Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:19][CH:18]=1)[N:12]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH2:11][CH2:10]2.CO>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]1[CH:18]=[CH:19][C:20]([O:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=1)[N:12]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C3c4ccc(O)cc4CCN3C(=O)C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 134.6 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (16.2 ml, 16.2 mmol) was added slowly to a solution of toluene-4-sulfonic acid 4-(6-methoxy-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl ester (7.459 g, 14.8 mmol) in anhydrous CH2Cl2 (500 ml) at 0° C. under N2. After stirring at 0° C. for 1 hr, the reaction mixture was warmed to rt and stirred at rt for 18 hr. MeOH (250 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to give 9.793 g of brown residue. Purification by flash chromatography, eluting with hexane:EtOAc (7:3) gave 2.764 g (38% yield) of white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][N:13]=1>O1CCCC1.C(OCC)(=O)C>[Cl:11][C:12]1[N:17]=[C:16]([S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a suspension of sodium hydride (60% dispensed in mineral oil, 0.97 g, 24 mmol) in anhydrous tetrahydrofuran (80 mL), was added 4-aminobenzenethiol (2.77 g, 22 mmol) dissolved in tetrahydrofuran (20 mL) over 5 minutes. The mixture was stirred at room temperature for 30 minutes, to this was added a solution of 2,4-dichloropyrimidine (3.00 g, 20 mmol) dissolved in tetrahydrofuran (20 mL) over 5 minutes. The resulting mixture was stirred at room temperature for 64 hours, diluted with ethyl acetate (100 mL), washed with water and brine. After being dried (Na2SO4), the organic solution was concentrated in vacuo. The residue was flash chromatographed on silica gel using 5% of acetone in dichloromethane as eluant to give the product (3.60 g, 75%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:33]1[C:41]2[C:36](=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([F:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C>>[F:42][C:38]1[C:37]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]3[N:11]=[C:10]([CH2:12][NH:13][CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:36]2[C:41](=[CH:40][CH:39]=1)[NH:33][CH:34]=[CH:35]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2nc(CNC3CCOCC3)ccc2n1
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CNC3CCOCC3)ccc2n1

Procedure:
N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (0.17 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 79.1 mg of 142 following reverse phase HPLC purification. MS (Q1) 463.2 (M)+
Reaction SMILES: [NH3:1].Cl[C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]>C(O)C>[NH2:1][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(Cc2ccccn2)ccc1Cl
Reactant: N
Solvent: CCO
Product: Nc1ccc(Cc2ccccn2)cc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
Ethanol(1700 ml.) was saturated with ammonia at -20° to a total volume of 3l., then 49.7 g. (0.2 mol) of 2-(4-chloro-3-nitrobenzyl)pyridine was added. The entire mixture was first autoclaved at 100° C. for 24 hours, then 185° C. for 24 hours. The resulting solution was then evaporated in vacuo to a brown solid, which was thereafter dissolved in acetone, dried with magnesium sulfate. filtered and evaporated in vacuo to a light brown solid. The resulting solid was crystallized from water using Norite to give 2-(4-amino-3-nitrobenzyl)-pyridine as yellow-orange prisms, mp. 128- 132° C. (water).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1.Cl>CN(C)C=O.O>[CH3:11][C:5]([CH3:12])([CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH2:4][O:3][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Clc1ccc2ncnn2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(COc1ccc2ncnn2n1)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
In 15 ml of dimethylformamide was suspended 0.42 g of 60% sodium hydride in oil, followed by addition of 0.878 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperature for 30 minutes. Then, 0.773 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1 hour. Following addition of 40 ml of iced water, the reaction mixture was adjusted to pH 6 with 1N-hydrochloric acid and the resulting crystals were collected by filtration and washed with 20 ml of water and 20 ml of ethyl ether. The washed crystals were recrystallized from hot ethanol to provide 1.16 g of the title compound. m.p. 181°-184° C.
Reaction SMILES: B(O)O.[CH2:4]1[C:6](=O)[CH2:5]1.B.[CH2:9]([O:11]BO)[CH3:10]>>[C:9]12([OH:11])[CH2:4][CH:6]([C:5]1([CH3:5])[CH3:6])[CH2:10][CH2:9][C:10]2([OH:11])[CH3:4]
Reactant: O=C1CC1
Reactant: CCOBO
Agent: B
Agent: OBO
Product: CC1(O)CCC2CC1(O)C2(C)C

