Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=2[C:11]=1[CH2:12]Br)=[O:6])[CH3:3].[CH2:34]([OH:36])[CH3:35]>>[CH2:2]([O:4][C:5]([C:7]1[O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=2[C:11]=1[CH2:12][O:36][CH2:34][CH3:35])=[O:6])[CH3:3]
Reactant: CCOC(=O)c1oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c2c1CBr
Reactant: CCO
Agent: [Na]
Product: CCOCc1c(C(=O)OCC)oc2cccc(OCCCN(C(=O)OC(C)(C)C)C(C)(C)C)c12
Reaction time: 0.42 h

Procedure:
To ethanol (2.0 ml) was added sodium metal (15 mg) at room temperature. After 25 minutes, 3-bromomethyl-4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (98 mg) was added to the reaction mixture. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (10 ml) and water (20 ml). The product was extracted with ethyl acetate (10 ml) 3 times. Organic layer was combined and dried over anhydrous sodium sulfate, concentrated in vacuo to dryness. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate to give 4-[3-(tert-butoxycarbonyl-tert-butyl-amino)-propoxy]-3-ethoxymethyl-benzofuran-2-carboxylic acid ethyl ester (70 mg) as a pale yellow oil. FAB-MS: m/z 478 (MH+); 1H-NMR (CDCl3): δ 1.22 (3H, t, J=6.9 Hz), 1.37-1.47 (21H, m), 2.09 (2H, quintet, J=7.3 Hz), 3.54 (2H, t, J=7.3 Hz), 3.62 (2H, q, J=6.9 Hz), 4.12 (2H, t, J=7.3 Hz), 4.45 (2H, q, J=7.3 Hz), 5.06 (2H, s), 6.65 (1H, d, J=7.9 Hz), 7.14 (1H, d, J=7.9 Hz), 7.33 (1H, dd, J=7.9 Hz, 7.9 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:32][O:33][CH2:34][CH2:35][NH:36][CH3:37]>CN1C(=O)CCC1>[CH3:32][O:33][CH2:34][CH2:35][N:36]([CH3:37])[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNCCOC
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccnc(Cl)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COCCN(C)c1nccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)n1
Temperature: 120 °C

Procedure:
To 31.4 mg (0.10 mmol) N-(1-(4-((2-chloropyrimidin-4-yl)ethynyl)phenyl)propan-2-yl)-acetamide (170) and 25.8 μl (0.15 mmol) DIPEA in 1 mL NMP are added 26.7 mg (0.30 mmol) N-(2-methoxyethyl)methylamine. The reaction mixture is stirred in a sealed tube at 120° C. over night and purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C(N(CC)CC)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:22](=[O:23])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([F:13])([F:25])[F:24]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(F)(F)F)c1c(O)c2ccccc2oc1=O

Procedure:
According to the procedure of example 17, 4-hydroxycoumarin (2.00 g. 12.8 mmol) and 2-trifluoromethylphenylisocyanate(1.93 ml, 12.8 mmol) were reacted in the presence of triethylamine (0.05 ml) to generate the title compound as an off-white solid, mp 157°-159°]C., (2.2 g, 6.30 mmol, 49.3%). Analysis: Calculated for C17H10NO4F3 : C, 58.45; H, 2.86; N, 4.01. Found: C, 58.47; H, 3.04; N, 4.02. 1H NMR (CDCl3): 8.06 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.38 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([OH:25])=O)=[CH:13][C:12]=2[N:11]=1.S(Cl)(Cl)=O.[CH:30]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C1COCC1>[CH:30]1([CH2:36][NH:37][C:23]([C:14]2[C:15]3[O:19][C:18]([CH3:20])=[N:17][C:16]=3[C:21]3[NH:22][C:10]([NH:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])=[N:11][C:12]=3[CH:13]=2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NCC1CCCCC1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)NCC1CCCCC1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Yield: 32.1 %

