Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][C@:10]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][NH:27][O:28][CH3:29]>>[CH3:29][O:28][N:27]([CH3:26])[C:13]([C@H:12]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][C@@:10]2([C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[CH2:11]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1C[C@@]2(C[C@H]1C(=O)O)C(=O)Nc1ccccc12
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)[C@@H]1C[C@]2(CN1C(=O)OC(C)(C)C)C(=O)Nc1ccccc12

Procedure:
(3S,5′S)-tert-butyl 5′-(methoxy(methyl)carbamoyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was prepared by the procedures described in Example 10, Step 5, substituting (R)-2-(1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yl)acetic acid with (3S,5′ S)-1′-(tert-butoxycarbonyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxylic acid, and substituting NH4Cl with N,O-dimethylhydroxylamine hydrochloride. LCMS (APCI+) m/z 376 [M+H]+; Rt=2.88 min.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:36])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)(=O)C.Br>[C:30]1([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]2[CH2:19][CH2:18][N:17]([CH2:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[O:36])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Agent: Br
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(O)cc1
Yield: 62 %

Procedure:
12.5 g (26 mmol) of 1-(4-benzyloxyphenyl)-2-(4-diphenylmethyl-piperazinyl)ethanone and 2.8 g (26 mmol) of anisole were dissolved in a mixture of 37.5 ml of acetic acid and 12.5 ml of 47% hydrobromic acid. The resultant mixture was heated to reflux for 1 hour. After being cooled to room temperautre, the reaction mixture was washed with 200 ml of ether and then with 50 ml of ether to remove acetic acid. The resultant solution was neutralized with an aqueous 2N solution of sodium hydroxide. Separated organic substances were extracted with 120 ml of ethyl acetate and then washed with saturated saline. The ethyl acetate solution was dried over anhydrous sodium sulfate and then concentrated. The residue was taken up in 60 ml of isopropanol and allowed to stand at room temperature to give 6.28 g of crude crystals of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone (yield: 62%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[CH:15][C:14]=1[F:28])(=[O:7])[CH3:6].C(=O)(O)[O-].[Na+]>O>[C:5]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[C:14]([F:28])=[CH:15][C:16]([NH:19][C:20]([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[C:17]([N+:1]([O-:4])=[O:2])[CH:18]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCCC1c1ccc(NC(=O)c2cnccn2)cc1F
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCCC1c1cc([N+](=O)[O-])c(NC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40 ml of fuming nitric acid was added to 3.9 g of N-(4-(1-acetylpyrrolidin-2-yl)-3-fluorophenyl)pyrazine-2-carboxamide with cooling with ice, and the reaction liquid was stirred at room temperature for 2 hours. The reaction liquid was diluted with water with ice, made basic with aqueous saturated sodium bicarbonate, and then extracted with chloroform. The organic layer was washed with saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].IC.[C:20](=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:20])=[O:9])[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: Cc1ncnc(C(=O)O)c1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ncnc(C)c1C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 79.1 %

Procedure:
To a solution of 9.12 g (38 mmol) of the material from Step B in 100 mL of N,N-dimethyl formamide (DMF) was added 3.1 mL (50 mmol) of iodomethane and 3.7 g (50 mmol) of lithium carbonate. The reaction mixture was heated at 60° C. for 3 hours. After cooling the reaction mixture was partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate) and the solvent was removed with a rotary evaporator and then a vacuum pump. The residue was purified by MPLC with a gradient of 20-30% ethyl acetate in hexanes as eluant to afford 7.58 g of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Fc1ccccc1-c1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 305(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@H:15]([CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@H:15]([CH:16]=[O:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CO)[C@@H](c2ccc(Cl)c(Cl)c2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C=O)[C@@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 10 °C
Reaction time: 4 h
Yield: 43.6 %

