Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[CH2:22][C:23]1[CH:32]=C2C(C=CC=C2)=C[CH:24]=1.CC(CCl)=C>CCCCCC.CC(C)=O>[CH:22]([O:13][C:3]1[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[Br:1])=[C:23]([CH3:32])[CH3:24]
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1O
Agent: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C)=COc1c(Br)cc(Br)cc1C(C)(C)C
Temperature: 23 °C
Reaction time: 56 h

Procedure:
In a 3000 mL 3-neck flask, equipped with Ar inlet and magnetic stirrer, is placed 2,4-dibromo-6-tert-butylphenol (70.0 g, 226 mmol), K2CO3 (37.6 g, 276 mmol, 1.2 eq), Nal (3.38 g, 22.6 mmol, 0.1 eq), β-methallyl chloride (33.9 mL, 339 mmol, 1.5 eq), and acetone (1500 mL). The reaction mixture is vigorously stirred at 23° C. for 56 hrs, and monitored by TLC analysis (pet. ether). The solids are removed by filtration, washed with acetone, and the filtrates rotoevaporated (bath temperature kept below 35° C.) to give an oil. The oil is dissolved in hexane (100 mL), and stirred with silica gel (80 g). The slurry is filtered through a pad of Celite, and eluted with additional hexane (6×100 mL). The filtrate is evaporated to give 2,4-dibromo-6-tert-butylphenyl isobutenyl ether as a yellow oil. The material is stored in the freezer and is used as soon as possible.
Reaction SMILES: C(O)C.O.NN.[CH3:7][N:8]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([CH3:17])([CH3:16])[C:10]2[CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=[CH:21][C:9]1=2>[Pd].O>[NH2:22][C:19]1[CH:20]=[CH:21][C:9]2[N:8]([CH3:7])[C:14](=[O:15])[CH2:13][CH2:12][C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Yield: 98.7 %

Procedure:
Added 16 mL of ethanol, 10% Palladium on activated carbon, 50% wet with water for safety (129 mg), and hydrazine monohydrate (200 ul) to 1,5,5-Trimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (257 mg, 1.035 mmol). Heated reaction to 60° C. overnight. Filtered reaction through Celite, and concentrated under reduced pressure to obtain a colorless sticky solid, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (223 mg, 99%). LCMS: m/z=219.04 (M+H+), 1H NMR (400 MHz, DMSO-d6) δ 6.95 (d, 1H, J=8.3 Hz), 6.57 (d, 1H, J=1.5 Hz), 6.48 (dd, 1H, J=8.3, 1.3 Hz), 5.09 (s, 2H), 3.07 (s, 3H), 2.09 (m, 2H), 1.88 (m, 2H), 1.19 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5].[OH-].[K+].Cl[CH:27]([F:29])[F:28]>CC(O)C>[F:28][CH:27]([F:29])[O:1][C:2]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(I)ccc2O)CC1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(I)ccc2OC(F)F)CC1
Temperature: 80 °C

