Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])/[CH:3]=[N:4]/[S:5]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6].C1C(=O)N([Br:29])C(=O)C1.ClC1C=CC=CC=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>[CH3:1][N:2]([CH3:21])/[CH:3]=[N:4]/[S:5]([C:8]1[C:9]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][Br:29])=[CH:18][CH:19]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)/N=C/N(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 100 °C
Yield: 41 %

Procedure:
4′-Methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide (540.0 mg, 1786 μmol), NBS (318 mg, 1.8 mmol), and benzoyl peroxide (4.3 mg, 17.8 μmol) were dissolved in chlorobenzene (7.0 mL, 69 mmol) and the resulting solution was heated at 100° C. for 90 minutes. The mixture was cooled to room temperature and water was added. The mixture was extracted with DCM, washed with saturated NaHCO3 and saturated aqueous NaCl, extracted again with DCM, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (40 g, 0-100% EtOAc in hexanes), then taken up in EtOAc (4.5 mL) and DCM (1.5 mL). Additional DCM (3.0 mL) was added and the mixture was heated at 60° C. The mixture was cooled in the freezer overnight, then concentrated. The material was taken up in DCM (2 mL), EtOAc (6 mL) was added, and the resulting solution placed in the freezer. A precipitate formed and was filtered to yield the title compound (279 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:26][O:27][C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)=[O:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[C:28]([O:27][CH3:26])=[O:29])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: COC(=O)C1CCCN1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(methyloxycarbonyl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.30 minutes; C23H22C12N4O4 (489.36); mass spectrum: (M−H)−=488/490/492 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[C:38]([Cl:43])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:33]=[C:34](/[C:36]3[CH:37]=[C:38]([Cl:43])[CH:39]=[C:40]([Cl:42])[CH:41]=3)\[CH3:35])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC(=CBr)c1cc(Cl)cc(Cl)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and potassium phosphate (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-3,5-dichlorobenzene (318 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. Yield: 135 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.50 (s, 1H), 6.25 (s, 1H), 7.18 (d, 1H), 7.10 (d, 1H), 7.0 (s, 2H), 6.90 (s, 1H), 4.40 (m, 2H), 3.60 (m, 2H), 3.0 (s, 3H), 2.90 (m, 2H), 2.30 (s, 3H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)=[O:36])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccccn2)CC1
Yield: 80.1 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.064 g, 0.22 mmol) and diisopropylethylamine (0.089 g, 0.69 mmol) in methylene chloride stirring at 0° C. was added picolinoyl chloride hydrochloride (0.043 g, 0.24 mmol) at room temperature. After 2 h the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography (silica gel, 95:5 to 90:10 dichloromethane/methanol) to provide (4-(2-tert-butylphenyl)piperazin-1-yl)(pyridin-2-yl)methanone (0.057 g, 80%) as a brown solid, mp 140-145° C.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:19]1)=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.Cl.CO.[OH-].[Pd+2].[OH-].[C]>[NH2:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:19]1)=[O:15]
Reactant: [H][H]
Reactant: O=C(CCNC(=O)OCc1ccccc1)NC[C@H]1CCCN(CC2CCCCC2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: NCCC(=O)NC[C@H]1CCCN(CC2CCCCC2)C1
Reaction time: 44 h
Yield: 75 %

Procedure:
To a solution of 770 mg of 3-(benzyloxycarbonyl)amino-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}propanamide in 12 ml of methanol, 0.5 ml of 10% hydrochloric acid-methanol and 15 mg of 20% palladium hydroxide-carbon catalyst were added, followed by 44 hours' stirring under 3 atmospheres of hydrogen. Filtering the catalyst off, the solvent was distilled off under reduced pressure, and the residue was rendered weakly basic with saturated aqueous sodium bicarbonate solution. The product was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by means of silica gel column chromatography (eluting solvent: chloroform-chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 391 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:29][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccncc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccncc1
Yield: 55 %