Procedure:
Scheme 12 illustrates the preparation of boronic acid analogs containing a substituted cyclohexyl ring in the P1 site. Cyclohexadione monoethylene ketone 38 was converted to the alkene 39 using a Wittig reaction. 39 was hydroboronated using diiisopinocamphyl borane and converted to the boronic acid ethyl ester using the general procedure described by Brown et al. J. Org. Chem. 47, 5065, 1982. Transesterification with pinanediol gave 40. The α-chloro compound 41 was prepared by the homologation reaction of 40 with the anion of methylene chloride using the procedure of Matteson et al. J. Am. Chem. Soc. 105, 2077, 1983. Nucleophillic displacement of the α-chloride with the lithium salt of hexamethyldisilazane gave the bis-silyl protected amine 42. The trimethylsilyl protecting groups were removed by treatment with anhydrous HCl. The α-amino group was coupled to either an acyl group or N-protected peptide or amino acid using the mixed anhydride or other standard peptide coupling reaction conditions. The peptide 43 was treated with an aqueous suspension of a sulfonic acid substituted ion exchange resin to yield the side chain ketone which was converted to the amino cyclohexylpeptide 44 by reductive amination using ammonium acetate and sodium cyanoborohydride. ##STR35##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[CH2:7][OH:8].[C:9]([Si:13]([CH3:16])([CH3:15])Cl)([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>ClCCl>[Si:13]([O:8][CH2:7][C@@H:2]1[CH2:3][O:4][CH2:5][CH2:6][NH:1]1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:16])[CH3:15]
Reactant: OC[C@@H]1COCCN1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1COCCN1
Yield: 90 %

Procedure:
(3R)-Morpholine-3-methanol (84.8 mg, 0.72 mmol), t-butyldimethylchlorosilane (0.11 g, 0.72 mmol), and imidazole (59.1 mg, 0.87 mmol) were allowed to react in 1 mL of dichloromethane at room temperature for 2 hours. The reaction product was purified by silica gel chromatography (dichloromethane:methanol:acetone=15:1:0.5) to obtain (3S)-3-(t-butyldimethylsilyloxy)methylmorpholine (0.15 g, 92%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8]1>>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: Clc1cccs1
Reactant: O=C1CCC(=O)O1
Product: O=C(O)CCC(=O)c1ccc(Cl)s1
Yield: 74 %

Procedure:
As described for Example 1, 0.3 mole of 2-chlorothiophene is reacted with succinic anhydride to give 4-(5-chloro-2-thienyl)-4-ketobutyric acid (74%), m.p. 121°-123° C. The preceding compound is coupled to L-proline to give 1-[3-(5-chloro-2-thenoyl)propionyl]-L-proline (94%) as crystals, m.p. 131°-133° C. The above compound is reacted with bromine in acetic acid to give 1-[3-bromo-3-(5-chloro-2-thenoyl)-propionyl]-L-proline as a glass. As for Example 1, reaction of the preceding compound with sodium thioacetate in ethanol gives the desired product (84%) as a glass.
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:3]([Cl:2])[C:4]=3[C:5]3=[N:22][O:21][C:20]([CH3:23])=[C:6]3[C:7]2=[O:19])[CH2:14]1)[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a suspension of 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (446 mg, 1.0 mmol) in tetrahydrofuran (20 mL) add ethylbromoacetate (0.11 mL, 1.0 mmol) and follow by potassium carbonate (346 mg, 2.5 mmol). Stir the mixture at room temperature under nitrogen overnight. Concentrate the mixture, partition between water and 20% isopropanol/chloroform, and separate. Wash the organic layer with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/chloroform) to give 261 mg of the title compound as a clear oil, 65% yield. 1H NMR: consistent with structure. MS (ion spray) 404 (M+).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C>CCCCCC>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Ic1ccc2oc3ccccc3c2c1
Reactant: Nc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(Nc2ccc3oc4ccccc4c3c2)cc1