Procedure:
The title compound was prepared following the procedure described for Example-181 using 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.050 g, 0.132 mmol), thionyl chloride (2.0 mL), 1-cyclohexylmethanamine (0.023 g, 0.138 mmol), THF (5.0 mL) and DIPEA (0.086 g, 0.663 mmol). The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH: DCM to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.04-1.31 (m, 6H), 1.62-1.75 (m, 5H), 2.54 (s, 3H), 3.00 (t, J=18.6 Hz, 2H), 7.34 (s, 1H), 7.53-7.59 (m, 3H), 7.94 (s, 1H), 9.39 (s, 1H), 11.51 (s, 1H); MS [M+H]+: 472.43.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH2:39](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:40]1[CH:45]=CC=C[CH:41]=1>>[CH2:6]([NH:8][C@H:9]([C:14]([NH:36][C@@H:33]1[C@@H:31]2[C@@H:30]([CH2:29][N:28]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:37])[F:38])=[CH:24][CH:23]=3)(=[O:26])=[O:27])[CH2:32]2)[CH2:35][CH2:34]1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:40]([CH3:45])([CH3:41])[CH3:39]
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-4-methyl-2-(neopentylamino)pentanoic acid from Step A of Example 244 for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.20-8.23 (m, 1H), 8.13-8.16 (m, 2H), 7.89-7.92 (m, 2H), 4.21-4.29 (m, 1H), 3.86 (dd, J=9.9, 2.8 Hz, 1H), 3.22-3.28 (m, 1H), 3.15-3.22 (m, 2H), 2.99 (dd, J=9.6, 7.0 Hz, 1H), 2.50-2.62 (m, 2H), 2.43-2.47 (m, 1H), 2.28-2.32 (m, 1H), 1.92-2.02 (m, 1H), 1.80-1.92 (m, 2H), 1.64-1.76 (m, 1H), 1.69 (ddd, J=13.5, 7.7, 5.8 Hz, 1H), 1.50-1.61 (m, 2H), 1.25-1.40 (m, 1H), 0.93 (d, J=6.8 Hz, 3H), 0.93 (s, 9H), 0.86 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 518 (M+H)+.
Reaction SMILES: Br[CH:2]=[CH:3]Br.[Li]CCCC.[CH3:10][O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3>C1COCC1.C(Cl)Cl>[C:2]([C@@:23]1([OH:31])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:13]2([CH3:14])[C@H:15]3[CH2:16][CH2:17][C@@H:12]2[O:11][CH3:10])[CH2:22]1)#[CH:3]
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrC=CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 4.3 %

Procedure:
A solution of 1,2-dibromoethylene (1.7 mL, 21 mmol) in dry THF (25 mL) was treated with n-BuLi (16.8 mL, 2.5M in THF, 42 mmol) at -65° C. After stirring the mixture at -70° C. for 0.25 hr, a solution of 17β-methoxy-5α-androstan-3-one (2.128 g, 7 mmol) in THF (22 mL) was added and the mixture was stirred at -78° C. for 30 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3-hydroxy-17β-methoxy-5α-androstane (100 mg) as a colorless solid; mp 138-145° C.; TLC Rf (hexane:acetone 7:3)=0.45; and then 3β-ethynyl-3α-hydroxy-17β-methoxy-5α-androstane (1.6 g) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:15]3[CH2:14][CH2:13][CH:12]([N:10]4[CH:11]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[NH:8][C:9]4=[O:18])[CH2:17][CH2:16]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C1=O
Yield: 46 %

Procedure:
Title compound was prepared from 4-phenyl-1-(piperidin-4-yl)-1H-imidazol-2(3H)-one in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 46% yield. MS m/e (M+H)+=589.2. 1H NMR (500 MHz, DMSO-D6): δ=13.55 (s, 1H), 10.68 (s, 1H), 8.37 (s, 1H), 7.50 (d, J=7.63, 2H), 7.32 (t, J=7.02, 2H), 7.24 (s, 1H), 7.16 (m, 2H), 5.37 (d, J=14.34, 1H), 4.63 (d, J=16.79, 1H), 4.51 (t, J=10.83, 1H), 4.13 (m, 2H), 3.89 (m, 1H), 3.57 (m, 1H), 3.18 (m, 1H), 3.03 (m, 3H), 2.89 (t, J=15.11, 1H), 2.66 (m, 1H), 2.34 (d, J=16.17 1H), 1.84 (m, 3H), 1.60 (m, 1H), 0.73 (d, J=13.73, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1(C(OCC)=O)[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][NH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl.[C:24](=O)(O)[O-:25].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH2:24][OH:25])[N:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])O
Reactant: CCOC(=O)C1(NC(=O)OC(C)(C)C)C=C(Cl)C=CN1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(Cl)cc(CO)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
To a mixture of 1.00 g (3.3 mmol) of ethyl 2-(t-butoxycarbonyl)amino-4-chloropicolinate and 20 mL of anhydrous ethanol, 0.38 g (10.0 mmol) of sodium borohydride was added, followed by stirring at room temperature for 17 hours. To the reaction solution, dilute hydrochloric acid was added thereby adjusting the pH to 2 and the solution was neutralized by adding saturated sodium bicarbonate aqueous solution. After ethanol was removed under reduced pressure, the resultant was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1 (v/v)) to obtain 0.75 g (2.9 mmol, yield of 87%) of 2-(t-butoxycarbonyl)amino-4-chloro-6-hydroxymethylpyridine.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:19])C=1.C(OO)(=O)C.C(Cl)(Cl)Cl>CCOCC.C(Cl)Cl>[O:19]1[CH:4]2[CH:3]1[CH2:2][O:1][C:10]1[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C1=Cc2ccccc2OC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(=O)OO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc2c(c1)OCC1OC21
Temperature: 25 °C

