Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22]C(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Al](C)(C)C>O1CCOCC1.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]>[CH3:22][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Agent: [Pd]
Agent: C[Al](C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(C)nc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 2155.9 %

Procedure:
A suspension of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.34 mmol, 1.00 equiv), Pd2(dba)3 (12 mg, 0.01 mmol, 0.04 equiv), x-phos (6 mg, 0.01 mmol, 0.04 equiv), and Al(CH3)3 (0.5 mL, 3.00 equiv, 2.5M) in 1,4-dioxane (3 mL) was placed in a 10-mL sealed tube under an inert atmosphere allowed to react, with stirring, for 6 hr while the temperature was maintained at 100° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate:petroleum ether (1:1)). The resulting mixture was concentrated under vacuum. The residue was purified via silica gel column (ethyl acetate/petroleum ether (1:20)) yielding 60 mg (64%) of methyl 3-methyl-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=5[Cl:28])[CH:20]=4)[OH:15])=[CH:4][CH:3]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2c(Cl)cccc2Cl)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5c(Cl)cccc5Cl)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2,6-dichloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[CH3:9][C:10]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C(C)C>CCOC(C)=O.O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:14](=[O:15])[O:13][C:10]([CH3:11])([CH3:9])[CH3:12])[CH2:22][CH2:21]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Brc1cncc(I)c1
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(Br)c2)CC1
Temperature: 70 °C
Reaction time: 43 h
Yield: 26.3 %

Procedure:
A mixture of 3-bromo-5-iodopyridine (600 mg, 2.113 mmol, Aldrich), 4-(n-boc-amino)-piperidine (466 mg, 2.325 mmol, Aldrich), Cut (40.3 mg, 0.211 mmol, Aldrich) and cesium carbonate (1377 mg, 4.23 mmol, Strem) was capped, degassed and backfilled with argon (3×). Dioxane (2 mL) and 2-isobutyrylcyclohexanone (0.141 mL, 0.845 mmol, Aldrich) were added, and the reaction was stirred at 70° C. After 43 h, the reaction mixture was cooled to 23° C., diluted with EtOAc (50 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 15-40% EtOAc/hexane), affording tert-butyl 1-(5-bromopyridin-3-yl)piperidin-4-ylcarbamate (198 mg, 26%). MS (ESI, pos. ion) m/z: 356.0 (M+1), 358.0 (M+3).
Reaction SMILES: C([N-:4]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:15]=C[C:13](S(CCC2OCCO2)(=O)=O)=[CH:12][CH:11]=1.C(O)(=O)C.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:10]12[CH2:15][N:4]([CH2:9]1)[CH2:13][CH2:12][CH2:11]2
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)CCC2OCCO2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Product: c1coc(C23CCCN(C2)C3)c1
Temperature: -65 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of lithium diisopropylamide (4.0 ml of 1 5M cyclohexane solution; 0.0060 mole) in dry tetrahydrofuran (100 ml ) at -65° C. under nitrogen was treated with a solution of 2-[2-(4-methylphenylsulphonyl)ethyl ]-1,3-dioxolane (compound D5 in EP-0322182, 1.54 g, 0.0060 mole) in dry tetrahydrofuran (5 ml). After stirring the resulting solution at -65° C. for 10 minutes, a solution of crude 1-azabicyclo[3.1.1]hept-5-ylcarboxaldehyde (D6, 550 mg, 0.0044 mole) in dry THF (8 ml ) was added. The reaction mixture was allowed to warm up to -20° C. over 30 minutes, then treated with glacial acetic acid (5 ml ) and concentrated in vacuo. The residue was dissolved in glacial acetic acid (100 ml ), treated with 4-toluenesulphonic acid (20 mg) and heated under reflux for 24 h. The solution was concentrated in vacuo and the residue basified with concentrated potassium carbonate solution and extracted with chloroform (2×80 ml ). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a brown oil, which was distilled in a Kugelrohr apparatus. The material boiling at 130°-150° C. at 0.1 mmHg was collected and then chromatographed on basic alumina eluting initially with ether to remove impurities, then with 10% methanol/ethyl acetate to remove the title compound (E12), which was obtained as a colourless oil (4 mg).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>O1CCOCC1>[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([N:20]1[C:21](=[O:22])[C:23]([F:25])=[CH:24][N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[C@@H:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]2)[C:18]1=[O:19])=[O:37]
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CC
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(=O)CC
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
2.0 Grams of 2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.7 g of 2-methylbenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at 70° C. for 30 minutes. The reaction liquid is cooled and triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the oily residue is purified by column chromatography on silica gel (elution solvent: chloroform). The The purified oily substance is dissolved in about 15 ml of dimethyl sulfoxide and the solution is added dropwise to about 400 ml of ice water under vigorous agitation whereupon a precipitate is formed. The resultant precipitate is collected by filtration, washed with water and dried at room temperature under reduced pressure whereby 1.5 g (yield: 56.4%) of powdery 3-(2-methylbenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([S:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:23][CH2:22]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCC(O)CC3)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). 4-Hydroxypiperidine (66.1 mg; 0.65 mmol; 2 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, Compound (10) is obtained as white-off solid (33 mg; 23%). 1H NMR (DMSO-d6) δ 1.40-1.60 (m, 2H), 1.72-1.85 (m, 2H), 2.14 (s, 3H), 2.42 (s, 3H), 2.80-2.92 (m, 2H), 3.15-3.30 (m, 2H), 3.59 (m, 1H), 4.71 (d, J=3 Hz, 1H), 7.30 (d, J=4.5 Hz, 1H), 7.58 (d, J=4.5 Hz, 1H), 12.18 (br s, 1H). M−(ESI): 400.20; M+(ESI): 402.10. HPLC, Rt: 2.86 min (purity: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:24]3[C:33]4[C:28](=[CH:29][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: Nc1ccc(CN2CCN(c3cc(Cl)ccc3Cl)CC2)cc1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: FC(F)(F)c1ccc2c(Nc3ccc(CN4CCN(c5cc(Cl)ccc5Cl)CC4)cc3)ccnc2c1

