Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19](Cl)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH:25]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[CH:30][CH:31]=4)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(Oc2ccnc3c(Cl)cccc23)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCC(Oc2ccnc3c(-c4ccc(OC(C)C)cc4)cccc23)CC1

Procedure:
In a 25 mL round-bottomed flask equipped with a reflux condenser and N2 inlet septum was placed a stir bar, 4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (200 mg, 0.57 mmol), 4-isopropoxyphenylboronic acid (304 mg, 1.7 mmol), 2M sodium carbonate (0.6 mL) and toluene (4 mL). The mixture was degassed for a few minutes. Tetrakis(triphenylphosphine) palladium (98 mg, 0.085 mmol) was added to the above mixture. The reaction mixture was refluxed overnight under N2. The resulting mixture was diluted with ethyl acetate and extracted with H2O. The organic extract was dried and concentrated to give the crude product. The crude product was purified by column chromatography to using 50% EtOAc/Hexane and preparative HPLC to give the desired product. 1H NMR (CDCl3, 400 MHz) δ 1.28 (d, 6H), 1.39 (d, 6H), 2.03 (m, 2H), 2.17 (m, 2H), 3.59 (m, 2H), 3.85 (m, 2H), 4.63 (m, 1H), 4.97 (m, 1H), 5.12 (m, 1H), 7.04 (s, 1H), 7.22 (d, 1H), 7.37 (d, 2H), 7.81 (t, 1H), 7.90 (d, 1H), 8.36 (d, 1H), 9.06 (d, 1H). Exact mass calculated for C27H32N2O4 448.24, found 449.4 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:8]([C:10]([O-:12])=[O:11])[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:19]>>[ClH:19].[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N[C@H](C(=O)[O-])C(c1ccccc1)c1ccccc1
Agent: Cl
Product: N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Crude ethyl N-(diphenylmethylene)-DL 3,3-diphenylalaninate is added to 2.5 L of 6N hydrochloric acid solution and heated at reflux for 6 hours. The reaction mixture is allowed to cool to room temperature overnight. The product is collected, washed with water (3×), diethyl ether (4×), and dried at 50° C./200 mm Hg. This affords 93.6 g of the title compound as a white crystalline material; mp >210° C. (dec).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CS(C)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][OH:30]>C(Cl)Cl>[N:1]1([C:10]2[N:18]=[C:17]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH2:29][OH:30])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: OC[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CS(C)=O
Product: OC[C@@H]1CCCN1c1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 110 °C
Yield: 64.6 %

Procedure:
250 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 470 mg of (S)-(+)-2-pyrrolidinemethanol. The mixture is then heated at 110° C. for approximately 16 hours. The mixture is allowed to return to ambient temperature. A paste is formed in CH2Cl2 (methylene chloride). Drying is carried out under vacuum. 200 mg of expected product are obtained.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.C1CCCCC1.S(=O)(=O)(O)O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[CH:40]=[C:39]([C:44]([O:46][CH3:47])=[O:45])[CH:38]=[CH:37]3)=[CH:30][CH:29]=1>C(O)C>[C:5]12([C:29]3[CH:30]=[C:31]([C:34]4[CH:35]=[C:36]5[C:41](=[CH:42][CH:43]=4)[CH:40]=[C:39]([C:44]([O:46][CH3:47])=[O:45])[CH:38]=[CH:37]5)[CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc2cc(-c3ccc(OC)cc3)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: C1CCCCC1
Product: COC(=O)c1ccc2cc(-c3ccc(OC)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Reaction time: 2 h
Yield: 68.5 %

Procedure:
