Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:18]=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:13].CN(C=O)C>O>[Br:1][C:18]1[CH:19]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:15]([O:14][CH2:12][CH3:13])=[CH:16][C:17]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: CCOc1cc(-c2ccccc2F)ccc1C(=O)OC
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccccc2F)c(Br)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 178.9 %

Procedure:
Dibromoisocyanuric acid (0.631 g) was added to a mixture of methyl 3-ethoxy-2′-fluorobiphenyl-4-carboxylate (1.14 g) and DMF (10 mL), and the resultant mixture was stirred at room temperature for 2 hours. Dibromoisocyanuric acid (0.238 g) was further added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.39 g).
Reaction SMILES: C(OC(OCC)OCC)C.[C:11](O)(=O)C.Cl.[CH2:16]([O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][NH2:23])[CH3:17].[N-:25]=[N+:26]=[N-:27].[Na+]>C(OCC)(=O)C>[CH2:16]([O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][N:23]1[CH:11]=[N:27][N:26]=[N:25]1)[CH3:17]
Reactant: CCOC(=O)CCCN
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)CCCn1cnnn1

Procedure:
4 ml of orthoformic acid triethyl ester and 6 ml of acetic acid are added to 0.84 g of 4-aminobutyric acid ethyl ester hydrochloride and 0.9 g of sodium azide and the whole is heated under reflux for 7 hours. After cooling, the reaction mixture is taken up in ethyl acetate and aqueous sodium bicarbonate solution, the organic phases are separated off and washed four times with aqueous sodium bicarbonate solution. After washing with water and brine, the ethyl acetate phase is dried over sodium sulphate and concentrated to form the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14](O)[CH3:15])=[C:9]([O:17][CH2:18][CH3:19])[C:8]=1[C:20]1[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[N:24][CH:25]=1)#[N:6]>C(Cl)Cl.CN(C)C=O>[Cl:3][CH:14]([C:10]1[C:9]([O:17][CH2:18][CH3:19])=[C:8]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[N:24][CH:25]=2)[C:7]([C:5]#[N:6])=[C:12]([CH3:13])[CH:11]=1)[CH3:15]
Reactant: CCOc1c(C(C)O)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 3 h
Yield: 91 %

Procedure:
Thionyl chloride (900 μL, 10 mmol) was added dropwise to a solution of 5-[2-cyano-6-ethoxy-5-(1-hydroxyethyl)-3-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (2.3 g, 6.5 mmol) in methylene chloride (100 mL) and N,N-dimethylformamide (100 μL) at room temperature. The reaction was stirred for 3 hrs, was diluted with methylene chloride (100 mL) and washed with water saturated NaHCO3. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude 5-[3-(1-chloroethyl)-6-cyano-2-ethoxy-5-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (2.2 g, 91%). LCMS calculated for C20H23ClN3O2(M+H)+: m/z=372.1; found: 372.2.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:49])=[C:11]([CH:17]([C:19]2[N:23]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]3[CH:43]=[C:44]([CH3:48])[C:45]([CH3:47])=[CH:46][C:21]=3[N:20]=2)[OH:18])[CH:12]=[C:13]([CH2:15][CH3:16])[CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:47][C:45]1[C:44]([CH3:48])=[CH:43][C:22]2[N:23]([C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]([CH:17]([OH:18])[C:11]3[C:10]([F:49])=[C:9]([OH:8])[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=3)=[N:20][C:21]=2[CH:46]=1
Reactant: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(O)c(F)c(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.7 %