Procedure:
In the manner given in Example 1C, 1-(2,5-dichlorophenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(2,5-dichlorophenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12](C(OCC3C=CC=CC=3)=O)[CH2:13][CH:14]2[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[NH:12][CH2:13][CH:14]([CH2:16][O:17][S:38]([CH3:37])(=[O:40])=[O:39])[CH:15]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(CO)CN2C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2NCC(COS(C)(=O)=O)C21
Reaction time: 1 h

Procedure:
A solution of alcohol 77 (0.78 g, 2.1 mmol) in DCM (12 mL) was cooled to 0° C. and treated with DIPEA (0.55 mL, 3.2 mmol) followed by methanesulfonyl chloride (0.22 mL, 2.8 mmol). After 1 h, the solution was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford mesylate 79 as a light yellow-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.36-7.31 (m, 5H), 5.19-5.09 (m, 2H), 4.45 (m, 1H), 4.29-4.04 (m, 3H), 3.71-3.44 (m, 4H), 3.22-3.12 (m, 1H), 2.96 (s, 3H), 2.85-2.70 (m, 1H), 2.21-1.99 (m, 2H), 1.49 (s, 9H) ppm.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.Cl[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]([Cl:32])=[CH:23][C:22]=1[Cl:33].[O:34]1CC[CH2:36][CH2:35]1>>[Cl:33][C:22]1[CH:23]=[C:24]([Cl:32])[C:25]2[C:30](=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:21]=1[CH2:20][CH2:36][CH:35]=[O:34]
Reactant: C1CCOC1
Reactant: ClCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=CCCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyl lithium in hexane (3.2 ml, 4.3 mmoles) was added dropwise (3 minutes) to a solution of diisopropylamine (0.45 g, 4.5 mmoles) in dry tetrahydrofuran (10 ml) with cooling (ice bath). After stirring under nitrogen for 15 minutes, ethylidene cyclohexylimine (0.55 g, 4.3 mmole) was added dropwise (5 minutes) at 0° C. The mixture was stirred for 15 minutes and then the ice bath was replaced by a dry-ice-acetone bath. A solution of 1-chloromethyl-2,4,7-trichloronaphthalene (1.0 g, 3.8 mmoles) in tetrahydrofuran (15 ml) was added (5 minutes) at -75° C. The reaction mixture was stirred at -70° C. for 30 minutes and at room temperature overnight (20 hours) and then concentrated to dryness in vacuo. The residual oil was taken up in ether (100 ml) and 5% aqueous oxalic acid (100 ml) and the mixture stirred at room temperature for 31/2 hours. The layers were separated and the aqueous phase extracted (2X) with ether. The ether extracts were combined, washed with cold water and brine, and dried over MgSO4. The solution was filtered and concentrated in vacuo to give a red-brown oil (1.1 g). This material was chromatographed using a 50 mm flash column containing 150 g of silica gel (230-400 mesh) eluting with 30% methylene chloride in hexane (v/v) to give 0.21 g of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[C:20]([NH:25][CH2:26][CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:4]([NH:18][C:19]2[C:20]([NH:25][CH2:26][CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:6])=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Reactant: CCNc1ncccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCNc1ncccc1NC(=O)c1cc([N+](=O)[O-])cnc1Cl

