Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[N:22]=[CH:21]1
Reactant: Oc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1cccc(-c2c[nH]cn2)c1

Procedure:
A solution of 0.170 g of 3-(1-trityl-1H-imidazol-4-yl)phenol, 4.5 ml of methanol, 1.5 ml of chloroform and 1.5 ml of 2N HCl is stirred at 55° C. for 2 hours. After cooling, the reaction mixture is admixed with 35 ml of aqueous saturated sodium hydrogencarbonate solution and extracted twice with 75 ml of dichloromethane. The combined organic phases are washed with 35 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.14 (200:10:1 dichloromethane-methanol-conc. ammonia); Rt=2.08.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[C:7]([Cl:9])[C:6]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1cc(Cl)c(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2cc(Cl)c(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 50.6 %

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-4-chloro-1H-pyrazol-3-yl)-2-chlorobenzonitrile (518 mg, 1.75 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (270 mg, 1.75 mmol), HOBt (285 mg, 2.1 mmol), DIPEA (0.367 mL, 2.1 mmol) and EDCI (404 mg, 2.1 mmol) using DCM as solvent using the method of Example 34(d) to afford 382 mg of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 1.15 (d, 3H), 2.42 (s, 3H), 4.30 (m, 2H), 4.44 (m, 1H), 6.86 (s, 1H), 8.01 (m, 3H), 8.12 (s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:14])[CH3:13].[C:23](Cl)(=[O:25])[CH3:24]>O>[C:12]([C:16]1[CH:21]=[C:20]([C:23](=[O:25])[CH3:24])[CH:19]=[CH:18][C:17]=1[OH:22])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
Aluminium chloride (44.4 g, 333 mmol) was cooled to −45° C., followed by addition of toluene (1.25 L). 2-tert-butylphenol (50.0 g, 333 mmol) was added further and stirred for 2 hours. Further, acetyl chloride (26.1 g, 333 mmol) was added dropwise and stirred for 2.5 hours. The resultant reaction solution was added to ice-cooled water (250 mL) dropwise and stirred at room temperature. Crystals were collected by filtration and dried under reduced pressure (50° C.) to give 48.7 g of the captioned compound as white crystals (yield: 76.1%; HPLC purity: 99.8%).
Reaction SMILES: C(Cl)([Cl:3])=O.C(=O)([O-])[O-].[K+].[K+].[C:11]1([CH:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)N2CC(OC3C=CC(Cl)=C(Cl)C=3)C2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[C:11]1([CH:17]([Cl:3])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: ClC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 14 g (0.144 mole) of phosgene weighed into 200 mL of methylene chloride was treated with 19.9 g (0.144 mole) of anhydrous potassium carbonate and stirred for 1 h then 45.9 g (0.12 mole) of 1-(diphenylmethyl)-3-(3,4-dichlorophenoxy)azetidine in 100 mL of methylene chloride was added dropwise and stirring was continued for 72 h. The reaction mixture was filtered to remove the inorganic salts and then concentrated in vacuo to a pale yellow oil (67 g). Trituration of the residue with cyclohexane yielded a crude pale yellow solid (23.6 g). The filtrate was treated with ligroin and upon standing an additional 13.3 g of tacky material was obtained (contaminated with diphenylmethyl chloride). After several recrystallizations from cyclohexane to remove traces of diphenylmethyl chloride a portion was obtained as fine white crystals, mp 96°-99° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.N1CCCCC1.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd]Cl.[Cu]I>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([C:36]#[C:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:3][N:4]=1
Reactant: C#Cc1ccccc1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C#Cc3ccccc3)c2c1
Reaction time: 20 h
Yield: 65 %

