Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13](=O)[CH3:14].[CH3:16][C:17]1[N:18]=[C:19]([C:25]2S[CH:27]=[CH:28][CH:29]=2)S[C:21]=1[C:22](=O)[CH3:23].[NH3:30]>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:13][C:3]2[C:2](=[CH:27][CH:28]=[C:29]([CH2:25][CH2:19][N:18]3[CH2:23][CH2:22][CH2:21][C@H:17]3[CH3:16])[CH:4]=2)[N:30]=1
Reactant: CC(=O)c1cnn(-c2ccccn2)c1C
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Reactant: N
Product: Cc1c(-c2ccc3cc(CCN4CCC[C@H]4C)ccc3n2)cnn1-c1ccccn1

Procedure:
The title compound was prepared using the procedure described in Example 1G using 1-(5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-ethanone (Singh, S. P., et. al. Heterocycl. Commun., 2001, 7(1), p. 49-54) for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CDCl3) δ 1.14 (d, J=6.10 Hz, 3H), 1.46 (m, 1H), 1.77 (m, 2H), 1.96 (m, 1H), 2.25 (q, J=8.82 Hz, 1H), 2.40 (m, 2H), 3.01 (m, 2H), 3.06 (s, 3H), 3.13 (m, 1H), 3.30 (td, J=8.56, 2.54 Hz, 1H), 7.26 (m, 1H), 7.61 (m, 3H), 7.87 (m, 2H), 8.03 (d, J=8.48 Hz, 1H), 8.11 (d, J=8.82 Hz, 1H), 8.13 (s, 1H), 8.53 (m, 1H); MS (DCI-NH3) [M+H]+ at 398.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([CH:13]=[CH2:14])[C:9]1=[O:15])=[O:7])([CH3:4])(C)C.[H-].[Na+].Cl[CH:19]1[CH2:23]CC[O:20]1>O1CCCC1.C(OCC)C>[O:20]1[CH2:19][CH2:23][CH2:4][CH:1]1[O:5][C:6]([CH:8]1[CH2:12][CH2:11][N:10]([CH:13]=[CH2:14])[C:9]1=[O:15])=[O:7]
Reactant: ClC1CCCO1
Reactant: C=CN1CCC(C(=O)OC(C)(C)C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CN1CCC(C(=O)OC2CCCO2)C1=O
Yield: 100 %

