Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC2[O:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[CH:14]=4)=[CH:9][C:8]=3C=2C=1.C([Li])CCC.[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C.Cl.[CH3:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>ClCCl.C1COCC1>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]2[O:6][C:47]3[CH:48]=[CH:49][C:44]([B:30]([OH:35])[OH:31])=[CH:45][C:46]=3[C:8]=2[CH:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2oc3ccc(-c4ccc5ccccc5c4)cc3c2c1
Reactant: CCCCCC
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: OB(O)c1ccc2oc3ccc(-c4ccc5ccccc5c4)cc3c2c1
Temperature: -60 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
In argon atmosphere, a liquid mixture of 7.47 g (20.0 mmol) of 2-bromo-8-(naphthalene-2-yl)dibenzofuran and 75 ml of dry THF was cooled to −60° C. and 15.5 ml (24.0 mmol) of a 1.55 M hexane solution of n-butyllithium was added dropwise under stirring. Further, the reaction mixture was stirred at −70° C. for 2 h. The reaction solution was cooled again to −70° C., and 11.29 g (60.0 mol) of triisopropyl borate was added dropwise. The reaction mixture was heated up to room temperature, stirred for one hour, and left standing overnight. The reaction mixture was cooled on an ice bath, added with a 6 N hydrochloric acid, and stirred at room temperature for one hour. After adding dichloromethane, the reaction mixture was allowed to separate into liquid phases, and the organic phase was washed with water and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography to obtain 3.65 g (yield: 54%) of 8-(naphthalene-2-yl)dibenzofuran-2-ylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:28](=[O:30])[CH3:29])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: CC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 36 mg, 100 μmol) and acetic anhydride (30 mg, 300 μmol). Yield 37 mg (92%).
Reaction SMILES: [O:1]=[C:2]([C:9]([F:12])([F:11])[F:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13]I.[Cl-].[NH4+].O>C(COC)OC.[Cl-].[Na+].O>[O:1]=[C:2]([C:9]([F:10])([F:11])[F:12])[CH:3]([CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CI
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (7.05 g of a 50% oil dispersion, 0.15 mol) was washed 3 times with 25 ml of dimethoxyethane to remove the oil and then suspended in 220 ml of dimethoxyethane, under an argon atmosphere and cooled in an ice bath. A solution of ethyl 3-keto-4,4,4-trifluorobutanoate (25.77 g, 0.14 mol) in 25 ml of dimethoxyethane was added dropwise from an addition funnel to the stirred suspension. After the addition was completed, the cooling bath was removed and the reaction mixture stirred for 30 minutes past the cessation of hydrogen gas evolution. Methyl iodide (43.0 ml, 0.70 mole) was added by syringe and the reaction mixture refluxed overnight. The reaction was cooled to room temperature and poured into a separatory funnel containing a 1:1:1 mixture of saturated ammonium chloride:brine:water. The layers were separated and the aqueous phase extracted with 100 ml ether. The combined organic phase and ether extract was washed with brine, dried over magnesium sulfate and filtered. The solvents were removed by distillation at atmospheric pressure using a Vigreaux column leaving ethyl 3-keto-2-methyl-4,4,4-trifluorobutanoate as the pot residue. Rf: (EtAc/hexane--20:80)
Reaction SMILES: C1O[C:8]2[CH:7]=[CH:6][C:5]([Br:10])=[CH:4][C:3]=2O1.[N+:11]([O-:14])(O)=[O:12].[C:15]([OH:18])(=[O:17])C>>[CH2:15]1[O:18][C:3]2[CH:8]=[CH:7][C:6]([N+:11]([O-:14])=[O:12])=[C:5]([Br:10])[C:4]=2[O:17]1
Reactant: CC(=O)O
Reactant: Brc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2c(c1Br)OCO2
Temperature: 10 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
3,4-Methylenedioxy-bromobenzene (5 g, 23 mmol) was slowly added to a stirred solution of 35ml concentrated nitric acid and 105 ml glacial acetic acid maintained at 10° C. The reaction mixture was stirred at 15° C. for 1 h and then diluted with 200 ml ice cold water. The resulting mixture was extracted twice with 200 ml portions of ether. The combined organic phase was dried and evaporated in vacuo to give the crude product. The crude product was recrystallized from ethanol to give bright yellow needle shaped crystals of the nitro compound in 90% yield; mp 87-89° C.; IR(KBr) 1528, 1333; 1H NMR (CDCl3) δ6.14(2H,s), 7.12(1H, s), 7.45(1H, s); 13C NMR(CDCl3) δ104.0, 107.0, 109.0,114.3, 146.2, 148.0, 152.1; HRMS calcd for C3H4BrNO4: 244.9323; found: 244.9324.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][S:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([CH2:24][NH2:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.CCOC(C)=O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([NH:25][CH2:24][C:22]2[CH:21]=[CH:20][C:18]3[N:19]=[C:15]([S:14][CH3:13])[S:16][C:17]=3[CH:23]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CSc1nc2ccc(CN)cc2s1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(NCc2ccc3nc(SC)sc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of 2-chloro-6-methoxy-3-nitropyridine (430 mg, 2.3 mmol) in DMF (6 mL) was added (2-(methylthio)benzo[d]thiazol-6-yl)methanamine (437 mg, 2.1 mmol) from Step 4 of this Example slowly at 0° C. The reaction mixture was stirred at rt overnight. The resulting reaction mixture was diluted with 60 mL of EtOAc and washed with saturated aq NaHCO3 and brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using CH2Cl2 as eluent to give 6-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine as a yellow solid (431 mg, 57%). LCMS (ESI) m/z 363 (M+H)+.