Procedure:
To a solution of tert-butyl (6S,7R)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (3.0 g) in acetonitrile (20 mL) was added Dess-Martin reagent (5.1 g), and the mixture was stirred at 10° C. for 4 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.3 g).
Reaction SMILES: S([N:11]1[CH2:16][C:15](=[O:17])[C:14]2[S:18][CH:19]=[CH:20][C:13]=2[CH2:12]1)(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[K+]>OC(C)(C)C>[S:18]1[C:14]2[C:15](=[O:17])[CH2:16][N:11]=[CH:12][C:13]=2[CH:20]=[CH:19]1
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)c3sccc3C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1CN=Cc2ccsc21
Yield: 178.9 %

Procedure:
To a solution of 5,6-dihydro-5-tosylthieno[3,2-c]pyridin-7(4H)-one (1.24 g, 4.03 mmol, 1.0 equiv) in HOt-Bu (15.0 mL) was added KOt-Bu (904 mg, 8.06 mmol, 2.0 equiv) and heated to reflux for 2 h. The mixture was quenched with water and then extracted with ethyl acetate. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 1.09 g of white solid, 89%.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:12]#[N:13].C(N)CN>CN(C=O)C>[O:10]1[C:6]2=[CH:5][CH:4]=[CH:3][C:2]([C:12]#[N:13])=[C:7]2[CH:8]=[CH:9]1
Reactant: N#C[Cu]
Reactant: Brc1cccc2occc12
Solvent: CN(C)C=O
Solvent: NCCN
Product: N#Cc1cccc2occc12
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Combine 4-bromo-benzofuran (1.0 g, 5.07 mmol), copper(I) cyanide (0.9 g, 10.2 mmol), anhydrous DMF (16 ml) and reflux for 17 h. Cool the reaction mixture to ambient temperature, treat with 50% (v/v) aqueous ethylenediamine (25 mL). Extract the reaction mixture with diethyl ether (3×15 mL), combine the organic extracts, wash with brine (15 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the desired intermediate as a colorless oil (0.3 g, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:37]([F:38])=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][C:26]=3[F:39])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:40][CH3:41].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:26]([F:39])=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][C:37]=3[F:38])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:40][CH3:41]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)OC(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100550.6 %

Procedure:
To a solution of tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoate (95 g, 0.16 mmol) in CH2Cl2 (500 mL) at 0° C. was added TFA (500 mL) and then was stirred at room temperature. After 3 h, the reaction mixture was evaporated and the residue was diluted with CH2Cl2(1.5 L), washed with water (600 mL×2). To the organic layers more water (600 mL) was added, it was neutralized with slow addition of aq. NaHCO3 solution and organic layer was separated. Water (600 mL) was added to the organic layer and adjusted aqueous layer to pH 3-4 with 1N HCl. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. Toluene (600 mL) was added to the residue and the solution was evaporated and same process was repeated one more time to give the title compound as a white solid (88 g, quant). 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.46-7.49 (d, 2H), 7.16-7.19 (m, 1H), 6.92-6.97 (t, 2H), 6.69-6.71 (t, 2H), 6.62 (s, 1H), 6.49-6.51 (d, 1H), 3.84 (s, 3H), 3.53 (s, 2H), 1.58 (s, 6H); MS (EI) m/z 547 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.C[O:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18](O)[CH:17]=1>>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[C:15]([OH:25])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: OCCc1cccc(CCO)c1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Product: COc1ccc(C(=O)O)cc1OCCc1cccc(CCO)c1

