][CH3:33])=[O:31])=[CH:19][CH:18]=2)([CH3:29])[CH3:28]
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of 1-methyl-1H-indazol-5-ylboronic acid (180 mg, 1.02 mmol) in dioxane (3 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 109 mg, 0.37 mmol), K3PO4 (175 mg, 0.83 mmol), Pd(PPh3)4 (29 mg, 0.03 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 10% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylate as a light yellow solid (110 mg, 76%).
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1.[Br:26]N1C(=O)CCC1=O>C(#N)CC>[Br:26][CH2:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:24]#[N:25])=[CH:21]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc2ccc(C#N)cc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCC#N
Product: N#Cc1ccc2ccc(CBr)cc2c1
Temperature: 80 °C
Yield: 25.7 %

Procedure:
2,2′-azobisisobutyronitrile (491 mg, 3 mmol) and propionitrile (50 ml) were added to 7-methyl-2-naphthalene carbonitrile (5.0 g, 30 mmol) at room temperature. N-bromosuccinimide (5.3 g, 30 mmol) was added thereto, and the mixture was heated at an internal temperature of 80° C. for 4 hours. After that, the experiment was conducted in the same way as Example 12. Analysis by reversed-phase chromatography by use of the obtained product from Example 11 as a standard sample revealed that 1.9 g of the title compound was obtained (26% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[Mg].[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([C:19]([C:6]2[CH:7]=[CH:8][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: C[Si](C)(C)c1ccc(Cl)cc1
Agent: [Mg]
Product: CN(C)c1ccc(C(=O)c2ccc([Si](C)(C)C)cc2)cc1

Procedure:
A Grignard reagent prepared from 0.2 mole of 4-trimethylsilylchlorobenzene and 0.2 mole of magnesium was reacted with 0.2 mole of 4-dimethylaminobenzaldehyde. The resulting reactant was subjected to oxidation by the Oppenauer method, to yield 4-dimethylamino-4'-trimethylsilyl benzophenone.
Reaction SMILES: [CH3:1][N:2]([C:4](/[CH:6]=[CH:7]/[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5])[CH3:3].[Br:14]Br.C(N(CC)CC)C>ClCCl.CCOCC>[CH3:1][N:2]([C:4](/[C:6](/[Br:14])=[CH:7]/[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:5])[CH3:3]
Reactant: CN(C)C(=O)/C=C/C1CCCCC1
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)C(=O)/C(Br)=C/C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To an ice cold solution of 1.18 g (6.51 mmol) of 1-cyclohexyl-3-dimethylamino-propenone in 8 mL of dichloromethane was added dropwise 1.04 g (6.51 mmol) of bromine via an addition funnel. The reaction mixture was stirred at 0° C. for 0.5 h and then 0.9 mL (6.51 mmol) of triethylamine in 10 mL of ether was added dropwise. The mixture was stirred at 0° C. for 1 h and allowed to warm up to rt. A light yellow solid precipitated from the solution, and it was separated by filtration. The filtrate was then concentrated to give 1.69 g of 2-bromo-1-cyclohexyl-3-dimethylamino-propenone as a brown solid as indicated by 1H NMR. The product was used in the next reaction without any further purification.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[C:17](Cl)([Cl:19])=[O:18]>ClCCl>[CH2:1]([N:3]([CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:17]([Cl:19])=[O:18])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCNC1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(=O)Cl)C1CCOCC1
Temperature: 25 °C