Reaction SMILES: [CH2-]C(C)=O.C1N2CCN(CC2)C1.CCN(C(C)C)C(C)C.[CH3:22][Si:23]([CH2:26][CH2:27][O:28][CH2:29]Cl)([CH3:25])[CH3:24].[CH3:31][CH2:32][O:33][C:34](C)=[O:35]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:22][Si:23]([CH2:26][CH2:27][O:28][CH2:29][O:35][CH2:34][O:33][CH2:32][CH2:31][Si:23]([CH3:25])([CH3:24])[CH3:22])([CH3:25])[CH3:24]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(C)=O
Agent: C1CN2CCN1CC2
Agent: [CH2-]C(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOCOCC[Si](C)(C)C
Temperature: 40 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
The glycal alcohol 10 was prepared as described above by the irradiation of alkynyl diol 7 (2.0 g, 8.5 mmol) in toluene (0.20 M, 43 mL) with DABCO (1.9 g, 17 mmol) and W(CO)6 (750 mg, 2.1 mmol) for 20 hours. The crude mixture containing 10 was then dissolved in CH2Cl2 (1.0 M, 8.5 mL), and DIPEA (7.4 mL, 43 mmol) was added to the solution all at once. Then SEMCl (3.0 mL, 17 mmol) was carefully added to the reaction. The reaction was stirred at 40° C. for 3 hours. The reaction was then diluted with EtOAc (100 mL) and washed with H2O (3×50 mL). The organic layer was dried with MgSO4. After filtration, the volatiles were evaporated under reduced pressure, and chromatography (9:1 hexanes:EtOAc) provided glycal 13 (3:1 mixture of benzylidene acetal diastereomers) as a yellow oil (2.3 g, 75%).
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@@H:28]([CH2:30]CS([O-])(=O)=O)[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:16]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1COCC1.C(O)(C)C.[OH-].[NH4+:48]>C(Cl)Cl>[C:1]([N:11]1[CH2:12][C@@H:13]2[C@@H:17]([CH2:16][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH2:48])[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:14]2)[CH2:18]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: [NH4+]
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3ccc(N4C[C@@H](CCS(=O)(=O)[O-])OC4=O)cc3F)C[C@@H]2C1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: ClCCl
Product: NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)OCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Temperature: 95 °C

Procedure:
To a flame dried flask equipped with a nitrogen inlet is introduced (R)-[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methanol (1.75 g, 3.84 mmol) and methylene chloride (100 mL) cooled to 0° C. Triethylamine (0.80 mL, 5.76 mmol) and methanesulfonyl chloride are added, stirred at 0° C. for 2 hours, and warmed to ambient temperature for 1 hour. The reaction is washed with water (30 mL), saturated sodium bicarbonate (30 mL), and saline (30 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude (R)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate. (R)-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate is combined in a resealable tube with THF (5 mL), isopropanol (5 mL), and concentrated ammonium hydroxide (10 mL) and heated to 95° C. for 10 hours. The reaction is diluted with methylene chloride (50 mL) and washed with saline (30 mL), dried over sodium sulfate, concentrated in vacuo to give (S)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]amine. The crude (S)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]amine (1.67 g, 3.67 mmol) is dissolved in methylene chloride (20 mL), cooled to 0° C. under nitrogen, pyridine (0.89 mL, 11.02 mmol) and acetic anhydride (0.43 mL, 4.59 mmol) are added, and the reaction is stirred 15 hours at ambient temperature. The reaction is diluted with methylene chloride (50 mL), washed with 1N HCl (25 mL), saturated sodium bicarbonate (25 mL), saline (25 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 200 mL), eluting with chloroform/methanol (98/2). The appropriate fractions are combined (Rf =0.15, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 165-168° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:25][C:26]1[CH:34]=[C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[CH:41][CH:40]=2)=[O:36])[CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.