Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:12]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH:38](=O)[CH2:39][CH:40]([CH3:42])[CH3:41]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=2)[CH:12]=[C:13]([N:15]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(NCc2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)CC=O
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(CCC(C)C)Cc2ccc(C(F)(F)F)cc2)c1

Procedure:
Following the procedure of Example 39, step (a), reaction of 4-Methyl-2-[4′-trifluoromethyl-5-(4-trifluoromethyl-benzylamino)-biphenyl-3-yl]-pentanoic acid methyl ester, compound 44a with isovaleraldehyde gave the title compound; Calcd.MW 593.66. Found MH+ 594.3.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C:12]([OH:14])=O)[CH2:6][CH2:5]2.Cl.Cl.[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[OH:20]>>[OH:20][C@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][NH:17][C:12]([C@@H:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[O:8]1)=[O:14]
Reactant: O=C(O)[C@@H]1CCc2cc(I)ccc2O1
Reactant: NC[C@H](O)c1cccnc1
Agent: Cl
Product: O=C(NC[C@H](O)c1cccnc1)[C@@H]1CCc2cc(I)ccc2O1
Yield: 87 %

Procedure:
Using the same procedure described in Method A, using (2S)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method B) and (1R)-2-amino-1-(3-pyridinyl)ethanol dihydrochloride (U.S. Pat. No. 6,051,586), the title compound was obtained as a white solid in 87% yield. 1H NMR (DMSO-d6) δ 8.47 (d, J=2.2 Hz, 1 H), 8.43 (dd, J=6.6, 1.8 Hz, 1 H), 7.90 (t, J=7.1 Hz, 1 H), 7.69-7.60 (m, 1 H), 7.40-7.37 (m, 2 H), 7.30-7.26 (m, 1 H), 6.66 (d, J=9.1 Hz, 1 H), 5.66 (d, J=4.6 Hz, 1 H), 4.72 (q, J=5.0 Hz, 1 H), 4.52 (dd, J=8.3, 3.3 Hz, 1 H), 4.12 (dd, J=6.1, 1.8 Hz, 1 H), 3.36-3.32 (m, 1 H), 2.77-2.65 (m, 1 H), 2.58-2.52 (m, 1 H), 2.08-2.00 (m, 1 H), 1.85-1.73 (m, 1 H). LC-MS m/z 425.1 (MH+), RT=2.07 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19](Br)[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2Br
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: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2c1ccccc1
Temperature: 90 °C
Yield: 68.4 %

Procedure:
A mixture of intermediate 15, ethyl 3-(benzyloxy)-9-bromo-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, (0.477 g, 1.18 mmol) in acetonitrile (15 ml) and water (15 ml) was treated with phenylboronic acid (0.190 g, 1.53 mmol), sodium carbonate (0.275 g, 2.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.200 g). The reaction mixture was degassed, flushed with argon and heated at 90° C. for 30 min. The reaction mixture was then concentrated in vacuo, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.325 g (68% yield) of the title material as a clear oil. 1HNMR 400 MHz (CDCl3) δ (PPM): 1.26 (3H, t, J=7.1 Hz, CH3), 2.68 (2H, m, CH2), 4.27 (2H, q, J=7.1 Hz, OCH2), 4.32 (2H, t, J=7.6 Hz, CH2), 5.34 (2H, s, OCH2), 6.73 (1H, t, J=4.8 Hz, CH), 7.3–7.55 (10H, m, aromatics). HRMS (ESI+) calculated for C24H23N2O4 [M+H+]: 403.1658; found: 403.1659.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C)C.O>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:26])([F:27])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(-c4ccccc4F)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h
Yield: 27.9 %

