Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[N:12]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)=[C:13]=[S:14]>C1C=CC=CC=1.C(N(CC)CC)C>[F:27][C:25]([F:26])([F:28])[C:17]1[CH:16]=[C:15]([NH:12][C:13]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=2)=[S:14])[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[N:18]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)n1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(NC(=S)Nc2cc(C(F)(F)F)nc(C(F)(F)F)c2)cc1
Yield: 72.9 %

Procedure:
A mixture of 4-aminobenzotrifluoride (1.48 g) and 4-isothiocyanato-2,6-bis(trifluoromethyl)pyridine (2.5 g, 0.01 mole) in dry benzene (25 ml) containing several drops of triethylamine was heated under reflux for 7 hours. Removal of the solvent and triethylamine gave the title compound as a colorless solid 2.9 g, m.p. 125°-132° C. Crystallization from benzene furnished a sample, m.p. 132° C.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:19])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:19])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2ccccc2c1=O
Product: CCCC(=O)c1cnc2ccccc2c1Cl

Procedure:
3-Butyryl-4(1H)-quinolone (21.5 g) and phosphoryl chloride (80 ml) were heated under reflux for 45 minutes. Excess phosphoryl chloride was evaporated in vacuo, the residue poured onto ice and neutralised with sodium hydrogen carbonate. Extraction with dichloromethane, drying and evaporation gave 3-butyryl-4-chloroquinoline (22 g) as a brown oil, which solidified on standing. This was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OC(C)(C)C)=O)=[N:11][C:7]=1[CH:6]=[CH:5]2.Cl.[CH3:28][O:29][C:30]([NH:32][C@@H:33]([CH:37]([CH3:39])[CH3:38])[C:34](O)=[O:35])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:34](=[O:35])[C@@H:33]([NH:32][C:30](=[O:31])[O:29][CH3:28])[CH:37]([CH3:39])[CH3:38])=[N:11][C:7]=1[CH:6]=[CH:5]2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
(S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.50 g, 3.60 mmol) was dissolved in DCM (25 mL) and HCl (4 M solution in dioxane, 5 mL, 20 mmol) was added at once. After stirring for 3 h, the solution was concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (631 mg, 3.60 mmol), HATU (1.37 g, 3.60 mmol) and DMF (18 mL). The stirred solution was cooled to 0° C. and DIPEA (1.9 mL, 10 mmol) was added dropwise. After stirring for 20 min, the reaction mixture was warmed to RT. After an additional 10 min, it was diluted with EtOAc (150 mL) and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc) to afford the title compound (1.70 g, 100%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH2:27]([O:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH3:28]>>[CH2:27]([O:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:28]
Reactant: CCOCn1ccnc1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: CCOCn1ccnc1C(=O)c1cn(-c2cccc(-c3cc(F)ccc3OC)c2)cn1

Procedure:
This compound is prepared by method C using compound 12b and 1-(ethoxymethyl)imidazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:27]([NH2:29])=[O:28])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)[CH:8]=3.[Cl:30][C:31]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][C:32]=1[CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:30][C:31]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]([C:27]([NH2:29])=[O:28])[C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][CH:10]=[C:9]([C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH:8]=4)[CH:41]=[CH:40][C:32]=1[CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)c(Cl)c2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(-c3ccc(N4CCOCC4)nc3)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(CN3CCOCC3)c(Cl)c2)cc2c1[nH]c1cc(-c3ccc(N4CCOCC4)nc3)ccc12
Temperature: 105 °C

Procedure:
To the reaction mixture above (482A) was added 4-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine 477B (0.098 g, 0.289 mmol) and additional PdCl2(dppf)-CH2Cl2 adduct (0.020 g, 0.024 mmol). The mixture was heated in microwave at 105° C. for 1 hr. The mixture was filtered and then purified using preparative HPLC to give titled product. MS (ESI) m/z 582.21 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=O)=[C:8](C)[C:7](OC)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[K+].O.N1C=CC=C[CH:27]=1>>[OH:3][C:1]1[C:4]2[C:9](=[CH:8][C:7]([CH3:27])=[CH:6][CH:5]=2)[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[CH:2]=1
Reactant: c1ccncc1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2cccc(C)n2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(O)cc(-c3cccc(C)n3)nc2c1
Temperature: 150 °C
Yield: 95 %