In a 100 ml three-necked flask, are placed 1 g of 1-acetoxyadamantane and 50 ml of cyclohexane in a nitrogen environment. After total dissolution, 0.25 g of concentrated sulfuric acid is added drop by drop and 1 g of methyl 6-(4-methoxyphenyl)-2-naphthoate is added slowly. After leaving in vigorous agitation for 48 hours, 20 ml of denatured ethanol are added and the mixture is agitated for 2 hours. The solid obtained is filtered with sintered glass and washed abundantly with water until neutrality is reached. After drying at 30° C. for 24 hours in a vacuum oven, 1 g of desired raw product was obtained (Melting point: 221°-227° C.).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[CH:31]=2)=[N:27][C:26]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:42][CH2:41][C:26]3[N:27]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)[CH:31]=4)[O:29][C:25]=3[CH3:24])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:23])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3cccs3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(Cl)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-(4-chlorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-2-ylphenyl)-oxazol-4-yl]ethyl ester (0.030 mmol) (see Ex. 5, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(4-chlorophenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]ethoxy}-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.87 (d, 1H, J=8.21 Hz), 7.69–7.67 (m, 1H), 7.46 (d, 1H, J=8.21 Hz), 7.42 (dd, 1H, J=3.52 Hz, 2.74 Hz), 7.32 (dd, 1H, J=5.08 Hz, 2.74 Hz), 7.19–7.15 (m, 3H), 7.18 (dd, 2H, J=6.26 Hz, 2.74 Hz), 6.82 (dd, 4H, J=8.60 Hz, 2.74 Hz), 4.22 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.10 (d, 1H, J=14.08 Hz), 3.05 (t, 2H, J=6.26 Hz), 2.42 (s, 3H), 1.40 (s, 3H). MS (ES+) m/z mass calcd for C32H29ClNO5S 574.15, found 574.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([O:34]CC)=O)[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[N:37]1([CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])[CH2:41][CH2:40][CH2:39][CH2:38]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:46][CH2:45][CH2:44][CH2:43][CH2:42][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:34])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NCCCCN1CCCC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCCCN2CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 67 %

Procedure:
Intermediate A and 4-pyrrolidin-1-ylbutan-1-amine were reacted together using an analogous method to that described in Step 1 of Example 1 to afford 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-6-methyl-2-oxo-N-(4-pyrrolidin-1-ylbutyl)-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide as a white solid (169 mg, 67%); 1H NMR (500 MHz, DMSO) δ 1.50-1.36 (4H, m), 1.63 (4H, dd), 1.73 (3H, s), 2.40-2.30 (6H, m), 3.24 (2H, q), 6.72 (1H, d), 7.65 (2H, d), 7.71 (1H, d), 7.87-7.81 (2H, m), 7.95-7.89 (4H, m), 8.06 (1H, s), 9.30 (1H, t); APCI-MSm/z: 589[MH+]
Reaction SMILES: [CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](I)=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].[C:35]([NH2:39])(=[O:38])[CH:36]=[CH2:37].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](/[CH:37]=[CH:36]/[C:35]([NH2:39])=[O:38])=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)c2cc(F)ccc21
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(/C=C/C(N)=O)ccc3N2)=C(O)c2cc(F)ccc21
Temperature: 100 °C
Yield: 55.6 %

Procedure:
A solution of the compound of Example 20B (65 mg, 0.11 mmol), acrylamide (9 mg, 0.12 mmol), triethylamine (45 μL, 0.33 mmol), and palladium (II) acetate (1.2 mg, 0.005 mmol) in N,N-dimethylformamide (1.5 mL) in a resealable pressure tube was degassed by evacuation and purging with nitrogen. The pressure tube was sealed and warmed at 100° C. for 1 h. The solution was cooled and diluted with ethyl acetate and water. The mixture was acidified by addition of citric acid solution (1 M, 2 mL). The organic layer was extracted with water (2×) and with saturated NaCl solution. Drying (Na2SO4) and concentration in vacuo afforded a solid, which was purified by flash chromatography eluting with methanol in dichloromethane. These procedures afforded the title compound (33 mg, 56%) as a light amber solid.