Procedure:
At −30° C., a solution of 19 g (0.15 mol) of ethyl(tetrahydro-2H-pyran-4-yl)amine and 14.8 g (0.15 mol) of triethylamine in 10 ml of dichloromethane was slowly added dropwise to a solution of 44 g (0.44 mol) of phosgene in 100 ml of dichloromethane. The mixture was slowly warmed to room temperature (over a period of approximately 3 hours) and then heated under reflux for 30 minutes, excess phosgene was removed using a nitrogen stream, and the solution was concentrated. 200 ml of hexane were added, the solids were filtered off and the filtrate was concentrated. Yield 25.3 g. MS (m/z): 192 [M+H]+, 156 [M−Cl]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11]C(=O)CC)[CH2:5]2.O.[ClH:17]>CCOCC.C1COCC1>[ClH:17].[NH2:11][CH:6]1[CH2:7][C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH2:5]1
Reactant: CCC(=O)NC1Cc2ccc(N)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NC1Cc2ccccc2C1
Temperature: 25 °C
Yield: 90 %

Procedure:
Amide 25 (0.62 g, 3.0 mmol) was dissolved in 8 mL of dry ether, and BH3 (16 mL of a 1 M solution in THF) was added dropwise, over a 1 h period. After the addition was completed, the reaction mixture was heated to reflux for 1 h. The mixture was cooled to room temperature, and 1.6 mL of water was added cautiously. Subsequently, 3.2 mL of 10% HCl was added, and all volatile solvents were evaporated under reduced pressure. The remaining aqueous solution was basified with 10% NaOH and extracted with ethyl acetate (2 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure, which yielded 23 as a clear oil (0.52 g, 90%): 1H-NMR (CDCl3, 200 MHz) 0.92 (t, J=7.3, 3H), 1.43-1.61 (m, 2H), 2.58-2.71 (m, 4H), 3.00-3.11 (m, 2H), 3.52-3.65 (m, 3H), 6.49 (d, J=7.8, 1H), 6.55 (s, 1H), 6.96 (d, J=7.8, 1H); 13C NMR 11.6, 23.2, 38.9, 39.9, 50.0, 59.8, 111.5, 113.4, 125.0, 131.6, 142.9, 145.0; MS (EIPI) m/e 190 (M+). Part of the product was converted to the dihydrochloride and recrystallized from ethanol, yielding white crystals: mp 238-242° C. Anal Calcd (Obsd) for C12H18N2.2HCl: C: 54.96 (54.59), H: 7.63 (7.66), N: 10.69 (10.46).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:28])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:17]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[N:10]=1)=[O:19])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH3:28]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(C2CCCC2)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 386.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[C:21]([O:23]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21](=[O:23])[C:12]2=[CH:13][NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1
Reactant: CCOC(=O)c1cnc2ccccc2c1NNc1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
The mixture of 3.5 g of ethyl 4-(2,4-dichlorophenyl-hydrazino)-quinolin-3-carboxylate and 40 ml of eutectic diphenyl ether-biphenyl is heated to 175° for 4 hours, cooled to room temperature and diluted with diethyl ether. The resulting suspension is filtered, the residue washed with diethyl ether and dissolved in N aqueous sodium hydroxide. The solution is washed with diethyl ether, its pH adjusted to 8.5 with ammonium chloride and the precipitate formed collected. It is washed successively with hot water, methanol and diethyl ether, to yield the 2-(2,4-dichlorophenyl)-pyrazolo[4,3-c]-quinolin-3(5H)-one, showing peaks in the IR-spectrum at 890, 867, 845, 832, 816, 796, 775, 767, 756, 730 and 701 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(CNC(=O)C(C)(C)C)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Yield: 94.7 %

Procedure:
The title compound was prepared following the procedure described in step-3 of Intermediate-2 using methyl 2-chloro-5-(pivalamidomethyl)benzoate (2.00 g, 7.05 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (564 mg, 14.1 mmol) to afford 1.8 g of the title product. 1H NMR (300 MHz, DMSO d6): 12.3 (br s, 1H), 8.14 (br t, 1H), 7.61 (s, 1H), 7.47-7.44 (d, J=8.1 Hz, 1H), 7.34-7.32 (d, J=7.8 Hz, 1H), 4.22 (d, J=6.0 Hz, 2H), 1.18 (s, 9H).