Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)=O.[CH3:4][C:5](C)=O.N#N.C([Zn]CC)C.[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][CH2:22][C:23]2=[C:26]2[C:31](=[O:32])[O:30][C:29]([CH3:34])([CH3:33])[O:28][C:27]2=[O:35])=[CH:19][CH:18]=1>COCCOC.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[CH2:4]([C:23]1([CH:26]2[C:27](=[O:35])[O:28][C:29]([CH3:33])([CH3:34])[O:30][C:31]2=[O:32])[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([O:16][CH3:15])[CH:25]=2)[CH2:21][CH2:22]1)[CH3:5]
Reactant: COc1ccc2c(c1)C(=C1C(=O)OC(C)(C)OC1=O)CC2
Reactant: CC(C)=O
Agent: [Cu+2]
Agent: CC[Zn]CC
Agent: N#N
Solvent: COCCOC
Product: CCC1(C2C(=O)OC(C)(C)OC2=O)CCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
A 200 mL round bottom flask was charged with copper(II) trifluoromethanesulfonate (0.087 g, 0.24 mmol) and DME (12 mL), cooled to −40° C. (dry ice/acetone), and subjected to 3 cycles of evacuation/back-filling with N2. To the cold solution were added diethylzinc (1.0 M solution in hexanes, commercially available from Aldrich) (12 mL, 12 mmol) and a solution of 18.1 (0.694 g, 2.4 mmol) in DME (12 mL) slowly under N2. The mixture was warmed to room temperature and stirred for 2 days. The reaction was carefully quenched with 1 N HCl (15 mL) and diluted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (0-30% EtOAc/hexanes) to afford 42.1 (0.31 g, 40% yield) as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:3].FC(F)(F)C(O)=O.[CH3:18][NH:19][CH2:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH:34]3[S:38][C:37](=[O:39])[NH:36][C:35]3=[O:40])=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>ClCCl.O>[O:39]=[C:37]1[NH:36][C:35](=[O:40])[CH:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:19]([CH3:18])[C:2](=[O:3])[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:22]=3)=[CH:32][CH:31]=2)[S:38]1
Reactant: CCCCCCOC(=O)Cl
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCOC(=O)N(C)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 400 μl (2.5 mmol) of hexyl chloroformate in 5 ml of dichloromethane is added dropwise to a solution of 1 g (2.3 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)-thiazolidine-2,4-dione trifluoroacetate and 1 ml (7.0 mmol) of triethylamine in 15 ml of dichloromethane. The reaction medium is stirred at room temperature for 3 hours, placed in water and extracted with ethyl acetate. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (8/2). After evaporation of the solvents, 300 mg (30%) of hexyl N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylcarbamate are obtained in the form of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([O:24][CH2:25][CH3:26])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([NH:34][C:35](=[N:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])SC)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C.C(Cl)Cl>C1COCC1.CO.C(Cl)Cl>[C:42]([O:41][C:39]([NH:38][C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][C@H:20]([O:24][CH2:25][CH3:26])[C:21]([OH:23])=[O:22])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1)=[N:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCO[C@@H](Cc1ccc(OCCCCc2ccc(N)cc2)cc1)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(OCCCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 288 h
Yield: 37.4 %

