Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].C1COCC1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][C:21](=O)[CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])=O)=[CH:11][CH:10]=1>C(O)(=O)C.O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2[N:2]([CH3:1])[C:21]([CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])=[CH:20][N:19]=2)=[CH:11][CH:10]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)CCc1ccc(Br)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCC(C)(C)Cc1cnc(CCc2ccc(Br)cc2)n1C
Temperature: 25 °C

Procedure:
Acetic acid (1.08 mL, 18.9 mmol) and 2M methylamine in THF (1.09 mL, 2.2 mmol) were added to a solution of 3-(4-bromophenyl)-N-(4,4-dimethyl-2-oxohexyl)propanamide in xylenes (20 mL). The solution was stirred at reflux with azeotropic removal of water for 1 h. Another batch of acetic acid and methylamine were added and stirring was continued at reflux for another 4 h. After cooling to rt, the solution was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give 2-[2-(4-bromophenyl)ethyl]-5-(2,2-dimethylbutyl)-1-methyl-1H-imidazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.I[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:32]([O:30][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:25])([F:26])[F:24])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1)[CH3:33]
Reactant: CCI
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Temperature: 80 °C

Procedure:
A mixture of 1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (0.053 g), iodoethane (0.011 mL) and powdered potassium carbonate (0.090 g) in 1 mL of anhydrous DMF was heated at 80° C. for 18 hours, cooled to room temperature, and diluted with water and filtered. The solid was purified with flash silica gel chromatography using ethyl acetate as the eluent. The product rich fraction were concentrated in vacuo and provided 1-[4-(2-ethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one, m.p. 195° C.-196° C.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:9][C:10]1[C:11]([O:44][CH3:45])=[C:12]([S:18]([NH:21][C@H:22]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH:33]2[C:39]([O:41]CC)=[O:40])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])(=[O:20])=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][CH2:7][CH3:8].[OH-].[Na+]>C(O)C.O>[CH2:5]([O:9][C:10]1[C:11]([O:44][CH3:45])=[C:12]([S:18]([NH:21][C@H:22]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH:33]2[C:39]([OH:41])=[O:40])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:28])[NH2:29])(=[O:20])=[O:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOc1c(OC)ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N2CCC(C)CC2C(=O)OCC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1c(OC)ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N2CCC(C)CC2C(=O)O)c1OC
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of 5.8 g of ethyl 1-[N2 -(3-butoxy-2,4-dimethoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate acetate in 80 ml of ethanol and 40 ml of water was added 10 ml of 2N NaOH aqueous solution at room temperature and stirring was continued overnight at room temperature. At the end of this period, the reaction solvent was distilled off under reduced pressure at a temperature below 30° C. The residue was dissolved in a small amount of water and then neutralized with 2N NCl to precipitate a white gummy substance. The aqueous solution was separated by decantation and the white precipitate was dissolved in 200 ml of chloroform, washed with 30 ml of water and then dried over anhydrous sodium sulfate. Upon evaporation of solvent, there was obtained 4.0 g (79%) of 1-[N2 -(3-butoxy2,4-dimethoxyphenylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid in the form of an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O>O.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(N)c1
Yield: 57.6 %

Procedure:
4-Bromo-3-nitroanisole (10 g, 43 mmol) and iron powder (21.72 g, 385 mmol) were stirred in a mixture of water (10 mL) and acetic acid (100 mL) for 1.5 h. The solvent was removed in vacuo, the brown residue was taken up in water (200 mL) and treated with 10% aq K2CO3 until pH 10. The mixture was extracted with EtOAc (4×150 mL) and the combined organic extracts were dried (MgSO4) and evaporated to give the desired aniline (5.0 g, 57%) as a brown oil; δH (CDCl3, 400 MHz) 3.72 (3H, s), 4.05 (2H, br), 6.22 (1H, dd), 6.32 (1H, d), 7.26 (1H, d); MS m/z (TS+) 202, 204 (MH+).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([O-])=O.[C:14]([O:18][C:19](=[O:22])[CH2:20]Br)([CH3:17])([CH3:16])[CH3:15].CN(C=[O:27])C>>[C:14]([O:18][C:19](=[O:22])[CH:20]([OH:27])[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[C:6]([NH2:3])[CH:7]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN(C)C=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)C(O)Cc1cccc(N)c1
Temperature: 65 °C
Yield: 41 %