Procedure:
A stirred slurry of tert-butyl 4-(2-hydroxy-5-iodobenzoyl)piperazine-1-carboxylate (7.06 g, 16.33 mmol) and potassium hydroxide (30% aqueous, 120 mL) in 2-propanol (200 mL) at 50° C. was treated with chlorodifluoromethane by bubbling a stream of the gaseous reagent through the stirring reaction mixture for 6 min. The reaction mixture was placed in a Parr high pressure reaction vessel, heated at 80° C. for 16 h and then cooled to ambient temperature. The resulting solution was concentrated to remove 2-propanol and the aqueous portion was extracted with ethyl acetate (3×200 mL). The organic portions were dried (Na2SO4) and concentrated. The residue was purified by reverse phase HPLC to give 5.55 g of tert-butyl 4-(2-(difluoromethoxy)-5-iodobenzoyl)piperazine-1-carboxylate as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].O>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A stirred solution of 1-methylpiperazine (14.6 mL) and triethylamine (19.2 mL) in dry dichloromethane (132 mL) at 10° C. was treated with 4-nitrobenzoyl chloride (23.2 g) portion wise whilst maintaining the temperature below 15° C. After stirring at 10° C. for a further 1 hour the reaction mixture was allowed to warn to room temperature and treated with water (100 mL). The organic phase was then separated and the aqueous phase further extracted with dichloromethane (50 mL). The combined organic extracts were washed with a 0.5 M aqueous solution of sodium carbonate (100 mL), then with brine (100 mL), and then evaporated to low bulk and treated with petroleum ether (80–100° C.) (100 mL). After removal of further solvent, and trituration, the insoluble material collected was washed with petroleum ether (40–60° C.) to give the title compound (30.4 g) as pale orange crystalline solid, m.p. 100–101° C. 1H NMR [(CDCl3]: δ 8.29 (d, 2H), 7.59 (d, 2H), 3.94–3.71 (bs, 2H), 3.52–3.29 (bs, 2H) and 2.58–2.30 (2×brs and s overlapping, 7H).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3C[O:11]3)[CH:7]=[CH:6][C:5]=12>CO>[N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=12
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CO
Product: OCc1ccc2nnnn2c1

Procedure:
A solution of this amine (907 mg) and (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (745 mg) in 20 ml of methanol was heated at reflux for 39 hours. The reaction mixture was concentrated to dryness and chromatographed on silica gel (95:5:1 CH2Cl2 :MeOH:NH4OH) to give 1.27 g of (R)-α-[[(1,1-dimethyl-2-(2-methyl-1H-indol-3-yl))ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C.ClCCl.[Na+].[Cl-]>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 3.5 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A mixture of 2.0 g of 4-nitrobenzoic acid (11.97 mmol), 10.42 mL of diisopropylethylamine (59.84 mmol) and 1.46 mL of 1-methylpiperazine (13.16 mmol) in 40 mL of DMF is cooled to 2-5°C. on an ice bath. 11.53 g (35.9 mmol) of O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU, CAS No.=125700-67-6) are then added portionwise and the mixture is stirred at temperature overnight. The reaction mixture is diluted with dichloromethane and saturated aqueous NaCl solution. After separation of the phases by settling, the aqueous phase is extracted with dichloromethane. The organic phases are combined, dried over Na2SO4, filtered and concentrated under vacuum. The oily residue containing insoluble material is drained by suction and then rinsed with dichloromethane and a small amount of methanol. 1.67 g of the expected product are obtained in the form of a pale pink solid, which is used as obtained without further purification. Yield=56%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([OH:7])[CH2:5][OH:6].[CH3:8][C:9]1([CH3:34])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([CH:21]3[N:26](C4C=CC=CN=4)[CH2:25][CH2:24][C:23](=O)[CH2:22]3)[CH:12]=[CH:11][C:10]1=2.Cl>>[CH3:8][C:9]1([CH3:34])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3[N:26]=[C:25]([N:26]4[CH2:21][CH2:22][CH:23]([NH:1][CH2:2][CH2:3][C@@H:4]([OH:7])[CH2:5][OH:6])[CH2:24][CH2:25]4)[CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: NCC[C@@H](O)CO
Reactant: CC1(C)CCC(C)(C)c2cc(C3CC(=O)CCN3c3ccccn3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(NCC[C@@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS1008 starting from 21 mg (0.199 mmol) of (R)-4-aminobutane-1,2-diol and 80 mg (0.199 mmol) of 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: Cl[CH:2]([C:7](=O)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][N:22]=[N:21][C:20]=1[NH2:25]>O>[CH3:6][O:5][C:3]([C:2]1[N:21]2[N:22]=[CH:23][CH:24]=[C:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[C:20]2=[N:25][C:7]=1[CH2:8][CH3:9])=[O:4]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: Cc1ccc(-c2ccnnc2N)c(C)c1
Solvent: O
Product: CCc1nc2c(-c3ccc(C)cc3C)ccnn2c1C(=O)OC
Temperature: 155 °C
Yield: 37 %