Procedure:
An 8 mL vial is charged with N-[5-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.044 g, 0.11 mol), (2-fluorophenyl)boronic acid (Combi-Blocks, 28 mg, 0.2 mmol), Na2CO3 (0.032 g, 0.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (7 mg, 0.01 mmol) and isopropanol-water (1 mL, 3:1). The reaction mixture is stirred at 80° C. for 16 hr, then cooled, concentrated, taken into EtOAc and CH2Cl2 (1:1), filtered, concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (25.4 mg, 55% yield). LCMS m/z=456.5 [M+H]+, tR=2.69 min. (compound same as Example 83)
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][C@@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCN2CCC[C@H](Cl)C2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Sixty-percent sodium hydride (470 mg, 12 mmols) was washed with petroleum ether, and then suspended in 50 ml of dimethyl sulfoxide. To the suspension were added 1.5 g (7.5 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 3.2 g (11 mmols) of (S)-(+)-3-chloro-1-(3,4-dimethoxyphenethyl)piperidine [[α]D25 =+20.3° (c=0.9, ethano l)] in 30 ml of dimethyl sulfoxide, and the mixed solution was stirred at 50° C. for 5 hours. The reaction solution was poured into ice wate r, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:3. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform and methanol at a ratio of 300:1. The mixed solvent was then distilled off under reduced pressure to give 2.8 g of (R)-(+)-5,11-dihydro-5-[1-(3,4-dimethoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 85%.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH3:41])[C:9]=2[C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:39][CH2:40][CH3:41])[C:9]=2[C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)cc4)c(C4CC4)c3)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(OCC)c(-c4ccc(F)cc4)c(C4CC4)c3)CC1)CC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 6-(1-((2-cyclopropyl-6-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (730 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with 6 M hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the mixture was concentrated. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol) to obtain the title compound (486 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1>O1CCCC1.C(OCC)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:14])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:18]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Brc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 27.6 %

Procedure:
Into a 1-L 3-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-bromo-4-iodobenzene (25.0 g, 88.4 mmol) in tetrahydrofuran/diethyl ether (400/200 mL). The solution was cooled to −78° C. then n-BuLi (2.5 M, 37.1 mL, 92.8 mmol) was added drop-wise over 10 min. To the resulting mixture was added tert-butyl 3-oxoazetidine-1-carboxylate (16.6 g, 97.0 mmol) in THF (100 mL) drop-wise at −78° C. The resulting mixture was stirred for 1.5 h at −78° C., then carefully quenched with water (300 mL). The aqueous phase was extracted with ethyl acetate (200 mL) and the combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:20-1:5) as the eluent followed by re-crystallized from ethyl acetate:PE in the ratio of 1:100 to yield 8.0 g (28%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:18]([O-:20])=[O:19])=[C:11]([CH:15]=[CH:16][CH:17]=1)[NH:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>ClCCl>[C:28]([N:12]([CH2:13][CH3:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[N+:18]([O-:20])=[O:19])(=[O:30])[CH3:29]
Reactant: CCNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(C)=O)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
To a solution of 3-benzyloxy-N-ethyl-2-nitroaniline (2.20 g) and triethylamine (1.23 g) in dichloromethane (21 ml) was added acetyl chloride (698 mg) under ice-cooling, and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was washed with water, saturated sodium bicarbonate solution, water and brine successively, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (dichloromethane-ethyl acetate) to give N-acetyl-3-benzyloxy-N-ethyl-2-nitroaniline (1.71 g).
Reaction SMILES: [C:1]([C@H:4]([N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CCOC(C)=O.O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([C@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:1]([NH2:2])=[O:3])[CH2:20][C:21](=[O:23])[NH:27][CH:24]2[CH2:26][CH2:25]2)(=[O:11])=[O:12])=[CH:14][CH:15]=1
Reactant: NC1CC1
Reactant: CC(C)C[C@H](C(N)=O)N(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](C(N)=O)N(CC(=O)NC1CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
To a solution of {N-[(1R)-1-carbamoyl-3-methyl-butyl]-N-(4-chlorobenzenesulfonyl)amino}acetic acid (Example 59, 175 mg, 0.480 mmol), cyclopropylamine (41 uL, 0.58 mmol)in CH2Cl2 (3 mL) was added 1-hydroxybenzotriazole (47 mg, 0.72 mmol), and 1,3-dicyclohexylcarbodiimide (144 mg, 0.720 mmol). The reaction was stirred for 18 h at rt, and then was poured into an EtOAc/water mixture. The organic layer was separated, dried over MgSO4, and concentrated to a clear oil residue. The residue was further purified by Biotage 40S (eluted in 40% EtOAc in hexanes) to afford a white solid (54 mg, 29%). MS(ESI), (M+H)+402.2; 1H NMR (CDCl3, 500 MHz) δ7.85 (dd, 2H, J=1.9, 8.9), 7.50 (dd, 2H, J=2.0, 8.7), 7.40 (br s, 1H), 6.55 (br s, 1H), 6.30 (br s, 1H), 4.23 (dd, 1H, J=2.9, 8.9), 3.92 (d, 1H, J=17), 3.83 (d, 1H, J=17), 2.68-2.73 (m, 1H), 1.75-1.83 (m, 1H), 1.50-1.57 (m, 1H), 1.40-1.49 (m, 1H), 0.88 (d, 3H, J=6.4), 0.87 (d, 3H, J=6.7), 0.80 (d, 2H, J=7.0), 0.51 (t, 2H, J=4.0).
Reaction SMILES: OC1C=C(C=C(O[C@@H](C)CO)C=1)C(OC)=O.[N:17]1([C:21]([C:23]2[CH:57]=[CH:56][C:26]([O:27][C:28]3[CH:29]=[C:30]([CH:41]=[C:42]([O:44][C@@H:45]([CH3:55])[CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:43]=3)[C:31]([NH:33][C:34]3[CH:39]=[N:38][C:37]([CH3:40])=[CH:36][N:35]=3)=[O:32])=[C:25](F)[CH:24]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1.[Cl:59]C1C=C(C=CC=1F)C(N1CCC1)=O>>[N:17]1([C:21]([C:23]2[CH:57]=[CH:56][C:26]([O:27][C:28]3[CH:29]=[C:30]([CH:41]=[C:42]([O:44][C@@H:45]([CH3:55])[CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:43]=3)[C:31]([NH:33][C:34]3[CH:39]=[N:38][C:37]([CH3:40])=[CH:36][N:35]=3)=[O:32])=[C:25]([Cl:59])[CH:24]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Agent: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1