Procedure:
(2S)-3-{4-[4-(4-Aminophenyl)butoxy]phenyl}-2-ethoxypropanoic acid (140 mg, 0.392 mmol) was dissolved in THF (10 ml). 1,3-Bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (116 mg, 0.392 mmol) was added and then N,N-diisopropylethylamine (126 mg, 0.979 mmol) was added. The mixture was stirred at room temperature for 12 days and thereafter evaporated in vacuum to dryness. Water and ethyl acetate were added into the residue. The mixture was then acidified with 1% hydrochloric acid, pH˜3. The two phases were separated. The water phase was extracted with ethyl acetate (×2). All organic phases were combined and washed with brine and dried with magnesium sulfate. The solvent was evaporated. Chromatography of the residue on an ISOLUTE column (SI, 2 g/6 ml) using DCM and then MeOH/DCM (1:99) as eluant gave an oil. Re-chromatography of the oil on an ISOLUTE column (SI, 2 g/6 ml) using DCM and then MeOH/DCM (0.5:99.5) gave 88 mg desired product, yield 37.5%.
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([NH:28][C:29]1[N:34]=[C:33]([C:35]([OH:37])=O)[C:32]([Br:38])=[CH:31][CH:30]=1)(=[O:27])[CH3:26].C(N(CC)C(C)C)(C)C.Cl.CNOC>ClCCl>[C:25]([NH:28][C:29]1[N:34]=[C:33]([C:35]([N:9]([O:8][CH3:4])[CH3:10])=[O:37])[C:32]([Br:38])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1ccc(Br)c(C(=O)O)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nc(NC(C)=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (4.56 g, 12.0 mmol) was added to a solution of 6-acetamido-3-bromopicolinic acid (2.6 g, 10.0 mmol) and DIPEA (N,N-diisopropylethylamine)(5.2 ml, 30 mmol) in DCM (dichloromethane)(10 ml). After 10 minutes, N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.0 mmol) was added to the reaction. The reaction was stirred at room temperature for 5 min. The reaction mixture was partitioned between EtOAc (ethyl acetate) and saturated NH4Cl solution. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was used in the next step without further purification. MS (m/z) 302.1 [M+H]+. 1H NMR (400 MHz, cd3cl) δ 8.14 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 3.56 (s, 3H), 3.37 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C([Li])(C)(C)C.CCCCC.[Sn:35](Cl)([CH3:38])([CH3:37])[CH3:36].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:36][Sn:35]([CH3:38])([CH3:37])[C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7]([CH2:16][OH:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2ccc(Br)cc2c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: C[Sn](C)(C)c1ccc2cc(CO)c3ccccc3c2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Bromophenanthrene 5 (1.02 g, 2.5 mmol) was dissolved in anhydrous THF (15 mL) and cooled to -78° C. under nitrogen. To this stirred solution was added a solution of t-Butyllithium in pentane (2.2 equiv.; 5.5 mmol; 3.0 mL). After 30 minutes at -78° C., the reaction was warmed to -50° C. for 20 minutes, after which time Me3SnCl (1.1 equiv.; 2.75 mmol; 548 mg) was added as a solid. The cold bath was removed and the reaction allowed to reach ambient temperature. After 75 minutes, the reaction was quenched with water. The solvent was removed in vacuo and the residual dissolved in Et2O. Washing with water and brine was followed by drying over MgSO4, filtering and removal of solvent. The residual was dissolved in anhydrous THF and treated with a 1.0M solution of n-Bu4NF in THF (1.1 equiv.; 2.75 mmol; 2.75 mL) at ambient temperature for 5 minutes. Quenching the reaction with saturated NH4Cl was followed by removal of the solvent in vacuo. The residual was dissolved in EtOAc and washed with water and brine, dried (MgSO4), filtered and the solvent removed in vacuo. Purification by flash chromatography (25% EtOAc/hexanes) provided 733 mg (78%) of stannyl alcohol 5A as a white solid.
Reaction SMILES: O=O.[CH3:3][C:4]1([CH3:11])[C:9](=[O:10])[C:7](=[O:8])[O:6][CH2:5]1.CC(OC(N1[C@H](CP(C2C=CC=CC=2)C2C=CC=CC=2)C[C@H](P(C2C=CC=CC=2)C2C=CC=CC=2)C1)=O)(C)C.FC(F)(F)C([O-])=O.C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH3:11])[C@@H:9]([OH:10])[C:7](=[O:8])[O:6][CH2:5]1
Reactant: CC1(C)COC(=O)C1=O
Agent: CC(C)(C)OC(=O)N1C[C@@H](P(c2ccccc2)c2ccccc2)C[C@H]1CP(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)COC(=O)[C@@H]1O
Reaction time: 1.2 h

Procedure:
A 500 ml steel autoclave was loaded in a glove box (O2 -content less than 1 ppm) with 40.0 g (0.31 mol) of ketopantolactone, 210 ml of toluene, 180.6 mg (0.389 mmol) of [Rh(COD)2 ]PF6, 237.3 mg (0.389 mmol) of mCH3 --BPPM and 138.3 mg (0.389 mmol) of tetrabutylammonium trifluoroacetate. The hydrogenation was carried out at a constant pressure of 40 bar of H2 at 30° C. and with intensive stirring. By virtue of the exothermic reaction the temperature rose to 55° C. A conversion of above 99% was achieved after 1.2 hours. After a total hydrogenation time of 2 hours the mixture was worked-up as described in Example 2. Pure (R)-pantolactone was obtained. [α]D20 =-46.0°. Optical purity 89.1%.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[F:11][C:7]1[CH:8]=[C:9]([F:10])[C:2]2[S:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(F)cc(F)c1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cc(F)cc(F)c2s1

