Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][NH:8][C:9]2[C:18](/[CH:19]=[CH:20]/[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:31])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.CC1C=CC(S(NN)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>COCCOC.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:18]([CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:31])[CH:15]=3)[N:10]=2)=[CH:32][CH:33]=1
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2/C=C/C(=O)NCC2CCCCC2)cc1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2CCC(=O)NCC2CCCCC2)cc1
Temperature: 86 °C

Procedure:
To a stirred solution of (E)-3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)acrylamide (representative compound 10; 3.7 g, 7.3 mmol) in DME (100 mL) was added 4-methylbenzenesulfonohydrazide (13.6 g, 72.8 mmol). The mixture was brought to reflux at 86° C. and then via addition funnel was added dropwise a solution of sodium acetate (10.4 g, 127 mmol) in water (60 mL) over 1.5 h. Once the addition was complete, the reaction was refluxed for an additional 30 min, and then cooled to RT and concentrated to remove organic solvent. The crude material was dissolved in DCM (150 mL) and washed sequentially with 1N NaOH, 1N HCl, and then water. The organic layer was dried over MgSO4, filtered and concentrated to give a yellow oil. Purification via flash chromatography (5% EtOAc/dichloromethane) afforded 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)propanamide (representative compound 11). Step 2 In a sealed tube was combined 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(cyclohexylmethyl)propanamide (0.16 g, 0.31 mmol), 2-chlorophenylboronic acid (0.074 g, 0.47 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.0044 g, 0.0063 mmol), potassium acetate (0.062 g, 0.63 mmol), EtOH (6.0 ml) and water (0.41 mL). The flask was sealed and heated in an oil bath at 85° C. for 16 h. The reaction mixture was cooled to RT, adsorbed onto silica and purified by flash chromatography (5% MeOH/dichloromethane) to afford 3-(2-(4-methoxybenzylamino)-6-(2-chlorophenyl)quinolin-3-yl)-N-(cyclohexylmethyl)propanamide. Step: 3 Following the same procedure as in Step 9 of Scheme II, 3-(2-amino-6-(2-chlorophenyl)quinolin-3-yl)-N-(cyclohexylmethyl)propanamide (representative compound 6) was obtained after 3 hours of refluxing in TFA. MS (ESI, pos. ion) m/z: 422 (M+1).
Reaction SMILES: C[NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1.[C:12]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH3:16])(=[O:14])[CH3:13].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:11][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][NH:2][S:23]([C:20]2[CH:19]=[CH:18][C:17]([N:15]([C:12](=[O:14])[CH3:13])[CH3:16])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH:10]=[CH:9][CH:8]=1
Reactant: CNCCc1cccc(C)n1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NCCc2cccc(C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[2-(6-methyl-2-pyridyl)ethyl]amine (14.66 g, 97.7 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino) benzenesulfonyl chloride (24.2 g, 97.3 mmol) prepared in Preparative Example 12 and sodium acetate (24.0 g) in ethanol (140 ml). The obtained mixture was stirred at room temperature overnight, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-[2-(6-methyl-2-pyridyl)ethyl]-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless oil. This oil was dissolved in 4N aqueous hydrochloric acid. The solution was heated under reflux for 2 hours. The pH of the mixture was adjusted to about 8 by the addition of an aqueous solution of sodium hydrogencarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give an oily residue. This residue was purified by flash column chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3) to give the title compound as a light brown oil (25.8 g, overall yield of two steps: 83%).
Reaction SMILES: [CH2:1]1[CH2:32][O:31][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:4][CH2:5][C@H:6]2[CH:10]=[CH:9][C:8](=[O:11])[C@@H:7]2[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[O:2]1.[C:33](C1C=CC=CC=1)(=[O:40])C1C=CC=CC=1>CO>[CH:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][C@H:7]1[C:8](=[O:11])[CH2:9][C@@H:10]([CH2:33][OH:40])[C@@H:6]1[CH2:5][CH2:4][C:3]1([O:2][CH2:1][CH2:32][O:31]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH3:22])[CH3:23]
Reactant: CCCCCCCC1(CC[C@H]2C=CC(=O)[C@@H]2C/C=C\CCCC(=O)OC(C)C)OCCO1
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CO
Product: CCCCCCCC1(CC[C@H]2[C@H](CO)CC(=O)[C@@H]2CC=CCCCC(=O)OC(C)C)OCCO1