Procedure:
A suspension of 6-methoxy-7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (300 mg, 1.06 mmol) in thionyl chloride (5 ml) containing DMF (50 μl) was heated at reflux for 1 hour. The mixture was allowed to cool, diluted with toluene and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and a cooled solution of aqueous sodium hydrogen carbonate was added. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-chloro-6-methoxy-7-(4-pyridylmethoxy)quinazoline (175 mg, 55%).
Reaction SMILES: [CH:1]([O:6][CH3:7])([O:4][CH3:5])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:19]([O:26][CH:27]1[CH2:32][CH2:31]C(=O)[CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>CO.ClCCl>[CH3:7][O:6][C:1]1([O:4][CH3:5])[CH2:29][CH2:28][CH:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:32][CH2:31]1
Reactant: COC(OC)OC
Reactant: O=C1CCC(OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC1(OC)CCC(OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
529 mL of trimethyl orthoformate and 32 mg of p-toluene sulfonic acid were added to a solution of 4-benzyloxy cyclohexanone in 20 mL of dry methanol and the mixture was stirred overnight. 20 mL of saturated aqueous sodium bicarbonate solution and 20 mL of dichloromethane were added, the aqueous layer was extracted several times with dichloromethane and the combined organic layers were dried and evaporated to dryness to yield 1.50 g of the desired product, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11](CC(C)C)[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]([NH2:29])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]#[N:29])=[CH:15][CH:14]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(C(N)=O)ccc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1[nH]c(=O)c2ccc(C#N)cc2c1-c1ccc(Cl)cc1
Yield: 90.3 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (Example 186 (4)) (0.48 g, 1 mmol) and cyanuric chloride (0.55 g, 3 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-(4-chlorophenyl)-6-cyano-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.37 g, 80.4%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21](OCC)(OCC)(OCC)[CH3:22]>C(O)(=O)C>[CH3:21][C:22]1[N:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cnc2ccccc2c1NCCc1ccccc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Product: Cc1nc2cnc3ccccc3c2n1CCc1ccccc1

Procedure:
Using the method of Example 31, 3-amino-4-[2-(phenyl)ethylamino]quinoline (from Example 130, Part A) was reacted with triethyl orthoacetate and acetic acid to provide 2-methyl-1-[2-(phenyl)ethyl]-1H-imidazo[4,5-c]-quinoline.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I-].[K+].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29]O)=[CH:23][CH:22]=1)(=[O:20])=[O:19].O>CO>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH2:31][CH:32]([CH3:33])[CH3:34])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: C1COCCN1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCCO)cc2)c(C)c1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCCN3CCOCC3)cc2)c(C)c1
Temperature: 150 °C

Procedure:
To a microwave vial was added morpholine (5.10 μL, 0.058 mmol), potassium iodide (19.26 mg, 0.116 mmol), [Cp*IrCl2]2 (0.639 mg, 0.580 μmol), N-(2,4-dimethylphenyl)-4-[(2-hydroxyethyl)oxy]-N-(2-methylpropyl)benzenesulfonamide (43.8 mg, 0.116 mmol), a stirrer bar and water (0.1 mL). The vial was then sealed and the mixture was heated to 150° C. by microwaves (Biotage Initiator) for 3 hours. Reaction mixture was then diluted with methanol (1 mL) and passed down a pre-conditioned sulfonic acid (SCX) solid phase extraction (SPE) cartridge, eluting with methanol and then 2N methanolic ammonia. The fractions from the methanolic ammonia wash were concentrated in vacuo and the residue purified by mass-directed autoprep, using a formic acid modifier. Product containing fractions were evaporated under a stream of nitrogen to provide product, 2.6 mg. LCMS [LCMS1] Rt 1.01 min, m/z (ES+) 447 (M+H).
Reaction SMILES: ClC1C=CC([N+]([O-])=O)=C(CCC(C)CC)C=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([CH:27]([CH3:32])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH:19]=1>>[CH3:32][CH:27]([C:20]1[CH:19]=[CH:18][CH:23]=[CH:22][C:21]=1[NH2:24])[CH2:28][CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)CC(C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: CCC(C)CCc1cc(Cl)ccc1[N+](=O)[O-]
Product: CC(C)CC(C)c1ccccc1N

