Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([NH:36][CH:37]5[CH2:42][C:41]([CH3:44])([CH3:43])[N:40]([CH3:45])[C:39]([CH3:47])([CH3:46])[CH2:38]5)[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]>O1CCOCC1>[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:36][CH:37]5[CH2:42][C:41]([CH3:43])([CH3:44])[N:40]([CH3:45])[C:39]([CH3:47])([CH3:46])[CH2:38]5)[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CN1C(C)(C)CC(Nc2cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc2C(=O)OC(C)(C)C)CC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(C)(C)CC(Nc2cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc2C(=O)O)CC1(C)C
Temperature: 100 °C
Yield: 39 %

Procedure:
7.7 ml of 1N hydrochloric acid are added to a solution of 0.79 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]benzoate in 5 ml of dioxane. The reaction mixture is heated at 100° C. in a microwave for 2 hours and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/5 by volume), so as to give 280 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]benzoic acid in the form of a pale yellow powder, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[N:4][N:5]([CH2:7][CH:8]([F:10])[F:9])[CH:6]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].Cl.CN(C)CCCN=C=NCC>>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH2:7][CH:8]([F:10])[F:9])[N:4]=1)=[O:13]
Reactant: CNOC
Reactant: O=C(O)c1nn(CC(F)F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CON(C)C(=O)c1nn(CC(F)F)cc1Cl
Yield: 98 %

Procedure:
In a manner analogous to that described in Example 1d), the condensation of 4-chloro-1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxylic acid and N,O-dimethylhydroxylamine hydrochloride by N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride yielded the title compound (98% yield) as a colorless oil. MS (ISP): m/z=254.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]N(C)C=O.CI>O>[CH3:20][N:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1)[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Nc1cccc(-c2ccc(Cl)nn2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Reaction time: 1 h

Procedure:
A mixture of 2.25 g of N-[3-(6-chloro-3-pyridazinyl)-phenyl]acetamide, 0.48 g of sodium hydride (50% in oil) and 100 ml of dimethylformamide was stirred under argon for 1 hour. To the mixture was added 0.6 ml of methyl iodide and after stirring 5 hours, an additional 0.6 ml of methyl iodide. After stirring overnight, 0.3 g of sodium hydride (50% in oil), then 0.6 ml of methyl iodide were added and stirring continued for 2 hours. The mixture was poured into water, filtered and the filtrate extracted with 60 ml portions of dichloromethane. The extracts were combined, evaporated in vacuo and the residue triturated with hexane. The resulting solid was chromatographed as described in Example 26 to give 1.45 g of product which was recrystallized from dichloromethane-ether to give the desired compound as crystals, mp 118°-120° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH2:35][C:36]([O-:38])=[O:37])[CH2:10]1)(=[O:8])=[O:7].[OH-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:27])([CH3:26])[C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=2)[C@@H:11]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH2:35][C:36]([OH:38])=[O:37])[CH2:10]1)(=[O:8])=[O:7]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCOCC2CC(=O)[O-])cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCOCC2CC(=O)O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A 25-mL round-bottomed flask was charged with (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetate (70 mg, 0.116 mmol, Example 113), is aqueous 10 M NaOH (0.5 mL, 5.00 mmol) and MeOH (5 mL) and stirred at room temperature for 2 h. The reaction was concentrated to give (4-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-3-morpholinyl)acetic acid (65 mg) as a mixture of four isomers. This material was used crude in the next reaction.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH:15]1([N:19]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:19]2[CH2:25][CH2:24][CH2:23][N:22]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCCN(C2CCC2)CC1