Procedure:
Methyl 2-chloro-3-oxopentanoate (5 mL) was added to 4-(2,4-dimethylphenyl)-3-pyridazineamine (640 mg, 3.2 mmol), and the mixture was heated at 155° C. for 30 minutes. Water was added to the resulting reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 5N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: N-hexane=1:3) to give the title compound (373 mg, 37%) as a brown oil.
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.CS([Cl:16])(=O)=O.CCN(CC)CC>C(Cl)Cl>[CH3:11][N:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:3]1[CH2:2][Cl:16]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(CO)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(CCl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A stirred solution of the above alcohol (43) (0.13 g, 0.83 mmol) in dry CH2Cl2 (5 mL) at 0° C. was treated with methanesulfonyl chloride (0.36 mL. 1.25 mmol), followed by Et3N (0.50 mL). After stirring at 0° C. for 15 min, the mixture was evaporated to dryness under reduced pressure at room temperature, and the resulting brown solid was partitioned between water and EtOAc. Workup of the organic layer gave a crude product which was was chromatographed on silica gel. Elution with CH2Cl2 /petroleum ether (1:1) gave 1-methyl-2-chloromethyl-5-nitropyrrole (44) (0.13 g, 88%), mp (EtOAc/petroleum ether) 82.5-83.5° C. 1H NMR (CDCl3) δ 7.16 (d, J=4.4 Hz, 1 H, H-4), 6.26 (d, J=4.4 Hz, 1 H, H-3), 4.60 (s, 2 H, CH2Cl), 4.02 (s, 3 H, CH3). Anal. Calculated for C6H7ClN2O2 : C, 41.3; H, 4.0; N, 16.0. Found: C, 41.4; H, 4.0; N, 15.9%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([F:15])[CH:7]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[N:22]1([CH:28]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=2)[CH3:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH:38][CH2:37][CH2:36][C:33]3[CH:32]=[CH:31][C:30]([CH:28]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH3:29])=[CH:35][CH:34]=3)=[O:12])=[C:8]([F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(c1ccc(CCN)cc1)N1CCCCC1
Reactant: O=C(O)c1ccc(OCC2CC2)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(c1ccc(CCNC(=O)c2ccc(OCC3CC3)cc2F)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-2-fluorobenzoic acid (242 mg, 1.15 mmol) and dimethylformamide (1 drop) in tetrahydrofuran (3 ml) was added dropwise oxalyl dichloride (113 μl, 1.30 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in tetrahydrofuran (3 ml). The solution was added dropwise to a solution of 2-{4-[1-(1-piperidinyl)ethyl]phenyl}ethylamine (310 mg, 1.02 mmol) obtained in Reference Example 15 and triethylamine (558 μl, 4.00 mmol) in tetrahydrofuran (2 ml) at 0° C., and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (200 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:6]=1[C:14](=O)[C:15]([N:17]([CH3:24])[N:18]=[C:19]([CH3:23])[CH2:20][S:21][CH3:22])=[O:16])[CH3:4].O>O1CCCC1>[CH2:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:6]=1[C:14]1[C:15](=[O:16])[N:17]([CH3:24])[N:18]=[C:19]([CH3:23])[C:20]=1[S:21][CH3:22])[CH3:4]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CSC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1-c1c(SC)c(C)nn(C)c1=O
Yield: 40.6 %