Procedure:
The compound 5 is oxidized with an oxidizing agent such as m-chloroperbenzoic acid and peracetic acid in a solvent such as chloroform, methylene chloride and ether, under cooling to room temperature to give 3,4-epoxychroman (compound 6 wherein R1, R2 and R3 are as defined above).
Reaction SMILES: C(O)C[OH:3].[CH3:5][CH2:6][CH2:7][CH2:8][CH:9]([C:12]([O-:14])=[O:13])CC.CCC[CH2:18][CH:19]([C:22]([O-:24])=[O:23])CC.[Sn+2].C(Cl)Cl>C(OCC)C>[C:12]1(=[O:14])[O:13][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1.[C:22]([OH:24])(=[O:23])[CH:19]([CH3:18])[OH:3]
Reactant: OCCO
Reactant: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(O)C(=O)O
Product: O=C1CCCCCO1
Temperature: 25 °C

Procedure:
4 g of poly(ethylene glycol) methyl ether (PEG 2,000, Mn=2,000) and 0.02 g of stannous octoate, which is a catalyst, were put into a reactor, and were then dried in a vacuum at a temperature of 110° C. for 4 hours in order to remove moisture therefrom. Subsequently, the dried reactants were cooled, and then 4.97 g of ε-caprolactone (4.61 ml), which is a biodegradable polyester polymer compound, was added to the dried reactant in a nitrogen atmosphere and then dried in a vacuum at a temperature of 65° C. for 1 hour. Thereafter, the dried reactants were cooled to room temperature, and then 1.43 g of D,L-lactide was added to the dried reactants and then cooled in a vacuum at a temperature of 85° C. for 1 hour to form a reaction mixture. Then, the reaction mixture was slowly heated to a temperature of 135° C. in a nitrogen atmosphere and then polymerized for 24 hours to form a reaction product. After the polymerization reaction, the reaction product was cooled to room temperature, and was then dissolved by adding a small amount of methylene chloride thereto. The dissolved reaction product was added to excess ethyl ether and then precipitated to remove unreacted materials therefrom. Then, the reaction product, from which unreacted material was removed, was dried in a vacuum at a temperature of 40° C. for 48 hours, thereby obtaining a triblock copolymer (PCLA-PEG-PCLA) of the formed poly(ethylene glycol) and biodegradable polyester polymer compound, ε-caprolactone and lactic acid. The yield of the triblock copolymer thus obtained was 91%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.CCO.O>[Fe].CC(O)=O>[NH2:1][C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: C[C@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a refluxing solution of 59A (1.7 g, 5.9 mmol), EtOH (60 mL), water (15 mL) and AcOH (4 mL) was added portion-wise Fe powder (1.6 g, 29.5 mmol) over 30 min. Mixture was heated for 45 min. before cooling to ambient temperature and filtering through celite. Filtration and concentration in vacuo afforded 59B (1.5 g, 94%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (d, J=6.59 Hz, 3 H) 5.00-5.17 (m, 2 H) 5.40 (d, J=7.47 Hz, 1 H) 6.53-6.60 (m, 2 H) 6.69 (d, J=7.47 Hz, 1 H) 7.11 (t, J=7.69 Hz, 1 H) 7.29-7.39 (m, 5 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15]Br)=[CH:12][CH:11]=1>>[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][CH:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH3:2])=[CH:12][CH:11]=1
Reactant: CCc1ccncc1
Reactant: Cc1ccc(CCBr)cc1
Product: Cc1ccc(CCC(C)c2ccncc2)cc1
Yield: 98.3 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 1.86 g (9.35 mmol) of 4-methylphenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 2.07 g of the desired compound (yield: 98.4%). The resulting compound was identified as 1-(4-methylphenyl)-3-(4-pyridyl)-butane (hereinafter referred to as compound 7) by the following analytical results.
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][C:17]=2[O:28][CH2:29][CH3:30])[CH:13]=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:29]([O:28][C:17]1[CH:18]=[C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:20]=[CH:21][C:16]=1[C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:9][CH3:8])[N:15]=1)[CH3:30]
Reactant: CCOc1cc(CCC(=O)OC)ccc1-c1cccc(NCC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(CCC(=O)OC)ccc1-c1cccc(NC)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
g of methyl 3-{4-[6-(tert-butoxycarbonylmethylamino)pyrid-2-yl]-3-ethoxyphenyl}propionate is dissolved in 10 mL of dichloromethane and 4 mL of trifluoroacetic acid are then added. The mixture is stirred for 48 hours at room temperature. After hydrolysis of the reaction with sodium hydrogen carbonate solution and then extraction with ethyl acetate, the solvents are evaporated off. 615 mg of methyl 3-[3-ethoxy-4-(6-methylaminopyrid-2-yl)phenyl]propionate are obtained. Yield=81%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][CH2:10][NH:11]C(=O)C(F)(F)F)[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]([OH:28])([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])#[CH:20]>>[NH2:11][CH2:10][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][C:21]([OH:28])([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:3]=1)=[O:18]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(CCNC(=O)C(F)(F)F)c1cccc(Br)c1
Product: CCCC(O)(C#Cc1cccc(C(=O)CCN)c1)CCC
Reaction time: 3 h