Procedure:
To a solution of 6-methylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methyl-phenyl)-amide (96) in pyridine (15 mL) was added 2.5 equivalent of freshly grounded KOH along with water (200 μL). The mixture was heated by microwave irradiation at 150° C. for 30 min, then 80-85% of the pyridine was evaporated under reduced pressure. The residue was poured on ice and neutralized with acetic acid. The precipitate was filtered off, then dried to give the title compound (1.8 g, 95%): m/z=299 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[OH-].[Na+].[C:12]([O:16][C:17](OC([O-])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC(O)(C)C.O>[C:12]([O:16][C:17]([N:5]1[CH2:6][CH2:7][CH2:8][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C1CCCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 4-oxohomopiperidine.HCl (1.2 g, 8.05 mmol), NaOH (0.68 g, 16.9 mmol) in t-BuOH/H2O (1:1, 10 mL) was added t-butyldicarbonate (1.93 mL, 8.9 mmol) drop-wise. The reaction was stirred at RT overnight, extracted with EtOAc (2×10 mL) and the organic layer separated. The organic layer was dried over Na2SO4 and concentrated under vacuo. Pure 1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 84%) was isolated via silica gel flash chromatography eluting with 50% EtOAc/hexane. 1H NMR CDCl3 δ: 44 (9H, s), 1.72–1.84 (2H, m), 2.60–2.65 (4H, m), 3.55–3.61 (4H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[C:27]([C:30]1[CH:60]=[CH:59][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:43](=[O:58])[CH2:44][NH:45][C:46](=[O:57])[C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=3)[CH2:37][CH2:36]2)=[CH:32][CH:31]=1)(O)=[O:28]>CN(C=O)C>[N:1]1([C:27]([C:30]2[CH:60]=[CH:59][C:33]([CH2:34][N:35]3[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:43](=[O:58])[CH2:44][NH:45][C:46](=[O:57])[C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:56])[F:55])[CH:48]=4)[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: C1CCNCC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)N3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Piperidine (0.048 mg), and a DMF (0.15 mL) solution of diisopropylcarbodiimide (0.45 mmol) and 1-hydroxybenzotriazole hydrate (0.45 mmol) were added to a DMF (1.0 mL) solution of 1-(4-carboxybenzyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (0.040 mmol), and the resulting mixture was shaken at room temperature for 17 hours, then loaded onto a Varian™ SCX column and washed with chloroform/methanol=1:1 (5 mL) and methanol (5 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated to thereby provide 1-[4-(piperidinocarbonyl)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 0.1572) (14.3 mg, 66%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 545 (M++H, C29H35F3N4O3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28].C([O-])(O)=O.[Na+]>CCO>[CH2:27]([N:29]([CH2:30][CH2:31][OH:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1)[CH3:28]
Reactant: O=S(=O)(N[C@H]1CC[C@H](CCCCCBr)CC1)c1ccc(C(F)(F)F)cc1
Reactant: CCNCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCN(CCO)CCCCC[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 90 °C

Procedure:
A solution of 2.4 mg (5.26 mmol) of trans-N-[4-(5-Bromo-pentyl)-cyclohexyl]-4-trifluoromethyl-benzenesulfonamide in 36 ml of EtOH was treated with 2.1 ml (21.53 mmol) of ethyl-(2-hydroxy-ethyl)-amine, 1.8 g (21.43 mmol) of NaHCO3 and stirred over night at 90° C. The reaction cooled, filtered, evaporated and the residue extracted with aqueous saturated NaHCO3/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (EtOAc/EtOH/NH3 25% 98:2:1) gave 1.96 g (80%) of trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide, MS: 463 (M−H−).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1([F:22])[CH2:12][CH2:11][CH:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9]1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O1CCOCC1>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:27]=[CH:28][C:29]([S:32]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([CH:10]3[CH2:11][CH2:12][C:8]([F:7])([F:22])[CH2:9]3)=[CH:14]2)(=[O:33])=[O:34])=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: FC1(F)CCC(c2c[nH]c3ccccc23)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Reaction time: 0.08 h
Yield: 223.5 %