Procedure:
This example was prepared according to Example 4 utilizing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-N-cyclobutyl-1,4-diazepane dihydrochloride, which was prepared according to Zaragoza, et. al. J. Med. Chem. 2004, 47, 2833-2838. m/z (ES+) M+1=299.2; HPLC tR=1.62 min. 1H NMR (500 MHz, CDCl3) δ 7.26 (t, J=7.6 Hz, 2H), 7.20-7.15 (m, 1H), 7.13-7.08 (m, 2H), 3.73-3.59 (m, 4H), 2.92-2.83 (m, 1H), 2.54-2.36 (m, 5H), 2.08-1.98 (m, 2H), 1.97-1.90 (m, 1H), 1.89-1.74 (m, 4H), 1.66 (ddd, J=9.2, 5.3, 4.1 Hz, 2H), 1.63-1.55 (m, 1H), 1.25 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([F:12])[C:3]=1[F:13].[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([F:12])[C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: [H][H]
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(F)c1F
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Cl)c(F)c(F)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2,3-difluoro-6-nitroaniline (11.4 g, 54.4. mmol), Raney nickel (Aldrich, Milwaukee, slurry in water, 2.2 g wet) and ethanol (200 mL) were combined in a stirred Parr reactor which was pressurized with hydrogen (250 psig). The mixture was allowed to stir at rt overnight, after which time the reactor was depressurized and the mixture was filtered through Celite and the solvents were removed in vacuo. The remaining residue was dissolved in ethyl acetate, dried over magnesium sulfate and the solvents were removed in vacuo to afford a brownish solid (11.6 g, crude weight); 1H NMR (DMSO-d6) δ: 6.43 (d, J=5.7 Hz, 1H, Ar—H), 5.25 (very br s, 4H, overlapping NH2).
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:10]=3[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2nc3ccc(OC)cc3n2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2nc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.1 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (151 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 2.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (124 mg, 87%) as a white solid.
Reaction SMILES: Cl.[Cl-].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([N+:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11]2)=[CH:6][CH:5]=1.Cl.[NH2:20][C:21]1[C:22]([Cl:29])=[C:23]([OH:28])[C:24]([CH3:27])=[CH:25][CH:26]=1.[OH-].[NH4+].OO>O>[Cl-:29].[NH2:20][C:21]1[C:26](=[N:3][C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:14][CH2:13][CH:12]([N+:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11]3)=[CH:8][CH:9]=2)[CH:25]=[C:24]([CH3:27])[C:23](=[O:28])[C:22]=1[Cl:29]
Reactant: Cc1ccc(N)c(Cl)c1O
Reactant: C[N+](C)(C)C1CCN(c2ccc(N)cc2)C1
Agent: Cl
Agent: OO
Agent: [Cl-]
Solvent: O
Product: CC1=CC(=Nc2ccc(N3CCC([N+](C)(C)C)C3)cc2)C(N)=C(Cl)C1=O
Reaction time: 24 h
Yield: 39.1 %

Procedure:
292.5 mg of 1-(4-aminophenyl)-N,N,N-trimethylpyrrolidin-3-aminium chloride hydrochloride and 194.1 mg of 3-amino-2-chloro-6-methylphenol hydrochloride are weighed out in a flask, 1 ml of water is added and the pH is adjusted to 9.5 with 20% ammonium hydroxide in water. 1.1 ml of 30% aqueous hydrogen peroxide solution are added dropwise. The mixture is left stirring for 24 hours. The precipitate is filtered off and rinsed with acetone. 80 mg of 1-(4-{[2-amino-3-chloro-5-methyl-4-oxocyclohexa-2,5-dien-1-ylidene]amino}phenyl)-N,N,N-trimethylpyrrolidin-3-aminium chloride (1t) are thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH2:16][NH2:17])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH2:15][CH2:16][NH:17][S:24]([CH3:27])(=[O:26])=[O:25])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)([O-:3])=[O:2]
Reactant: NCCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCOc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2-((3-Nitro-5-(trifluoromethyl)phenyl)oxy)ethylamine (4.05 g, 16.2 mmols, 1 eq) was dissolved in 100 mL of CH2Cl2. The solution was cooled to 0° C. Pyridine (2.6 mL, 32.4 mmols, 2 eq) was added followed by mesyl chloride (1.25 mL, 16.2 mmols, 1 eq). The reaction was stirred for 18 h during which time it was warmed slowly to RT. The solvent was removed in vacuo, and the residue dissolved in EtOAc. The resulting solution was washed twice with 2 N HCl, once with water, and 3× with brine. After being dried over Na2SO4 the solution was filtered and concentrated. The crude was purified by silica gel chromatography eluting with 50% to 60% EtOAc:hexane to yield the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:43]([C:45]1[CH:54]=[C:53]2[C:48]([CH:49]=[C:50]([C:57]3[CH:58]=[C:59]([NH:64]/[C:65](/[NH2:68])=[N:66]/O)[CH:60]=[CH:61][C:62]=3[CH3:63])[C:51](=[O:56])[N:52]2[CH3:55])=[CH:47][N:46]=1)[CH3:44]>CN(C=O)C>[CH2:43]([C:45]1[CH:54]=[C:53]2[C:48]([CH:49]=[C:50]([C:57]3[CH:58]=[C:59]([NH:64][C:65]4[N:66]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[O:9][N:68]=4)[CH:60]=[CH:61][C:62]=3[CH3:63])[C:51](=[O:56])[N:52]2[CH3:55])=[CH:47][N:46]=1)[CH3:44]
Reactant: CCc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4ccccn4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of picolinic acid (10 mg, 0.09 mmol) in DMF (1 mL) were added DIPEA (16 μL, 0.09 mmol) and HATU (33 mg, 0.09 mmol). After stirring at rt for 15 min, 17a (30 mg, 0.09 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17a was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 7-ethyl-1-methyl-3-(2-methyl-5-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A105). 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 9.09 (s, 1H), 8.81 (s, 1H), 8.18 (d. J=8 Hz, 1H), 8.10 (m, 2H), 7.75 (s, 1H), 7.71 (m, 1H), 7.47 (d, J=8 Hz, 1H), 7.41 (s, 1H), 7.28 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.01 (q, J=7.6 Hz, 2H), 2.10 (s, 3H), 1.36 (t, J=7.6 Hz, 3H). MS m/z 439.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[Cl:30]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14]([Cl:30])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[N:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccc(F)cc2)c1O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc2c(c1O)c(Cl)c(-c1ccc(F)cc1)n2-c1ccc(F)cc1
Yield: 74.7 %