Procedure:
To a solution of Intermediate 415.2 (115 mg, 0.171 mmol) in 2 mL THF at rt, was added TBAF (1 M in THF, 171 μL, 0.171 mmol). The mixture was stirred at rt for 20 min, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 80% EtOAc/hexanes gradient) to afford 34 mg of 3-((5,6-dimethyl-1-trityl-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-ethyl-2-fluorophenol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([O:28]C(=O)C)[CH:26]=2)[N:21]=[CH:20][N:19]=1.CC(O)(C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([OH:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.9 g, 16.62 mmol) and acetic acid 4-chloro-7-methoxy-quinazolin-6-yl ester (4.62 g, 18.28 mmol) were dissolved in a 1:1 mixture of DCE:t-BuOH (50 mL). The reaction mixture was refluxed for 19 hours and then cooled to room temp. Solvent was removed via rotovap. The crude residue was then suspended in MeOH (80 mL) and NH4OH (8 mL, 30% in water) was added to the mixture. Stir for 15 hours at room temp. The reaction was heated to 100° C. and stirred for 1 hour. Cool to 0° C. and product was isolated by filtration and washed with cold MeOH to give 5 g (12.2 mmol, 67% over two steps) of desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)(=[O:7])=[O:6].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]3[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=3)[CH2:28][CH2:27]2)=[CH:20][CH:19]=1.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.COCCOC>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=4)[CH2:28][CH2:27]3)=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Reactant: O=S(=O)(NCCO)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCO)cc4)cc3)CC2)n1
Yield: 2 %

Procedure:
The title compound (4 mg, 2%) was prepared as a white solid from (4-{[(2-hydroxyethyl)amino]sulfonyl}phenyl)boronic acid (98 mg, 0.4 mmol), 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (prepared as in Example 24, Step 1, 152 mg, 0.4 mmol), Pd(PPh3)2Cl2 (100 mg, 0.14 mmol), 2M Na2CO3 (2 mL) and DME (2 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, 2H, J=8.6 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.8 Hz), 4.84 (t, 1H, J=6.1 Hz), 4.26-4.16 (m, 2H), 3.89 (d, 2H, J=6.2 Hz), 3.76-3.70 (m, 2H), 3.20-3.07 (m, 4H), 2.98-2.85 (m, 1H), 2.38-2.18 (m, 1H), 2.10-2.04 (m, 1H), 2.03-1.93 (m, 2H), 1.57-1.40 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 501 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:15])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[N:6][NH:5][C:4](=[O:15])[CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2n[nH]c(=O)cc2Br)cc1
Reactant: OB(O)c1cccc(Cl)c1
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
Product: Cc1ccc(-c2n[nH]c(=O)cc2-c2cccc(Cl)c2)cc1
Temperature: 130 °C
Yield: 57.1 %

Procedure:
In a 10 mL heavy-walled sealed tube, a mixture of 5-bromo-6-p-tolylpyridazin-3(2H)-one (0.05 g, 0.189 mmol), 3-chlorophenylboronic acid (0.029 g, 0.189 mmol), Pd(Ph3P)4 (10.90 mg, 9.43 μmol) and K2CO3 (0.283 mL, 0.566 mmol) in dioxane (2 mL) was heated under microwave irradiation at 130° C. for 2 h. The reaction was purified by preparative HPLC to give the title compound (0.032 g). LCMS m/z=297.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][NH2:8].[F:9][CH:10]([F:19])[C:11]([O:13][C:14](=[O:18])[CH:15]([F:17])[F:16])=[O:12]>>[F:9][CH:10]([F:19])[C:11]([OH:13])=[O:12].[F:17][CH:15]([F:16])[C:14]([NH:8][NH:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:18]
Reactant: NNc1cnccn1
Reactant: O=C(OC(=O)C(F)F)C(F)F
Product: O=C(NNc1cnccn1)C(F)F
Product: O=C(O)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
Pyrazin-2-yl-hydrazine 23a (1 g, 9 mmol) was added in an eggplant-shaped bottle (25 mL), followed by dropwise addition of difluoroacetic anhydride (4 g, 22.98 mmol) at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure to obtain crude 2,2-difluoro-N′-pyrazin-2-yl-acetohydrazide difluoroacetate 23b (2 g) as a brown oil. The product was used directly in the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].CO[C:20]1[CH:25]=[C:24](O)[C:23]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])=[CH:22][C:21]=1S(O)(=O)=O.[C:39](Cl)(Cl)=[O:40]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:39](=[O:40])[C:20]2[CH:21]=[CH:22][C:23]([C:27](=[O:28])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:24][CH:25]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(O)c(C(=O)c2ccccc2)cc1S(=O)(=O)O
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc(C(=O)c3ccccc3)cc2)cc1OC
Reaction time: 8 h
Yield: 145.8 %

