Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1.Cl>CC(O)C.CC(C)=O>[ClH:1].[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][C:19]=3[F:24])=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Yield: 90 %

Procedure:
A mixture of 4,7-dichloro-6-nitroquinazoline (24.4 g, 0.1 mol), 4-chloro-2-fluoroaniline and ethereal hydrogen chloride (100 ml of a 1M solution) in 2-propanol (600 ml) was heated at reflux for 1.5 hours. The mixture was allowed to cool and diluted with acetone. The solid product was collected by filtration, washed with acetone and dried to give 7-chloro-4-(4-chloro-2-fluoroanilino)-6-nitroquinazoline hydrochloride (35.0 g, 90%) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([O:28]CC)=O)[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][NH:39][C:38]1=[O:42]>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][NH:39][C:38]4=[O:42])=[O:28])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: NCCN1CCNC1=O
Product: O=C(NCCN1CCNC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(2-aminoethyl)-2-imidazolidinone using conditions similar to those employed in Example 563 to provide a white solid: ES+ MS: 537 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([NH:16][C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([CH3:24])[N:18]=2)[CH:8]=1)=[O:5]>C(O)C.[Pd]>[NH2:13][C:12]1[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([Cl:1])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:29])=[CH:8][C:9]([NH:16][C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([CH3:24])[N:18]=2)=[N:10][CH:11]=1
Reactant: Cc1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)c([N+](=O)[O-])cn2)nc(C)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)c(N)cn2)nc(C)n1
Reaction time: 1 h
Yield: 18.7 %

Procedure:
To a solution of 2,6-dichloro-N-(2-(2,6-dimethylpyrimidin-4-ylamino)-5-nitropyridine-4-yl)benzoamide (0.057 g, 0.13 mmol) in dry ethanol (8 mL) was added palladium (0.015 g, 0.14 mmol) (10% on activated carbon powder, 50% water wet) in one portion at room temperature under N2. The resulting mixture was stirred under H2 balloon for 60 mins The mixture was filtered with Celite and the filtrate was concentrated by vacuum. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product (9.8 mg, yield: 18%). 1H NMR (DMSO-d6, 400 MHz): δ 10.2 (d, J=24.6 Hz, 1H), 9.58 (s, 1H), 8.17 (d, J=28.7 Hz, 1H), 7.85 (s, 1H), 7.59 (s, 3H), 7.08 (s, 1H), 4.81 (s, 2H), 2.38 (s, 3H), 2.25 (s, 3H). LCMS (ESI) m/z: 403.0 [M+H+].
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].Br[CH2:17][C:18](=[CH2:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].[H-].[Na+]>C(#N)C>[CH3:6][O:5][C:3]([CH:2]([CH2:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH2:17])[C:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:4]
Reactant: C=C(CBr)C(=O)OCC
Reactant: COC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: C=C(CC(C(=O)OC)C(=O)OCc1ccccc1)C(=O)OCC
Yield: 43 %

Procedure:
The title compound was prepared stepwise. In the first step, benzyl methyl malonate was reacted with an equimolar amount of ethyl 2-(bromomethyl)propenoate and sodium hydride in acetonitrile to give the product, benzyl 2-methoxycarbonyl-4-ethoxycarbonyl-pent-4-enoate, in 43% yield [1H-NMR (CDCl3) δ(ppm): 1.28 (t, 3H); 2.92 (d, 2H); 3.60 (s, 3H); 3.83 (t, 1H); 4.20 (q, 2H); 5.17 (s, 2H); 5.58 (s,1H); 6.18 (s, 1H) and 7.32 (m, 5H)]. In the second step, to a cooled suspension of sodium hydride (0.30 g, 0.01 mol, 80% dispersion in oil) in acetonitrile (20 mL), was added benzyl 2-methoxycarbonyl-4-ethoxycarbonyl-pent-4-enoate (2.68 g, 0.0084 mol). The resulting mixture was allowed to stir for 10 minutes before a solution of t-butyl 2-(bromomethyl)propenoate (1.85 g) in acetonitrile (5 mL) was added and stirring continued at room temperature overnight under nitrogen. After work-up, the title product (21) was obtained in 72% yield as a colourless liquid. 1H-NMR (CDCl3) δ(ppm): 1.28 (t, 3H); 1.46 (s, 9H); 2.94 (s, 2H); 2.96 (s, 2H); 3.58 (s, 3H); 4.16 (q, 2H); 5.10 (s, 2H); 5.60 (s, 1H); 5.67 (s, 1H); 6.17 (s, 1H) and 7.32 (m, 5H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:12]=[N:13][CH3:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.COC1C=C(C=CC=1OC)CN=CC1SC2N=CN=CC=2C=1.CC1C=CC(S([CH:47]([C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][CH:51]=2)[N+:48]#[C-:49])(=O)=O)=CC=1>>[I:56][C:53]1[CH:52]=[CH:51][C:50]([C:47]2[N:48]=[CH:49][N:13]([CH3:14])[C:12]=2[C:10]2[S:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=3[CH:11]=2)=[CH:55][CH:54]=1
Reactant: CN=Cc1cc2c(SC)ncnc2s1
Reactant: [C-]#[N+]C(c1ccc(I)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Product: CSc1ncnc2sc(-c3c(-c4ccc(I)cc4)ncn3C)cc12