Procedure:
The Rf values of the objective substance, 2-iododibenzofuran, and aniline were respectively 0.28, 0.59, and 0.07, which were found by silica gel thin layer chromatography (TLC) (with a developing solvent of ethyl acetate and hexane in a ratio of 1:10).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([CH2:30][CH2:29][OH:33])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: COc1ccccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1
Reactant: C#CCCO
Product: COc1ccccc1Nc1ccc(C(=O)c2cc(-n3cc(CCO)nn3)ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 442 (0.27 mmol) and but-3-yn-1-ol (0.30 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 20:80 as the eluent to afford the title compound. 13C NMR (DMSO-d6) δ 193.6, 152.4, 150.2, 145.6, 141.1, 135.9, 134.4, 134.2, 134.0, 132.3, 128.2, 125.3, 124.6, 123.4, 121.0, 120.6, 118.8, 115.1, 112.2, 111.7, 60.1, 55.4, 29.1, 19.0
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[O:6][C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[OH:23])=[CH:11][CH:10]=[CH:9][N:8]=1)#[N:2].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH:27]1[C:1]([C:3]2[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=2)[O:6][C:7]2[C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[OH:23])=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:2][N:29]=[N:28]1
Reactant: N#Cc1cccc(Oc2ncccc2OCCCc2ccncc2O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cnccc1CCCOc1cccnc1Oc1cccc(-c2nnn[nH]2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
2-(3-Cyanophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]-pyridine (0.85 g, 2.5 mmol) obtained in Example 28 is dissolved in DMF (10 ml), and thereto are added sodium azide (0.20 g, 3.0 mmol) and ammonium chloride (0.16 g, 3.0 mmol). The mixture is stirred at 130° C. for one hour, and the reaction solution is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent: acetic acid/ethanol), and recrystallized from ethanol to give the title compound (0.31 g) as pale brown crystals, m.p. 220-240° C. (decomposed).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:17]=[C:18]1OC(=O)[N:20]2[CH:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[S:25][CH2:26][CH:19]12>CS(C)=O.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:18]([CH:19]3[CH2:26][S:25][CH:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:20]3)=[O:17])[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OC(=O)N2C1CSC2c1cccnc1
Reactant: c1ccc(CCCN2CCNCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of 40 mg of 1-(3-phenylpropyl)piperazine in 0.5 ml of dimethyl sulfoxide was added to a solution of 50 mg of 1,3-dioxo-5-(3-pyridyl)thiazolidino[3,4-c]oxazolidine hydrochloride in 1 ml of dimethyl sulfoxide at room temperature. The reaction mixture was stirred for 2 hours at room temperature, then diluted with ethyl acetate, washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 70 mg of 1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine. The physicochemical properties of this product were in agreement with those of the compound of Example 108.
Reaction SMILES: [C:1]1([S:7]([OH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Ca+2].[Cl-].[F:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][C@H:20]2[O:25][CH:24](OC)[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(Cl)Cl>[C:1]1([S:7]([C@@H:24]2[O:25][CH:20]([CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:29][CH:28]=3)[CH2:21][CH2:22][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(O)c1ccccc1
Reactant: COC1CCC[C@@H](COc2ccc(F)cc2)O1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)[C@H]1CCCC(COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67.9 %

Procedure:
25% HCl was added dropwise to benzenesulfinic acid sodium salt (2.0 g), till the solid dissolved. This mixture was extracted with ethyl acetate (30 ml), dried (Na2SO4) and concentrated to give benzenesulfinic acid (1.5 g). To an ice-cooled mixture of benzenesulfinic acid (1.48 g, 10.5 mmol) and calcium chloride (1.15 g, 10.5 mmol) in dry CH2Cl2 a solution of (2RS,6S)-6-(4-fluorophenoxymethyl)-2-methoxytetrahydropyran (0.5 g, 2.1 mmol) in dry CH2Cl2 (5 ml) was added. The reaction mixture was stirred for 4 h, filtered through celite and washed with CH2Cl2. The combined organic layer was washed with saturated aqueous Na2CO3, water, brine and dried (Na2SO4). The solvent was removed under vacuum and the residue was purified on a silica gel column using light petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS,6S)-6-benzenesulfonyl-2-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g, 70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): 8 1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H) m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=O)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>C(O)C>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[N:19][OH:20])[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=O)CO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2c1C(=NO)CO2
Temperature: 23 °C
Yield: 100 %

Procedure:
A mixture of 4-methoxy-benzofuran-3-one (CAS no: 7169-35-9) (4.9 g, 19 mmol), sodium acetate (3.06 g, 38 mmol) and hydroxylamine hydrochloride (2.58 g, 38 mmol) in ethanol (40 mL) was refluxed for 6 h. Cooled to 23° C., filtered the precipitate off, washed with ethanol and dried in high vacuum to give the title compound as a white solid (5.93 g, 100%); MS: m/e=180.2 (M+H+).
Reaction SMILES: S([NH:11]/[N:12]=[CH:13]/[C:14]([OH:16])=[O:15])(C1C=CC(C)=CC=1)(=O)=O.O[N:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[O:24]=[C:19]1[CH2:20][CH2:21][C:22](=[O:23])[N:18]1[O:16][C:14](=[O:15])[CH:13]=[N+:12]=[N-:11]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccc(S(=O)(=O)N/N=C/C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: [N-]=[N+]=CC(=O)ON1C(=O)CCC1=O
Reaction time: 17 h
Yield: 53.9 %

