Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Li+].C(OCC)C>O1CCCC1.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a stirred mixture of (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (900 mg, 2.65 mmol) in tetrahydrofuran (10 mL) and water (3 mL) was added lithium hydroxide (135 mg, 3.19 mmol). After addition was complete the mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into water and diethyl ether and the layers separated. The aqueous layer was made acidic with 2N aqueous hydrochloric acid and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate fractions were washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to afford (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (710 mg, 82%) as a yellow solid: LR-ES-MS m/z calculated for C16H17F2NO4 [M]+ 325, observed [M+H]+ 326.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[CH2:5][C:6](=O)[CH3:7]>[Pd].C(O)C>[CH3:1][O:2][C:3]([C@H:4]1[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:15][C@@H:6]([CH3:7])[CH2:5]1)=[O:18]
Reactant: COC(=O)C(CC(C)=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@H](C)Nc2ccccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 67.3 %

Procedure:
A round bottom flask with magnetic stirrer was charged with 2-(2-nitro-phenyl)4-oxo-pentanoic acid methyl ester (4.74 g, 19.1 mmol) and anhydrous ethanol (50 mL). To the reaction was added 10% palladium on carbon (0.948 g, 20% by weight) and the reaction stirred at room temperature under a hydrogen gas atmosphere (balloon) for 18-20 hours. The reaction was filtered through a pad of celite and the celite pad washed with warm ethanol. The combined filtrates were concentrated in vacuo to afford an off-white colored solid. This material was purified via Isco flash system (0-20% ethyl acetate/hexanes) to yield 2.64 g of cis-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester as a white solid (68%). 1H-NMR (CDCl3) δ: 1.23 (3H, d), 1.95 (1H, dd), 2.10-2.18 (1H, m), 3.34-3.46 (1H, m), 3.74 (3H, s), 3.94 (1H, dd), 6.51 (1H, dd), 6.60-6.67 (1H, m), 6.94-7.03 (2H, m). MS m/z: 206 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:34]([O:33][C:32](=[O:41])[NH:31][CH2:30][CH2:29][NH:28][C:24](=[O:26])[C@@H:15]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 79A from 300 mg (0.82 mmol) of N5-[(benzyloxy)carbonyl]-N-(tert-butoxycarbonyl)-L-ornithine and 246 mg (1.06 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride in 6 ml of dimethylformamide with the addition of 204 mg (1.06 mmol) of EDC, 33 mg (0.25 mmol) of HOBt and 148 mg (1.15 mmol) of N,N-diisopropylethylamine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([O:14][CH3:15])[CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-fluoronicotinic acid (10 g, 70.9 mmol) in DCM (200 ml), was added N,O-Dimethylhydroxylamine hydrochloride (7.3 g, 74.8 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (15 g, 78.5 mmol), and triethylamine (22 ml, 156 mmol). The reaction mixture was allowed to stir at room temperature for 16 hours. The reaction was partitioned with water, layers were cut, and organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue obtained was purified by a silica gel filtration using EtOAc-DCM (4:1) to give 7.2 g (55% isolated yield) of the title compound. 1H NMR: 8.48 (s, 1H) 8.21 (t, J=8.29 Hz, 1H) 7.27 (dd, J=8.29, 3.01 Hz, 1H) 3.54 (s, 3H) 3.27 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCCCNC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 105.3 %

Procedure:
The above amide (265 mg, 0.750 mmol) was dissolved in EtOH (25 mL). The reaction mixture was charged with ammonium formate (500 mg) and 10% palladium on carbon (100 mg) and stirred for 4 days at ambient temperature. The reaction was filtered through diatomaceous earth and concentrated to recover 265 mg of [6-(4-amino-benzoylamino)-hexyl]-carbamic acid tert-butyl ester as a white crystalline solid (quantitative yield).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.O>C(OCC)(=O)C>[CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[N:24]([CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3ccccc3)c3ccc(Cl)c(Cl)c3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 38 h

Procedure:
Combine N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)benzamide (1.35 mmol), ethyl 4-bromobutyrate (5.4 mmol), and potassium carbonate (2.24 g, 16.2 mmol) in 13/1 acetone/water (25 mL). Heat to reflux. After 38 hours, cool to ambient temperature and dilute with ethyl acetate. Extract with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution. Dry the organic layer over MgSO4, filter, and concentrate invacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-])=O)=[C:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:3]=1>[Pd].CO>[NH2:14][C:5]1[C:6](=[O:13])[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:2]([CH3:1])=[CH:3][C:4]=1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)Cn1c(C)cc(Cc2ccccc2)c([N+](=O)[O-])c1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cn1c(C)cc(Cc2ccccc2)c(N)c1=O
Reaction time: 2 h

Procedure:
10 g (31.6 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-(phenylmethyl)-1,2-dihydropyridine-1-acetate are placed in a Parr flask and 150 ml of methanol are added. 1 g of 10% palladium on carbon is then introduced and the mixture is hydrogenated at 0.28 MPa (40 psi) at room temperature for 2 hours. The mixture is filtered on celite and the solvent is evaporated to dryness.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:11][NH2:12].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:11][NH:12][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1cc2ccccc2o1
Agent: Cl
Product: O=C(O)c1ccncc1NCc1cc2ccccc2o1
Yield: 3 %