Procedure:
Add potassium tertbutoxide (368 mg, 3.28 mmol, 1.1 eq) to a 3 ml dioxane solution of 3-(3,3-difluoro-cyclopentyl)-1H-indole (660 mg, 2.98 mmol, 1.0 eq) under N2. Stir solution for 5 minutes. Add 4-Chlorosulfonyl-benzoic acid methyl ester 117 mg, 0.497 mmol, 1.1 eq). Stir reaction for 4 hours at room temperature. Strip reaction of solvent and purify by silica gel chromatography to give 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-benzoic acid methyl ester (466 mg, 37% yield).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][C:6]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:5]1)([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[CH:1]([N:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccs2)nn1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2cccs2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 1-isopropyl-3-(thiophen-2-yl)-1H-pyrazole-5-carboxylate (0.88 g, 3.3 mmol) in THF (10 mL) was added aq. LiOH solution (0.42 g, 10 mmol, 5 mL) and the mixture was stirred for 16 h at RT. Solvents were removed and the thick liquid was diluted with water (5 mL) and acidified with 3M HCl solution to pH 4-5. The product precipitated and was filtered, washed with water and dried to afford 1-isopropyl-3-(thiophen-2-yl)-1H-pyrazole-5-carboxylic acid as a white solid (0.69 g, 88% yield).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.[H][H]>C(O)C>[NH3:9].[NH2:20][CH2:19][C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:10]([NH:9][CH2:8][CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:18]=1
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: [H][H]
Agent: N
Solvent: CCO
Product: NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 30 h
Yield: 153.7 %

Procedure:
A solution of 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile (5.70 g, 13.18 mmol) (Preparation 5) in ethanol (200 ml) saturated with ammonia gas was treated with Pearlmann's catalyst (1.00 g), pressurised to 60 psi with hydrogen in a sealed vessel and stirred at room temperature for 30 hours. The mixture was filtered through a pad of Arbocel (trade mark) and the solvent was removed under reduced pressure. The residue was azeotroped from dichloromethane (×2) and then purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol:0.88 ammonia (90:10:0.5 by volume) to afford the title compound (4.34 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12](B(O)O)=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:28]=[CH:27][C:26](Br)=[CH:25][C:22]=1[CH:23]=[O:24].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:26]2[CH:27]=[CH:28][C:21]([F:20])=[C:22]([CH:23]=[O:24])[CH:25]=2)=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1B(O)O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1ccc(F)c(C=O)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 116.6 %

Procedure:
(4-(Benzyloxy)-2,6-dimethylphenyl)boronic acid 12b (256 mg, 1 mmol), 2-fluoro-5-bromo-benzaldehyde (203 mg, 1 mmol), 2M aqueous sodium carbonate solution (1 mL, 2 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (37 mg, 0.08 mmol) and tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) were dissolved in 3 mL of a mixture of the solvents ethylene glycol dimethyl ether and toluene (V/V=1:2). The reaction mixture was heated at 100° C. for 2 hours, and then at 120° C. for 0.5 hours under microwave conditions. The resulting mixture was mixed with 10 mL of water and extracted with ethyl acetate (10 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 4′-(benzyloxy)-4-fluoro-2′,6′-dimethylbiphenyl-3-carbaldehyde 18a (390 mg, yield 58.4%) as a colorless slime.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]1([CH2:21][C:22](O)=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:21][C:22]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1sccc1N
Reactant: O=C(O)Cc1cccc2ccccc12
Product: COC(=O)c1sccc1NC(=O)Cc1cccc2ccccc12