Procedure:
8.9 g of 3-(t-butoxycarbonyl)-1-vinyl-2-pyrrolidinone (BCVP) was dissolved in 50 ml of tetrahydrofuran free of moisture. To this solution 1.0 g of sodium hydride and 4.4 g of 2-chlorotetrahydrofuran were added and allowed to react at room temperature for 1 hour. This solution was diluted with diethylether and washed many times with pure water. The organic solvent of the organic phase was evaporated and the residue was subjected to silica gel column chromatography, to obtain 9.3 g of pure 3-(tetrahydrofuranyloxycarbonyl)-1-vinyl-2-pyrrolidinone (hereinafter referred to as "TFVP"). Its chemical structure was determined by IR spectra and NMR.
Reaction SMILES: C([CH2:4][NH:5][C:6]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:7]=1[C:8](O)=O)(O)=O.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+].C(O[C:25](=[O:27])[CH3:26])(=O)C>>[C:25]([N:5]1[C:6]2[C:7](=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:8]([O:18][C:16](=[O:19])[CH3:17])=[CH:4]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CNc1ccc(Cl)cc1C(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Oc1cn(C(C)=O)c2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
2-(N-carboxymethylamino)-5-chlorobenzoic acid (1.20 g, 5.2 mmol) and anhydrous sodium acetate (0.6 g, 7.3 mmol) were dissolved in 8 ml acetic anhydride. After stirred for 5 hours at 60° C., the reaction mixture was cooled down to room temperature, and the sodium acetate was filtered off. The filtrate was concentrated, and the residue was dissolved in 100 ml ethyl acetate. 100 ml water and 20 ml saturated sodium bicarbonate were added to the solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml×2). The combined organic phases were washed with saturated sodium bicarbonate (100 ml×2), dried, and evaporated, to obtain a white solid (1-acetyl-5-chloro-3-acetoxyindole) (0.84 g, yield: 64%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[OH:27]>C1(OC2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O>[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3ccsc23)c(F)c1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A mixture of 2 (500 mg, 2.95 mmol), potassium carbonate (1.62 g, 11.8 mmol) and 2-fluoro-4-nitrophenol (603 mg, 3.85 mmol) were heated to 170° C. in diphenyl ether (10 ml) for 5 hrs. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic phase was collected, dried over anhydrous sodium sulfate and the solvents were removed under reduced pressure. The residue was purified by column chromatography, eluent gradient EtOAc-hexane (9:1) to EtOAc, to afford the title compound 3 (660 mg, 76% yield). 1H NMR (400 MHz, CDCl3) 6 (Ppm) 8.60 (d, J=5.54 Hz, 1H), 8.14 (m, 3H), 7.80 (d, J=5.47 Hz, 1H), 7.61 (d, J=5.48 Hz, 1H), 7.36 (t, J=7.63 Hz), 6.65 (m, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[O:6])[CH2:3][CH2:2]1>CN(C=O)C.[Pd]>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=3)[C:11]=2[CH2:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2nccs2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCc2nccs2)cc1
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(E)-2-(1,3-thiazol-2-yl)vinyl]-1H-1,2,3-triazole-4-carboxamide (130 mg) obtained in Example 321 in DMF (10 ml) was added 10% Pd/C (50% wet, 15 mg), and the mixture was stirred for 3 days under a hydrogen atmosphere. After the reaction mixture was filtered through celite, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate to ethyl acetate/methanol=4/1) to give the title compound as a white powder (100 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:40]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][O:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][O:50]3)[CH:45]=2)[N:39]=[C:38]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:55]([C:38]1[CH:37]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:40]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][O:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][O:50]3)[CH:45]=2)[N:39]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCOC3CCCCO3)c2)n1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of Intermediate 96c (200 mg, 0.51 mmol), Intermediate 108b (261 mg, 0.51 mmol) and DIPEA (178 μL, 1.02 mmol) in dioxane (5 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM to afford the title compound (364 mg, 95%) as a glassy white solid %). LCMS (Method 4): Rt 3.69 min, m/z 751 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19](OCC2C=CC=CC=2)=[O:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][OH:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(C(=O)OCc1ccccc1)nn2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CO)nn2Cc1ccccc1
Yield: 104.4 %

Procedure:
To a solution of benzyl 1-benzyl-5-methoxy-1H-indazole-3-carboxylate (17.7 g; 0.05 mol), diethyl ether (100 ml) and tetrahydrofuran (THF) (170 ml) stirred at room temperature was slowly added LiAlH4 (3.8 g; 0.1 mol). Once the addition was complete, the suspension was stirred at reflux for 24 hours. The reaction was completed by destroying the excess LiAlH4 via addition of water (40 ml) and 5N NaOH (10 ml). The organic phase was separated out and the solvent was evaporated off under reduced pressure. The crude residue obtained was purified by crystallization from 95° ethanol, to give 14 g of (1-benzyl-5-methoxy-1H-indazol-3-yl)methanol with a melting point of 97°-98° C.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][O:36][CH:37]([CH3:39])[CH3:38]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][O:36][CH:37]([CH3:39])[CH3:38])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)OCCBr
Product: CC(C)OCCN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 86.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.229 mmol) and 2-(2-bromoethoxy)propane (200 mg, 0.252 mmol) gave 7-cyclopentyl-2-{5-[4-(2-isopropoxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (103 mg, 86%). MS (ESI) m/z 521.3 (M+H)+
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1C(Cl)=O)(=[O:3])[CH3:2].[N-:14]=[N+:15]=[N-:16].[Na+].[N-:18]=[N+]=[N-].[CH3:21][C:22]([CH3:24])=[O:23]>O.C1C=CC=CC=1>[C:22]([C:24]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:5]([N:14]=[N+:15]=[N-:16])=[O:4])(=[O:23])[CH3:21].[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[N:18]=[C:22]=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)=O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccccc1N=C=O
Product: CC(=O)c1ccccc1C(=O)N=[N+]=[N-]