Procedure:
The title compound was prepared by a similar process to that described for Example 6 but using N-[4-(methylthio)thieno[2,3-d]pyrimidin-6-ylmethylidene]methanamine (Intermediate 16) in place of N-(3,4-Dimethoxybenzyl)-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine (intermediate 14) and using (4-Iodophenyl)(isocyano)methyl 4-methylphenyl sulfone (Intermediate 61) in place of PhTosMIC. Solid (0.8 g, 37%);
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:28][C:29]1[CH:56]=[CH:55][C:54](Br)=[CH:53][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>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.O.COCCOC>[CH2:21]([O:28][C:29]1[CH:56]=[CH:55][C:54]([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)=[CH:53][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccoc2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Water (0.5 mL), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan (0.070 g), sodium carbonate (0.076 g), and bis(triphenylphosphine)palladium(II) dichloride (4.2 mg) were added to an ethylene glycol dimethyl ether (1.7 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.17 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 40 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-80% hexane/ethyl acetate] to obtain 0.14 g of tert-butyl 2-(2-(benzyloxy)-5-(furan-3-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([CH3:12])[CH:3]=1.Cl.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=3)[N:10]=[C:6]2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)n2nc(N)nc2c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: Cc1cc(Cl)n2nc(NC(=O)c3cccnc3)nc2c1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridin-2-amine (282 mg; 1.54 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (330 mg; 1.85 mmol; 1.20 eq.) as a off-white powder (244 mg, 55%). HPLC, Rt: 1.51 min. (purity 90.4%). LC/MS, M+(ESI): 288.1, M−(ESI): 286.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COC(=O)c1cc2ncc(Cl)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ncc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of methyl 3-chlorothieno[2,3-b]pyrazine-6-carboxylate 92 (2.62 mmol, 600 mg) in 5 mL THF was added sodium hydroxide 2N in water (13.12 mmol, 6560 μl) and stirred at rt for 2 h. The reaction was quenched in 2N HCl extracted with CH2Cl2/methanol (9/1) (3×). Organic layers was dried and concentrated under reduced pressure to give 3-chlorothieno[2,3-b]pyrazine-6-carboxylic acid 93 (563 mg, 100%).
Reaction SMILES: O1CCN(C[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])CC1.C([O:23]C1C(C)=CC(C(O)=O)=CC=1C)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:8]([NH2:9])(=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(CN1CCOCC1)c1ccccc1
Reactant: Cc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-morpholino-1-phenylethanamine represented by Formula 113 (38.4 mg, 0.186 mmol) was slowly added to 4-benzyloxy-3,5-dimethylbenzoic acid represented by Formula 144 (52.5 mg, 0.205 mmol, purchased from Medizin Co. Ltd.) and diisopropylethylamine (0.13 mL, 0.745 mmol) in DMF (3 mL) solution at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 77.9 mg, 0.205 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (2 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate (K2CO3) solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was moved to a cartridge tube (6 mL, benzenesulfonic acid, 904030-WJ, UCT) using a small amount of ethyl acetate. Impurities were eliminated using methanol (15 mL) then separation and purification were conducted (using ethyl acetate/methanol/triethylamine, 20:2:1, v/v/v) to produce a benzamide compound represented by Formula 74 as a desired product (VVZ-080; 31 mg, 37% yield).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][O:8][N:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:10]([C:12]1[CH2:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=1[OH:17])=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:9]([C:10]([C:12]2[CH2:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=2[OH:17])=[O:11])[O:8][CH2:7][C:6]([OH:28])=[O:5])=[CH:26][CH:25]=1
Reactant: CN1CC(C(=O)N(Cc2ccc(F)cc2)OCC(=O)OC(C)(C)C)=C(O)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(C(=O)N(Cc2ccc(F)cc2)OCC(=O)O)=C(O)C1=O
Temperature: 22 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A solution of [(4-fluorobenzyl)-(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-aminooxy]-acetic acid tert-butyl ester (0.041 g, 0.104 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at 22° C. for 2 h. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and hexane to give 0.027 g (80% yield) of the tittle material as white crystals; mp 147–150° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.95 (3H, s, NCH3), 4.14 (2H, s, CH2), 4.62 (2H, s, CH2), 4.92 (2H, s, CH2), 7.17 (2H, m, aromatics), 7.36 (2H, m, aromatics), 11.4 (1H, broad s, OH), 13.1 (1H, broad s, OH). HRMS (ES+) calculated for C15H16FN2O6, [M+H]+: 339.099240. found: 339.100624.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Si:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1>[Si:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]3=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]3[CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 42.0 g) in THF (dry) (350 mL) was added 2-chloroethanesulfonyl chloride (44.5 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-((tert-butyl(dimethyl)silyl)oxy)phenyl)pyridin-2-amine (78.8 g) in THF (dry) (350 mL) was added at 0° C. and the mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0° C. carefully. Additional water was added to form precipitates which were washed with water and EtOAc and collected to give the title compound (65.5 g) as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]([C:11]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])=[C:4]2[C:3]=1[F:29].[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[C:16]([O:15][C:14]([N:13]([CH3:21])[C:11]([C:10]1[C:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:8][N:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:31]=3[CH3:30])[C:35]([OH:37])=[O:36])=[C:3]([F:29])[C:4]=12)=[O:12])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)c(F)c12
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccn2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1F
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a degassed solution containing tert-butyl 5-chloro-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate (0.10 g, 0.24 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.078 g, 0.30 mmol), sodium carbonate (0.075 g, 0.71 mmol), dioxane (2.0 mL) and water (0.40 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.008 g, 0.007 mmol). The mixture was stirred at 95° C. for 18 h. The solution was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2×15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-4-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.467 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire C18, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 522 (MH+).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=[CH:9][C:4]2=[CH:3][CH:2]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]#[C:25][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([N:1]=[CH:2][CH:3]=3)[CH:6]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#Cc1ccccc1
Reactant: O=S(=O)(Oc1ccc2ccnn2c1)C(F)(F)F
Product: C(#Cc1ccc2ccnn2c1)c1ccccc1

