Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18]>C(O)C>[C:8]([C:7]1[C:2]([NH:20][CH2:19][CH2:17][OH:18])=[N:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][CH:11]=2)[CH:6]=1)#[N:9]
Reactant: NCCO
Reactant: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1Cl
Solvent: CCO
Product: N#Cc1cc(-c2cc[n+]([O-])cc2)cnc1NCCO

Procedure:
5 g 2-Chloro-3-cyano-5,4'-bipyridine-1'-oxide and 8 ml ethanolamine are refluxed in 50 ml ethanol for 4 hours and then concentrated under vacuum. The residue is taken up in water, filtered off with suction, washed with water, dried at 110° C. and crystallized from ethanol/glacial acetic acid with addition of activated charcoal. Yield: 4.5 g (81.3% of the theoretical yield), with a melting point of 229° C.-231° C.
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18](Cl)=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1>ClCCl>[F:30][C:31]1[CH:32]=[C:33]([F:37])[CH:34]=[CH:35][C:36]=1[C:18](=[O:19])[C@H:17]([N:14]1[C:15](=[O:16])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:25])([F:1])[CH:22]([F:24])[F:23])=[CH:6][CH:7]=2)[CH:12]=[N:13]1)[CH3:21]
Reactant: Fc1cccc(F)c1
Reactant: C[C@H](C(=O)Cl)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@H](C(=O)c1ccc(F)cc1F)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 0 °C
Yield: 61 %

Procedure:
(2R)-2-[4-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoyl chloride (1 g) was dissolved in 20 ml of dichloromethane, to which 2.5 ml of 1,3-difluorobenzene and 1.50 g of anhydrous aluminium chloride in a powdery form were added. The mixture was refluxed with heating for eight hours. After cooling, the reaction solution was poured into 50 ml of ice water and extracted from a mixture of 100 ml of ethyl acetate and 50 ml of diisopropyl ether. The extract was washed with 30 ml of 1N-hydrochloric acid and 30 ml of a saturated aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 60 g, eluent; hexane:ethyl acetate:acetic acid=2:1:0.03) to give 0.77 g of 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (yield: 61%) as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:23]=[CH:22][C:8]([CH:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]/[C:11]/2=[N:20]\[OH:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:24](I)[CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl.O>[CH2:24]([O:21]/[N:20]=[C:11]1/[C:10](=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=2)[C:19]2[C:14]([CH2:13][CH2:12]/1)=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:25]
Reactant: CS(=O)(=O)c1ccc(C=C2/C(=N/O)CCc3ccccc32)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCO/N=C1\CCc2ccccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Temperature: 62.5 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
(E)-1-(4-methanesulfonyl-benzylidene)-3,4-dihydro-1H-naphthalene-2-one oxime (50 mg, 0.15 mmol), ethyl iodide (0.0147 ml, 0.18 mmol) and potassium carbonate (0.063 g, 0.46 mmol) were added into dimethylformamide (2.0 ml). Then, the solution was stirred at 60-65° C. overnight, and cooled to room temperature. Again, water and dichloromethane were added, and an organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to remove organic solvent. The residue was purified through silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2, v/v). As a result, 44 mg of the present compound (productive yield 81%) was obtained as a white solid crystal.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[O:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:7][CH2:6]1.N1C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([NH2:38])=[N:35][C:36]=2[CH3:37])[CH:27]=[CH:26][N:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([NH:38][C:1]([N:13]3[CH2:14][CH2:15][N:11]([CH:8]4[CH2:7][CH2:6][O:5][CH2:10][CH2:9]4)[C:12]3=[O:16])=[O:2])=[N:35][C:36]=2[CH3:37])[CH:27]=[CH:26][N:25]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Reactant: O=C1NCCN1C1CCOCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(Cl)c1
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
Phosgene (20% in toluene, 2.62 g, 5.3 mmol) was treated with a solution of Example B1 (0.27 g, 1.59 mmol) and pyridine (0.43 mL, 5.3 mmol) in DCM (5 mL), stirred for 15 min, then concentrated to dryness. The residue was dissolved in DCM (5 mL), treated with a solution of Example A7 (0.25 g, 1.06 mmol) and TEA (0.74 mL, 5.3 mmol) in DCM (5 mL) and stirred at RT for 1 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (0.24 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1 H), 8.27 (d, J=5.8 Hz, 1 H), 7.90 (d, J=8.8 Hz, 1 H), 7.65 (d, J=8.8 Hz, 1 H), 7.02 (d, J=2.3 Hz, 1 H), 6.92 (dd, J=5.8, 2.3 Hz, 1 H), 3.94-3.84 (m, 5 H), 3.48-3.35 (m, 4 H), 2.21 (s, 3 H), 1.74-1.66 (m, 2 H), 1.60 (d, J=12.5 Hz, 2 H); MS (ESI) m/z: 432.1 (M+H+).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]([NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([C:40]4[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[CH:41]=4)=[N:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:14]=3[CH:13]=2)=[O:10])=CC=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>O1CCOCC1>[OH:55][C:49]([C:51]([F:54])([F:53])[F:52])=[O:50].[CH3:46][C:42]1[CH:41]=[C:40]([C:18]2[C:15]3[CH:16]=[N:17][C:12]([NH:11][C:9]([NH2:8])=[O:10])=[CH:13][C:14]=3[NH:20][N:19]=2)[CH:45]=[CH:44][N:43]=1
Reactant: COc1ccc(CNC(=O)Nc2cc3c(cn2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1cc(-c2n[nH]c3cc(NC(N)=O)ncc23)ccn1
Reaction time: 5 h
Yield: 19 %