Procedure:
Using 3.94 g (24.6 mmol) of 2,3,5-trifluorobenzaldehyde, 1.48 g (36.9 mmol) of sodium hydride (60% pure) and 2.88 g (27.1 mmol) of methyl mercaptoacetate,
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(Nc1ccccc1Br)N1CCOCC1
Product: Nc1ncc(-c2ccc(-c3ccccc3NS(=O)(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and N-(2-bromophenyl)morpholine-4-sulfonamide. MS (ESI): mass calcd. for C20H20FN5O3S, 429.13; m/z found, 430.4 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.63 (d, J=1.2, 2H), 7.70-7.54 (m, 2H), 7.48-7.25 (m, 5H), 3.70-3.55 (m, 4H), 3.05 (dd, J=5.7, 3.8, 4H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[CH:16]([NH:18][C:19]1[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH2:29])[CH:25]=3)[N:20]=1)[CH2:15][CH2:14]2>>[CH:1]([NH:4][C:5]([NH:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([NH:18][CH:16]1[C:17]3[C:13](=[CH:12][CH:11]=[CH:10][C:9]=3[O:8][CH3:7])[CH2:14][CH2:15]1)[CH:28]=[CH:27]2)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CC(C)N=C=O
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from isopropyl isocyanate and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=391.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17](=O)[C:16]3[CH:15]=[C:14]4[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][C:13]4=[CH:12][C:11]=3[C:10]2=[O:29])=[CH:4][CH:3]=1.Cl>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:10](=[O:29])[C:11]3[CH:12]=[C:13]4[CH2:21][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:19][C:14]4=[CH:15][C:16]=3[CH2:17]2)=[CH:4][CH:3]=1
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(Cl)cc1)C3=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(Cl)cc1)C3

Procedure:
Using procedure 47, 2-[(4-Chlorophenyl)methyl]-6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (102, 0.59 g, 1.43 mmol) was reduced with Zinc dust (0.94 g, 14.3 mmol) in glacial HOAc (100 mL). Purification using silica gel, eluting with 4:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 129 as a white solid (m.p. 233-234° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[N:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:13]O>>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([NH2:11])[N:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cc(C(=O)O)cc(N)n1
Agent: Cl
Product: COC(=O)c1cc(N)nc(N)c1
Yield: 77 %

Procedure:
A suspension of 11 g (70 mmol) 2,6-diamino-isonicotinic acid in 270 ml methanol was treated at 0° C. for 2 h with gaseous HCl. The mixture was concentrated, the residue was dissolved in water and saturated NaHCO3 was added to pH=8. Exhaustive extraction with ethylacetate, drying of the combined organic phases with MgSO4 and removal of the volatiles yielded 9.3 g (77%) 2,6-diamino-isonicotinic acid methyl ester as yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5](=[O:16])[C:4]=1[C:17]([O:19]CC)=[O:18])[CH3:2].O1CCCC1.[OH-].[Na+]>CO>[CH2:1]([C:3]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5](=[O:16])[C:4]=1[C:17]([OH:19])=[O:18])[CH3:2]
Reactant: CCOC(=O)c1c(CC)n(C)n(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1C
Yield: 88.7 %

Procedure:
In the same manner as in Reference Example 65 and using ethyl 5-ethyl-2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (1.9 g, 6.4 mmol), tetrahydrofuran (4 mL), methanol (4 mL) and 4N aqueous sodium hydroxide solution (5 mL) as starting materials, the title compound (1.5 g, 92%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[OH:10].C(N(CC)C(C)C)(C)C.Cl[CH2:21][O:22][CH3:23].Cl>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:21][O:22][CH3:23]
Reactant: COCCl
Reactant: O=Cc1ccc(F)c(O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C=O)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Fluoro-3-hydroxybenzaldehyde (11.9 g) and N,N-diisopropylethylamine (44 mL) were dissolved in dichloromethane (100 mL). To the mixture was added chloromethylmethylether (13 mL), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added dropwise 1 mol/L hydrochloric acid (250 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (14.5 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:15]2=[O:26])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:27][C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH:20]3[CH2:21][CH2:22][N:23]([C:31]4[CH:30]=[N:29][C:28]([Cl:27])=[CH:33][N:32]=4)[CH2:24][CH2:25]3)[C:15]2=[O:26])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1[C@@H](Nc2ncc(C(F)(F)F)cc2Cl)CCCN1C1CCNCC1
Reactant: Clc1cnc(Cl)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1[C@@H](Nc2ncc(C(F)(F)F)cc2Cl)CCCN1C1CCN(c2cnc(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A flask was charged with (S)-3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-1,4′-bipiperidin-2-one hydrochloride (0.075 g, 0.18 mmol), 2,5-dichloropyrazine (0.030 g, 0.20 mmol), Hunig's base (0.095 mL, 0.54 mmol), and DMF (3 mL). The reaction was stirred at 100° C. overnight. The organic solvents were removed under reduced pressure. The residue was purified using silica gel column chromatography with 50-100% ethyl acetate in hexanes to provide (S)-3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-1′-(5-chloropyrazin-2-yl)-[1,4′-bipiperidin]-2-one (0.037 g, 0.076 mmol, 42% yield) as yellow solid. Mass spectrum (apci) m/z=489.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.O.[NH2:12][NH2:13]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:12][NH2:13])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: NN
Reactant: CSc1nc(F)cc(F)n1
Solvent: O
Solvent: CCO
Product: CSc1nc(F)cc(NN)n1
Yield: 94.7 %