Procedure:
A solution of 2.21 g of 2-chloro-5-nitronicotinoyl chloride (obtained by nitration of 2-hydroxynicotinic acid, followed by conversion to 2-chloro-5-nitronicotinic acid, which was then treated with thionyl chloride) in 10 mL of tetrahydrofuran was slowly added over 15 minutes to a cooled, stirred mixture of 1.34 g of 3-amino-2-ethylaminopyridine, 1.29 g of diisopropylethylamine, and 40 mL of tetrahydrofuran. The resulting mixture was allowed to stir overnight at room temperature, and then was concentrated in vacuo. The title compound (2.30 g, m.p. 185°-186° C.), which precipitated out when the residue was treated with methylene chloride, was suitable for use in the next reaction.
Reaction SMILES: [CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21]CC4C=CC=CC=4)=[CH:17][C:16]=3[O:29]CC3C=CC=CC=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(OCC)(=O)C.[Pd]>[CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[OH:29])[CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCCC1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)N1CCC(c2ccc(O)cc2O)C1
Reaction time: 18 h

Procedure:
In a 25 ml round-bottomed flask, 0.23 g of 3-(2,4-bis(benzyloxy)phenyl)pyrrolidine-1-carboxylic acid cyclohexylamide is dissolved in 4 ml of methanol in the presence of 3 ml of ethyl acetate and of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 18 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then chromatographed on silica gel (7/3 heptane/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)C=O)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1([Mg]Br)CC1.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([C:33]5([CH2:34][OH:30])[CH2:31][CH2:32]5)[CH:21]=[CH:22][CH:23]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=Cc1cccc(-c2ccn3nc(-c4ccc(Cl)cc4)cc3c2)c1
Agent: Br[Mg]C1CC1
Product: OCC1(c2cccc(-c3ccn4nc(-c5ccc(Cl)cc5)cc4c3)c2)CC1
Yield: 59 %

Procedure:
The procedure described in stage 6.2 is followed. Starting from 0.15 g (0.45 mmol) of 3-[2-(4-chlorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde, obtained according to the process described in 6.1, in solution in 8 ml of tetrahydrofuran, followed by addition of 1.80 ml (0.9 mmol) of a cyclopropylmagnesium bromide solution (0.5M in tetrahydrofuran) and after chromatographing on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.1 g (59%) of the expected product is obtained in the form of a beige powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:28]([Cl:29])=[C:27](F)[N:26]=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=3)[C:24]=2[Cl:42])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([O:47][C:48]([NH:50][C@@H:51]1[CH2:56][C@H:55]([NH:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:54][NH:53][CH2:52]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][N:11]([C:23]2[C:28]([Cl:29])=[C:27]([N:53]3[CH2:54][C@@H:55]([NH:57][C:58]([O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[O:59])[CH2:56][C@@H:51]([NH:50][C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])[CH2:52]3)[N:26]=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=3)[C:24]=2[Cl:42])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Nc2nc(F)c(Cl)c(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Nc2nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c(Cl)c(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)c2Cl)cc1
Temperature: 110 °C
Yield: 42.8 %