Procedure:
Isopropyl (Z)-7-[(1R,2S)-2-(3,3-ethylenedioxydecyl)-5-oxo-cyclopent-3-enyl]hept-5-enoate (3) (0.81 g) and benzophenone were dissolved in methanol. Under argon atmosphere, the solution was irradiated with 300-W high-pressure mercury lamp for 4 hours and 40 minutes. After evaporation of the solvent, the crude product was chromatographed on silica gel (n-hexane/ethyl acetate=3/2) to give isopropyl-7-[(1R,2S,3R)-2-(3,3-ethylenedioxydecyl)-3-hydroxymethyl-5-oxocyclopentyl]hept-5-enoate (4). Yield 0.41 g, 47%.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:35]([O:37][C@H:38]1[CH2:42][CH2:41][O:40][CH2:39]1)=[O:36]>CN(C=O)C>[O:40]1[CH2:41][CH2:42][C@H:38]([O:37][C:35](=[O:36])[NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=4)[N:12]=[C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[N:10]=3)[CH2:4]2)[CH2:39]1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CCC[C@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCC[C@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-((R)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.57 mmol) in DMF under an N2 atmosphere at 0° C. was added triethylamine (115 mg, 1.14 mmol) followed by the dropwise addition of (S)-tetrahydrofuran-3-yl chloroformate (86 mg, 0.57 mmol). The reaction was allowed to warm to room temperature and was stirred for 2 h. The mixture was partitioned between H2O and CH2Cl2 and separated, and the aqueous layer was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 4:1 CH2Cl2:EtOAc afforded (S)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate. LC/MS: m/z 463.5 (M+H)+ at 2.34 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1
Reactant: C1=C(c2cc3ccccc3[nH]2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: c1ccc2[nH]c(C3CCNCC3)cc2c1
Yield: 29.7 %

Procedure:
A mixture of 0.521 gm (1.8 mMol) 2-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 0.1 gm 5% palladium on carbon were stirred together in ethanol under hydrogen (1 atm) for 48 hours. The reaction mixture was filtered through a bed of celite and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 20% methanol in dichloromethane containing a trace of ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.107 gm (30%) 2-(piperidin-4-yl)-1H-indole as a light yellow solid. A portion of this material was treated with oxalic acid to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[C:9](/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)\[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:10]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[CH:8][C:4]1[CH:3]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[CH:7]=[CH:6][CH:5]=1)#[N:11]
Reactant: COc1ccc(/C(C#N)=C/c2cccc(N)c2)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(C#N)=Cc2cccc(NC(C)=O)c2)cc1OC
Yield: 84 %

Procedure:
Compound 57 (50 mg) was acetylated with acetic anhydride and pyridine in accordance with a customary method, to thereby produce the target product (48 mg, yield: 84%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)CC1COc2cc(O)ccc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC1COc2cc(OCCCCl)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
Methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (2.71 g, 13.0 mmol) and 1-bromo-3-chloropropane (2.46 g, 15.6 mmol) were dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (1.98 g, 14.3 mmol) was added, and the mixture was stirred under nitrogen atmosphere at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, and water added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-30% ethyl acetate/hexane) to give the title compound (2.95 g, yield 80%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[C:27]([C:29]#[CH:30])[CH:28]=2)[O:25][C:24]([CH3:32])([CH3:31])[CH2:23][C:22]3([CH3:34])[CH3:33])=[O:18])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10].O1CCOCC1>C(O)=O>[C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:16][C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[C:27]([C:29]#[CH:30])[CH:28]=2)[O:25][C:24]([CH3:31])([CH3:32])[CH2:23][C:22]3([CH3:34])[CH3:33])=[O:18])=[CH:3][C:2]=1[F:1])([OH:11])=[O:10]
Reactant: C#Cc1cc(C(=O)Oc2ccc(CC(=O)OC(C)(C)C)c(F)c2)cc2c1OC(C)(C)CC2(C)C
Solvent: C1COCCO1
Solvent: O=CO
Product: C#Cc1cc(C(=O)Oc2ccc(CC(=O)O)c(F)c2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following General Procedure E and using 8-ethynyl-2,2,4,4-tetramethyl chroman-6-carboxylic acid-3-fluoro-4-tert-butoxycarbonylmethyl-phenyl ester (Compound 28, 0.085 g, 0.21 mmol), 1,4-dioxane (2 mL) and formic acid (8 mL) followed by recrystallization from 10-20% ethyl acetate in hexane, the title compound was obtained (0.055 g, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:20])[CH3:19])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC2(CCN(C(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 2,7-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (140 mg, 0.58 mmol) in DCM (5.8 mL) was added acetic anhydride (82 μL, 0.87 mmol) and triethylamine (244 μL, 1.75 mmol) and the reaction mixture was stirred (rt, 16 h). The reaction mixture was diluted with DCM (6 mL), washed with water (3×4 mL) and brine (1×4 mL). The organic layer was dried, filtered and concentrated in vacuo to provide 7-acetyl-2,7-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester as a brown oil (164 mg, 100%). This intermediate was dissolved in DCM (0.75 mL), treated with HCl (4M in dioxane, 0.75 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to yield then desired product (128 mg, 100%). MS (ESI): mass calcd. for C10H18N2O, 182.14; m/z found, 183.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:3].[OH-].[Na+:32]>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:23])[CH2:16][CH:17]([OH:22])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:32]
Reactant: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 96.9 %