Procedure:
A solution of 15.8 g (0.097 mol) of 4,6-di-fluoro-2-methylthiopyrimidine in 50 ml of ethanol was added slowly with stirring to a solution of 11.6 ml (12.0 g, 0.214 mol) of hydrazine monohydrate in 100 ml of ethanol, keeping the temperature below 0° C. by external cooling. The mixture was allowed to react for an additional 30 min and the volatiles were then removed by evaporation under reduced pressure. The residue was diluted with ethyl acetate and the resulting solution extracted with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 16.0 g of the title compound as a white powder melting at 153° C.-154° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]2[N:12]=[N:13][N:14]=[C:7]2[C:6]=1[NH2:15].C(N(CC)CC)C.[CH2:24]([O:26][CH2:27][C:28](Cl)=[O:29])[CH3:25]>ClCCl>[CH2:24]([O:26][CH2:27][C:28]([NH:15][C:6]1[C:7]2[N:8]([N:12]=[N:13][N:14]=2)[C:9]([CH3:11])=[CH:10][C:5]=1[NH:4][CH2:3][CH:2]([CH3:16])[CH3:1])=[O:29])[CH3:25]
Reactant: CCOCC(=O)Cl
Reactant: Cc1cc(NCC(C)C)c(N)c2nnnn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(NCC(C)C)cc(C)n2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of N7-(2-methylpropyl)-5-methyltetraazolo[1,5-α]pyridine-7,8-diamine (8.4 g, 38.1 mmol) in anhydrous dichloromethane (300 mL) was cooled to 0° C. under a nitrogen atmosphere, and triethylamine (5.3 mL, 38.1 mmol) was added. A solution of ethoxyacetyl chloride (4.7 g, 38.1 mmol) in dichloromethane (100 mL) was added dropwise over a period of five minutes, and a homogeneous solution resulted. After the solution was stirred for one hour, it was allowed to warm to room temperature, washed with water (2×200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 11.2 g of 2-ethoxy-N-{7-[(2-methylpropyl)amino]-5-methyltetraazolo[1,5-α]pyridin-8-yl}acetamide as a light tan solid, m.p. 182-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13]3([CH2:14][OH:15])[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:13]3([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[C:10]([CH3:16])([CH2:11][O:12]3)[CH2:9][CH2:8]2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC12CCC(Cc3ccc(Cl)cc3)C1(CO)OC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC12CCC(Cc3ccc(Cl)cc3)C1(COS(C)(=O)=O)OC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 6 ml of toluene, 300 mg of Compound 8a-1 synthesized in Production Example 19 was dissolved. To the solution thus obtained, 235 μl of triethylamine and 122 μl of methanesulfonyl chloride were added, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction, water was added to the reaction solution thus obtained, and extraction with ethyl acetate was carried out. The organic layer thus extracted was washed with an aqueous solution of hydrochloric acid, an aqueous solution of sodium hydrogen carbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 378.3 mg of Compound 9a-1-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43](Cl)=[O:44])[CH2:39][CH2:38]1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]5)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:44])[CH2:39][CH2:38]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (88 mg, 0.44 mmol,) in CH2Cl2 (2 mL) was added Et3N (92 μL, 0.66 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of 4-methylpiperazine-1-carbonyl chloride hydrochloride and 3 equivalents of Et3N were added. Continued to stir at ambient temperature for 16 hours. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (8:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(1-methylpiperazine-4-carboxamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (160 mg, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][CH:10]([CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]([OH:13])=[O:12])=[O:8])=[CH:5][CH:4]=1.Cl.[CH2:29](O)[CH3:30]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH:10]([CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]([O:13][CH2:29][CH3:30])=[O:12])=[O:8])=[CH:26][CH:27]=1
Reactant: CCO
Reactant: COc1ccc(C(=O)NC(Cc2cc3ccccc3[nH]c2=O)C(=O)O)cc1
Agent: Cl
Product: CCOC(=O)C(Cc1cc2ccccc2[nH]c1=O)NC(=O)c1ccc(OC)cc1

Procedure:
1.8 Grams of 2-(4-methoxybenzoyl)amino-3-(2-quinolon-3yl)propionic acid was dissolved in 100 ml of ethanol, then to this solution was introduced and saturated with hydrogen chloride gas under an ice-cooled condition with stirring. The reaction mixture was then refluxed for 5 hours and after completion of the reaction, the solvent was removed by distillation under a reduced pressure, the residue obtained was recrystallized from ethyl acetate-ethanol to obtain 1.5 g of ethyl 2-(4-methoxybenzoyl)amino-3-(2-quinolon-3-yl)propionate in the form of white powder product.