Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])(C)C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[N:25][CH:26]=1.F[C:39](F)(F)[C:40]1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=C[CH:41]=1>>[F:37][C:20]([F:19])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH:35][C:10]([C@@H:9]4[CH2:13][C:14]5[C:18](=[CH:39][CH:40]=[CH:41][CH:17]=5)[NH:8]4)=[O:12])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[N:25][CH:26]=1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Product: O=C(N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21)[C@@H]1Cc2ccccc2N1

Procedure:
The title compound was prepared by substituting (S)-1-(tert-butoxycarbonyl)indoline-2-carboxylic acid for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 262 Step B for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.63 (dd, J=1.6, 0.8, 1H), 8.21 (d, J=7.6, 1H), 7.67 (dd, J=9.0, 2.5, 1H), 7.19-7.07 (m, 2H), 6.83 (dd, J=11.7, 4.3, 2H), 6.54-6.46 (m, 1H), 6.35 (d, J=8.9, 1H), 4.69 (td, J=10.8, 3.5, 1H), 4.46-4.30 (m, 1H), 3.82-3.71 (m, 1H), 3.65-3.48 (m, 3H), 3.42-3.24 (m, 2H), 2.80-2.62 (m, 2H), 2.19-2.03 (m, 1H), 1.97-1.80 (m, 1H), 1.62 (dq, J=12.8, 8.2, 1H), 1.45-1.28 (m, 1H); MS (ESI+) m/z 417 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([NH2:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C([Sn]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(CCCC)CCCC)CCC.C(N1C2C(=CC=C(C3ON=CC=3)C=2)C(=O)C(C(N)=O)=C1)C>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:11]=3)[C:6](=[O:22])[C:7]([C:19]([NH2:21])=[O:20])=[CH:8]2)=[CH:13][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O
Agent: CCn1cc(C(N)=O)c(=O)c2ccc(-c3ccno3)cc21
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccccc3)ccc2c1=O

Procedure:
1,4-Dihydro-1-(4-fluorophenyl)-4-oxo-7-phenyl-3-quinolinecarboxamide [I; R=H, R1 =4-FC6H4, R2 =H, R6 =H, R7C6H5 ] was prepared from 2.22 g 1,4-dihydro-7-chloro1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxamide (Example 42c), 3.30 g tributylstannylbenzene (prepared from tributyltin chloride and bromobenzene) and 2.50 g dichlorobis-triphenylphosphine palladium according to the procedure of Example 37, part (c), and was obtained (1.4 g) as colorless crystals, m.p. 289-292° C. when recrystallized from acetonitrile.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:20]([C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[N:25][N:24]=2)[CH2:21][OH:22])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[C:20]([C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[N:25][N:24]=2)[CH:21]=[O:22])=[CH:15][CH:14]=1
Reactant: CCn1nnnc1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Pyridinium chlorochromate (0.9 g) was added to a solution of 0.8 g (2.3 mmoles) of the 3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenol in methylene chloride. The solution became bright yellow and then darkened with the formation of a dark gummy precipitate. After stirring at room temperature for 16 hours, the mixture was poured directly onto a silica gel column and eluted with methylene chloride to give 0.65 g (83%) of the title compound; m.p.=144°-145° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:21])[C:7]([Cl:20])=[C:8]([O:18][CH3:19])[CH:9]=2)[C:4]1=[O:22])[CH3:2].[CH3:23]I.C[O-].[Na+].O>CN(C)C=O.C1C=CC=CC=1>[CH2:1]([C:3]1([CH3:23])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:21])[C:7]([Cl:20])=[C:8]([O:18][CH3:19])[CH:9]=2)[C:4]1=[O:22])[CH3:2]
Reactant: CI
Reactant: CCC1C(=O)c2c(cc(OC)c(Cl)c2Cl)C1c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: CCC1(C)C(=O)c2c(cc(OC)c(Cl)c2Cl)C1c1ccccc1
Reaction time: 1 h

Procedure:
2-Ethyl-3-phenyl-6,7-dichloro-5-methoxy-1-indanone (10.05 g., 0.03 mole) and methyl iodide (12.5 ml., 0.2 mole) dissolved in dimethylformamide (100 ml.)-benzene (100 ml.) at 0° C. under nitrogen are treated portionwise with sodium methoxide (3.54 g., 0.033 mole) over a 30 minute period. The reaction mixture is stirred in an ice-water bath for one hour, then poured into water (500 ml.), extracted with benzene, the organic layer separated, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give an oily residue which on trituration with hexane gives 7.64 g. (71%) of 2-ethyl-2-methyl-3-phenyl-6,7-dichloro-5-methoxy-1-indanone which melts at 132° C. on crystallization from cyclohexane.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:40])[CH:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH3:33])=[CH:26][CH:25]=1.O>C1COCC1>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([C:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][O:21][CH3:20])=[CH:29][CH:28]=2)([OH:40])[CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][CH3:33])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCC(C(=O)c1ccc(OCOC)cc1)c1ccccc1
Reactant: CCOC(OCC)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)c1ccc(C(O)(c2ccc(OCOC)cc2)C(CC)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 122.8 %