Procedure:
2-[3-(2-Hydroxy-ethyl)-phenyl]-ethanol and 3-hydroxy-4-methoxybenzoic acid methyl ester were coupled in analogy to step 1 of example 1 and the methyl ester was hydrolyzed in analogy to step 2 of example 1 to yield the title compound.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[C:14]([C:16]1[CH:17]=[C:18]([Zn]I)[CH:19]=[CH:20][CH:21]=1)#[N:15].[BH4-].[Na+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([C:16]1[CH:21]=[C:20]([CH:2]([OH:3])[C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH:19]=[CH:18][CH:17]=1)#[N:15]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: N#Cc1cccc([Zn]I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [BH4-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 3.0 g (15 mmole) of methyl 4-(chlorocarbonyl)benzoate and 183 mg (0.2 mmole) of tris(dibenzylideneacetone)dipalladium(0) was cooled to 0° C. under N2. After 5 min, 32 mL of a 0.5 M solution of (3-cyanophenyl)(iodo)zinc in THF was added dropwise and the solution was stirred at rt. After 4 h, the reaction was quenched by addition of saturated NH4Cl solution and 30 mL ether. The layers were separated and the aqueous layer was washed with three 30 mL portions of ether. The combined organic extracts were washed with 30 mL of saturated NaHCO3 solution and 30 mL brine before being dried over MgSO4 and concentrated. The residue was dissolved in 50 mL of 1:5 CH3OH-THF and cooled to 0° C. To this was added 500 mg (13.5 mmole) of NaBH4 in two portions over 10 minutes. After 20 min, the reaction was quenched by addition of 1 mL saturated Na2SO4 solution and concentrated. The resulting slurry was diluted with ether and filtered. The solid residue was washed with ether and the combined filtrates were washed with brine, dried over Na2SO4 and concentrated to an oil that was purified by silica gel chromatography using a step-gradient of 10 to 25% EtOAc-hexane. Homogeneous fractions were combined and concentrated to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4](Cl)[C:3]=1[Cl:10].[OH-].[K+].[CH2:13]([OH:16])[CH2:14][OH:15]>>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:15][CH2:14][CH2:13][OH:16])[C:3]=1[Cl:10]
Reactant: OCCO
Reactant: Nc1c(Cl)cnc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Product: Nc1c(Cl)cnc(OCCO)c1Cl
Temperature: 108 °C

Procedure:
A mixture of 200 grams (1.1 mole) of 4-amino-2,3,5-trichloropyridine in 500 milliliters of ethylene glycol was heated at 108° C., with agitation, until a solution was obtained. To this solution was added over a 20-minute period, while the temperature was raised to 123° C., a solution of 70 grams (1.25 mole) of potassium hydroxide dissolved in 300 milliliters of ethylene glycol. The temperature was raised to 150°-151° C. and agitation was maintained for 2 hours. The reaction mixture was cooled and filtered under reduced pressure. The filtrate was diluted with 1500 milliliters of cold water and extracted with methylene chloride. The solvent was removed by evaporation under reduced pressure. The liquid residue which remained was crystallized from hexane and dissolved in hot chloroform. The solution was cooled and the 4-amino-3,5-dichloro-2-(2-hydroxyethoxy)pyridine product was recovered by filtration under reduced pressure. The purified product was recovered in a yield of 75 grams which melted at 77.5°- 81° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6](/[CH:20]=[CH:21]/[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[NH:4][N:3]=1.CO.C1COCC1.[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:1][C:2]1[C:10]2[C:5](=[C:6](/[CH:20]=[CH:21]/[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[NH:4][N:3]=1
Reactant: CN(C)C(=O)/C=C/c1ccc(-c2ccc([N+](=O)[O-])cc2)c2c(N)n[nH]c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CN(C)C(=O)/C=C/c1ccc(-c2ccc(N)cc2)c2c(N)n[nH]c12
Temperature: 85 °C
Yield: 72.9 %

