Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:12]2=[C:13]([N:21]3[CH2:24][CH2:23][CH2:22]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17](I)[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)#[CH:28].C(N(CC)CC)C>[Cu]I.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:12]2=[C:13]([N:21]3[CH2:24][CH2:23][CH2:22]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([C:28]#[C:27][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3c(I)cnn3c(N3CCC3)c2CC1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2nc3c(C#Cc4ccccn4)cnn3c(N3CCC3)c2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.1 g (0.21 mmol) 10-azetidin-1-yl-3-iodo-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in a sealed tube under nitrogen was added 3 mL of dioxane and the mixture was degassed with nitrogen for 3 minutes. 14.7 mg (0.02 mmol) 1,1′-bis-(diphenylphosphino)-ferrocenedichloro palladium (II) was added and the reaction mixture was stirred at room temperature for 30 minutes. 86 μL (0.85 mmol) 2-ethynyl pyridine was added followed by 0.53 mL (3.8 mmol) triethylamine and 4 mg (0.02 mmol) CuI, and the reaction was stirred at 60° C. for 16 hours under nitrogen. The mixture was cooled to room temperature and partitioned between 20 mL EtOAc and 20 mL saturated ammonium chloride. The mixture was extracted with EtOAc (3×10 mL), the organic layers combined, washed with 20 mL brine, and dried with MgSO4. After filtration and evaporation of the solvent the desired product was purified by column chromatography (silica, heptane/EtOAc 9:1 to 3:7).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.Cl[S:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][S:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(=[O:33])=[O:32])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: CCOC(=O)CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCS(=O)(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 200 mg (0.512 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 309 mg (1.54 mmol) ethyl 3-(chlorosulfonyl)propanoate and 0.21 ml (1.54 mmol) triethylamine. The mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient) to yield 41 mg (14% of th.) of the title compound.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].Cl>O1CCCC1>[C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(COCCCCCO)=NOC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COCCCCCOS(C)(=O)=O)=NOC(C)(C)C

Procedure:
First, 0.23 g of 5-hydroxypentyloxyacetone O-tert-butyloxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran are placed in a reaction vessel, to which 0.14 g of methanesulfonyl chloride is slowly added with stirring under ice cooling. After completion of the addition, the reaction mixture is further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which affords 5-(methanesulfonyloxy)pentyloxyacetone O-tert-butyloxime.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C1COCC1.O.[OH-].[Li+]>CO.O>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([N:37]5[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]5)=[O:32])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: OC1CCNCC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Using the conditions of General Procedure D for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-hydroxypiperidine (available from Aldrich Chemical Company, Inc.; 42 mg, 0.42 mmol) to give the crude amide product. The crude amide was hydrolyzed by adding THF (2 mL), water (0.05 mL), MeOH (1 mL), and lithium hydroxide monohydrate (12.3 mg, 0.29 mmol) and stirring the mixture overnight at room temperature. The reaction mixture was concentrated to dryness under vacuum at 40° C. 1 M HCl (3 mL) was added, and the mixture was stirred, concentrated to dryness, and purified using HPLC Purification Conditions A to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(4-hydroxy-piperidine-1-carbonyl)-biphenyl-2-carboxylic acid (48 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 8.47 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.42-7.49 (m, 4H), 3.73-3.79 (m, 1H), 3.36-3.52 (m, 2H+water peak), 3.15-3.27 (m, 2H), 1.70-1.82 (m, 2H), 1.32-1.47 (m, 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2[CH:17]=[C:16]([C:18]3[C:19]([N:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[O:15][N:14]=2)(=O)=O)=CC=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1C=C(C2C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=CC=2)ON=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:12][C:13]2[CH:17]=[C:16]([C:18]3[C:19]([N:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])=[N:20][CH:21]=[CH:22][CH:23]=3)[O:15][N:14]=2)=[CH:49][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2cc(-c3cccnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Reactant: OB(O)c1ccc(COc2ccccn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(-c2cccnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, to a mixture of (5-{2-[bis(tert-butoxycarbonyl)amino]pyridin-3-yl}isoxazol-3-yl)methyl 4-methylbenzenesulfonate (82 mg, 0.15 mmol), {4-[(pyridin-2-yloxy)methyl]phenyl}boronic acid (34 mg, 0.15 mmol), potassium phosphate (35 mg, 0.17 mmol), triphenylphosphine (7.9 mg, 0.03 mmol), and toluene (1.0 mL) was added palladium acetate (1.7 mg, 5 mol %), which was stirred for 16 hours at 90° C. After cooling, ethyl acetate and water were added thereto, and the mixture was transferred to a separatory funnel and separated. The organic layer was washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography, so as to obtain a mixture of the titled compound, (5-{2-[bis(tert-butoxycarbonyl)amino]pyridin-3-yl}isoxazol-3-yl)methyl 4-methyl benzenesulfonate, and di-tert-butyl [3-(3-methylisoxazol-5-yl)pyridin-2-yl]imidodicarbonate (63 mg:molar ratio of 59:33:8), as a pale yellow oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:29]>>[Cl:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:4][N:3]=1
Reactant: COc1ccc2c(O)ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)ncc(N3CCNCC3)c2c1
Yield: 37.3 %