Procedure:
The title compound, light yellow solid, MS: m/e=219.2 (M+H+), can be prepared in accordance with the general method of example 1 from trifluoro-methanesulfonic acid pyrazolo[1,5-a]pyridin-6-yl ester (example 33, step 2) and phenylacetylene.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C:5]([CH3:20])([C:14]2[O:15][C:16]([CH3:19])=[N:17][N:18]=2)[CH2:4][O:3]1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:6][C:5]([C:14]1[O:15][C:16]([CH3:19])=[N:17][N:18]=1)([CH3:20])[CH2:4][OH:3]
Reactant: Cc1nnc(C2(C)COC(C)(C)N2C(=O)OC(C)(C)C)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc(C(C)(N)CO)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 84 mg of tert-butyl 2,2,4-trimethyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)-1,3-oxazolidine-3-carboxylate in 1.5 ml of dichloromethane was added 500 μl of trifluoroacetic acid, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, methanol was added thereto, and the solvent was evaporated again to obtain 76 mg of 2-amino-2-(5-methyl-1,3,4-oxadiazol-2-yl)propan-1-ol trifluoroacetate.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:12].[Na+].[Na+].CN[C@@H]1CCCC[C@H]1NC.Cl>CN[C@@H]1CCCC[C@H]1NC.C(#N)C.O>[C:4]([OH:6])(=[O:5])[C:3]1[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccccc1Br
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Under nitrogen, 2.00 g (9.95 mmol) of 2-bromobenzoic acid was combined with 10 g of H2O. 1.11 g (10.45 mmol) of Na2CO3 was then added. The mixture was heated to reflux with stirring for 30 min, remaining under a nitrogen atmosphere. Another 1.58 g (14.92 mmol) of Na2CO3 was added to the reaction mixture and reflux was continued for 30 min. Separately, 14 mg of CuBr and 28 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 1 mL acetonitrile under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a blue solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 2 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with 15% HCl, producing a white precipitate. The white precipitate was filtered and washed with water. After drying, a total of 1.34 g (9.7 mmol, 98% yield) salicylic acid was collected. The purity was determined by 1H NMR to be >99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].F[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:17]1[CH:22]=[N:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: COc1cc2nccc(O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])nc3)c2cc1OC
Temperature: 80 °C