Procedure:
To a stirred solution of 4-bromobenzaldehyde diethyl acetal (107 g, 0.41 mol) in anhydrous THF (750 mL) was added n-BuLi (1.6 M in hexanes, 268 mL, 0.43 mol) dropwise at −78° C. After stirring for 1 h at −78° C., a solution of 15 (97.6 g, 0.34 mol) in THF (750 mL) was cannulated into the reaction mixture portionwise. The mixture was stirred overnight at RT, H2O (500 mL) was added, and the volatiles were removed under reduced pressure. The residue was extracted with Et2O (3×500 mL) and the combined extracts washed with H2O (500 mL) and brine (500 mL). The mixture was dried over MgSO4 and concentrated to afford 194 g of 16 that was used without further purification. 1HNMR (400 MHz, DMSO-d6): δ 0.58 (t, J=7.3 Hz, 3H), 1.12 (m, 6H), 1.52 (m, 1H), 1.70 (m, 1H), 3.23 (s, 3H), 3.40-3.65 (m, 5H), 4.98 (s, 2H), 5.41 (s, 1H), 5.51 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 6.96-7.06 (m, 3H), 7.17-7.23 (m, 4H), 7.31 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([O:6][CH3:7])=[O:5])[CH3:3].Cl.[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:39])[C:15]=1[NH:16][C:17]1[C:26]2[C:21](=[C:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[O:20][C:19](=[O:38])[CH:18]=1>>[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:39])[C:15]=1[NH:16][C:17]1[C:26]2[C:21](=[C:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([NH:1][C@@H:2]([CH3:3])[C:4]([O:6][CH3:7])=[O:5])=[O:36])[C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[O:20][C:19](=[O:38])[CH:18]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from Ala-OMe•HCl and 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (Example 44) following the procedure outlined in Example 94. 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.81 (s, 2H), 8.20 (d, 1H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 4.22 (m, 1H), 3.96 (t, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 2.11 (t, 2H), 1.68 (m, 2H), 1.54 (m, 2H), 1.43 (m, 2H), 1.23 (d, 3H); MS (ESI): 552.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Br[CH:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[NH3:8].[CH2:36]([N:33]([CH2:34][CH3:35])[C:31]([CH:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:14][C:15]([C:17]3[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:16])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:32])[CH3:37]
Reactant: O=C(Nc1ccc(N2CCNCC2)c(F)c1)c1ccccc1-c1ccccc1
Reactant: CCN(CC)C(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2F)CC1
Product: N
Reaction time: 18 h

Procedure:
A solution of biphenyl-2-carboxylic acid (3-fluoro-4-piperazin-1-yl-phenyl)-amide (0.030 g, 0.08 mmol), 2-bromo-N,N-diethyl-2-phenyl-acetamide (0.025 g, 0.09 mmol), and Na2CO3 (0.013 g, 0.1 mmol) in DMF (2 mL) was stirred at room temperature. After 18 h, the reaction mixture was diluted with EtOAc (25 mL) and washed with H2O (3×15 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the resulting residue (SiO2: 2 M NH3 in MeOH/CH2Cl2) yielded the title compound.
Reaction SMILES: [C:1]1([N:7]([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][N:35]=1.C([O-])([O-])=O.[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>[Br:40][C:37]1[CH:38]=[CH:39][C:34]([C:4]2[CH:3]=[CH:2][C:1]([N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:5]=2)=[N:35][CH:36]=1
Reactant: Brc1ccc(I)nc1
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(-c2ccc(N(c3ccccc3)c3cccc4ccccc34)cc2)nc1
Temperature: 95 °C
Yield: 87 %

Procedure:
A mixture of N-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)naphthalen-1-amine (Compound 29) (2.32 g, 5.51 mmol), 2-iodo-5-bromo-pyridine (3.13 g, 11 mmol), Pd(PPh3)4 (0.346 g, 0.3 mmol) and K2CO3 (1.38 g, 10 mmol) in dioxane/water (60 mL/10 mL) was degassed and heated at about 95° C. overnight. The resulting mixture was mixed with ethyl acetate/brine, dried over Na2SO4, loaded on silica gel, and purified by flash column (hexanes to hexanes/dichloromethane 9:1 to 3:1). The desired fraction was collected and a light yellow solid (Compound 30) was obtained after removal of solvents (2.17 g, in 87% yield).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1.C=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH2:22])=[O:21].[C:26](=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:22][CH2:26][N:11]1[CH2:10][CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH2:13][CH2:12]1)=[O:21]
Reactant: O=C([O-])[O-]
Reactant: C1=C(c2ccccn2)CCNC1
Reactant: NC(=O)c1cccc(Cl)c1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(NCN1CC=C(c2ccccn2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl hydrochloride (20 mg, 0.10 mmol, Saari, W. S.; et al. J. Med. Chem. 1984, 27, 1182), paraformaldehyde (30 mg, 1 mmol), 3-chlorobenzamide (78 mg, 0.5 mmol, Lancaster), and 42 mg of potassium carbonate (0.3 mmol) in 2.5 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 20 mg (61%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 2.58 (m, 2H), 2.79 (t, J=4 Hz, 2H), 3.30 (m, 2H), 4.30 (d, J=5 Hz, 2H), 6.71 (m, 1H), 7.22 (m, 1H), 7.52 (m, 2H), 7.62 (d, J=6 Hz, 1H), 7.73 (t, J=6 Hz, 1H), 7.85 (d, J=6 Hz, 1H), 7.92 (s, 1H), 8.52 (m, 1H), 9.08 (t, J=5 Hz, 1H); MS (ESI/APCI−) m/e 326 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C(N(C(C)C)C(C)C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl.C(#N)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH:3]=[CH:4][C:5]=2[NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc(N)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A suspension of 5-amino-N-(5-chloropyridin-2-yl)-2-[(1-Boc-piperidin-4-yl)methylamino]benzamide (0.55 g, 1.2 mmol) in 12 mL of dichloromethane at 0° C. was treated with ethyldiisopropylamine (231 μL, 1.3 mmol) followed by methanesulfonyl chloride (93 μL, 1.2 mmol). The reaction mixture was allowed to reach room temperature overnight, then it was concentrated in vacuo to a crude residue. The residue was directly applied to an SCX column, which was washed with methanol and allowed to stand overnight. Elution with 1:1 dichloromethane-1 N ammonia in methanol provided yellow fractions, which were combined and concentrated in vacuo to a crude residue. Purification by silica gel chromatography, eluting with 9:1 dichloromethane-2 N ammonia in methanol, afforded solid material which was taken up in acetonitrile and sonicated for several minutes. The resulting suspension was filtered, giving rise to the title compound (0.29 g, 56%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:4][C:5]([C:8](OC)=[O:9])=[N:6][CH:7]=1.[BH4-].[Na+]>CO.CCOC(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2cccc(F)c2)c(Cl)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cc(-c2cccc(F)c2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 5-chloro-4-(3-fluorophenyl)picolinate (0.196 g, 0.738 mmol) in MeOH (6 mL) was added NaBH4 (0.152 g, 4.02 mmol). The reaction mixture was stirred at rt for 10 min, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (1×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% to 60% EtOAc in hexanes) gave (5-chloro-4-(3-fluorophenyl)pyridin-2-yl)methanol.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27](F)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15].Cl.[F:33][C:34]1([F:39])[CH2:38][CH2:37][NH:36][CH2:35]1.O>CS(C)=O>[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27]([N:36]3[CH2:37][CH2:38][C:34]([F:39])([F:33])[CH2:35]3)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15]
Reactant: FC1(F)CCNC1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(N3CCC(F)(F)C3)c(Cl)c2)cc1F

Procedure:
Triethylamine (0.21 mL, 1.51 mmol) was added to a mixture of 5-chloro-4-[5-chloro-6-fluoropyridin-3-yl)oxy]-2-fluoro-N-(methylsulfonyl)benzamide (Example 19, 150 mg, 0.38 mmol) and 3,3-difluoropyrrolidine hydrochloride salt (60 mg, 0.41 mmol), in DMSO (3.8 mL) and the reaction heated at 80° C. for 120 hours. The mixture was diluted to 5 mL by the addition of water and the mixture purified by preparative HPLC. The title compound was obtained as a beige solid (49 mg, 27%).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=1.C(N(C(C)C)CC)(C)C.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([OH:36])[CH:27]=1>CN(C)C=O.Cl.C(OCC)(=O)C>[ClH:1].[OH:14][C:6]1[CH:5]=[C:4]([CH2:3][NH:2][CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]([OH:36])[CH:27]=2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(CBr)cc1O
Reactant: COC(=O)c1ccc(CN)cc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNCc2ccc(C(=O)OC)c(O)c2)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
Dissolved methyl 4-aminomethyl-2-hydroxybenzoate hydrochloride (13.07 g, 60.1 mmole) and diisopropylethylamine (28.0 mL, 292 mmole) in 225 mL of N,N-dimethylformamide by heating slightly until a solution was obtained. Allowed the solution to cool to room temperature and added methyl 4-bromomethyl-2-hydroxybenzoate (9.81 g, 40.0 mmole). The reaction was stirred for 1 day at room temperature. The solution was diluted with 200 mL of 1N HCl and 250 mL of ethyl acetate and allowed to cool to room temperature. Precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo under a under high vacuum. Obtained 11.32 grams (74% yield) of product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([OH:26])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[NH:19][C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22].O1CCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([OH:26])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[NH:19][CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: COc1cccc([C@@H](O)c2ccc(Cl)cc2NC(=O)C(C)(C)C)c1OC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc([C@@H](O)c2ccc(Cl)cc2NCC(C)(C)C)c1OC
Temperature: 10 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A four-necked flask of 1 L capacity was charged with 60 g (0.159 mol) of (S)-α-(2,3-dimethoxyphenyl)-4-chloro-2-(pivaloylamino)benzyl alcohol, 240 ml of tetrahydrofuran, and 60 ml of methylene chloride and after the atmosphere in the flask was purged with N2 gas, the mixture was stirred with cooling at 10° C. Then, 144 ml of 70% NaAlH2 (OCH2CH2OCH3)2 (Red-Al)/toluene maintained at 10-25° C. was added dropwise under constant stirring. After completion of dropwise addition, the mixture was allowed to stand at room temperature overnight. Next morning, 100 ml of water was added dropwise under ice-cooling and stirring and the mixture was extracted with 923 ml of ethyl acetate. The aqueous layer was further extracted with 923 ml of ethyl acetate. The extracts were combined, and 100 g of anhydrous MgSO4 and 6 g of activated carbon powder for decolorization were added. The mixture was stirred for 10 minutes and, then, filtered. The residue on the filter was washed with 462 ml of ethyl acetate. The filtrate and wash were combined and concentrated under reduced pressure. By this procedure, the objective compound was obtained as a viscous oily residue. Crude yield 62.16 g (optical purity 92.9%, yield 99.6%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35](O)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:46][O:47][C@@H:48]([C@@H:64]1[CH2:68][CH2:67][CH2:66][NH:65]1)[C@@H:49]([CH3:63])[C:50]([NH:52][CH2:53][C:54]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:56][CH2:55]1)=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:44])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:40]([CH3:43])[CH2:41][CH3:42])[C@H:33]([O:38][CH3:39])[CH2:34][C:35]([N:65]3[CH2:66][CH2:67][CH2:68][C@H:64]3[C@H:48]([O:47][CH3:46])[C@@H:49]([CH3:63])[C:50](=[O:51])[NH:52][CH2:53][C:54]3([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[CH2:55][CH2:56]3)=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCC1(c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCC1(c2ccccc2)CC1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Yield: 75.4 %

Procedure:
According to general procedure D, from #32 (550 mg, 0.902 mmol, 1 eq.), #58 (350 mg, 0.992 mmol, 1.1 eq.) dichloromethane (10 mL, 0.08 M) and N,N-dimethylformamide (2 mL), HATU (446 mg, 1.17 mmol, 1.3 eq.) and triethylamine (0.503 mL, 3.61 mmol, 4 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 30% acetone in heptane), producing #59 (618 mg, 69%) as an off-white solid. LC-MS: m/z 908.7 [M+H+], 930.7 [M+Na+], retention time=1.07 minutes; HPLC (Protocol B at 45° C.): m/z 908.5 [M+H+], retention time=8.721 minutes (purity >97%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 7.89 (d, J=7.5 Hz, 2H), 7.38-7.44 (m, 2H), 7.30-7.36 (m, 2H), [4.49 (dd, J=8.5, 7.8 Hz) and 4.59 (dd, J=8.7, 6.9 Hz), total 1H], 4.18-4.26 (m, 3H), 3.93-4.01 (br m, 1H), 3.23 and 3.26 (2 s, total 3H), 3.16 and 3.16 (2 s, total 3H), 2.91 and 3.05 (2 br s, total 3H), 1.36 and 1.37 (2 br s, total 3H), 1.30 and 1.32 (2 br s, total 3H), [1.00 (d, J=6.7 Hz) and 1.02 (d, J=6.6 Hz), total 3H], 0.67-0.78 (m, 7H).