Procedure:
3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide was prepared from methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate in an analogous fashion to 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide but replacing 1-(3,4-difluorobenzoyl)azetidine with 1-(3-chloro-4-fluorobenzoyl)azetidine.
Reaction SMILES: C(Cl)Cl.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].N([C@@:13]1(O)[C@@H:19](O)[C@H:18](O)[C@@H:17]([CH2:22]O)O[CH:14]1O)=[N+]=[N-]>C(Cl)(Cl)(Cl)Cl>[C:6]1([CH:13]2[CH2:19][CH2:18][CH2:17][CH:22]=[CH:14]2)[CH:5]=[CH:4][CH:9]=[CH:8][CH:7]=1
Reactant: CCCCCC
Reactant: [N-]=[N+]=N[C@]1(O)C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C1=CC(c2ccccc2)CCC1

Procedure:
TLC Rf=0.67 (10% CH2Cl2/hexane); IR (CCl4) 3088 (m),3063 (m),3025 (s), 2938 (s), 2863 (s), 2838 (s), 1656 (w), 1606 (m), 1543 (m); 1H NMR (CDCl3) δ0.85-2.09 (m, 6H), 3.38 (bs, 1H), 5.70 (dd, J=10.0, 2.1, 1H), 5.86-5.88 (m, 1H), 7.16-7.30 (m, 5H); 13C NMR (CDCl3) δ21.2, 22.7, 32.6, 41.8, 125.9, 127.7, 128.2, 128.3, 130.2, 146.6; LRMS (EI) 159 ((M+1), 15), 158 ((M+), 100), 143 (43), 129 (79); HRMS (EI) calculated for C12H14 158.1096 (M+), found 158.1098. The IR, 1H NMR and 13C NMR, and MS matched spectral data reported by Arnold, D. R. and Mines, S. A., Can. J. Chem. 67:689-698 (1989).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH:13](OCC)=[O:14]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:8]([CH:13]=[O:14])[C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#CCc1cccnc1Cl
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C=O)c1cccnc1Cl
Reaction time: 0.25 h