Procedure:
The mixture of 1,2-bis-(4-fluoro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (80 mg, 0.203 mmol), N-chlorosuccinimide (NCS)(28 mg, 0.203 mmol) and BzOOBz (2.5 mg) in tetrachloromethane (6 mL) was refluxed overnight, then the solvents were removed, the residue was purified on column to give the desired title compound (65 mg); ESI MS (m/z): 429 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[CH3:2].[N:12]1[CH:17]=[C:16]([C:18](Cl)=[O:19])[CH:15]=[N:14][CH:13]=1>>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[C:18](=[O:19])[C:16]1[CH:17]=[N:12][CH:13]=[N:14][CH:15]=1)[CH3:2]
Reactant: O=C(Cl)c1cncnc1
Reactant: CCOC(=O)CC(=O)C1CC1
Product: CCOC(=O)C(C(=O)c1cncnc1)C(=O)C1CC1
Yield: 40 %

Procedure:
In analogy to the procedure described in Example 162A], 3-cyclopropyl-3-oxo-propionic acid ethyl ester and pyrimidine-5-carbonyl chloride gave the title compound as a yellow oil (40%). MS: 261.3 (M−H−).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[N:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl.CO>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([N:38]4[CH2:39][CH2:40][N:35]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][CH2:37]4)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.9 %

Procedure:
To a solution of 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylic acid (50 mg, 0.110 mmol) in dry DMF (0.55 mL) was added tert-butyl piperazine-1-carboxylate (24.6 mg, 0.132 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.6 mg, 0.16 mmol), 1-hydroxybenzotriazole (22.3 mg, 0.165 mmol) and triethylamine (23.0 μL, 0.165 mmol). The mixture was stirred at ambient temperature for 12 hours, diluted with dichloromethane and methanol and filtered. The filtrate was concentrated under a stream of nitrogen. The residue was purified using preparative thin layer chromatography, eluting with 8% methanol and 0.5% ammonium hydroxide in dichloromethane to give the product (10.2 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:34][CH2:35][CH3:36])=[C:16]([CH:23]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.FC(F)(F)C(O)=O>C(Cl)Cl.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17]([C:21]#[N:22])=[C:16]([CH:23]4[CH2:24][NH:25][CH2:26]4)[C:15]=3[O:34][CH2:35][CH3:36])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
A solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidine-1-carboxylate (peak 1 enantiomer from step 5) (2.2 g, 4.2 mmol) in methylene chloride (11 mL) was treated with trifluoroacetic acid (11 mL) dropwise and stirred at room temperature for 30 min. The reaction mixture was concentrated to an oil that was reconcentrated from ethanol (2×) to give a residue. This material was dissolved in a minimum amount of methanol, added dropwise to ice cooled saturated sodium bicarbonate solution (100 ml), and extracted several times with 2:1 dichloromethane/isopropanol to give the desired product (1.8 g, quantitative) that was used without further purification. A small amount of the desired product was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.47 (s, 1H), 6.23 (q, J=7.0 Hz, 1H), 4.37-4.26 (m, 1H), 3.91-3.61 (m, 6H), 2.54 (s, 3H), 1.71 (d, J=7.1 Hz, 3H), 1.32 (t, J=7.0 Hz, 3H). LCMS for C20H23ClN7O (M+H)+: m/z=412.2; Found: 412.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[N:14]=[CH:15][C:16]([C:19]2[CH:20]=[C:21]([C:29]3[C:33](=[O:34])[C:32]([CH3:36])([CH3:35])[O:31][N:30]=3)[CH:22]=[CH:23][C:24]=2[C:25]([CH3:28])([CH3:27])[CH3:26])=[N:17][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[C:25]([C:24]1[CH:23]=[CH:22][C:21]([C:29]2[C:33](=[O:34])[C:32]([CH3:36])([CH3:35])[O:31][N:30]=2)=[CH:20][C:19]=1[C:16]1[N:17]=[CH:18][C:13]([NH:12][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])=[N:14][CH:15]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC1(C)ON=C(c2ccc(C(C)(C)C)c(-c3cnc(N)cn3)c2)C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)ON=C(c2ccc(C(C)(C)C)c(-c3cnc(NC(=O)c4c(F)cccc4F)cn3)c2)C1=O
Temperature: 0 °C