Procedure:
A solution of Example 84C (113 mg, 0.32 mmol) in a mixture of ethanol (1 mL), methanol (1 mL), and THF (1 mL) was treated with iron powder (144 mg) and NH4Cl (17 mg), heated to 85° C. for 4 hours, cooled to room temperature, and filtered. The filtrate was partitioned between water and ethyl acetate and the organic phase was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 75 mg of the desired product. MS (ESI(+)) m/e 322 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[N:19][CH:20]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([C:15]1[CH:20]=[N:19][CH:18]=[C:17]([CH:16]=1)[CH:21]=[O:22])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cncc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cncc(C=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (158 μL, 1.819 mmol) in methylene chloride (10 mL) was placed in a two-necked flask at −78° C., followed by the addition of dimethyl sulfoxide (129 μL, 1.819 mmol). Stirring was continued for 20 min, followed by addition of (5-tert-butylpyridin-3-yl)methanol (0.2 g, 1.21 mmol) in methylene chloride (10 mL). After the mixture was stirred at −78° C. for additional 20 min, triethylamine (0.59 mL, 4.24 mmol) was added. The cooling bath was removed and the suspension was allowed to warm to room temperature. Water (50 mL) was added, the yellow organic layer was separated, and the aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic solution was dried and concentrated to give 5-tert-butylnicotinaldehyde as an orange-yellow liquid which was used directly for next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:4][N:5]([CH3:7])[CH:6]=1.[Li]CCCC.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:3]1[C:2]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:6][N:5]([CH3:7])[N:4]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cn1cc(Br)c(-c2ccccc2F)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.9 %

Procedure:
To a solution of 4-bromo-3-(2-fluorophenyl)-1-methyl-1H-pyrazole (3.03 g, 11.9 mmol, 1.0 eq.) in THF (40 mL) under nitrogen at −78° C. was added nBuLi (hexane, 2.5 M, 5.3 mL, 13.2 mmol, 1.1 eq.) over 10 min. After 45 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.7 mL, 13.2 mmol, 1.1 eq.) was added. After 1 h 45 min, saturated aqueous NH4Cl and EtOAc were added. The cold bath was removed, and the reaction mixture was stirred to room temperature. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography using hexanes:EtOAc (3:1) as eluent afforded 3-(2-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a white solid (1.83 g, 51% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24](F)[N:23]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:29][C:30]1[CH:31]=[C:32]([CH2:36][NH2:37])[CH:33]=[CH:34][CH:35]=1>CS(C)=O>[Cl:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:37][CH2:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)[N:23]=2)=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Reactant: NCc1cccc(F)c1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 40 h
Yield: 89.3 %

Procedure:
A mixture of tert-butyl 4-(5′-chloro-6-fluoro-2,4′-bipyridin-2′-yl-amino)piperidine-1-carboxylate (200 mg, 0.492 mmol), DMSO (2 ml), TEA (0.137 ml, 0.983 mmol) and (3-fluorophenyl)methanamine (554 mg, 4.42 mmol) reaction mixture was flushed with argon and stirred at 100° C. for 40 hr, as the reaction mixture progress was followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (2×), water (3), saturated salt solution (1×), dried over sodium sulfate, filtered and concentrated to yield a crude material, which was purified by silica gel chromatography using a 12 g column, eluting from 0%-35% ethyl acetate with hexane. The desired fractions were collected and concentrated to constant mass, giving 225 mg of the title compound as a free base. LCMS (m/z): 512.3 (MH+), retention time=0.91 min.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:31]=[CH:32][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:35]=[CH:36][C:4]([NH:3][S:43]([C:40]6[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=6)(=[O:45])=[O:44])=[CH:5][CH:6]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:20][CH:21]=2)[S:28]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc4nc(COc5ccc(CC6SC(=O)NC6=O)cc5)n(C)c4c3)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51.6 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), p-toluenesulfonyl chloride (153 mg), triethylamine (234 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate. and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→4:1 as the eluant and the product was recrystallized from a mixture of ethyl acetate and diisopropyl ether to afford the title compound (237 mg, mp 132.0-135.6° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(OC2CCNCC2)c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Product: Cc1cccc(C(OC2CCN(CCCOc3ccccc3[N+](=O)[O-])CC2)c2ccccc2)c1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(3-methylphenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(3-methylphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.