Procedure:
4.0 g of (−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)-benzene (compound B4) are dissolved in 40 ml of methylene chloride and 10.0 ml of triethylamine. A solution of 4.9 g of benzophenone-4-carbonyl chloride in 100 ml of methylene chloride is added dropwise at RT and the mixture is extracted, after stirring overnight, with 50 ml each of water, 2N hydrochloric acid, satd sodium hydrogencarbonate solution and water again. The organic phase is dried using sodium sulfate and concentrated. 7.78 g of the title compound are obtained as a crystallizing oil. M.p. 119-122.5° C.
Reaction SMILES: [CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[I-:18].[Na+]>CC(C)=O>[CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][I:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [I-]
Reactant: CCCCCCCCC(CCl)CCCCCC
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCC(CI)CCCCCC
Temperature: 60 °C
Yield: 84.8 %

Procedure:
To a reaction vessel, 2.682 g (10.3 mmol) of 2-hexyl-1-chlorodecane, 7.483 g (49.9 mmol, 4.8 eq) of sodium iodide, and 100 mL of acetone were added. The whole was refluxed at 60° C. overnight. The reaction mixture was allowed to reach room temperature, and acetone was removed by evaporation. The residue was extracted with ethyl acetate, and then the organic phase was washed with a saturated brine three times. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated, and the concentrate was dried under vacuum to give 3.075 g (8.73 mmol) of 2-hexyl-1-iododecane as a dark red liquid (crude yield: 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:19](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:19])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)[C@H]1C[C@H](C)CN1C(=O)OC(C)(C)C

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514-522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1)=[O:11].[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:21]([O:25][C:26](=[O:27])[NH:28][C@@H:29]([CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C:30]([N:13]1[CH2:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:12]1[C:10](=[O:11])[NH:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:31])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(Nc1c(F)cccc1F)[C@H]1NCc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of (S)-2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide (160 mg, 412 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonylamino)-2-cyclohexylacetic acid (106 mg, 412 μmol, Eq: 1.00) and HATU (172 mg, 453 μmol, Eq: 1.1) in DMF (500 μL) at 0° C. was added DIEA (160 mg, 216 μL, 1.24 mmol, Eq: 3). The reaction was stirred at RT for 1 h, diluted with water and extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give {(S)-1-cyclohexyl-2-[(S)-1-(2,6-difluoro-phenyl-carbamoyl)-1,3-dihydro-isoindol-2-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (174 mg) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]3[CH2:25][C@H:24]3[N:26]([CH2:34][CH:35]3[CH2:37][CH2:36]3)C(=O)OC(C)(C)C)=[CH:19][CH:18]=2)=[O:15])=[CH:10][CH:9]=1.Cl.COC1CCCC1>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C@@H:23]3[CH2:25][C@H:24]3[NH:26][CH2:34][CH:35]3[CH2:37][CH2:36]3)=[CH:21][CH:22]=2)=[O:15])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(-c3ccccc3Cl)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: COC1CCCC1
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCC2CC2)cc1)c1ccc(-c2ccccc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 128.9 %

Procedure:
tert-Butyl [trans-2-(4-{[(2′-chlorobiphenyl-4-yl)carbonyl]amino}phenyl)cyclopropyl](cyclopropylmethyl)-carbamate (115 mg) was dissolved in THF (0.5 mL), and the mixture was ice-cooled to 0° C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (5 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (65.0 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6].[CH3:20]I>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH3:20])[C:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:10]([CH3:12])[CH:11]=1)=[O:6]
Reactant: CI
Reactant: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.9 %