Procedure:
2-Acetylbenzoic acid azide was prepared by reacting 2-acetoxybenzoyl chloride with sodium azide in acetone and water at 0-5° C. for 24 hours. It had an IR peak at 2245 cm−1 (azide). The crude azide was then heated in benzene at 70-75° C. under nitrogen for 2 hours to give 2-acetoxyphenylisocyanate.
Reaction SMILES: O[CH2:2][C@H:3]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(S(F)(F)[F:28])CC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:28][CH2:2][C@H:3]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](CO)Cc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1[C@@H](CF)Cc1ccccc1
Temperature: 25 °C
Yield: 4.3 %

Procedure:
(R)-2-(1-hydroxymethyl-2-phenylethyl)isoindole-1,3-dione (1.20 g) was added to a methylene chloride (20 mL) solution of DAST (825 mg) at −78° C. and the reaction solution was agitated at room temperature. DAST (500 mg) was added to the reaction solution after 2 hours, and the reaction solution was agitated at 50° C. for 3 hours. Saturated sodium bicarbonate solution was added for reaction solution to the reaction solution after allowing the reaction solution to be cooled to room temperature, and the organic layer was partitioned. The organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system), and 52 mg of the title compound was obtained.
Reaction SMILES: [C:1]([OH:6])(=O)/[CH:2]=[CH:3]/[CH3:4].[O:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.ClCC(OC(=O)CCl)=O>C1(C)C=CC=CC=1>[C:8]([C:1]1[O:6][CH:4]=[CH:3][CH:2]=1)(=[O:7])/[CH:9]=[CH:10]/[CH3:11]
Reactant: C/C=C/C(=O)O
Reactant: c1ccoc1
Agent: O=C(CCl)OC(=O)CCl
Solvent: Cc1ccccc1
Product: C/C=C/C(=O)c1ccco1
Temperature: 50 °C
Reaction time: 6.5 h
Yield: 41.1 %

Procedure:
In 50 ml of toluene were dissolved 4.31 g (0.05 mole) of crotonic acid, 4.43 g (0.065 mole) of furan and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution was added 0.71 g of boron trifluoridediethyl ether complex and the resulting mixture was then stirred at 50° C. for 6.5 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 2.8 g of 2-crotonylfuran.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:27][CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[OH:35][CH:30]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:29][CH2:28][NH:27][C:10]([C:9]1[C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][C:8]=1[CH3:13])=[O:12]
Reactant: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)O
Reactant: CC(C)(C)C(O)CCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)NCCC(O)C(C)(C)C
Reaction time: 18 h
Yield: 49 %

Procedure:
To a solution of 2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized similar to the methods described in sections a) to d) of example X1) (1.86 g, 7.05 mmol) in tetrahydrofuran (60 ml) are added triethylamine (2.9 ml, 21.1 mol) and 0-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.69 g, 7.05 mmol). The mixture is stirred for 15 min at RT, before 1-amino-4,4-dimethylpentan-3-ol (1.02 g, 7.76 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 30% ethyl acetate/cyclohexane) to yield N-(3-hydroxy-4,4-dimethyl-pentyl)-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example X5) (1.30 g, 3.44 mmol, 49%). [M+H]+378.3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([C:11]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[O:12])[N:10]=[C:4]2[CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:57][C:42]([F:41])([F:56])[C:43]1[CH:44]=[CH:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52]([O:1][C:2]3[CH:7]=[CH:6][N:5]4[CH:8]=[C:9]([C:11]([NH:13][CH:14]5[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]5)=[O:12])[N:10]=[C:4]4[CH:3]=3)[CH2:51][CH2:50]2)=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn3ccc(O)cc3n2)CC1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cn3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a stirred solution of tert-butyl 4-(7-hydroxyimidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate (0.18 g, 0.50 mmol) in toluene (4 mL) at room temperature was added diisopropyl azodicarboxylate (0.12 g, 0.6 mmol), 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.12 g, 0.5 mmol), and triphenylphosphine (0.16 g, 0.6 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/methanol/30% ammonium hydroxide=20/1/0.01) to afford tert-butyl 4-(7-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)imidazo[1,2-a]pyridine-2-carboxamido)piperidine-1-carboxylate as a off-white solid (0.13 g, 44%). 1H-NMR (CDCl3, 300 MHz): δ 7.97 (m, 2H), 7.47 (m, 2H), 7.18 (m, 1H), 6.95 (m, 2H), 6.81 (s, 1H), 6.58 (m, 1H), 4.56 (m, 1H), 4.11 (m, 3H), 3.61 (m, 2H), 3.26 (m, 2H), 2.92 (m, 2H), 2.15 (m, 2H), 2.03 (m, 4H), 1.66 (m, 2H), 1.47 (s, 9H) ppm; MS (ESI): 588.4 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([O:14][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 6 h