Procedure:
Fluvastatin (3.52 g) was stirred in a solution of H2O (9.9 ml) and NaOH (s) (0.32 g) at room temperature to obtain a mud-like suspension. The suspension was stirred at room temperature over night. The product was filtered under nitrogen flow, washed with H2O (2×3 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 3.36 g (65.8%) of fluvastatin sodium Form LIV.
Reaction SMILES: [C:1]([C:4]1[N:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:14]=2)[N:10]=[C:9]2[C:5]=1[N:6]([CH3:31])[C:7](=[O:30])[NH:8]2)(=[O:3])[CH3:2].[CH3:32][Mg]Br.Cl>O1CCCC1.C(OCC)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:15]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C:13]([C:11]2[N:10]=[C:9]3[C:5]([N:6]([CH3:31])[C:7](=[O:30])[NH:8]3)=[C:4]([C:1]([OH:3])([CH3:32])[CH3:2])[N:12]=2)=[N:14]1
Reactant: C[Mg]Br
Reactant: CC(=O)c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)n(C)c12
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(C(C)(C)O)c21
Reaction time: 1 h

Procedure:
237 mg (0.568 mmol) of the compound obtained in example 134 in tetrahydrofuran were cooled to 0° C. and admixed with 0.568 ml of a 3M solution of methylmagnesium bromide in diethyl ether, and the mixture was stirred at this temperature for 1 h and then at RT overnight. Then 2 portions, each of 0.379 ml, of a 3M solution of methylmagnesium bromide in diethyl ether were added and the mixture was stirred at RT for a further night. After cooling, first ice and then 4N hydrochloric acid (20 ml) were added and the mixture was stirred vigorously. The mixture was then extracted three times with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the mixture was filtered and concentrated, and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 29 mg of the title compound were obtained (10% of theory).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][CH:31]4[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[C:32]4=[O:38])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.N1(C(C2N=CC(OC3C=C(C=C(O[C@@H]4CCN(CC)C4=O)C=3)C(NC3C=NC(C)=CN=3)=O)=CC=2)=O)CCC1>>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C@H:31]4[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[C:32]4=[O:38])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCC(Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3cnc(C)cn3)c2)C1=O
Agent: CCN1CC[C@@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3cnc(C)cn3)c2)C1=O
Product: CCN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3cnc(C)cn3)c2)C1=O
Yield: 26 %

Procedure:
From racemic 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-(1-ethyl-2-oxo-pyrrolidin-3-yl)oxy-N-(5-methylpyrazin-2-yl)benzamide (197 mg, 0.38 mmol) (Example 10), 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-ethyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ column eluting with methanol at a flow rate of 60 mL/min. 197 mg of racemic material was separated in 1 injection of 5 mL at 40 mg/ml in methanol to afford the product which eluted after its enantiomer to afford the product (51 mg, 26%). 1H NMR δ (300 MHz, CDCl3) 1.18 (t, 3H), 2.13-2.26 (m, 1H), 2.36 (quintet, 2H), 2.52-2.69 (m, 4H), 3.36-3.58 (m, 4H), 4.25 (t, 2H), 4.71 (t, 2H), 4.95 (t, 1H), 6.98 (s, 1H), 7.22 (s, 1H), 7.39 (d, 1H), 7.47 (s, 1H), 8.12 (d, 1H), 8.14 (s, 1H), 8.33 (s, 1H), 8.56 (s, 1H), 9.53 (s, 1H); m/z 517 (M+H)+.
Reaction SMILES: IC1C=CN=C2C=NN(C)C=12.I[C:13]1[C:14]2[C:15](=[CH:19][N:20]([CH3:22])[N:21]=2)[N:16]=[CH:17][CH:18]=1.[F:23][C:24]1[C:25]([C:31]2[CH:36]=[C:35]([NH2:37])[C:34]([CH3:38])=[CH:33][N:32]=2)=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:24]1[C:25]([C:31]2[CH:36]=[C:35]([NH:37][C:13]3[C:14]4[C:15](=[CH:19][N:20]([CH3:22])[N:21]=4)[N:16]=[CH:17][CH:18]=3)[C:34]([CH3:38])=[CH:33][N:32]=2)=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1
Reactant: Cc1ccc(F)c(-c2cc(N)c(C)cn2)n1
Reactant: Cn1cc2nccc(I)c2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn(C)nc34)c(C)cn2)n1
Temperature: 110 °C