Procedure:
The title compound was prepared in 3% yield from (1-benzofuran-2-ylmethyl)amine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.44 (br s, 1H), 8.39 (s, 1H), 7.97 (br s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.52-7.60 (m, 3H), 7.19-7.29 (m, 2H), 6.81 (s, 1H), 4.79 (s, 2H). [M+H] calc'd for C15H12N2O3, 269. found 269.
Reaction SMILES: [C:1]([CH2:3][C:4](N)=O)#N.[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][N:9]=1>>[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:1]=[CH:3][C:4]3[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=3)=[CH:20][CH:21]=2)[S:10][N:9]=1
Reactant: N#Cc1c(O)nsc1Nc1ccccc1
Reactant: N#CCC(N)=O
Product: N#Cc1c(O)nsc1Nc1ccc(C=Cc2ccccc2)cc1

Procedure:
The title compound was prepared from 1-isothiacyanato-4-styryl-benzene and 2-cyanoacetamide by the procedure analogous to Method 2 for 3-Hydroxy-5-phenylamino-isothiazol-4-carbonitrile. 1H NMR (300 MHz, DMSO-d6) δ: 7.22–7.65 (m, 11H). MS (ES, m/z): 320.3, [M-H]+, 318.1 [M-H]−.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:35]2[C:36]([CH2:41]CCC)=[N:37]OC=2C)=NC=1>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:37][CH:36]([CH3:41])[CH3:35])=[O:23])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCC3)noc2C)nc1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: Cc1onc(C2CCCC2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 62 %