Procedure:
To a 200 ml volume four-necked flask, tetrahydrofuran (anhydrous) (27.0 ml) and sodium hydride (1.90 g) were added under a nitrogen atmosphere at about 0° C., and stirred. Then, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(1)-39) (14.2 g) dissolved in tetrahydrofuran (anhydrous) (45 ml) was added dropwise over 30 minutes, and then the mixture was stirred at 0° C. for 2 hours. Then, to the mixture was added water (100 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:ethyl acetate=4:1) to give 5.45 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfanyl-2,3-dihydro-3-pyridazinone.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[C:17](=[O:25])[C@@H:16]1[CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49](O)([CH3:52])([CH3:51])[CH3:50].CCN=C=NCCCN(C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:49]([O:23][C:22](=[O:24])[CH2:21][N:18]1[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C@@H:16]([CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C:17]1=[O:25])([CH3:52])([CH3:51])[CH3:50]
Reactant: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)O)C(=O)[C@@H]2CCCNC(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)N2CCN(CC(=O)OC(C)(C)C)C(=O)[C@@H]2CCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 50 ml of dichloromethane were dissolved 1.7 g of (S,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid produced in Reference Example 34, 2 ml of tert-butanol and 1.6 g of 4-dimethylaminopyridine. To the solution was then added 0.6 g of WSC, and the mixture was stirred for 24 hours at room temperature. Dichloromethane was distilled off, and the residue was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous saline solution, which was then dried (Na2SO4), followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (AcOEt), followed by crystallization from ether/hexane to afford 1.02 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)=[CH:3][CH:2]=1.BrC1C=CC(C2C=CC([C:31]#[N:32])=CC=2)=CC=1>CO>[O:9]1[CH:10]=[CH:11][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:12]3[CH:17]=[CH:16][C:15]([C:31]#[N:32])=[CH:14][CH:13]=3)=[CH:2][CH:3]=2)=[CH:8]1
Reactant: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cc1
Solvent: CO
Product: N#Cc1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Yield: 53 %

Procedure:
As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, crude 4′-bromo-biphenyl-4-carbonitrile (200 mg, 0.775 mmol) and 3-fuiranboronic acid (see Thompson, W. J.; Gaudino, G. J. Org. Chem. 1984, 49, 5237-5243; 105 mg, 0.937 mmol) in MeOH (2 mL) were coupled to give a yellow solid, which was purified via preparative TLC. Elution with EtOAc:benzene (1:99) provided 100 mg (53%) of 4′-furan-3-yl-biphenyl-4-carbonitrile as a grey powder, mp 199-203° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]=O.[CH3:13][C:14]([CH3:16])=[O:15]>O>[Cl:3][C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: CC(C)=O
Reactant: O=Cc1cc(F)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydroxide (0.78 g) was dissolved in water (55 ml) and treated dropwise with acetone (55 ml) followed by a solution of 2-chloro-5-fluorobenzaldehyde (2.8 g) in acetone (10 ml). The reaction mixture was stirred at room temperature for 2 hours. Acetone was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and concentrated under reduced 5 pressure to obtain 4-(2-chloro-5-fluorophenyl)-3-buten-2-one (0.24 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)([C:11]#N)[CH3:10])[CH:7]=1.CC(C[AlH]CC(C)C)C.CC[O:41]CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6]([CH2:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)([CH:11]=[O:41])[CH3:10])[CH:7]=1
Reactant: COc1c(CC(C)(C#N)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COc1c(CC(C)(C=O)c2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 34 %