Procedure:
A mixture of N-tert-butoxycarbonylisonipecotic acid (12.0 g, 52.3 mmol), benzyl alcohol (6.0 mL, 58 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (11.04 g, 57.6 mmol), and 4-dimethylaminopyridine (642 mg, 5.25 mmol) in anhydrous dichloromethane (100 mL) was stirred at room temp. for 6 h. The resultant mixture was diluted with dichloromethane and washed successively with water, 10% aqueous citric acid, saturated sodium bicarbonate, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentration under vacuum. The residual oil was subjected to column chromatography on silica eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions afforded the title product as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:18]([CH3:20])([CH3:19])[O:17][CH2:16][CH2:15][C:13]=2[N:14]=1)=[O:8].[CH3:24][C:25]([CH3:28])([O-])[CH3:26].[K+].BrCC(C)C>CN(C=O)C.C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]2[C:18]([CH3:19])([CH3:20])[O:17][CH2:16][CH2:15][C:13]=2[N:14]\1[CH2:24][CH:25]([CH3:28])[CH3:26])=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)C(C)(C)OCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CC(C)CBr
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
To a solution of Example 89F (1.0 g, 2.8 mmol) in DMF/THF (1:4, 20 mL) were added potassium tert-butoxide (0.35 g, 3.1 mmol, Aldrich), 1-bromo-2-methylpropane (0.43 g, 3.1 mmol, Aldrich) and tetrabutylammonium iodide (0.1 g, 0.3 mmol, Aldrich). The reaction mixture was stirred at 80° C. for 16 h, cooled to room temperature, quenched with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-1% methanol in dichloromethane) to afford 90 mg (29%) of the title compound. MS (ESI+) m/z 409 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[BH4-].[Na+]>CO.C(OCC)(=O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[F:11][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Nc1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
Nickel chloride hexahydrate (2.32 g, 9.83 mmol) was added to a solution of 4-(2,6-difluoro-4-nitrophenyl)morpholine (1.2 g, 4.92 mmol), obtained in Preparation 1, in methanol (50 mL). NaBH4 (749 mg, 19.6 mmol) was added to the reaction mixture in portions and was allowed to stir at room temperature for 0.5 h. It was diluted with ethyl acetate (100 mL) and the organic portion was washed with water (60 mL×2) followed by brine (50 mL) and dried over sodium sulfate. Evaporation of the volatiles produced the title compound (0.95 g, 90%).
Reaction SMILES: [CH2:1]([C@H:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:44][C:32]1[N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:25][CH:26]=2)[C:39]2[C:34]([C:33]=1[CH3:43])=[CH:35][C:36]([C:40](=[O:41])[NH:10][C@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][CH3:2])=[CH:37][CH:38]=2
Reactant: CC[C@H](N)c1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: CC[C@H](NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (S)-α-ethylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([C:2]2[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=3)[N:3]=2)=[CH:22]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3coc4ccccc34)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 0.67 h
Yield: 57.5 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme 1,150 mg, 0.51 mmol) in 1,4-dioxane (3 mL) was added 2-(benzofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (312 mg, 1.28 mmol), K3PO4 (326 mg, 1.53 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (3 drops). After stirring 40 min at 95° C. under nitrogen atmosphere, the reaction mixture was dissolved in water (10 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(benzofuran-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (110 mg, 57%).