Procedure:
As described for example 5d, 6-(3-cyclopentyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (230 mg, 0.73 mmol) was converted, instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (155 mg, 62%) which was obtained as a white solid after purification by chromatography (silica, 0 to 80% ethyl acetate in heptane). MS: m/e=344.0 [M+H]+.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[F:28][C:29]([F:36])([F:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1.[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([N:31]4[CH2:32][CH2:33][CH2:34][C@H:30]4[C:29]([F:36])([F:35])[F:28])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: FC(F)(F)[C@@H]1CCCN1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 350 mg, 0.79 mmol), (S)-2-(trifluoromethyl)pyrrolidine (purchased from Sigma Aldrich) (219 mg, 1.57 mmol), potassium fluoride (229 mg, 3.93 mmol), DMSO (2.4 mL), and N,N-diisopropylethylamine (0.69 mL, 3.93 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C25H26ClF3N6 [M+H]+ 503. found 503.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2].[H-].[Na+].Cl[CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[N:12]([CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(C#N)cccc21
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Prepared using General Procedure 9. To a solution of (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate INT-9 (3.0 g, 1.16 mmol) in DMF (20 mL) was added NaH (1.39 g of 60% dispersion in mineral oil, 34.8 mmol) at 0° C. with stirring for 3 h before the addition of 2-chloro-N,N-dimethylacetamide (2.82 g, 23.2 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and then warmed to room temperature for 1 h. The reaction mixture was quenched with water (3 mL) slowly at 0° C. The mixture was partitioned between EA (3×20 mL) and water (50 mL). The combined organic layers were concentrated and purified by chromatography (DCM/MeOH) to provide product 3.82 g (96.0%) of (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-yl(2-(dimethylamino)-2-oxoethyl)carbamate as a light brown solid. LCMS-ESI (m/z) calculated for C19H25ClN6O6; 343.4. found 366.1 [M+Na]+, tR=3.16 min.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:85]1([NH2:90])[CH2:89][CH2:88][CH2:87][CH2:86]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH:85]1([NH:90][C:2]2[N:7]3[N:8]=[C:9]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([N:17]5[CH2:21][CH2:20][CH2:19][CH2:18]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][C:3]=2[C:29]([F:32])([F:31])[F:30])[CH2:89][CH2:88][CH2:87][CH2:86]1
Reactant: NC1CCCC1
Reactant: Fc1ccc(-c2nn3c(Cl)c(C(F)(F)F)ccc3c2-c2ccnc(N3CCCC3)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2nn3c(NC4CCCC4)c(C(F)(F)F)ccc3c2-c2ccnc(N3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (54 mg, 0.12 mmol) in toluene (3 mL) was added successively racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (9.2 mg, 0.013 mmol), cesium carbonate (57 mg, 0.17 mmol), cyclopentylamine (0.5 mL, 5.0 mmol), and palladium (II) acetate (2 mg, 0.009 mmol). The resultant mixture was heated at 85° C. for 6 hours at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ether was added. The organic layer was washed with water and brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (12:1 to 8:1 hexanes-ethyl acetate) provided N-cyclopentyl-2-(4-fluorophenyl)-3-[2-(1-pyrrolidinyl)-4-pyrimidinyl]-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-7-amine (37 mg, 63%) as an oil. 1H NMR (CDCl3): δ 8.16 (d, 1H), 7.84 (d, 1 H), 7.68 (dd, 2 H), 7.49 (d, 1 H), 7.18 (t, 2 H), 6.55 (d, 1 H), 6.29 (d, 1 H), 4.57 (m, 1 H), 3.68 (m, 4 H), 2.13-2.05 (m, 6 H), 1.84-1.65 (m, 6 H); 19F NMR (CDCl3) δ −55.33, −112.78; MS m/z 511 (M+1). This material was taken up in ether and treated with hydrochloric acid in ether to yield a bright yellow powder which was isolated by filtration as a hydrochloride salt.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@@H:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([O:38]CC)=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[N:46]=2)[CH:7]=1)[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@@H:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([OH:38])=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[N:46]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@@H]2CCN(CCN3CCOCC3)C2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C[C@@H]2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
(R)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-(2-morpholinoethyl)pyrrolidin-3-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 235, 320 mg) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). To this solution was added 24 wt % sodium hydroxide (1 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated to remove the organic solvents. Water (10 mL) was added and the aqueous layer was acidified to pH 6˜7 with 1N hydrochloric acid. The solution was centrifuged to help isolate the solid that precipitated, and the precipitate was washed with cold water once to give a light yellow solid (260 mg, 86.9%) after drying.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]4[C:34]([NH:35][CH:36]([CH3:38])[CH3:37])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)(=[O:10])=[O:9])C(=O)C2=CC=CC=C12.C1(=O)N(CCS(NC2(C(C3CNCCC3N(C)C3C(NC(C)C)=CC=CN=3)=O)C=C3C(C=CC=C3)=N2)(=O)=O)C(=O)C2=CC=CC=C12>>[NH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]3[C:34]([NH:35][CH:36]([CH3:38])[CH3:37])=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:27][CH2:28]1)=[O:22])=[CH:15]2)(=[O:9])=[O:10]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN4C(=O)c5ccccc5C4=O)ccc3[nH]2)CC1
Agent: CC(C)Nc1cccnc1N(C)C1CCNCC1C(=O)C1(NS(=O)(=O)CCN2C(=O)c3ccccc3C2=O)C=c2ccccc2=N1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN)ccc3[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 32, and making non-critical variations but substituting 1-[5-(2-phthalimidoethanesulfonamido)indole-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine (EXAMPLE 33, 605 mg) for 1-[5-(2-(phthalimidoethanesulfonamido)indole -2-carbonyl]-4-[N -methyl-N-(3-(1-methylethylamino)-2pyridinyl)amino]-piperidine, the title compound is obtained, NMR (CDCl3) 10.62, 7.68, 7.55, 7.25, 7.07, 6.93, 6.84, 6.69, 4.20, 4.04, 3.90-3.50, 3.14 and 1.25 δ.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([C:34](O)=[O:35])=[N:4]1)[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:33])[C:5]([CH2:34][OH:35])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1nc(CO)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a suspension of 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (2.25 g, 4.59 mmol) in tetrahydrofuran (THF) (60 mL) was added triethylamine (2.110 mL, 15.14 mmol) and ethyl chloroformate (1.322 mL. 13.76 mmol). The resulting yellow solution was stirred at room temperature for 2 h, and was then added to a solution of sodium borohydride (2.083 g, 55.0 mmol) in ethanol (60 mL). After being stirred for 2 h, the reaction was quenched by addition of water (5 mL). The organic solvent was removed in vacuo, the residue was then taken in water (50 mL) and extracted with dichloromethane (2×50 mL). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by automatic silica gel column chromatography (Combiflash RF), eluting with methanol/dichloromethane (0-10%) to afford 1-ethyl-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)cinnolin-4(1H)-one (1.97 g, 3.64 mmol, 79% yield) as a white solid. LCMS: (M+H)+: 477.1
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[N:3]=[CH:2]1.[NH2:9][C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:40])=[C:24]([NH:26][C:27](=[O:39])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([C:37]#[N:38])([CH3:36])[CH3:35])[CH:29]=3)[CH:25]=1)[N:13]=2>N1C=CC=CC=1>[C:37]([C:34]([C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[C:27]([NH:26][C:24]1[CH:25]=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:40])[O:19][C:14]1[N:13]=[C:12]2[S:11][C:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][O:1][CH:5]=3)=[O:7])=[N:18][C:17]2=[CH:16][CH:15]=1)=[O:39])([CH3:36])[CH3:35])#[N:38]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: O=C(Cl)c1cocn1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)c4cocn4)sc3n2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
1,3-Oxazole-4-carbonyl chloride synthesized above was suspended in pyridine (4.0 mL) at 0° C., N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.451 mmol) produced in Example C33(iv) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. 5% Aqueous sodium hydrogen carbonate solution (20 mL), ethyl acetate (20 mL) and hexane (20 mL) were added to the residue, and the yielded pale-yellow precipitate was collected by filtration. The obtained precipitate was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (108 mg, 45%) as a colorless powder.