Procedure:
The desired compound was prepared by carrying out the same procedures as described in Example 9(2) except that 4-chloro-2-(3-methylpentyl)nitrobenzene was replaced by 4-chloro-2-(1,3-dimethylbutyl)nitrobenzene.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.N[C:11](N)=[O:12].[OH-].[Na+]>O.C1(C)C(C)=CC=CC=1>[OH:12][C:11]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: Nc1ccccc1N
Reactant: NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Oc1nc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Into a four-necked flask of 1 l capacity were charged 64.8 g (0.6 mol) of o-phenylenediamine, 31.3 g (0.5 mol) of hydrochloric acid, 36.0 g (0.6 mol) of urea and 50 ml of xylene, and a reaction was effected at 140°-150° C. for 5 hours while distilling out 20 ml of water. Then, the reaction product was charged into a four-necked flask of 1 l capacity, into which 30 g (0.75 mol) of sodium hydroxide and 600 ml of water had been previously charged, and the resulting mixture was stirred at 80° C. for 15 hours. Then, thus treated mixture was filtered while it was hot, and the filtrate was cooled to form a precipitate. The resulting precipitate was filtered, and the filter cake was washed with water to obtain the aimed 2-hydroxybenzimidazole having a melting point of 316°-317° C. in an yield of 53.6 g (66.6%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H](CO)O)O)O>>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The yJML123+SUT4 strain was able to use both glucose and xylose at a faster rate than the control strain. Neither strain was able to use all of the xylose. The yJML123+SUT4 strain produced a higher yield of xylitol (18.45 g/L) than the control strain (15.51 g/L). Further, the yJML123+SUT4 strain produced a higher yield of xylitol faster than the control.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH3:18])=[C:16](O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:17]=1[CH3:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1O
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl

Procedure:
Prepared according to procedure S using 2-(2-fluorophenyl)-3-methylquinolin-4-ol (0.13 g, 0.51 mmol) in POCl3 (1 mL, 10 mmol). The resulting precipitate was collected by filtration to have 4-chloro-2-(2-fluorophenyl)-3-methylquinoline. Mass Spectrum (ESI) m/e=272 (M+1).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH:1][N:2]2[N:11]=[C:10]([CH:12]3[CH2:13][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:15])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(C2CC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(C2CC2)c2ccccc2c1=O