Procedure:
Under argon atmosphere, to a solution of (E)-2-(2-tosylhydrazono)acetic acid (1.42 g) in 1,4-dioxane (14 ml) were sequentially added N-hydroxysuccinimide (677 mg) and dicyclohexylcarbodiimide (1.21 g) at room temperature, and the mixture was stirred for 17 hours. This reaction mixture was filtered through Celite, and eluted with 1,4-dioxane. This filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/diethyl ether=1/3) to give the titled compound (579 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26]>CO.Cl[Pd]Cl>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:22]=[CH:23][C:24]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)c(F)c2)c1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
Methyl 2-chloroisonicotinate (2.86 g, 16.67 mmol), PdCl2 (dppf) (0.278 g, 0.38 mmol) and potassium carbonate (1.161 mL, 19.24 mmol) were distributed equally over 3 microwave reaction vials. 2-(3-Fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (3.72 g, 12.82 mmol) dissolved in methanol (45 mL) was split into 3 equal portions and added to the vials. The vials were capped and heated in a single node microwave reactor at 100° C. for 10 min each. The contents of the vials was combined and the solvent evaporated. The residue was dissolved in DCM and washed with water. The organic phase was filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. 7:1 of heptane:EtOAc over 10 CV was used as mobile phase. Crude methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)isonicotinate (2.92 g, 76%) was isolated. MS m/z 300 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:32][CH:33]=1)(=[O:36])[CH3:35]
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2)cc1
Yield: 56.2 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(phenyl)benzamide (503.8 mg, 1.13 mmol) and acetic anhydride (0.128 ml, 1.36 mmol), the procedure of Inventive Example 94 was repeated to obtain 309.9 mg (71.0%) of the title compound in a light brown amorphous form.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1CC[C:17]2N(C3N=CC(F)=CN=3)N=N[C:16]=2[C@H:15]1[CH3:30])=[O:13].Cl.CCN(CC)CC.ClC1C(C(F)(F)[F:50])=CC=CC=1C(Cl)=O>C1COCC1>[CH3:30][C@@H:15]([NH:14][C:12](=[O:13])[C:3]1[CH:4]=[C:5]([F:50])[CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[Cl:1])[C:16]#[CH:17]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: C[C@@H]1c2nnn(-c3ncc(F)cn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#C[C@@H](C)NC(=O)c1cc(F)cc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To the suspension of (R) but-3-yn-2-amine.HCl salt (10 g, 94.7 mmol, 1.0 equiv.) in THF (150 mL), Et3N (27.5 mL, 199 mmol, 2.1 equiv.) and (2-chloro-3-(trifluoromethyl)benzoyl chloride (23.1 g, 94.7 mmol, 1.0 equiv.) were added sequentially at 0° C. The reaction mixture was then stirred at room temperature for 16 hours. The precipitate was filtered off and washed with THF. The filtrate solution was concentrated and re-dissolved in EtOAc. The EtOAc solution was washed with saturated NaHCO3 and brine, dried over Na2SO4, concentrated. Trituration of the crude product from EtOAc/hexanes afforded the title compound (23 g, 83.8 mmol, 88%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 7.82-7.75 (dd, J=7.9, 1.6 Hz, 1H), 7.73-7.66 (dd, J=7.7, 1.6 Hz, 1H), 7.48-7.41 (dd, J=8.2, 7.3 Hz, 1H), 6.35-6.02 (d, J=7.9 Hz, 1H), 5.09-4.90 (dqd, J=8.1, 6.9, 2.3 Hz, 1H), 2.47-2.20 (m, 1H), 1.58-1.54 (d, J=6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.7, 137.9, 132.5, 129.4 (q, JC—F=31.5 Hz), 129.1, 129.0 (q, JC—F=5.2 Hz), 127.1, 122.5 (q, JC—F=273.4 Hz), 83.2, 71.2, 37.8, 22.1. HRMS-ESI (m/z): [M+H]+ calcd for C12H10ClF3NO, 276.0398. found, 276.0390.