Procedure:
A solution of 2-(2-chloropyridin-3-yl)acetonitrile (2.0 g, 13 mmol) in THF (5 mL) was slowly added to a suspension of sodium hydride, 60% in mineral oil (1.31 g, 33.0 mmol) in THF (10 mL) at 0° C. The mixture was stirred for 15 minutes, and ethyl formate (1.1 mL, 13 mmol) was slowly added. The mixture was stirred at RT, and monitored by LCMS. Upon completion, the reaction was extracted into EtOAc, washed organics 2×H2O, dried with Mg2SO4, filtered through fritted funnel, and lyophilized to yield 2-(2-chloropyridin-3-yl)-3-oxopropanenitrile as reddish brown solid. The crude was used without further purification. MS m/z=181 [M+1]+. Calc'd for C8H5ClN2O: 180.59.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[OH-].[Na+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of dimethyl 5-bromoisophthalate (6.2 g, 22.7 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) was added dropwise NaOH (1.0 M in water; 20.4 mL, 20.4 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, the mixture was concentrated. Ethyl acetate was added and the mixture was extracted with water (2×). The combined aqueous layer was adjust to pH=3 using HCl (6.0 M in water). This mixture was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated (4.9 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Li+].CCC[CH2-].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:22](=[O:36])(=[O:35])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])=[CH:17][CH:16]=1.O>C1COCC1>[CH3:34][O:33][C:26]1[CH:27]=[C:28]([O:31][CH3:32])[CH:29]=[CH:30][C:25]=1[CH2:24][NH:23][S:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:13])=[CH:16][CH:17]=1)(=[O:36])=[O:35]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(CS(=O)(=O)NCc2ccc(OC)cc2OC)cc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(C(=O)N3CCOCC3)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of morpholine (0.69 ml) in THF (10 ml) was added, at −78° C., N-butyllithium (1.6 M, 3.3 ml), and the solution was stirred for 10 min. A solution of 4-[(2,4-dimethoxybenzylsulfamoyl)methyl]benzoic acid methyl ester (1 g) was added and the solution was warmed up to room temperature and stirred for a further 30 minutes. After the addition of water (100 ml), the mixture was extracted with ethyl acetate (2×50 ml). The organic phases were dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (450 mg) with a molecular weight of 434.5 g/mol (C21H26N2O6S).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][N:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Br[CH2:16][CH2:17]Br.Cl>C(OCC)C.CS(C)=O.O>[CH:7](=[N:6][C:5]1([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CN=Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(N=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
260 g (2.3 moles) of potassium tert.-butylate are added a little at a time to 200 g (1.05 moles) of N-benzylideneglycine ethyl ester and 90.5 ml (1.05 moles) of 1,2-dibromoethane in 900 ml of dry diethyl ether and 300 l of dry dimethylsulfoxide, so that the well-stirred mixture remains at from 25° to 35° C. The mixture is stirred at room temperature overnight and excess base is then neutralized by addition of 4N hydrochloric acid. The mixture is diluted with 1.5 l of water and the ethereal phase is separated off, washed with twice 300 ml of water, dried with sodium sulfate and evaporated to give 155 g (68%) of ethyl N-benzylidene-1-aminocyclopropanecarboxylate as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([CH3:19])[CH:4]=1)#[N:2].C(O)C.O.[H][H]>[Pd].C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([CH3:19])[CH:4]=1
Reactant: [H][H]
Reactant: Cc1cc(C#N)ccc1C(=O)NC1CCCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(CN)ccc1C(=O)NC1CCCCCC1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
Add 4-cyano-N-cycloheptyl-2-methyl-benzamide (0.82 g, 3.2 mmol), ethanol (23 mL), water (8 mL) and acetic acid (1 mL) to a pressure vessel. Heat vessel to 50° C. to dissolve all solids. Add 10% Pd/C (Degussa type E101, 250 mg) under a nitrogen atmosphere, then pressurize the vessel to 55 psi with hydrogen at ambient temperature. Stir the mixture for 40 min. Filter the mixture through Celite® and wash the cake with warm ethanol (50 mL) followed by dichloromethane (100 mL) under a nitrogen atmosphere. Concentrate the filtrate in vacuo to obtain the title compound as the acetic acid salt. Use SCX chromatography to obtain the title compound (820 mg, 98%). MS (ES+) m/z: 261.3 (M+H)+.
Reaction SMILES: C1CCCCC=1.[F:7][C:8]([F:29])([F:28])[CH2:9][CH2:10][CH2:11][CH:12]([NH:17]C(=O)OCC1C=CC=CC=1)[C:13]([OH:16])([CH3:15])[CH3:14].[ClH:30]>[Pd].C(O)C.C(OCC)C>[ClH:30].[NH2:17][CH:12]([CH2:11][CH2:10][CH2:9][C:8]([F:7])([F:28])[F:29])[C:13]([CH3:14])([OH:16])[CH3:15]
Reactant: CC(C)(O)C(CCCC(F)(F)F)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: C1=CCCCC1
Product: CC(C)(O)C(N)CCCC(F)(F)F

Procedure:
Under argon, 319 mg (0.30 mmol, 10% pure) of palladium on activated carbon and 9.1 ml (90.0 mmol) of cyclohexene were added to 1.0 g (3.0 mmol) of rac-benzyl (7,7,7-trifluoro-2-hydroxy-2-methylheptan-3-yl)carbamate Example 101A in ethanol (21 ml), and the reaction mixture was stirred at reflux overnight. The mixture was filtered through a Millipore® filter and the filter cake was washed with ethanol. 3 ml (6.0 mmol) of 2 N hydrochloric acid in diethyl ether were added to the filtrate and the mixture was concentrated and dried under high vacuum. This gave 785 mg (111% of theory) of the target compound. The product was used without further purification for the next reaction.