Procedure:
A mixture of 6,7-dimethoxyquinolin-4-ol (2.02 g, 9.8 mmol, 1.0 eq.), 5-fluoro-2-nitro-pyridine (1.96 g, 13.78 mmol, 1.4 eq.) and cesium carbonate (4.8 g, 14.7 mmol, 1.5 eq.) in dry DMF (10 mL) was heated for 1 h at 80° C. in a microwave oven. After cooling to RT the mixture was diluted with water and extracted with DCM. The combined organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 10:1) to yield the desired product W1 (1.28 g, 40%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.88 (s, 3H), 3.94 (s, 3H), 6.92 (d, J=5.2 Hz, 1H), 7.41 (s, 1H), 7.45 (s, 1H), 7.98 (dd, J=2.7 Hz, J=9.0 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.66 (d, J=2.7 Hz, 1H). MS (ES) C16H13N3O5 requires: 327. Found: 328 (M+H)+.
Reaction SMILES: [N:1]1([C:7](=[O:14])[CH2:8][C:9](=[CH2:13])[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:15]([O-:18])(=[S:17])[CH3:16].[K+]>CN(C=O)C>[C:15]([S:17][CH2:13][CH:9]([CH2:8][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:14])[C:10]([OH:12])=[O:11])(=[O:18])[CH3:16]
Reactant: CC([O-])=S
Reactant: C=C(CC(=O)N1CCOCC1)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCC(CC(=O)N1CCOCC1)C(=O)O
Temperature: 25 °C

Procedure:
2-(2-morpholin-4-yl-2-oxo-ethyl)-acrylic acid (55.19 g, 277.0 mmol) was dissolved in 120 mL DMF and set to stir at room temperature. Potassium thioacetate (25 g, 219.0 mmol) was added in one portion, and the reaction mixture was allowed to stir at ambient temperature for 20 hours. Upon completion (LCMS), DMF was removed by vacuum under reduced pressure. Crude Yield: 75 g. Percent Purity (LCMS): 40%. The crude product was used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:25]=1)[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: O=C(O)c1cc(Cl)cc(OC(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(OC(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-chloro-5-(trifluoromethoxy)benzoic acid (CAS RN 158580-93-9) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Yellow solid (31%). MS (ESI): m/z=421.09 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[C:26](I)=[C:25]([CH3:28])[O:24][N:23]=1>>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=3)[N:7]=2)=[C:25]([CH3:28])[O:24][N:23]=1
Reactant: CC(C)c1nnc2ccc(I)nn12
Reactant: Cc1onc(-c2ccc(F)cc2F)c1I
Product: Cc1onc(-c2ccc(F)cc2F)c1-c1ccc2nnc(C(C)C)n2n1
Yield: 22.1 %

Procedure:
6-Iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.400 g, 1.25 mmol, Preparation #H.1) and 3-(2,4-difluorophenyl)-4-iodo-5-methylisoxazole (0.360 g, 1.25 mmol) were coupled using General Procedure I.1 to provide the title compound (0.098 g, 22%): LC/MS (Table 1, Method g) Rt=2.16 min; MS m/z: 356.0 (M+H)+.