Procedure:
To a stirred solution of sodium hydride (60% suspension in mineral oil) (0.529 g, 13.22 mmol) in DMF (5 ml) at 0° C. was added a solution of methyl-5-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (prepared according to the procedure reported in J. org. Chem., 2009, 74(2), 903-905, Org. Lett. 2007, 9(25), 5191-5194, 2.20 g, 8.81 mmol) in DMF (10 ml), which was then followed by the addition of methyl iodide (1.88 g, 0.83 ml, 13.22 mmol). The resulting reaction mixture was stirred at room temperature for 45 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was then quenched with water (10 ml). The mixture so obtained was then extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 15-20% ethyl acetate in hexanes as an eluent to obtain the title compound (1.9 g, 81.9%)
Reaction SMILES: [C:1]([O:6][OH:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])=[O:10].C([O:24]O)(C)(C)C.ClC(OC1C=CC=CC=1)=O>>[C:9](=[O:24])([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])[O:10][O:7][O:6][C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: Cc1ccc(OC(=O)Cl)c(C)c1
Reactant: CCC(C)(C)OO
Agent: O=C(Cl)Oc1ccccc1
Product: CCC(C)(C)OOOC(=O)Oc1ccc(C)cc1C
Yield: 65 %

Procedure:
A reaction was carried out in the same manner as described in Example 1, except that t-amyl hydroperoxide and 2,4-dimethylphenyl chloroformate were used in place of t-butyl hydroperoxide and phenyl chloroformate used in Example 1, to obtain 35.7 g (yield: 65%) of a compound having a GLC purity of 92%, which was a colorless liquid at room temperature.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9](=O)[NH:8][C:7]=1[CH:16]([CH3:18])[CH3:17])=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:16]([CH3:18])[CH3:17])=[N:8][C:9]([Cl:21])=[CH:10][C:11]=1[CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C(C)C)cc(=O)[nH]c1C(C)C
Product: CCOC(=O)c1c(C(C)C)cc(Cl)nc1C(C)C
Yield: 85 %

Procedure:
A solution of 2.2 g (8.76 mmol) 2,4-diisopropyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester in POCl3 (43.8 ml) was stirred at 120° C. for 2 h. Then excess POCl3 was evaporated. The residue was dissolved in EtOAc (60 ml) and the solution was washed with a sat. NaHCO3 sol, water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification of this residue by CC (hexane/EtOAc 97:3) provided 2.0 g (7.43 mmol, 85%) 6-chloro-2,4-diisopropyl-pyridine-3-carboxylic acid ethylester.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:20](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>ClCCl.CN(C=O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH2:14][C:18]#[N:20])[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CO)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanol (10.52 g, 41.67 mmol) in dichloromethane (80 ml) at 0° C. (ice bath), was added triethylamine (8.78 ml, 62.5 mmol) followed by methanesulfonyl chloride (3.87 ml, 50 mmol). After stirring for 2 hr, the reaction mixture was washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow oil. The crude product was then dissolved in anhydrous DMF (80 ml) and sodium cyanide (6.28 g, 128 mmol) was added into the mixture. The mixture was stirred in an oil bath (60° C.) for 2 hr. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 1:20 to 1:10)) to afford 8.2 g (75%) of a pale yellow oil. 1H NMR (200 MHz, CDCl3) δ 0.11 (6H, s), 0.95 (9H, s), 3.75 (2H, s), 4.75 (2H, s), 7.27-7.35 (4H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:34][N:33]=[C:32]([CH3:35])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]2[NH:19][C:20](=[O:36])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[O:34][N:33]=[C:32]([CH3:35])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M47) (0.23 g, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (157 mg, 88%).