Procedure:
A crude mixture of 1-(4-methoxybenzyl)-3-(3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea prepared according to Scheme 6 (35 mg, 0.055 mmol) in 1,4-dioxane (0.25 mL) was treated at room temperature with TFA (0.25 mL) and the reaction mixture stirred for 5 h, then additional TFA (0.25 mL) was added and the reaction mixture stirred for 16 h at room temperature and then concentrated in vacuo. The residue was purified by MS-directed reverse phase preparative-HPLC (C-18 stationary phase, eluting with a H2O/MeCN gradient with 0.1% TFA), to give 1-(3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)urea TFA salt as a yellow solid (4 mg, 0.01 mmol, 19%). MS ESI calc'd. for C13H13N6O [M+H]+ 269, found 269. 1H NMR (600 MHz, DMSO-d6) δ 13.82 (br s, 1H), 9.31 (s, 1H), 9.19 (s, 1H), 8.70 (s, 1H), 8.30-8.15 (m, 2H), 7.88 (s, 1H), 2.70 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[C:6]=1[Cl:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)Nc1cc(C(C)(C)C)[nH]n1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1n[nH]c(C(C)(C)C)c1Cl

Procedure:
5.8 g (0.03 mole) of 5-t-butyl-3-propionylaminopyrazole prepared in Example 5 was dispersed in 30 ml of chloroform, and the dispersion was stirred while adding dropwise thereto sulfuryl chloride. The mixture was further heated under reflux conditions for one hour, and the solvent was distilled off. To the residue was added a sodium bicarbonate aqueous solution whereby crystals were precipitated. The crystals were collected by filtration, washed with water and then dried to obtain 3.9 g of 5-t-butyl-4-chloro-3-propionylaminopyrazole. This product was recrystallized from hydrous methanol and found to have a melting point of 136° to 137° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C([N:14]([CH2:17][CH3:18])CC)C.O1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:5]([O:4][C:2]([NH:14][CH:17]([CH2:18][CH2:20][CH2:21][CH2:22][CH2:23][CH2:10][CH2:11][CH2:6][CH2:7][CH2:8][CH2:9][CH2:23][CH2:22][CH2:21][CH3:20])[C:2]([OH:4])=[O:3])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CCOC1
Product: CCCCCCCCCCCCCCCC(NC(=O)OCc1ccccc1)C(=O)O

Procedure:
6.82 g (40 mmol) of benzyl chloroformate (Z--Cl) is added in drops to 10 g (35.03 mmol) of the title compound of Example 19a and 8.86 g (87.57 mmol) of triethylamine in 200 ml of tetrahydrofuran at 0° C. It is stirred for 5 hours at 0° C. It is evaporated to the dry state in a vacuum, the residue is taken up in 300 ml of dichloromethane and washed twice with 200 ml of 5% aqueous hydrochloric acid each. The organic phase is dried on magnesium sulfate and evaporated to the dry state. The residue is recrystallized from diisopropyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]=[C:24]=[O:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:22][NH:23][C:24](=[O:25])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:9][CH2:10][C:11](=[O:21])[N:12]2[CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:3]=1
Reactant: CN=C=O
Reactant: O=C1CCC(c2cccc(O)c2)N1CCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCC(=O)N2CCN2CCOCC2)c1
Yield: 89 %

Procedure:
To a solution of 5-(3-hydroxyphenyl)-1-[2-(4-morpholinyl)ethyl]-2-pyrrolidinone (1.1 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.26 ml) at ambient temperature, with stirring, over ten mins. Milled potassium carbonate was added, and the reaction mixture was stirred for 17 hrs. The mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, ether/0-50% methanol). The appropriate fractions were collected and concentrated to give 1.2 g (89%) of product. Crystallization of the residue from ether gave the analytical sample, mp 100°-102° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][N:12]([CH2:20][CH2:21][CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:15]([O:14][C:13](=[O:19])[N:12]([CH2:20][CH2:21][CH:22]([O:27][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]([CH3:10])[N:9]=1)[C:23]([F:26])([F:25])[F:24])[CH3:11])([CH3:18])([CH3:16])[CH3:17]
Reactant: CN(CCC(O)C(F)(F)F)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C#N)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(OC(CCN(C)C(=O)OC(C)(C)C)C(F)(F)F)n1
Reaction time: 96 h
Yield: 31.2 %