Procedure:
4-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-3,5-dichloro-2-(4-acetylamino-phenyl-amino)-6-fluoro-pyridine (165) (0.29 g, 0.463 mmol) and cis-3,5-bis-(tert-butoxycarbonylamino)-piperidine (4) (0.219 g, 0.695 mmol) were combined and suspended in NMP (3.5 mL) in a 40 mL I-Chem vial. iPr2EtN (0.926 mmol) was added and the mixture was sonicated for 2 minutes. The mixture was heated to 110° C. and within 30 minutes all of the solids had dissolved. The solution continued to shake in the Teflon septum capped vial for 5 days. LC-MS indicated nearly complete reaction at this point. The solution was diluted with EtOAc (100 mL), washed with H2O (50 mL) and brine (50 mL), dried over MgSO4 and concentrated to give a brown oil which eventually solidified. Trituration of the solid with EtOAc followed by collection via filtration under reduced pressure gave the desired product (166) as a beige powder (0.183 g, 0.198 mmol, 43% yield). LC-MS (ESI): (exact mass: 921.43) m/e=922.6 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH2:23]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][NH2:32])[N:30]=1)[CH2:24][CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[N:12][CH:11]=[C:10]([CH:9]=2)[C:20]([NH:32][CH2:31][C:29]2[N:30]=[C:26]([CH2:23][CH2:24][CH3:25])[S:27][CH:28]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CCCc1nc(CN)cs1
Product: CCCc1nc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-82-5) and 2-propyl-4-thiazolemethanamine as starting materials, LC-MS (UV peak area/ESI) 99%, 470.090 (M+H)+.
Reaction SMILES: C([NH:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=O)C.[CH2:11]([N:13](CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O.[Cl:32]CCl>>[ClH:32].[NH2:3][CH2:4][C:6]1[S:7][CH:8]=[C:9]([C:11]#[N:13])[N:10]=1
Reactant: ClCCl
Reactant: CCN(CC)CC
Reactant: CCNC(=O)c1nccs1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: Cl
Product: N#Cc1csc(CN)n1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
75.0 g (0.29 mol) of BOC-protected thiazolecarboxamide (VI) were suspended in 524 ml of dichloromethane and, at from −5° to 0° C., admixed with 78.9 g (0.78 mol) of triethylamine and 79.5 g (0.38 mol) of trifluoroacetic anhydride. The mixture was stirred for one hour and allowed to warm to 20-25° C., 1190 ml of water were added and the phases were separated. 160 ml of 5-6 N isopropanolic HCl were added to the organic phase, the mixture was heated to the boil for 3 h, stirred at 20-25° C. overnight and cooled to from −5 to 0° C. for 2.5 h, and the solid was filtered off. It was washed with dichloromethane and dried. This gave 48.1 g of 2-aminomethyl-4-cyanothiazole of a purity by HPLC of 99.4 area %, which corresponds to a yield of 94.3% for these two steps.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:26][OH:27]>C(O)C.O.CO>[OH:27][N:26]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CCC(=O)c1ccc(-n2cccn2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-n2cccn2)cc1
Reaction time: 24 h
Yield: 78.5 %

Procedure:
To a stirred suspension of 4oxo-4(4-pyrazol-1-yl-phenyl)butyric acid (Sircar I., et al., Journal of Medicinal Chemistry, 1985;28:1405-13) (0.0277 g, 0.000113 mol) in absolute ethanol (0.55 mL) at room temperature was added potassium carbonate (0.010 g, 0.000072 mol) followed by a solution of hydroxylamine hydrochloride (0.010 g, 0.00014 mol) in water (0.25 mL), and the resulting mixture was stirred for 1 day. The volatiles were rotary evaporated. The residue was dissolved in methanol, silica gel (0.35 g, 230-400 mesh) was added, and the mixture was rotary evaporated to dryness. The residue was purified by chromatography on silica gel (6.0 g, 230-400 mesh) eluting with dichloromethane-methanol (12:1,25×5 mL) to give 0.0230 g of 4-hydroxyimino-4(4pyrazol-1-yl-phenyl)-butyric acid as an off-white solid; mp 128-130° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[CH2:10][O:9][C:8]1=[O:20].[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[F:19][C:14]1[CH:13]=[C:12]([C@H:11]2[CH2:10][O:9][C:8](=[O:20])[N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C1OC[C@H](c2ccc(F)c(F)c2)N1CCCCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN3C(=O)OC[C@@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (4S)-3-(5-chloropentyl)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.32 (d, 1H, J=8.6 Hz), 7.26–7.21 (m, 2H), 7.20–7.12 (m, 2H), 7.06 (m, 1H), 6.97 (d, 1H, J=6.96 Hz), 4.76 (dd, 1H, J=6.3, 8.3 Hz), 4.62 (t, 1H, J=9.0 Hz), 4.06 (dd, 1H, J=6.4, 8.7 Hz), 3.46 (m, 1H), 3.0 (d, 2H, J=9.0 Hz), 2.77 (q, 1H, J=6.8 Hz), 2.50 (q, 2H, J=6.8 Hz), 2.31 (t, 2H, J=6.8 Hz), 2.01 (m, 4H), 1.81 (m, 4H), 1.48 (m, 4H), 1.26 (d, 6H, J=7.3 Hz); Anal. Calcd for C28H37F2N3O3+HCl+0.25CHCl3: C, 60.6; H, 6.65; N, 7.25. Found: C, 60.7; H, 6.91; N, 7.05; ESMS m/e: 514.2 (M+H)+.