Reaction SMILES: [C:1]([O:9][C@@:10]12[O:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O[C@]12CCCC[C@H]1O2)c1ccccc1
Solvent: ClCCl
Product: O=C(O[C@H]1CCCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of (1R,2R)-2-benzoyloxy-1,2-epoxycyclohexane (0.030 g, 0.137 mmol, 93% ee) in anhydrous CH2Cl2 (0.4 mL) was added YbCl3 (0.0038 g, 0.0137 mmol). Upon stirring at room temperature for 30 min, the reaction mixture was quenched with saturated NaHCO3 solution, extracted with ether, dried over anhydrous Na2SO4, filtered, concentrated, and purified on buffered silica gel (0.5-1% Et3N) by flash column chromatography [EtOAc-CH2Cl2-hexane (3:7:40)] to afford (S)-2-benzoyloxy cyclohexanone (0.022 g, 73% yield, 88% ee).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[N:8]=1)(=O)=O.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>C1COCC1.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:18]1[C:19]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[N:8]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: O=S(=O)(Oc1nc(F)ccc1F)C(F)(F)F
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1cc(-c2nc(F)ccc2F)c(Cl)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A mixture of 3,6-difluoropyridin-2-yl trifluoromethanesulfonate (3.50 g, 13.30 mmol) and 5-chloro-2-fluoropyridine-4-boronic acid (3.27 g, 18.62 mmol) in THF (27 ml) was degassed by bubbling Argon gas for 10 min. Aqueous sodium carbonate (13.30 ml, 26.6 mmol) and PdCl2(dppf).CH2Cl2 adduct (0.652 g, 0.798 mmol) were added, and the mixture was degassed for an additional 5 min. The resulting reaction mixture was stirred at about 100° C. for 2 hr in a sealed vessel. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and water. The separated organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel (heptanes/ethyl acetate gradient) to yield 2.78 g (85% yield) of 5′-chloro-2′,3,6-trifluoro-2,4′-bipyridine as a crystalline solid. LCMS (m/z): 244.9 [M+H]+; retention time=0.86 min.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)[CH:8]=1)[CH3:2].[I-].[Na+].C(#N)C.Cl[Si](C)(C)C>O>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([C:9]2[N:13]=[CH:12][O:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2ncon2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(-c2ncon2)c(C)[nH]c1=O
Temperature: 65 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-3-yl)pyridine (56 mg, 0.256 mmol) and sodium iodide (117 mg, 0.78 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (4 mL) followed by drop-wise addition of chlorotrimethylsilane (97.5 μL, 0.776 mmol). The reaction mixture is stirred at 65° C. under nitrogen for 16 hr. The reaction mixture is allowed to cool, diluted with water and the resulting mixture is extracted with five portions of dichloromethane. The combined extract is dried over magnesium sulfate and evaporated to leave a brown residue. This material is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:methanol (49:1). Fractions containing the product are combined and the solvent evaporated, to give 3-ethyl-6-methyl-5-(1,2,4-oxadiazol-3-yl)-1H-pyridin-2-one (38 mg, 73% yield) as a off-white solid. LC/MS: RT: 2.27 min, m/e=206 (M+H); 1H NMR (400 MHz, δ, ppm): 12.02 (1H, s), 9.64 (1H, s), 7.74 (1H, s), 2.52 (3H, s), 2.41 (2H, q), 1.10 (3H, t).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C@H:5]2[CH2:4][N:3]1[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([Cl:20])[C:13]=1[CH3:21].[BH4-].[Na+]>CO.CC#N.CCOC(C)=O>[OH:11][C@H:10]1[CH2:9][CH2:8][CH2:7][N:6]2[C:2](=[O:1])[N:3]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([Cl:20])[C:13]=3[CH3:21])[CH2:4][C@H:5]12
Reactant: Cc1c(N2C[C@@H]3C(=O)CCCN3C2=O)ccc(C#N)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: Cc1c(N2C[C@@H]3[C@@H](O)CCCN3C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A mixture of 78A (5 mg, 0.016 mmol) and sodium borohydride (5 mg) in MeOH:CH3CN (1:1, 1.0 mL) was stirred at rt for 2 h. The reaction was diluted with EtOAc, washed with water (2×2 mL), dried (MgSO4), filtered and concentrated to give the crude product. Purification by chiral preparative HPLC (Chiralpak AD, 25% IPA/heptane isocratic) provided 78B (4 mg): HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 2.40 min (100%); MS (ES) m/z 306 [M+1]+; Chiral analytical HPLC (ChiralPak AD OD 4.6×250 mm, 25% IPA/hexane isocratic) retention time 12.1 min (97.6% ee); MS (ES) m/z 306.1 [M+1]+; HRMS calcd for C15H15ClN3O2 304.0853, Found 304.0846.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH:13]=O)([CH3:3])[CH3:2].[CH3:15][NH2:16].C(O)C.[BH4-].[Na+]>CO>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH2:13][NH:16][CH3:15])([CH3:3])[CH3:2]