Procedure:
Methyl 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate was prepared from methyl 3-aminothiophene-2-carboxylate (4.30 g, 27.3 mmol) and 2-(naphthalen-1-yl)acetic acid (3.10 g, 27.3 mmol) according to protocol A. Retention time (min)=8.738, method [7], MS(ESI) 326.1 (M+H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([N:12]1[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:14]2([CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:16][CH2:15]2)[CH2:13]1)C1C=CC=CC=1.Cl.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:29][C:27]1([CH3:30])[O:26][C:14]2([CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])[CH2:16][CH2:15]2)[CH2:13][NH:12][CH2:28]1
Reactant: CC1(C)CN(Cc2ccccc2)CC2(CCN(C(=O)C(F)(F)F)CC2)O1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CNCC2(CCN(C(=O)C(F)(F)F)CC2)O1

Procedure:
A mixture of acetic acid (100 μL, 1.76 mmol), Pd(OH)2 (11 mg, 0.02 mmol), 1-(8-benzyl-10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone (80 mg, 0.22 mmol), HCl (108 μL of 4 M in dioxane, 0.43 mmol) and ethanol (2 mL) was treated to an atmosphere of hydrogen at 85 psi for 3 days. The reaction mixture was filtered and the catalyst was washed with methanol, then concentrated in vacuo to give 1-(10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone acetic acid salt as a yellow solid. ESI-MS m/z calc. 280.1. found 281.5 (M+1)+; Retention time: 0.91 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(Br)cc2)c1-c1cn(-c2ncccn2)cn1
Yield: 73 %

Procedure:
As described for Example 49, 3-(4-bromo-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (61 mg, 0.2 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (56 mg, 73%) which was obtained as a light yellow solid. MS: m/e=382.0/384.1 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:64])[F:65])[CH:58]=2)[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:19]1[N:18]=[CH:17][N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:20]=1)=[O:23]
Reactant: O=C(O)c1cn(-c2ccccc2)cn1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(-c2ccccc2)cn1
Reaction time: 0.03 h
Yield: 85.3 %

Procedure:
DIPEA (186 mg, 1.4 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid (60 mg, 0.32 mmol) in DMF (5 mL) followed by HOBt (47 mg, 0.35 mmol) and EDCI (153 mg, 0.8 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (119 mg, 0.35 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water, the solid was collected to afford the 129 mg (86% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: Purity: 473 (M+1), 96.61%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.32 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6-7.48 (t, 3H), 7.46 (t, 1H), 7.36-7.24 (t, 3H), 4.9 (s, 1H), 4.2 (d, 2H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.5 (d, 2H), 2.1 (t, 2H), 1.8 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].O.[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccccc1Br
Yield: 93.9 %

Procedure:
To a solution of 2-(2-bromophenyl)acetic acid (2 g, 9.3 mmol) in anhydrous methanol (20 mL) was added 4-methylbenzenesulfonic acid hydrate (1.767 g, 9.3 mmol). The mixture was heated to reflux for 3 hr. The solvent was removed in vacuum. Ethyl ether and water was added. The organic phase was washed with water and brine, then dried over Na2SO4, filtered and concentrated to give methyl 2-(2-bromophenyl)acetate (2 g, 80%), which was used for next step without purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[NH:14]1[CH2:18][CH2:17][C@@H:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([N:14]3[CH2:18][CH2:17][C@@H:16]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:15]3)=[N:6][C:5]=2[CH:7]=1
Reactant: C1CCN([C@@H]2CCNC2)CC1
Reactant: Clc1nc2cc(Br)ccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2sc(N3CC[C@@H](N4CCCCC4)C3)nc2c1
Temperature: 100 °C

Procedure:
A stirred mixture of 2-chloro-5-bromobenzothiazole (CAS #824403-26-1, catalog #20284, Daxian Chemical Institute Ltd., #179, 10169 New Hampshire Ave., Silver Spring, Md. 20903, 2.485 g, 0.0100 mole), (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride (Reference Example 5c, 2.73 g, 0.0120 mole), and potassium carbonate (6.00 g, 0.04438 mole) in N,N-dimethylformamide (15 mL) is heated to 100° C. with an oil bath for 15 hours. The reaction mixture is cooled to room temperature then poured into water (300 mL). The resulting precipitate is collected by filtration and the filter cake is rinsed with water (600 mL). The solid is dissolved in dichloromethane and the solution is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure to give a solid that is crystallized from hot ethyl acetate to give (R)-5-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole.