Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH:12]C(=O)OCC2C=CC=CC=2)[CH:9]=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[NH2:12][C:10]1[N:11]=[C:6]([CH2:5][O:4][CH2:3][C:2]([CH3:24])([OH:1])[CH3:23])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(O)COCc1cccc(NC(=O)OCc2ccccc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)COCc1cccc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl {6-[(2-hydroxy-2-methylpropoxy)methyl]pyridin-2-yl}carbamate (368 mg, 1.11 mmol) in methanol (11 mL) was added palladium on carbon (10% w/w, 119 mg, 1.11 mmol). A hydrogen balloon was fitted on top of the flask and the flask was evacuated and then backfilled with hydrogen. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through CELITE, and the CELITE was washed with methanol. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-12% methanol/DCM, linear gradient) to afford 1-[(6-aminopyridin-2-yl)methoxy]-2-methylpropan-2-ol. MS ESI calc'd. for C10H17N2O2 [M+H]+ 197. found 197. 1H NMR (500 MHz, CDCl3) δ 7.42 (t, J=7.8 Hz, 1H), 6.69 (d, J=7.3 Hz, 1H), 6.39 (d, J=8.2 Hz, 1H), 4.53 (s, 2H), 4.49 (s, 1H), 3.41 (s, 2H), 1.23 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([O:32][C:33](=[O:36])[CH2:34]Br)[CH3:31]>C(#N)C.O>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][N:22]1[CH2:21][CH2:20][C:6]2[N:7]([CH2:11][CH:12]([OH:13])[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]=2[CH2:23]1)[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270 mg, 1.953 mmol) and bromo-acetic acid ethyl ester (163 mg, 0.977 mmol) were added and the reaction mixture was stirred at RT for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to yield [5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-acetic acid ethyl ester (220 mg). To a solution of [5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-acetic acid ethyl ester (120 mg, 0.305 mmol) in ethanol (2 mL), 1N NaOH (3 mL) was added and the reaction mixture stirred at RT for 1 h. The progress of reaction was monitored by LCMS. The reaction mixture was neutralized with aq HCl. The solvent was removed under reduced pressure and the residue diluted with 90% MeOH in DCM and filtered. The filtrate was concentrated and residue was purified by reverse phase HPLC to yield [5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-acetic acid. 1H NMR (CD3OD, formate salt) δ (ppm): 8.42 (d, 2H), 7.4 (d, 2H), 7.2 (d, 2H), 6.9 (d, 1H), 5.03 (t, 1H), 4.6 (bs, 1H), 4.57 (bs, 2H), 4.3 (m, 2H), 3.8 (s, 2H), 3.7 (bs, 2H), 3.0 (m, 1H), 2.3 (s, 3H). Separation by chiral HPLC provides enantiomers II-65a-b.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([C:9]1[CH:10]=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[OH-].[Na+]>CO>[CH3:25][O:24][CH2:23][CH2:22][CH2:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C:13]1[CH:14]=[C:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:36])=[O:2])[CH:10]=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH:12]=1
Reactant: COCCCC1CCCCN1c1cc(-c2ccc(C(F)(F)F)cc2)cc([C@@H](CC(C)C)C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCC1CCCCN1c1cc(-c2ccc(C(F)(F)F)cc2)cc([C@@H](CC(C)C)C(=O)O)c1
Temperature: 60 °C

Procedure:
To a solution of (R)-2-{5-[2-(3-methoxy-propyl)-piperidin-1-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid methyl ester (18 mg, 0.04 mmol) in MeOH (1 mL) was added 3N NaOH (0.200 mL) and heated to 60° C. for 14 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain (R)-2-{5-[2-(3-methoxy-propyl)-piperidin-1-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1O
Product: CCOC(=O)c1cnc2cc(F)ccc2c1Cl

Procedure:
Prepared as in Example 1b from ethyl 7-fluoro-4-hydroxyquinoline-3-carboxylate (Example 9c) and POCl3 as an off white solid (96%). MS 254, 256 (MH+).
Reaction SMILES: C(O[C:4](=[O:6])C)=O.ClCCl.[CH3:10][C:11]1[N:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1>ClCCl.CO>[CH3:10][C:11]1[N:15]2[N:16]=[C:17]([C:20]3[CH:21]=[C:22]([NH:26][CH:4]=[O:6])[CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: CC(=O)OC=O
Solvent: CO
Solvent: ClCCl
Product: Cc1nnc2ccc(-c3cccc(NC=O)c3)nn12
Reaction time: 12 h

Procedure:
To 5.53 ml of acetic-formic anhydride was added 250 ml dichloromethane followed by 10 g of 3-methyl-6-[3-(amino)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine. The solution was stirred for 12 hours, then diluted with 1 liter of dichloromethane-methanol (9:1). This solution was washed with saturated aqueous sodium bicarbonate, dried, and concentrated in vacuo. The residue was recrystallized from dichloromethane-methanol to give 6.7 g of an off-white powder, mp 265°-268° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[N:8]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=3)[CH2:7][CH2:6][C:5]=2[N:4]=1>Cl.O1CCOCC1>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[N:8]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=3)[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1cncc(N2CCc3nc(OC)ccc3C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cncc(N2CCc3nc(O)ccc3C2=O)c1
Temperature: 80 °C
Yield: 1.2 %

Procedure:
2-Methoxy-6-(5-methoxy-pyridin-3-yl)-7,8-dihydro-6H-[1,6]naphthyridin-5one (445 mg, 1.56 mmol) (example 97) was suspended in 2 mL of aq. conc. HCl in 1,4-dioxane (2:1) and heated at 80° C. for 3 hours before the solvent was removed in vacuo. After extraction between EtOAc and H2O, the organic layer was washed with aq. satd. NaHCO3 solution, brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to yield the title compound (4.9 mg) as a white solid. MS: 270.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20]([OH:22])=O)[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[C:20](=[O:22])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)[CH3:24]
Reactant: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)c1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1cccc(C)c1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[N:59]=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[N:59]=[N:60][NH:61][CH:62]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5c[nH]nn5)cccc4c3=O)cc2)CCC1
Agent: N
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5c[nH]nn5)cccc4c3=O)cc2)CCC1
Yield: 23 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[4-oxo-2-phenyl-8-(1H-[1,2,3]triazol-4-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was subjected to flash chromatography (SiO2, gradient 0 to 20% methanolic ammonia in DCM) to afford the title compound as a white solid (7 mg, 23%, 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.40 (dd, J=7.6 and 1.8 Hz, 1H), 8.14 (s, 1H), 8.08 (dd, J=7.9 and 1.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.48-7.44 (m, 2H), 7.41-7.31 (m, 5H), 7.11 (d, J=8.6 Hz, 2H), 3.26 (bs, 3H), 2.37-2.27 (m, 2H), 2.08-1.88 (m, 3H), 1.66-1.54 (m, 1H). LCMS (Method E): RT=2.98 min, [M+H]+=435.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:41]3[CH:40]=[CH:39][C:38]([N:35]5[CH2:34][CH2:33][O:32][CH2:37][CH2:36]5)=[CH:43][CH:42]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(N2CCOCC2)cc1)N1CCN(C2CCC2)CC1
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-morpholinophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (31%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](OC(Cl)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.C(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[CH2:8]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
To an ice cold solution of 5 g of 4-bromobutyric acid and 5.5 g of benzylchloroformate in 100 mL of dichloromethane was added 5 mL of triethylamine and then 700 mg of 4-dimethylaminopyridine. A vigorous exothermic reaction ensued with evolution of carbon dioxide. After stirring for 3 h, the mixture was diluted with 100 mL of dichloromethane and washed with 200 mL of saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated to an oil. Azeotropic drying with toluene gave 8 g of 4-bromobutyric acid benzyl ester as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH2:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=2[Cl:32])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:41]([C:40]2[CH:44]=[CH:45][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[O:42])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:7]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCN)CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCNC(=O)c2ccc(OC)cc2)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.1 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl)amino]-N-[[1-(2-aminoethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (0.2 mmol, 101 mg) and 4-methoxybenzoyl chloride (0.25 mmol, 52.1 mg) in dichloromethane (1 mL) was added DIPEA (0.3 mmol, 38.7 mg) at room temperature. The reaction mixture was stirred for 15 h at room temperature and then diluted with 20 mL of dichloromethane. The dichloromethane layer was washed successively with water (20 mL) and brine solution (20 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent afforded a crude product which was purified by revesrsed phase HPLC to obtain 0.1 g (78%) of a yellow syrup. HR MS (C33H35Cl2N3O6): Obs. mass, 662.1778. Calcd. mass, 662.1801 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][C:25]=1[F:31].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:27]2[CH:28]=[CH:29][C:24]([Br:23])=[C:25]([F:31])[CH:26]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(I)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Br)c(F)c2)CC1
Reaction time: 8 h

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (14AB) (4.0 g, 12.9 mmol, 1 equiv), 1-Bromo-2-fluoro-4-iodo-benzene (15AB) (5.84 g, 19.4 mmol, 1.5 equiv), potassium carbonate (5.4 g, 38.8 mmol, 3 equiv), and a (4v:1v) mixture of 1,4-dioxane and water (120 mL: 30 mL) were all added in a pressure vessel (350 mL) and the mixture was bubbled with nitrogen gas for about 10 minutes. To this mixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II)/dichloromethane adduct (1.05 g, 1.29 mmol, 0.1 equiv), and the reaction vessel was tightly capped, placed in an oil bath at 80° C., and stirred overnight.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[O:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:24])[C:3]([OH:25])=[O:2])=[CH:10][CH:9]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCOCCOc2ccccc2)cc1
Yield: 89.4 %

Procedure:
A mixture of 4-[[2-[[2-(phenoxy)ethyl]oxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.7 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction provided solids which were crystallized from benzene-hexane to give 0.6 g of colorless 4-[[2-[[2-(phenoxy)ethyl]oxy]ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 58°-59° C.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=CC=2)C=1C#N.[NH2:70][C:71]1[N:75]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[N:74]=[C:73]([C:83]2[CH:88]=[CH:87][C:86](O)=[CH:85][CH:84]=2)[C:72]=1[C:90]#[N:91].[S:92]1[C:96]2[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=2[N:94]=[C:93]1[N:101]([CH2:130][O:131][CH2:132][CH2:133][Si:134]([CH3:137])([CH3:136])[CH3:135])[C:102]([C:104]1[CH:105]=[CH:106][CH:107]=[C:108]2[C:113]=1[CH2:112][N:111]([C:114]1[S:115][C:116]([CH2:126][CH2:127][CH2:128][OH:129])=[C:117]([C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[N:118]=1)[CH2:110][CH2:109]2)=[O:103].NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC=C(O)C=2)C=1C#N>>[NH2:70][C:71]1[N:75]([C:76]([O:78][C:79]([CH3:80])([CH3:81])[CH3:82])=[O:77])[N:74]=[C:73]([C:83]2[CH:88]=[C:87]([CH:86]=[CH:85][CH:84]=2)[O:129][CH2:128][CH2:127][CH2:126][C:116]2[S:115][C:114]([N:111]3[CH2:110][CH2:109][C:108]4[C:113](=[C:104]([C:102](=[O:103])[N:101]([C:93]5[S:92][C:96]6[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=6[N:94]=5)[CH2:130][O:131][CH2:132][CH2:133][Si:134]([CH3:136])([CH3:135])[CH3:137])[CH:105]=[CH:106][CH:107]=4)[CH2:112]3)=[N:118][C:117]=2[C:119]([O:121][C:122]([CH3:125])([CH3:124])[CH3:123])=[O:120])[C:72]=1[C:90]#[N:91]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: CC(C)(C)OC(=O)n1nc(-c2cccc(O)c2)c(C#N)c1N
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1cccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)c1

Procedure:
The title compound 39A was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with compound 38E and compound 36A, respectively as a mixture of two inseparable isomers: MS (ESI(+)): 934 (M+H).
Reaction SMILES: II.[Mg].[CH2:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br-].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][N+:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.Cl.[NH4+].[OH-].[OH-].[Na+]>C(OCC)C.O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc[n+](Cc2ccccc2)cc1
Agent: Cl
Agent: II
Agent: [Br-]
Solvent: CCOCC
Solvent: O
Product: COC1=CC(Cc2ccccc2)N(Cc2ccccc2)C=C1
Yield: 100 %

Procedure:
Iodine (crystals) was added to magnesium turnings (8.63 g) in diethyl ether under N2. Benzyl bromide was added and the Grignard reaction was started. Benzyl bromide (60.65 g) in diethyl ether (443 ml) was added dropwise at reflux temperature while stirring, the reaction mixture was refluxed for 1 hour. The Grignard reagens was added dropwise to a suspension of 4-methoxy-1-(phenylmethyl)pyridinium bromide (75 g) in diethyl ether (1200 ml) and the mixture was stirred at RT for 18 hours. The mixture was poured into HCl (12M; 150 ml) and water (600 ml), alkalized with NH4OH and NaOH and extracted with CH2Cl2. The combined organic layers were washed with water, dried, filtered and the solvent was evaporated, yielding 76 g (100%) of (±)-1,2-dihydro-4-methoxy-1,2-bis(phenylmethyl)pyridine (interm 13).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:7]([F:17])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(OCC)(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:2][CH2:3][CH2:4][C:5]2[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:7]([F:17])[CH:6]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)COc1ccc(CCN)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1F
Reaction time: 2 h
Yield: 93.6 %

Procedure:
1 g of methyl 4-(2-aminoethyl)-2-fluorophenoxyacetate hydrochloride is added to a mixture of 30 ml of ethyl acetate, 1.58 g of potassium carbonate and 15 ml of water, and a solution of 0.78 g of 4-chlorophenylsulfonyl chloride in 15 ml of ethyl acetate is added dropwise thereto at room temperature. After the mixture is stirred for 2 hours, the ethyl acetate layer is separated therefrom, washed, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate, isopropylether and n-hexane. 1.39 g of methyl 4-[2-(4-chlorophenyl)sulfonylaminoethyl]-2-fluorophenoxyacetate are obtained as colorless prisms.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][N:51]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:40]2=[O:48])[C:36]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][N:51]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1ccc(Cl)cn1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 40.2 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-amino-5-chloropyridine (129 mg; 1.00 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 1, Step B) provided after flash chromatography (eluent: 25% ethyl acetate/hexanes) 160 mg of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-5-chloro-pyridin-2-yl-propionamide as a white foam: EI-HRMS m/e calcd for C22H24N3O2ClNa(M++Na+) 420.1449, found 420.1451.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[Cl-].[NH4+]>CN(C=O)C.CCOCC>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][S:10][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:32]
Reactant: CCOC(=O)CCCCBr
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride (989 mg, 24.47 mmol) in anhydrous DMF (60 mL) was added portion wise triphenylmethanethiol. After 15 minutes of stirring, ethyl 5-bromovalerate (2.8 mL, 17.48 mmol) was injected and the mixture was stirred at ambient conditions for 24 h. The reaction mixture was portioned between ether and saturated ammonium chloride. The water phase was extracted several times with ether. The recombined organic layer was washed with brine, dried, filtered and evaporated. The crude was flashed using 5–10% ethyl acetate in hexanes. 1H-NMR(CDCl3, 400 MH: 1.23(t, J=7.0 Hz, 3H); 1.42(m, 2H); 1.59(m, 2H); 2.16(m, 4H); 4.09(q, J=7.0 Hz, 2H), 7.21–7.30, 7.42(m, 15H).