Procedure:
To a solution of 288 (766 mg, 1.599 mmol) in DCM (10 mL) at 0° C. was added DIBAL (3.2 mL, 3.2 mmol, 1.0M in DCM). The reaction mixture was gradually warmed to RT overnight. LCMS indicated incomplete conversion. Additional DIBAL (3.2 mL, 3.2 mmol) was added and the reaction mixture was stirred for an additional 5 h. The reaction mixture was cooled to 0° C. and diluted with ether (20 mL). The reaction was quenched by careful addition of 6N HCl (1.5 mL). The resulting suspension was extracted with EtOAc and the organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatograph eluting with an EtOAc/hexane gradient (20% to 30% EtOAc) to afford 263 mg (34%) of N-{4-[2-(5-bromo-3-tert-butyl-2-methoxy-phenyl)-1-formyl-1-methyl-ethyl]-phenyl}-methanesulfonamide (292) as a tan oil.
Reaction SMILES: [11CH3][NH:2][C:3]([C:5]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11]([OH:21])([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:4].[OH-].[K+]>CC(O)(C)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2([OH:21])[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][C:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:3]([NH2:2])=[O:4])[CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: [11CH3]NC(=O)C(CCN1CCC(O)(c2ccc(Cl)cc2)CC1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: NC(=O)C(CCN1CCC(O)(c2ccc(Cl)cc2)CC1)(c1ccccc1)c1ccccc1
Yield: 37 %

Procedure:
Slow hydrolysis of the alkylation product (compound 1) with KOH in t-BuOH at 100° C. for 2-3 days gave the required precursor (4-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)-2,2-diphenylbutanamide; compound 2 in the scheme above) in about 37% yield. Intermediate nitrile and amide precursor were characterized by spectroscopic techniques including 1H and 13C NMR, and LC-MS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=O)[CH3:9])[CH:3]=1.O.[NH2:12][NH2:13]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[C:8](=[N:12]\[NH2:13])/[CH3:9])[CH:3]=1
Reactant: CC(=O)c1cc(Br)ccn1
Reactant: NN
Solvent: O
Solvent: CO
Product: C/C(=N/N)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 1-(4-bromopyridin-2-yl)ethanone (2.4 g, 12 mmol) in MeOH (40 mL) was added hydrazine monohydrate (2.9 mL, 60 mmol) in one portion. After stirring at room temperature for 2 hours, the mixture was concentrated to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=5.3 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.33 (dd, J=5.3, 1.8 Hz, 1H), 5.66 (br s, 2H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:33][CH3:34])[C@:4]1([CH3:32])[C@@H:9]([OH:10])[C@H:8]([N:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:12][C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)[C:7]2[CH:25]=[C:26]([N+:29]([O-])=O)[CH:27]=[CH:28][C:6]=2[O:5]1.[BH4-].[Na+].C(OCC)(=O)C>CO.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:29][C:26]1[CH:27]=[CH:28][C:6]2[O:5][C@@:4]([CH:3]([O:33][CH3:34])[O:2][CH3:1])([CH3:32])[C@@H:9]([OH:10])[C@H:8]([N:11]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:12][C:13]3[NH:14][CH:15]=[CH:16][N:17]=3)[C:7]=2[CH:25]=1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@@H]1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(OC)[C@@]1(C)Oc2ccc(N)cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@@H]1O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To the solution of the nitro compound (177 mg, 0.36 mmol) prepared from example 1 in methanol (2 mL) was added a 0.4 M aqueous solution of Cu(OAc)2 (0.38 mL, 0.15 mmol), then slowly added sodium borohydride (113 mg, 3.0 mmol) over 30 min. The reaction mixture was stirred for an hour at room temperature, and ethyl acetate (5 mL) was added to the reaction. The black precipitates were removed by filtration, then to the filtrate was added a saturated aqueous solution of NaHCO3 (5 mL). The mixture was extracted with ethyl acetate (30 mL), and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:4) to afford the title compound (58 mg, 35%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:12])([O-])=O>CC1CCCO1.[Pt](=O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=[O:12]
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Agent: O=[Pt]=O
Solvent: CC1CCCO1
Product: Nc1ccccc1CC(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
20.00 g (56.59 mmol, 1.0 eq) 2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-phenylacetamide from Example 1 are placed in 280 mL 2-methyltetrahydrofuran. The solution is hydrogenated in the presence of 2.00 g platinum dioxide at 20° C. The catalyst is filtered off and washed with 20 ml of 2-methyltetrahydrofuran. The product is not isolated, but used as a solution in the next step.