Procedure:
The product from Example 22B and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.92 (m, 2H) 0.92-1.07 (m, 2H) 2.45-2.55 (m, 1H) 3.67 (s, 2H) 7.32-7.52 (m, 4H) 7.92 (t, J=8.09 Hz, 1H) 7.99-8.14 (m, 1H) 8.31 (t, J=7.32 Hz, 2H) 11.50 (s, 1H); MS (ESI) m/z 354 (M+H)+.
Reaction SMILES: [CH:1]1([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)=[O:27])=[C:21]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH:20]=4)[CH:17]=3)[N:12](COC(=O)C(C)(C)C)[CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH:1]1([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])=[C:21]([C:34](=[O:38])[N:35]([CH3:36])[CH3:37])[CH:20]=4)[CH:17]=3)[NH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(C2OCc4ccccc42)cn3COC(=O)C(C)(C)C)ccc1NC(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(-c2cnc3[nH]cc(C4OCc5ccccc54)c3c2)ccc1NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-dimethyl-propionic acid 3-(1,3-dihydro-isobenzofuran-1-yl)-5-{3-dimethylcarbamoyl-4-[(morpholine-4-carbonyl)-amino]-phenyl}-pyrrolo[2,3-b]pyridin-1-ylmethyl ester was dissolved in tetrahydrofuran. 1 M sodium hydroxide in methanol was added to the mixture, and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried, filtered, and concentrated. The crude material was purified then by mass-triggered reverse-phase HPLC to afford morpholine-4-carboxylic acid {4-[3-(1,3-dihydro-isobenzofuran-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-dimethylcarbamoyl-phenyl}-amide. 1H NMR (250 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.75 (s, 1H), 8.47 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.55-7.49 (m, 3H), 7.44-7.22 (m, 4H), 7.10 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 5.13 (m, 2H), 3.62-3.58 (m, 4H), 3.42-3.35 (m, 4H in water peak), 2.98 (s, 3H), 2.94 (s, 3H); MS: m/z 512.3 (M+H+).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)(O)=[O:2].C(=O)(O)[O-].[Na+]>C1COCC1>[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH:4]([CH2:1][OH:2])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)#[N:21]
Reactant: COC(=O)c1ccc(CC(CCCCC#N)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(CO)CCCCC#N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
27.65 ml of a 1 M borane-THF complex solution are added dropwise to a solution of 3.835 g (13.83 mmol) of methyl 4-(2-carboxy-6-cyanohexyl)benzoate from Example 116A in 200 ml of THF at −10° C. After warming to 0° C., the mixture is stirred at this temperature for 2 hours. After reaction is complete, saturated sodium bicarbonate solution is added to the reaction mixture, and the solvent is concentrated to dryness. The residue is taken up in dichloromethane, dried over sodium sulfate and again freed of solvent. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 1:8→1:2). 2.95 g (77% yield) of a colorless solid are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25](Br)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([CH2:22][C:23]2[C:31]3[O:30][CH:29]=[CH:28][C:27]=3[CH:26]=[C:25]([C:41]3[CH:42]=[CH:43][O:39][CH:40]=3)[CH:24]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:9]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1cc(-c2ccoc2)cc2ccoc12)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
From cis-3-[(5-bromobenzofuran-7-ylmethyl)tert-butoxycarbonyl-amino]-2-phenyl-piperidine-1-carboxylic acid tert-butyl ester (473 mg) and 3-furanboronic acid (102 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[CH2:17][CH2:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[N:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1>[Ni].CO>[NH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([CH2:17][CH2:18][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])[CH:22]=[N:23][CH:24]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(C#N)ccc2NC(=O)OC(C)(C)C)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(CN)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Into a pressure bottle were added tert-butyl [5-(2-{2-[(tert-butoxycarbonyl)amino]-5-cyanophenyl}ethyl)pyridin-3-yl]carbamate (0.80 g, 1.8 mmol), tetrahydrofuran (3 mL), methanol (10 mL), and Raney nickel (0.30 g, 5 mmol). The reaction mixture was hydrogenated at 45 psi for 2 hours. After filtration to remove the catalyst, the mixture was concentrated under vacuum to give the desired product as an off-white powder (0.30 g, 99%). LCMS for C24H35N4O4 (M+H)+: m/z=443.2.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[NH:19]2)=[CH:14][CH:13]=1.[CH:26]([CH2:28][C:29](O)=[O:30])=[CH2:27].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C@H:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[N:19]2[C:29](=[O:30])[CH2:28][CH:26]=[CH2:27])=[CH:16][CH:17]=1
Reactant: C=CCC(=O)O
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(F)cc2)N1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Diethyl cyanophosphonate (2.1 mL) was added to a solution of (2R*,6S*)-2-(4-fluorophenyl)-6-vinylpiperidine (934 mg), vinylacetic acid (1.15 mL), and triethylamine (3.82 mL) in DMF (10 mL), and the reaction solution was stirred at room temperature for six hours. Ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 744 mg of the title compound. The property values of the compound are as follows.