Procedure:
A solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.52 g, 1.5 mmoles), prepared as described in example 45, in dry DMF (10 ml) under N2 was added with piperidine (1 ml, 10 mmoles), phenylacetylene (0.15 g, 1.5 mmoles), PdCl2 (0.013 g, 0.075 mmole), triphenylphosphine (0.039 g, 0.15 mmole) and CuI (0.014 g, 0.075 mmole). The mixture was stirred for 20 hours, poured into saturated NHCl (10 volumes) and extracted twice with CH2Cl2, then washed with 5% HCl, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: CH2Cl2/ethyl ether 9:1). The resultant solid was triturated in ethyl ether to give 0.41 g of the title compound (yield: 52%). m.p.: 213.4-214.4° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])N=1.[CH3:12]C(=O)OCC>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:12]=[C:4]([Cl:11])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (100 g, 0.518 mol) in acetic acid (1 L) was added iron powder (86.49 g, 1.555 mol) portion wise. The resulting reaction mixture was stirred at room temperature for 6 h. The completion of the reaction was confirmed by checking TLC system (PE/EA=8:2). The reaction mass was concentrated under high vacuum. The crude was dissolved in water (1 L) and EtOAc (2 L). While stirring, the pH of the aqueous solution was adjusted to 6.5 using powder Na2CO3. The mixture was filtered through CELITE® and the organic layer was separated, dried and concentrated to give 2,4-dichloroaniline (80 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.14-7.2 (2H, m); 5.78 (2H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:16][C:17]1[C:22](/[CH:23]=[CH:24]/[N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH3:16][C:17]1[C:22]([CH:23]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[CH:5]=3)[NH:1][CH:2]=2)[CH2:24][N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1cc2cc(N3CCOCC3)ccc2[nH]1
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2ccc(N3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.4 %

Procedure:
4-(1H-Indol-5-yl)morpholine (1.102 g, 5.45 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (1.2154 g, 3.89 mmol) were dissolved in THF and concentrated in vacuo to dryness. The mixture was then melted at 140° C. After 5 h, the reaction was cooled to room temperature and purified by flash chromatography using an ISCO 120 g column eluting with 0-60% EtOAc/hexanes to give the desired product (0.8047 g, 1.454 mmol, 37.4% yield) as a tan foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[N:10]=[CH:11][N:12]=[C:4]2[CH:3]=1.[OH-:13].[K+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([OH:13])[N:5]2[N:10]=[CH:11][N:12]=[C:4]2[CH:3]=1
Reactant: [OH-]
Reactant: CSc1nc(Cl)cc2ncnn12
Agent: [K+]
Solvent: CO
Product: Oc1nc(Cl)cc2ncnn12

Procedure:
A solution of 2.58 g (12.9 mmol) of 7-chloro-5-(methylthio)[1,2,4]triazolo[1,5-c]pyrimidine (Example 51A) is dissolved in 300 ml of methanol, and 28 ml of a 2 molar aqueous potassium hydroxide solution are added. The mixture is heated under reflux for 3 h. After the reaction is complete, the methanol is removed in vacuo, the mixture is neutralized with half-concentrated hydrochloric acid, and the crystals which have separated out are filtered off with suction. They are washed with water and methanol and then dried under high vacuum. 1.82 g (83% of theory) of the product are obtained.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH2:11]CS([O-])(=O)=O)[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.[Na+].[I-].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.CCOC(C)=O>[N:19]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[CH2:4][O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)=[N+:20]=[N-:21]
Reactant: O=S(=O)([O-])CCc1ccc2c(c1)B(O)OC2
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2c(c1)B(O)OC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 131 %

Procedure:
To the solution of (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methylmethanesulfonate (CIX) (0.48 g, 1.98 mmol) in DMF (20 mL) was added NaI (0.06 g, 0.40 mmol) and NaN3 (0.15 g, 2.38 mmol). The mixture was stirred at 60° C. overnight. The reaction mixture was diluted with EtOAc, washed with 10% aqueous Na2S2O3, brine, dried over anhydrous MgSO4, and concentrated under vacuum to give 6-(azidomethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CX) (0.49 g, impure). The crude product was used without further purification for step 7.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[C:5]([F:17])[CH:4]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:17][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[C:9]1[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1)[CH2:2][NH:1][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][N:18]=2)=[CH:32][CH:31]=1
Reactant: Cn1cc(-c2ccc(CN)cc2F)ccc1=O
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
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
Product: Cn1cc(-c2ccc(CNC(=O)c3ccc(-c4cnccn4)cc3)cc2F)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the 5-(4-(aminomethyl)-2-fluorophenyl)-1-methylpyridin-2(1H)-one 21-7 (obtained in Step 4), 4-(pyrazin-2-yl)benzoic acid 18-3 (5.0 mg, 0.025 mmol), and HATU (9.5 mg, 0.025 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to give N-(3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-4-(pyrazin-2-yl)benzamide 21 (2.5 mg). MS m/z 415.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:29]([C:14]1[C:15](=[O:28])[N:16]([CH2:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[C:17]2[C:12]([C:13]=1[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:30])[CH3:36]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCOCC2)c1=O
Reactant: CCOCCN
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(4-morpholinyl)-2-oxoethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.14 (1H, m), 8.55 (1H, s), 7.15 (2H, dd, J=8.5, 5.5 Hz), 7.04 (3H, m), 4.94 (2H, s), 4.11 (2H, s), 3.73-3.52 (14H, m), 1.22 (3H, t, J=7 Hz); HRMS calcd for C26H29FN4O6+H+: 513.2149. Found: 513.2134.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH:10]1([NH:15][C:16]2[C:25]3[C:20](=[CH:21][N:22]=[C:23](F)[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:27]#[N:28])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][N:22]=2)[N:19]=[CH:18][C:17]([C:27]#[N:28])=[C:16]3[NH:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cnc2cnc(Nc3ccc(F)c(Cl)c3)cc2c1NC1CCCC1
Temperature: 200 °C
Yield: 39.3 %