Procedure:
N-(3-(3-Bromophenyl)-3-oxopropyl)-2,2,2-trifluoroacetamide (63) was coupled with alkynol 20 following the procedure described in Example 18 except that the reaction was run at 80° C. for 3 h to give 3-amino-1-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propan-1-one as a dark amber oil after purification by flash chromatography (20% EtOAc in hexanes). Yield (28.1 g, 99.6%). 1H NMR (400 MHz, DMSO-d6) δ 9.40 (br. t, 1H), 7.84-7.92 (m, 2H), 7.58-7.63 (m, 1H), 7.50 (t, J=7.6 Hz, 1H), 5.19 (s, 1H), 3.51 (q, J=5.7 Hz, 2H), 3.30 (t, J=6.7 Hz, 2H), 1.40-1.63 (m, 8H), 0.90 (t, J=7.2 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:30][CH3:31])=[C:4]([CH:8]([CH3:29])[CH2:9][C:10]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH:11]=NC2C=CC=C3C=2C=CC(C)=N3)[CH:5]=[CH:6]C=1.B(Br)(Br)Br.C([O-])(O)=[O:37].[Na+].[CH2:41]([Cl:43])Cl>>[Cl:43][C:41]1[CH:6]=[CH:5][C:4]([CH:8]([CH3:29])[CH2:9][C:10]([OH:24])([C:25]([F:26])([F:27])[F:28])[CH:11]=[O:37])=[C:3]([O:30][CH3:31])[C:2]=1[F:1]
Reactant: O=C([O-])O
Reactant: ClCCl
Reactant: COc1c(F)cccc1C(C)CC(O)(C=Nc1cccc2nc(C)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Agent: [Na+]
Product: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F
Temperature: -5 °C

Procedure:
100 mg (0.3 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 48 mg (0.3 mmol) of 5-amino-2-methylquinazoline and 0.1 ml of titanium tetraethoxide are stirred in 9 ml of toluene at 100° C. for 2 h. After cooling, the mixture is poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are dried over sodium sulphate and the solvent is removed in vacuo to give 130 mg of 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol as a crude product. 130 mg of the crude imine in 6 ml of CH2Cl2 are admixed dropwise at −30° C. with 3 ml (3 mmol) of a 1 M of boron tribromide solution. The batch is allowed to warm to −5° C. over 3 hours. It is admixed with saturated NaHCO3 solution, the phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 30 mg as a mixture of the title compound and 5α,6α,8β)-3-chloro-2-fluoro-8-methyl-5-[(2-methylquinazolin-5-yl)amino]-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol (Ex. 23). Preparative thin-layer chromatography on amine phase (Merck) with ethyl acetate/methanol/triethylamine 25:3:1 yields 5 mg of product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][O:34][C:35]([CH:37]1[CH2:40][NH:39][CH2:38]1)=[O:36].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>[CH3:33][O:34][C:35]([CH:37]1[CH2:40][N:39]([C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])[CH2:38]1)=[O:36]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)C1CNC1
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: ClCCl
Product: COC(=O)C1CN(C(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), azetidine-3-carboxylate methyl ester hydrochloride (200 mg, 1.32 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to yield 1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid methyl ester (26 mg, 10.7%). The ester was taken directly to the hydrolysis step by dissolved in THF (0.6 mL) and methanol (0.2 mL), then 2N LiOH (0.2 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to rac-1-[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-azetidine-3-carboxylic acid (11.8 mg, 46.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H27Cl2F2N3O3+H [(M+H)+]: 550.1471. found: 550.1471.