[CH3:48][O:49][C:50](=[O:59])[CH:51]([P:53]([O:57][CH3:58])([O:55][CH3:56])=[O:54])[NH2:52].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:48][O:49][C:50](=[O:59])[CH:51]([P:53]([O:55][CH3:56])([O:57][CH3:58])=[O:54])[NH:52][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:33]([C:35]([NH:37][CH2:38][C:39]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[CH:41][CH:40]=2)=[O:36])=[CH:34][C:26]=1[Cl:25]
Reactant: O=C(NCc1ccc2cc[nH]c2c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2ccc3cc[nH]c3c2)cc1Cl)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.4 g, 6.4 mmol) was added to a solution of 2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoic acid (Example 117; 1.9 g, 5.8 mmol) and rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 2.10 g, 10.6 mmol) in N,N-dimethylformamide (20 mL). 1-hydroxybenzotriazole (861 mg, 6.4 mmol) was then added, followed by diisopropylethylamine (2 mL, 11.6 mmol). The solution was stirred overnight at room temperature and then it was concentrated under high vacuum to remove N,N-dimethylformamide. The residue was partitioned between water and ethyl acetate and the separated organic phase was washed in turn with cold 1N hydrochloric acid solution, cold saturated sodium bicarbonate solution and brine, then was dried (MgSO4), filtered and evaporated in vacuo. The crude product was chromatographed over silica gel (0-4% methanol/dichloromethane) to give rac.-N-[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (2.1 g, 72% yield) which was used in subsequent reactions without further purification.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:9]([C:19]([F:22])([F:21])[F:20])=[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:11]=O>C1COCC1.O.[OH-].[Na+]>[CH2:6]([O:5][C:3]([C:2]1[S:1][C:9]([C:19]([F:20])([F:22])[F:21])=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1)=[O:4])[CH3:7]
Reactant: O=CC(=C(Cl)C(F)(F)F)c1ccccc1
Reactant: CCOC(=O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reaction time: 0.75 h
Yield: 56.2 %

Procedure:
To a solution of ethyl 2-mercaptoacetate (0.88 g, 6.75 mmol) in THF (45 mL) NaH (271 mg, 6.75 mmol, 60% in mineral oil) is added at −10° C. The mixture is stirred at 0° C. for 30 min before a solution of 3-chloro-4,4,4-trifluoro-2-phenyl-but-2-enal 1.32 g (4.5 mmol) in THF (5 mL) is added. The reaction mixture is stirred at it for 45 min, then treated with 2 N aq. NaOH (2 mL). Stirring is continued for 15 min and the mixture is diluted with water (100 mL) and 1 N aq. NaOH (15 mL). The mixture is extracted with diethyl ether (70 mL). The organic extract is dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid ethyl ester (760 mg) as a brownish oil, LC-MS: tR=1.12 min; 1H NMR (CDCl3): δ 7.75-7.72 (m, 1H), 7.42 (s, 5H), 4.39 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:10]([CH3:14])[C:11]=2[CH:12]=O)=[CH:3][CH:2]=1.[ClH:21].[NH2:22][OH:23].N1C=CC=CC=1>CO>[ClH:21].[ClH:21].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:10]([CH3:14])[C:11]=2[CH:12]=[N:22][OH:23])=[CH:3][CH:2]=1
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C=O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C=NO
Yield: 42.5 %

Procedure:
A mixture of 2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde (0.14 g), hydroxylamine hydrochloride (0.04 g), and pyridine (0.04 mL) in MeOH (3 mL) was heated at reflux temperature for 16 hours. After cooling, the volatiles were removed by evaporation. The resulting residue was dissolved in 10% methanolic HCl (5 mL) and the solution was concentrated in vacuo again . The resulting solid was washed with water (50 mL) and CH2Cl2 (30 mL) to provide the title compound (0.045 g).