Procedure:
A mixture of 3-chloro-4-fluorobenzenamine (550 mg, 3.78 mmol, 38 eq), 4-(cyclopentylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile (28 mg, 0.1 mmol, 1 eq), and cesium carbonate (506 mg, 1.55 mmol, 15.5 eq) in DMF (4 mL) was heated to 200° C. in a microwave tube for 1 hr using microwave reactor. Preparative HPLC purification yielded 15 mg product (36% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 1.52-1.68 (m, 2 H) 1.70-1.91 (m, 4 H) 1.99-2.16 (m, 2 H) 4.58-4.76 (m, 1 H) 7.33 (t, J=9.09 Hz, 1 H) 7.45-7.56 (m, 1 H) 7.76 (s, 1 H) 7.80 (d, J=7.07 Hz, 1 H) 7.87-7.97 (m, 1 H) 8.32 (s, 1 H) 8.90 (s, 1 H) 9.64 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH3:37])[CH2:3][C@@H:4]([NH:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:37])[CH2:3][C@@H:4]([NH:21][C:22]1[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][N:23]=1)[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCNC(=O)c1ccc(N[C@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@@H](Nc1ccc(C(=O)NCCC(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 504.4 %

Procedure:
A round bottom flask was charged with (R)-methyl 3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido)propanoate (6.26 g, 10.2 mmol), tetrahydrofuran (60 mL) and methanol (60 mL). 1.0N NaOH (18.3 mL, 18.3 mmol) was added and the resulting solution was stirred at room temperature for 15 min. The organic solvents were removed under reduced pressure and the resulting crude was diluted with water. 10% Citric acid was added to acidify the solution to pH˜3. A white precipitate formed. After stirring for 30 minutes at room temperature, the solid was filtered off and dried under vacuum. Purification by column chromatography (0-10% methanol/dichloromethane) provided (R)-3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinamido)propanoic acid (25.7 g, 76.4%) as a white solid. 1H NMR (400 MHz, (CD3)2SO, δ): 0.91 (d, J=6.44 Hz, 3 H) 0.95 (d, J=6.44 Hz, 3 H) 1.48-1.59 (m, 1 H) 1.61-1.71 (m, 1 H) 1.72-1.82 (m, 1 H) 2.44 (t, J=7.12 Hz, 2 H) 3.34-3.42 (m, 2 H) 5.10 (br. s., 1 H) 6.52 (d, J=8.78 Hz, 1 H) 7.46-7.51 (m, 2 H) 7.57 (d, J=8.19 Hz, 1 H) 7.63-7.69 (m, 2 H) 7.74 (dd, J=8.88, 2.44 Hz, 1 H) 7.76-7.81 (m, 2 H) 7.83-7.89 (m, 2 H) 8.15 (t, J=5.46 Hz, 1 H) 8.40 (d, J=2.34 Hz, 1 H) 12.18 (br. s., 1 H). MS (M+1): 500.4.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:28])[CH2:26][CH3:27])=[CH:21][C:20]=3[CH2:29][CH2:30][CH3:31])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[CH2:33]([Mg]Br)[CH3:34]>>[CH2:26]([C:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17]2[C:16]([CH3:32])=[CH:15][CH:14]=[C:13]([CH2:12][CH2:11][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][OH:10])=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH:18]=2)=[C:20]([CH2:29][CH2:30][CH3:31])[CH:21]=1)([OH:28])[CH2:33][CH3:34])[CH3:27]
Reactant: CC[Mg]Br
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(CCc2ccc(CO)c(CO)c2)ccc1C
Product: CCCc1cc(C(O)(CC)CC)ccc1-c1cc(CCc2ccc(CO)c(CO)c2)ccc1C