Procedure:
A solution of tert-butyl 4-(1-hydroxy-6-methoxyisoquinolin-4-yl)piperazine-1-carboxylate (0.3 g, 1.157 mmol) in POCl3 (5 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.2 g, 37.3%) as a gummy compound. MS: MS m/z 278.56 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.O[C@@H:23]([CH3:32])[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][C@@H:23]([CH3:32])[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: C[C@H](O)C(=O)N1CCOCC1
Reactant: COC(=O)/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C(=O)O[C@@H](C)C(=O)N1CCOCC1
Yield: 50.4 %

Procedure:
Following general procedure B2, (2E)-3-(methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF) (0.50 g, 3.84 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (0.81 g, 4.20 mmol) in 10 mL of dichloromethane (DCM) at ca. 0° C. (2S)-2-Hydroxy-1-morpholin-4-yl-propan-1-one (0.48 g, 3.07 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes (ca. 3:2) afforded 0.42 g (51% yield) of the title compound (31) as a white solid. M.p.: 79-82° C.; 1H NMR (CD3CN, 400 MHz): δ 6.90-6.81 (m, 2H), 5.44 (q, J=6.8 Hz 1H), 3.78 (s, 3H), 3.65-3.60 (m, 4H), 3.51-3.50 (m, 4H), 1.42 (d, J=6.8 Hz 3H). MS (ESI): m/z 272.05 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CN(C=O)C>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:4]
Reactant: C=CCC(C)(C)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC(C)(C)C(=O)OCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 2,2-dimethyl-4-pentenoic acid (11.5 g, 90 mmol) in DMF (250 mL) at room temperature, was added potassium tert-butoxide (11.1 g, 99 mmol). The reaction mixture was stirred at 60° C. for 1 h. 4-Methoxybenzyl chloride (16.9 g, 108 mmol) was added and the reaction mixture was stirred at 60° C. for 4h. The DMF was evaporated under vacuum, the residue was dissolved in ether (500 mL) and washed with water (3×200 mL). The organic phase was dried with NASO, and evaporated to give 21.4 g of 4methoxybenzyl 2,2-dimethyl-4-pentenoate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4]([NH:11][CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:14][OH:15])[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][N:27](S(C3C=CC(C)=CC=3)(=O)=O)[C:24]2=[N:25][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.O.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]>[F:10][C:5]1[CH:6]=[C:7]([C:8]#[N:9])[C:2]([C:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([F:20])[CH:22]=3)[NH:27][CH:28]=2)=[N:3][C:4]=1[NH:11][CH:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:14][OH:15]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)C(CCO)Nc1nc(Cl)c(C#N)cc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(CCO)Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F
Temperature: 135 °C

Procedure:
To a racemic solution of 2-chloro-5-fluoro-6-(1-hydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile, 95a, (0.20 g, 0.70 mmol) and 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, 7a, (0.44 g, 1.05 mmol) in THF (15 mL) was added a solution of potassium phosphate (0.45 g) in 3 mL of water. The resulting mixture was degassed under a stream of nitrogen for 15 minutes. To the mixture was then added X-Phos (0.03 g, 0.07 mmol) and Pd2(dba)3 (0.02 g, 0.04 mmol). The reaction was warmed to 135° C. via microwave irradiation for 15 minutes and then extracted into EtOAc (3×15 mL) vs. water. The organic layers were combined and concentrated in vacuo to a dark oil which was redissolved in 20 ml, of THF. To the solution was added 5 mL of 2 N LiOH and the reaction was warmed to 65° C. for 12 hrs and then concentrated in vacuo. The resulting residue was purified via silica gel chromatography (EtOAc) to afford 108 mg of the desired product, 41, as a yellow solid: 1H NMR (300 MHz, d6-DMSO) δ 12.40 (s, H), 8.63 (dd, J=2.8, 10.1 Hz, H), 8.37-8.32 (m, H), 7.83 (d, J=11.4 Hz, H), 7.31 (d, J=9.7 Hz, H), 4.56-4.50 (m, H), 4.41 (dd, J=4.1, 5.2 Hz, H), 3.69 (s, H), 3.57 (s, H), 3.49 (t, J=6.6 Hz, H), 3.48 (s, H), 3.36-3.28 (m, H), 2.50 (qn, J=1.8 Hz, H), 1.86-1.67 (m, 2 H), 1.21 (dd, J=7.0, 16.1 Hz, H) and 0.94 (s, 9 H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.09 minutes (M+H) 386.39.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[CH2:17]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][NH2:28])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:28][CH2:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Reactant: CCCCN1CCC(CN)CC1
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(CC)nc23)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 3 of EXAMPLE 5 from 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 10, Step 2) and 1-(1-butyl-4-piperidinyl)methanamine (EXAMPLE 1, METHOD A, Step 5).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:49][CH2:48]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and methanesulfonyl chloride as starting materials in 43% yield. LCMS for C25H29ClN7O3S (M+H)+: m/z=542.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1OCC1CCCC1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1OCC1CCCC1)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-(cyclopentylmethoxy)benzyl)-N-ethylamino]pyridine-5-carboxylate (see reference example 5) (0.37 g, 0.83 mmol) in THF (4 ml) and methanol (4 ml) was treated with 1N aqueous sodium hydroxide solution (4 ml). The reaction was heated at 40° C. for 18 hours. The solvents were evaporated at reduced pressure and the residue was acidified with IN acetic acid (4 ml) and allowed to stir for 2 days. The precipitate was filtered, washed with water and dried in vacuo at 45° C. to give the title compound as a white solid (0.32 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][C:17]=1[Cl:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:27][C:17]1[CH:18]=[C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:21][C:16]=1[NH:15][C:12]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)=[O:14]
Reactant: O=C(O)c1nccc2ccc(F)cc12
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(NC(=O)c2nccc3ccc(F)cc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 51.2 %