Procedure:
A mixture of 7-iodo-1-methyl-1H-pyrazolo[4,3-b]pyridine and 7-iodo-2-methyl-2H-pyrazolo[4,3-b]pyridine (162 mg, 0.625 mmol), 3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-amine (136 mg, 0.625 mmol), tris(dibenzylideneacetone)dipalladium(0) (28.6 mg, 0.031 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (18.09 mg, 0.031 mmol) and sodium 2-methylpropan-2-olate (180 mg, 1.876 mmol) were combined in dioxane (15 mL) and heated at 110° C. for 15 minutes. The solvent was then removed in vacuo to give a residue which was purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 30-35% acetonitrile (containing 10 mM NH4HCO3) in water (containing 10 mM NH4HCO3) to give N-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-2-methyl-2H-pyrazolo[4,3-b]pyridin-7-amine: 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.84 (s, 3H) 0.91 (s, 3H) 1.72 (br. s., 1H) 2.54 (s, 3H) 5.58 (s, 1H) 5.62 (d, J=4 Hz, 1H) 5.72 (dd, J=12, 4 Hz, 1H) 5.94 (dd, J=12, 8 Hz, 1H) 6.58 (s, 1H) 6.80 (s, 1H) 6.83 (d, J=4 Hz, 1H). Melting point 102.9-103. Fractions were combined and further purified by a second preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 15-35% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to give N-(3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-7-amine as a TFA salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.90 (s, 3H) 0.98 (s, 3H) 1.54-1.64 (m, 1H) 2.63 (s, 3H) 5.59 (d, J=8 Hz, 1H) 5.87 (dd, J=12, 4 Hz, 1H) 6.06 (dd, J=12, 8 Hz, 1H) 6.69 (s, 1H) 6.90 (d, J=8 Hz, 1H) 7.00 (s, 1H) 7.09 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH2:8][CH2:7]2)([O-:3])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3cc([N+](=O)[O-])ccc32)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3cc([N+](=O)[O-])ccc32)CC1
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-Butyl 4-(5-nitroindolin-1-yl)piperidine-1-carboxylate (9.72 mmol, 3.377 g) was stirred at 0° C. in tetrahydrofuran (25 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (10.69 mmol, 2.427 g) in tetrahydrofuran was added dropwise. The reaction was stirred at <10° C. for 1 hour. The reaction was stirred for 2 hours at room temperature. Ethyl acetate was added and the reaction washed with saturated sodium bicarbonate solution. The mixture was passed through a celite plug before being separated. The organic phase was concentrated at reduced pressure to afford the title compound (3.123 g). MS (ESI) m/z 290.3 [M-Boc+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[Se:4][C:3]=1[C:11]#[N:12].C([OH:15])C>[OH-].[Na+]>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:9])([CH3:8])[CH3:10])[Se:4][C:3]=1[C:11]([NH2:12])=[O:15]
Reactant: CC(C)(C)c1cc(N)c(C#N)[se]1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Temperature: 7.5 °C
Yield: 83 %

Procedure:
To a suspension of 3-amino-5-(tert-butyl)selenophene-2-carbonitrile (2.0 g) in aqueous sodium hydroxide solution (50 mL, 10%) was added ethanol (50 mL) and the mixture refluxed for 1 h. Ethanol was distilled off under vacuum (appr. 25 mL) and the mixture was allowed to cool to 5-10° C. The separated crystals were filtered off, washed with cold water and dried to give the product as a off-white color solid (1.8 g, 83%), mp 160-162° C. 1H NMR (400 MHz, CDCl3): δ 6.58 (1H, s), 5.75 (2H, br s), 5.13 (2H, br s), 1.34 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:10]1([NH2:13])[CH2:12][CH2:11]1>>[CH:10]1([NH:13][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])[CH2:12][CH2:11]1
Reactant: Cc1ccccc1C=O
Reactant: NC1CC1
Product: Cc1ccccc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 2-methylbenzaldehyde and cyclopropylamine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:26][CH3:27])[C:15]2[C:20]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N1CCC(N(CC)C2C(NC(C)C)=CC=CN=2)CC1)C1C=CC=CC=1>>[CH2:26]([N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15]1[C:20]([NH:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:27]
Reactant: CCN(c1ncccc1NC(C)(C)C)C1CCN(Cc2ccccc2)CC1
Agent: CCN(c1ncccc1NC(C)C)C1CCN(Cc2ccccc2)CC1
Product: CCN(c1ncccc1NC(C)(C)C)C1CCNCC1

Procedure:
Following the general procedure of EXAMPLE 206 and making non-critical variations but substituting 1-benzyl-4-[N-ethyl-N-3-(1,1-dimethylethylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 143) for 1-benzyl-4-[N-ethyl-N-(3-(isopropylamino)-2-pyridinyl)amino]piperidine, the title compound is obtained.