Procedure:
To a 0° C. cooled and stirred, solution of 2,6-difluorobenzoyl chloride (0.083 mL, 0.66 mmol, 1.5 eq) in DCM (200 mL) was added drop wise a solution of 3-(3-(5-aminopyrazin-2-yl)-4-(tert-butyl)phenyl)-5,5-dimethylisoxazol-4(5H)-one, Intermediate 4b, (150 mg, 0.44 mmol, 1.0 eq) in DCM (50 mL) followed by pyridine (0.053 mL, 0.66 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 2 h. The reaction was diluted with DCM (100 mL), and washed with 10% hydrochloric acid (100 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, 10% ethyl acetate in hexane) to afford 40 mg of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 8.55 (s, 1H, D2O exchangeable), 8.28 (s, 1H), 8.14 (dd, J=9.0, 2.5 Hz, 1H), 7.86 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.52-7.45 (m, 1H), 7.07 (t, J=8.5 Hz, 2H), 1.43 (s, 6H), 1.23 (s, 9H); ESI-MS (m/z) 479 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:31])[C:17]3[CH:22]=[C:21]([O:23]C(=O)C)[CH:20]=[C:19]([O:27]C(=O)C)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=O)C.C(Cl)Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:31])[C:17]3[CH:18]=[C:19]([OH:27])[CH:20]=[C:21]([OH:23])[CH:22]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(c1cc(O)cc(O)c1)N1CCN(CCc2ccc(Cl)cc2)CC1

Procedure:
A solution of 1-[2-(4-chlorophenyl)-ethyl]-4-(3,5-diacetoxybenzoyl)-piperazine in 500 ml of methanol stirred with 285 ml of 1N NaOH for 16 hours at 20°. The reaction mixture is diluted with H2O and the pH is adjusted to 6 with acetic acid. The resulting oily precipitate is stirred with CH2Cl2 and filtered with suction. Crystallisation from ethanol yields 1-[2-(4-chlorophenyl)-ethyl]-4-(3,5-dihydroxybenzoyl)piperazine having a melting point of 217°-221°.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8](=O)[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH:15]1([C:13]([C:12]2[O:1][C:2]3[C:3](=[N:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[CH3:9])=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(=O)c1ncccc1O
Reactant: O=C(CBr)C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2cccnc12
Temperature: 25 °C
Reaction time: 60 h
Yield: 52.8 %

Procedure:
To a mixture of 1-(3-hydroxypyridin-2-yl)ethanone (4.37 g), 2-bromo-1-cyclohexylethanone (9.82 g) synthesized in Example A51(1) and N,N-dimethylformamide (50 mL) was added potassium carbonate (13.2 g), and the mixture was stirred at room temperature for 2.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (4.09 g, 53%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:8]([N:18]2[CH2:19][CH2:20][N:15]([CH2:13][CH3:14])[CH2:16][CH2:17]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a solution of 20.0 g of 4,5-dichloro-2-nitroaniline and 16.0 g of 1-ethylpiperazine in 50 ml of dimethylsulfoxide, 20.0 g of potassium carbonate was added, followed by 2 hours' stirring at 120° C. Water was added to the reaction liquid, followed by extraction with diethyl ether. The diethyl ether layer was successively washed with water and saturated brine, dried on anhydrous magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from chloroform-diethyl ether, to provide 20.3 g of the title compound.