Procedure:
A mixture of 2-chloro-6-methylnicotinonitrile (0.215 g, 1.41 mmol) and tert-butyl N-methyl-N-(4,4,4-trifluoro-3-hydroxybutyl)carbamate (0.345 g, 1.34 mmol) in DMF (6 mL) was treated with caesium carbonate (0.875 g, 2.69 mmol) at ambient temperature. After stirring for 4 days, the mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were washed (water, brine), dried, and evaporated to an orange oil/solid mixture. The crude material was purified by silica gel chromatography, eluting with 100% dichloromethane and 5% methanol/95% dichloromethane (v/v) to give the product as a yellow oil (0.156 g, 31%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[C:37]([Cu])#[N:38]>CN1CCCC1=O>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:9]2[C:10]3[N:11]([C:14](=[O:28])[N:15]([CH2:17][C:18]4[CH:19]=[N:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)[N:16]=3)[CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:37]#[N:38])=[CH:3][CH:4]=2)=[CH:30][CH:31]=1
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2c(-c3ccc(C#N)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Temperature: 250 °C

Procedure:
Into a microwave reaction vial were placed 7-(4-chlorophenyl)-8-(4-methoxyphenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (51 mg, 0.10 mmol), CuCN (89.5 mg, 1.0 mmol), and 1-methylpyrrolidin-2-one (1.0 mL, dry). This mixture was heated to 250° C. in a microwave reactor for 8 h. HPLC/MS analysis indicated 55% conversion to desired product. The reaction mixture was cooled to room temperature and poured into 10% aqueous ammonium hydroxide solution. The resulting mixture was stirred at room temperature for 1 h. Solid was filtered off and purified by reverse phase preparative HPLC (without TFA). The title compound (8.6 mg) was obtained as a light yellow solid. HPLC/MS: retention time=3.5 min, [M+H]+=502.
Reaction SMILES: [C:1](=S)(OCC)[S-:2].[K+].[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[C:12]=1[OH:18])=[O:10]>C(O)C>[C:9]([C:11]1[C:12]2[O:18][C:1]([SH:2])=[N:17][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:8]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1cccc2nc(S)oc12
Yield: 92.5 %

Procedure:
Potassium O-ethyl dithiocarbonate (241 mg, 1.5 mmol) was added to a solution of 3-amino-2-hydroxyacetophenone (113 mg, 0.75 mmol) in ethanol (10 ml) and the mixture was heated to reflux for 16 hours. The reaction was concentrated, water (20 ml) was added thereto and the mixture was adjusted to pH, 3-4 with diluted hydrochloric acid. The separated matter was collected by filtration and dried by heating in vacuo to provide 134 mg (yield 92%) of 7-acetyl-2-mercaptobenzooxazole as a dark solid.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([NH:16][CH:17]1[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:27][CH2:28]Cl)[C:18]1=[O:30])=[O:15])=[CH:8]2>CN(C=O)C.CCOC(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([NH:16][CH:17]1[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:27][CH2:28][S:2][CH3:1])[C:18]1=[O:30])=[O:15])=[CH:8]2
Reactant: C[S-]
Reactant: O=C(NC1Cc2ccccc2N(CCCl)C1=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 80 °C
Yield: 37.1 %