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11]O>>[CH3:11][C:10]1([CH3:14])[CH2:13][O:8][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9]1
Reactant: CCCCCC(=O)O
Reactant: CC(C)(N)CO
Product: CCCCCC1=NC(C)(C)CO1
Temperature: 185 °C
Yield: 81.2 %

Procedure:
Following the procedure under Example 11, 6.085 g (52.4 mmoles) of hexanoic acid and 10 ml (9.34 g, 104.8 mmoles) of 2-amino-2-methylpropanol was heated to 185°C. Work up and fractional distillation gave 7.2g (81%) of product, b.p. 90°-92° C./25mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:22])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]([CH3:23])=[C:4]([CH:3]=1)[C:24]([NH:25][CH2:26][C:27]1[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=1[CH3:33])=[O:36]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)C3CCN(C(=O)OC(C)(C)C)CC3)c2C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(N(C)C3CCNCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A stirred solution of tert-butyl 4-((5-chloro-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)(methyl)amino)piperidine-1-carboxylate (0.2 g, 0.632 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (0.15 mL) was added to it. Reaction mass was stirred at room temperature for 1 h. On completion, reaction was concentrated to dryness. Residue was purified by solvent washings to afford the desired compound (0.14 g, 53%) as its TFA salt. LCMS: 417.25 (M+1)+; HPLC: 96.16% (@ 254 nm) (Rt; 4.677; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.47 (s, 1H), 8.49 (bs, 1H), 8.20 (t, 1H), 8.18 (bs, 1H), 7.19 (s, 1H), 6.96 (s, 1H), 5.86 (s, 1H), 4.25 (d, 2H, J=4.4 Hz), 3.25 (d, 2H, J=12 Hz), 3.08 (m, 1H), 2.88 (bs, 2H), 2.56 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.76 (bs, 4H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12]([OH:15])[CH2:13][CH3:14])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12]([O:15][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: CC[C@H](O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
To a solution containing 300 mg (1.15 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide produced in Example 2 and pyridine (0.9 mL), 328.4 mg (1.72 mmol) of 4-methylbenzenesulfonyl chloride was added at 0° C. After stirring at 0° C. for 5 hours and at room temperature for further 5 hours, water (5 mL) was added and the resultant was stirred at room temperature for 2 hours. Extraction was carried out with ethyl acetate and after the organic layer was washed with saturated brine, the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and purifying was carried out on silica gel column chromatography to obtain (S)-N-[4-(trifluoromethyl)phenyl]-3-(4-methylphenyl)sulfonyloxypentanoic acid amide as a white solid (455.1 mg, isolated yield: 49%). 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.86 (3H, t), 1.75-1.82 (2H, m), 2.38 (3H, s), 2.72-2.83 (2H, m), 4.87-4.93 (1H, m), 7.23-7.26 (2H, m), 7.54-7.59 (4H, m), 7.74-7.78 (3H, m)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=[O:20]>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:19]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:20])[CH:21]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an oven-dried flask was added anhydrous THF (20 mL) and 3-bromopyridine (2 mL, 20 mmol). Isopropylmagnesium chloride in THF (11 mL, 2.0 M solution) was then added dropwise over several minutes. The mixture was stirred at room temperature for 1 hour, and then 5-bromo-2-fluorobenzaldehyde (2.4 mL, 20 mmol) was added. After stirring for 1 further hour at room temperature, the reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, dried over MgSO4, and purified by column chromatography (gradient 0 to 50% EtOAc in hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=1.9 Hz, 1H), 8.41 (dd, J=4.8, 1.5 Hz, 1H), 7.78-7.68 (m, 2H), 7.38 (ddd, J=8.7, 4.6, 2.6 Hz, 1H), 7.27 (dd, J=8.6, 4.2 Hz, 1H), 6.95-6.85 (m, 1H), 6.10 (s, 1H), 4.22 (br s, 1H).
Reaction SMILES: [Na].[C:2]([NH:5][OH:6])([NH2:4])=[NH:3].OS(O)(=O)=O.CO[C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)C>[NH2:3][C:2]1[N:4]=[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[O:6][N:5]=1
Reactant: CCCCCCCCCCCCCC(=O)OC
Reactant: N=C(N)NO
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCCCc1nc(N)no1
Reaction time: 0.25 h

Procedure:
Sodium metal (1.6 g, 0.068 mol) was added to 4 Å molecular sieves (12 g) and ethanol (200 mL) under nitrogen. The mixture was stirred for 15 minutes, then hydroxyguanidine sulfate (9.32 g, 0.035 mol) added and the mixture stirred for 30 minutes. Methyltetradecanoate (1.43 g, 0.006 mol) was then added and the mixture refluxed for 1.5 hours, allowed to cool, filtered, and concentrated. The concentrate was partitioned between CH2Cl2 and water. The organic layer was washed with water and brine, dried with Na2SO4, filtered, concentrated, and triturated with hexane. The resulting solid was filtered, washed with hexane, and dried in vacuo to yield 0.23 g, m.p. 90°-91° C.
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.[C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)#[N:33].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:37]3[CH:38]=[CH:39][C:34]([C:32]#[N:33])=[CH:35][CH:36]=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: N#Cc1ccc(B(O)O)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: N#Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 30 %

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-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a off-white foam (30%).