Procedure:
In a manner similar to that of Example 1(q), by reacting 300 mg (0.7 mmol) of 1-{5′-[2-(3,4-bis(hydroxymethyl)phenyl)ethyl]-2′-methyl-2-propylbiphenyl-4-yl}propan-1-one with 1.9 ml (5.6 mmol) of ethylmagnesium bromide (3M/ether), and after purification on a column of silica eluted with a mixture of heptane and ethyl acetate (40/60), 180 mg (56%) of (4-{2-[4′-(1-ethyl-1-hydroxypropyl)-6-methyl-2′-propylbiphenyl-3-yl]ethyl}-2-hydroxy-methylphenyl)methanol are obtained in the form of white crystals with a melting point of 76° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13]C(O)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C([N:23](CC)C(C)C)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13][N:23]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(CC(=O)O)CC(=O)c1ccc2c(c1)OCO2
Reactant: CCN(C(C)C)C(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(C)CN=C(c2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.2 %

Procedure:
To a solution of 5-(1,3-benzodioxol-5-yl)-3,3-dimethyl-5-oxopentanoic acid (444 mg, 1.68 mmol) and N,N-diisopropylethylamine (0.292 mL, 1.68 mmol) in chloroform, add diphenylphosphorylazide (0.364 mL, 1.68 mmol). Stir at room temperature for 2 days, then treat with 2N NaOH. After 1 h, dilute the reaction with chloroform and water, then separate the organic layer and dry with magnesium sulfate, filter, and concentrate under reduced pressure to obtain 132 mg (36%) of the title compound. MS: 218 [M+H]+; 1H NMR (300 MHz, CDCl3): δ 7.40 (s, 1H), 7.20-7.24 (m, 1H), 6.78-6.81 (m, 1H), 6.00 (s, 2H), 3.75-3.74 (m, 2H), 2.72-2.71 (m, 2H) and 1.16 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C@@:22]([OH:49])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[C@H:23]([S:25][C@@H:26]1[CH2:31][O:30][C@@H:29]([C:32]2[CH:41]=[CH:40][C:35]([C:36](OC)=[O:37])=[CH:34][C:33]=2[F:42])[O:28][CH2:27]1)[CH3:24]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:40]=[CH:41][C:32]([C@H:29]3[O:30][CH2:31][C@H:26]([S:25][C@H:23]([CH3:24])[C@:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[F:14])([OH:49])[CH2:43][N:44]4[CH:48]=[N:47][CH:46]=[N:45]4)[CH2:27][O:28]3)=[C:33]([F:42])[CH:34]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)c(F)c1
Reactant: N#Cc1ccc(N)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)cc3)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4) a reaction was carried out using commercially available 4-aminobenzonitrile (98 mg, 0.83,mmol), trimethylaluminium (0.78 ml, 1.07M n-hexane solution, 0.83 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-3-fluorobenzoate (109 mg, 0.21 mmol) obtained in Example 5(2) and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to give the title compound (95 mg, yield 75%) as a colorless oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH3:21])[CH:12]=1)=O)(C)(C)C.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][C@@H:9]([C:22]([O:24][CH3:25])=[O:23])[NH2:8])=[CH:12]1)[CH3:21]
Reactant: CCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCn1cc(C[C@H](N)C(=O)OC)c2ccccc21
Reaction time: 17 h
Yield: 74 %

Procedure:
To methylene chloride (175 mL) solution of the compound obtained in Example 140 (4.8 g) was added dropwise 4 mol/L of hydrogen chloride-dioxane solution (17.5 mL) at room temperature, and the mixture was allowed to stir for 17 hours. The crystals precipitated were filtered, and washed with diethyl ether, to give the captioned compound (2.9 g, 74%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=O)=O.[I-:22].[Na+].O>CC(C)=O>[I:22][CH2:6][CH2:7][CH2:8][C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCI
Yield: 86.8 %

Procedure:
1-Methanesulfonyloxy-4,4,5,5,6,6,7,7,7-nonafluoro-heptane (6.7 g, 18.8 mmol) and sodium iodide (8.5 g, 56.4 mmol) were stirred in acetone (400 ml) for 12 hours under heating. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ether. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-4,4,5,5,6,6,7,7,7-nonafluoroheptane (6.33 g, Yield 87%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1>>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1)=[O:6]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: COc1cccc(C(=O)NCCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c1N
Yield: 82 %

Procedure:
Starting from 2-amino-3-methoxybenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (179 mg; 82% yield).