Procedure:
Sodium thiomethoxide (280 mg, 4.00 mmol) and KI (10 mg, 0.06 mmol) were added to a soluton of 5-chloro-N-[1-(2-chloroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Method 3; 1.07 g, 2.67 mmol) in DMF (10 mL) under an inert atmosphere and heated at 80° C. for 2 hours. On cooling the mixture was diluted with EtOAc (100 mL), washed with water (20 mL), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:THF (2:23)) to give a white solid. The solid was triturated with refluxing Et2O (20 mL) and the solid filtered, washed with Et2O (10 mL) then hexane (10 mL) to afford the title compound (410 mg, 37%) as an off white solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:29][CH3:30])[C:25](OC)=[O:26])[C:5]1=[O:31])[CH:2]=[CH2:3].[BH4-].[Li+]>CCOCC.C1COCC1>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:29][CH3:30])[CH2:25][OH:26])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate and (R)-methyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate (1.73 g, 3.64 mmol) (mixture of stereoisomers from Example 91, Step A) in 27 mL of Et2O and 9 mL of THF was added a solution of lithium tetrahydroborate in THF (0.238 mL, 7.28 mmol) at 0° C. The resulting solution was stirred at 25° C. for 2 h. The reaction was quenched (10% citric acid), extracted (2×EtOAc) and washed (1×Sat. aq. NaCl solution). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0-60% EtOAc in hexanes) to give the title compound as the faster eluting isomer.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:34][C:35]3[CH:36]=[C:37]([C:45]([F:47])([F:48])[F:46])[CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)c1
Yield: 85.2 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (85 mg, 0.19 mmol) in CH3CN (5 ml) was added 1-Bromomethyl-3,5-bis-trifluoromethyl-benzene (88.0 mg, 0.29 mmol), and diisopropylethylamine (66 μl, 0.38 mmol). The reaction was microwaved at 130° C. for 10 minutes. The reaction was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (109 mg, 85%). Calcd for C35H36F9NO2 (M+H) 673.65, Found 675.4
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:51][CH:52]1[C@H:56]2[C@H:57](OC3CCCCO3)[N:58](C(OC(C)(C)C)=O)[C:59]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][C:53]1=[CH2:83])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[C@H:23]2[C@H:24](OC3CCCCO3)[N:25](C(OC(C)(C)C)=O)[C:26]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][C:20]1=[CH2:50].C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:17]([O:18][CH:19]1[C@@H:23]2[CH:24]=[N:25][C:26]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][C:20]1=[CH2:50])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:51][CH:52]1[C@@H:56]2[CH:57]=[N:58][C:59]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][C:53]1=[CH2:83]
Reactant: C=C1CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@@H]2C1OCCCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C=C1CN2C(=O)c3cc(OC)ccc3N=C[C@H]2C1OCCCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N=C[C@@H]12
Reaction time: 1 h
Yield: 61.9 %

Procedure:
95% TFA (2 mL) was added dropwise to dimer compound 28c (90 mg, 0.084 mmol) at 0° C. which was stirred for 1 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL) and the organic layer washed with water (20 mL), brine (20 mL), dried (MgSO4) and filtered. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 29c (34 mg, 0.052 mmol, 61%) as a solid: [α]26D=+309° (c=0.31, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.31-1.39 (m, 8H, 15-H, 16-H), 1.40-1.51 (m, 4H, 14-H), 1.80-1.93 (m, 4H, 13-H), 2.89-3.10 (m, 2H, 1-H), 3.06-3.19 (m, 2H, 1-H), 3.81-3.95 (m, 8H, 11a-H, 7-OMe), 3.98-4.11 (m, 4H, 12-H), 4.28 (s, 4H, 3-H), 5.16-5.18 (m, 4H, 2a-H), 6.80 (s, 2H, 9-H), 7.49 (s, 2H, 6-H), 7.66 (d, 2H, J=4.56 Hz, 11-H); 13C NMR (CDCl3, 100 MHz): δ 25.8, 28.8, 29.2, 29.4, 35.2, 51.3, 53.8, 56.2, 69.0, 109.3, 110.4, 111.4, 119.5, 140.7, 141.7, 151.1, 162.4, 164.8; IR (neat): 2933, 1599, 1506, 1464, 1429, 1380, 1262, 1216; 1096, 729, 628 cm−1; MS (ES+) m/z (relative intensity) 655 ([M+H]+., 100), 656 ([M+2H]+., 50), 346 (97).
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[NH2:7].[CH3:8][N:9](C)[CH:10]=[O:11]>>[NH2:7][CH:3]([C@H:4]1[CH2:8][NH:9][C:10](=[O:11])[CH2:5]1)[CH3:2]
Reactant: CN
Reactant: CN(C)C=O
Reactant: C1CCOC1
Product: CC(N)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 mg I.14 was suspended in 1 mL dimethylformamide, 1 mL tetrahydrofuran and 4 mL methylamine solution (40% in water) and stirred at 40° C. overnight. The mixture was concentrated half, 20 mL water and dioxane was added and the mixture stirred at ambient temperature for 30 min. The solid was filtered off and the filtrate was concentrated. The crude was dissolved in methanol and dichloromethane and purified via chromatography (amino phase: dichloromethane/methanol 80:20) and the appropriate fractions combined and concentrated.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>O>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:3][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH2:2])=[O:19])=[CH:21][CH:22]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1ccccc1
Solvent: O
Product: C=C(OC(=O)c1ccc(C(C)(C)C)cc1)c1ccccc1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
A mixture of 4.16 g (21.62 mmol) of acetophenone trimethylsilylenol, 4.33 g (22.01 mmol) of 4-tert-butylbenzoyl chloride and 136 mg of mercuric chloride was heated at 100° C. for 2 h. The mixture was then left to cool, water was added over the reaction crude and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. A 2.12 g sample was purified by flash chromatography (hexane:dichloromethane 3:1) giving 1.17 g of 1-phenylvinyl 4-tert-butylbenzoate. Yield 57%.