Procedure:
In DMF (5 ml) were dissolved 7-fluoro-1-isoquinolinecarboxylic acid (250 mg, 1.31 mmol), methyl 4-amino-3-chlorophenylacetate (262 mg, 1.31 mmol), HOBt (catalytic amount), and DMAP (192 m g, 1.57 mmol). To the resulting solution was added EDC HCl (290 mg, 6.93 mmol), followed by stirring at room temperature for 14 hours. The reaction mixture was poured into water (20 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with ether and then dried under reduced pressure to give methyl (3-chloro-4-((7-fluoro-1-isoquinolinylcarbonyl)amino)phenyl)acetate (250 mg, 51%) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[N:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[CH2:35][CH2:36][NH2:37]>>[CH3:1][N:2]1[C:10]([CH2:11][NH:37][CH2:36][CH2:35][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][N:29]=2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: NCCc1cnccn1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCCc3cnccn3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2-(pyrazin-2-yl)ethanamine were reacted to give 342. [M+H]+ 485.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])([O-:11])=[O:10].Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 84 °C
Yield: 36 %

Procedure:
250 mg of 4,6-Dichloropyrimidine and 178 mg of m-nitroaniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl were added. The mixture obtained was refluxed (84° C.) for 4 hours under nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-(3-nitrophenyl)pyrimidin-4-amine hydrochloride in the form of bright yellow crystals was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[OH-].[NH4+:11]>>[CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3]([NH2:11])=[O:4]
Reactant: CCCC(C)(C)C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Product: CCCC(C)(C)C(N)=O
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Ammonium hydroxide (250 ml) was stirred and cooled to 1° C. and 2,2-dimethyl valeroyl chloride (49.7 g, 95%, 318 mmol) was added dropwise over 30 minutes. After stirring at room temperature for an additional 1/2 hour, the white solid product was recovered by filtration, washed with water and allowed to air dry to give 35.4 g (86%) of the desired amide, mp 94°-95° (lit. mp 95°-96° C.).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[CH2:19][N:20]([C:23]([CH:25]2[CH2:27][CH2:26]2)=[O:24])[CH2:21][CH3:22])[CH:11]=1)C.[Li+].[OH-].CO>C1COCC1>[CH:25]1([C:23]([N:20]([CH2:19][C:13]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[C:10]2[CH:11]=[C:6]([CH2:5][C:4]([OH:28])=[O:3])[CH:7]=[N:8][CH:9]=2)[CH2:21][CH3:22])=[O:24])[CH2:27][CH2:26]1
Reactant: CCOC(=O)Cc1cncc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(F)ccc1-c1cncc(CC(=O)O)c1)C(=O)C1CC1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
(5-{2-[(N-Cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-fluoro-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.202 g, 0.53 mmol) was dissolved in THF (5.25 mL) and treated with 1N aqueous LiOH (2.63 mL, 2.63 mmol) and a small amount of MeOH. The reaction was stirred at 35° C. for 30 minutes. The mixture was concentrated, and the residue was diluted with H2O and washed with EtOAc. The aqueous layer was acidified with 1N aqueous HCl to pH 6 and extracted with EtOAc, and the combined organic layers were washed with H2O and brine, and then dried over Na2SO4, filtered, and concentrated to give Compound 23.