Reactant: CC(C)c1c(C=O)oc2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CNCc1oc2ccccc2c1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 3-isopropylbenzofuran-2-carbaldehyde (250 mg, 1.33 mmol) in anhydrous methanol (8 mL) is added a solution of n-methylamine in ethanol (0.281 mL, 5.32 mmol) and the reaction is stirred at room temperature overnight under an atmosphere of argon. The solution is then concentrated, and re-solvated in methanol (8 mL) and cooled in an ice bath. Sodium borohydride (0.152 g, 4 mmol) was added portion wise and the reaction was stirred at room temperature under argon for 6 h. The solution is concentrated, and re-solvated in 1.3N NaOH (5 mL) and ether (5 mL) and stirred for 1 h. The ether layer was collected. The aqueous layer was washed with ether (2×10 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica gel, 9:1 DCM:MeOH) yielded the title compound as a yellow oil (228 mg, 85%): 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J=4.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.25-7.16 (m, 2H), 3.75 (s, 2H), 3.15-3.22 (m, 1H), 2.25 (s, 3H), 1.36-1.34 (2s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][CH:22]=[CH2:23])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:24])[CH:3]=1.[H-].[Na+].Br[CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[C:29]([CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:24])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:15][C:16]=1[CH2:21][CH:22]=[CH2:23])([O:31][CH3:32])=[O:30]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.17 1 g (0.53 mmol) of the product of Step G dissolved in 2.5 mL of anhydrous DMF was added 0.023 g (0.58 mmol) of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under a nitrogen atmosphere for 30 minutes at room temperature. A solution of 0.134 g of methyl α-bromophenylacetate in 1.0 mL of DMF was then added via syringe and the reaction mixture was stirred an additional 1.5 hours. The reaction mixture was then partitioned between ethyl acetate and water, the organic layer was separated, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 75% ethyl acetate-hexane to afford after evaporation of the purified fractions and drying in vacuo 0.212 g (85%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[H-].[Na+].[CH3:15][N:16](C=O)C>>[C:15]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:16]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of compound 2 (6.46 g, 24.1 mmol) in DMF (30 mL) was treated with sodium hydride (1.94 g of 60% dispersion in mineral oil, 48.6 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 16 hours and then partitioned between water (100 mL) and EtOAc (350 mL). The layers were separated, and the organic layer was washed with water (4×150 mL). The organic phase was dried (Na2SO4) and concentrated to a white solid. Compound 3 (5.56 g, 24.0 mmol, quantitative yield) was dried under high vacuum and characterized using 1H NMR. It was used in the following step without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.[F:13][C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([F:26])[C:15]=1B(O)O>>[F:26][C:16]1[CH:17]=[C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[CH:19]=[C:14]([F:13])[C:15]=1[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: OB(O)c1c(F)cc(N2CCOCC2)cc1F
Product: NC(=O)c1cc(-c2c(F)cc(N3CCOCC3)cc2F)sc1[N+](=O)[O-]

Procedure:
The title compound was prepared as described in Intermediate 10 Step 5 using 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10 Step 4) (582 mg, 2.32 mmol) and (2,6-difluoro-4-morpholin-4-ylphenyl)boronic acid (TFA salt) (830 mg, 2.33 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:19][C:20]1[C:21]([N:27]=[C:28]=[S:29])=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:2]=1[NH:1][C:28](=[S:29])[NH:27][C:21]1[C:20]([Cl:19])=[CH:25][C:24]([Cl:26])=[CH:23][N:22]=1
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(Cl)cc2Cl)c1NCCCCO
Yield: 78.9 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(4-hydroxybutyl)amino]benzoate (2.00 g, 7.33 mmol) and 3,5-dichloro-2-isothiocyanatopyridine (1.80 g, 8.80 mmol) in tetrahydrofuran (20 mL) was stirred for 12 h at room temperature. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on NH-silica gel eluting with a 10-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (2.76 g, 5.78 mmol, 79%).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][N:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][N:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3Nc3ccc4ccncc4n3)ccc2C(C)(C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)CNCc2cc(NC(=O)c3ccccc3Nc3ccc4ccncc4n3)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4,4-dimethyl-7-[2-([1,7]naphthyridin-2-ylamino)-benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Step B, 200 mg, 0.38 mmol) in EtOAC (2 mL) was added concentrated HCl in EtOAc (5 mL). The mixture was stirred for 5 h at RT under N2 atmosphere. The solid was filtered off and dissolved in water. The aqueous solution was basified to pH 11-14 using 5N NaOH. The solution was extracted with EtOAc, and the organic layer was dried over Na2SO4. The volatiles were removed under reduced pressure and the crude was purified with flash chromatography (SiO2, 5% MeOH/CH2Cl2) to obtain the desired compound as a white solid. MS (ES+): 424.0 (M+H)+. Calc'd for C26H25N5O-423.51.