Procedure:
Sodium hydride (60% dispersion in oil) (1.32 g, 33.0 mmol) was added to a solution of 3-nitro-benzaldehyde (4.53 g, 30.0 mmol) and tert-butyl-bromoacetate (4.87 ml, 33.0 mmol) in DMF (100 ml). The resulting suspension was heated at 65° C. for 2 h, cooled, then quenched with water (10 ml). The mixture was diluted with ethyl acetate (100 ml), the organic phase was washed with water (150 ml), brine (2×150 ml), dried (MgSO4) and the solvent was evaporated. The residue was dissolved in dioxan (50 ml) and hydrogenated over palladium on charcoal (10%, 1.00 g) for 24 h. The catalyst was removed by filtration and the solvent was evaporated. The crude product was purified by flash column chromatography (silica, hexane/ethyl acetate 1:1) to afford colourless oil (2.95 g, 41%). 1H NMR (300 MHz, CDCl3) 7.07 (1H, m), 6.60 (3H, m), 4.30 (1H, dd), 3.61 (2H, br s), 3.00 (1H, dd), 2.85 (2H, m), 1.46 (9H, s).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=1.[C:18]([NH:25][C@H:26]([C:35]([OH:37])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C=O)C.O>[CH3:15][O:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][C:8]([O:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][CH:26]([NH:25][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.7 %

Procedure:
Potassium carbonate (1.23 g, 8.9 mmol) and methyl 6-chloronicotinate (1.8 g, 10.66 mmol) were added to a solution of Boc-tyrosine (1.0 g, 3.55 mmol) in anhydrous DMF (15 mL). The resulting suspension was refluxed at 70 deg C. under an atmosphere of argon. After 72 hrs, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The aqueous layer was collected, acidified with 5.0 M HCl to pH ˜2.5 and extracted with EtOAc (2×100 mL). The resulting EtOAc layer was extracted with water (1×150 mL) and brine (1×150 mL), dried over anhydrous magnesium sulfate, filtered and concentrated and flash chromatographed (30-40% ethyl acetate in hexane with 1% acetic acid) to yield desired ester, 17 as a solid (1.4 g). 1H NMR (400 MHz, DMSO-d6): 12.45 (s, 1H), 8.68 (br, 1H), 8.29 (dd, J=8.4 and 2.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.8 Hz, 1H), 7.08 (m, 3H), 4.12 (m, 1H), 3.85 (s, 3H), 3.05 (dd, J=14.0 and 4.0 Hz, 1H), 2.84 (dd, J=14.0 and 10.8 Hz, 1H) 1.33 (s, 9H)
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)n2cc(F)c(N)nc2=O)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 63.8 %

Procedure:
To commercially available 4-amino-5-fluoro-pyrimidin-2-ol (1.0 grams (g), 7.75 millimoles (mmol)) in acetonitrile (CH3CN; 50 milliliters (mL)) was added bis-N,O-trimethylsilylacetamide (BSA; 5.7 mL, 23.3 mmol) and the mixture was heated at 70° C. for 1 hour (h), resulting in a clear solution. After cooling to room temperature, 4-methoxybenzene-1-sulfonyl chloride (1.8 g, 8.5 mmol) was added, and the mixture was stirred for 24 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (EtOAc) and brine. The organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated to yield the product as a pale yellow solid (1.48 g, 64%): mp 182-185° C.; 1H NMR (300 MHz, CDCl3) δ 8.40 (br s, 1H), 8.11 (d, J=5.9 Hz, 1H), 8.04-7.98 (m, 2H), 7.02-6.96 (m, 2H), 5.77 (br s, 1H), 3.88 (s, 3H); ESIMS m/z 300 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C:11]3=[N:10][C:9]=2[C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:51][C:52]1[C:60]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:58]=[CH:57][C:53]=1[C:54](Cl)=[O:55]>ClCCl>[Cl:51][C:52]1[C:60]([C:61]([F:63])([F:64])[F:62])=[CH:59][CH:58]=[CH:57][C:53]=1[C:54]([N:15]1[CH2:14][CH2:13][N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:17]([F:18])([F:19])[F:20])[N:10]=[C:11]2[CH2:16]1)=[O:55]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: Fc1ccc(-c2c(C(F)(F)F)nc3n2CCNC3)cc1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nc(C(F)(F)F)c2-c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(4-Fluorophenyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I14) (285 mg, 1 mmol) and diethylaminomethyl polystyrene (1000 mg, 3.20 mmol) were slurried in dichloromethane (DCM) (10 mL) and treated with 2-chloro-3-(trifluoromethyl)benzoyl chloride (267 mg, 1.100 mmol). The slurry was stirred at RT for 24 h, whereupon the resin was filtered and washed with dichloromethane (20 mL). The filtrate was concentrated in vacuo to afford crude product. The product was purified by flash chromatography (Isolera, 10 g, 0-100% ethyl acetate/iso-hexane) to afford product in 428 mg.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[C:8]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CNC1
Product: CC(=O)N1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Azetidine carboxylic acid (2.25 g, 22.2 mmol) and acetic anhydride (80 ml) were heated gently until all of the acid had dissolved. The reaction was stirred at room temperature for 18 hours and then the acetic anhydride was removed under reduced pressure. Water was added and evaporated under reduced pressure. The residue was dissolved in hot ethyl acetate and filtered whilst hot and the filtrate was evaporated under reduced pressure to afford the title compound as a white solid, 1.54 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[CH2:11][C:12]([O:14][CH3:15])=[O:13].O.O.O.C([O-])(=O)C.[Na+].CO>O>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(N)c1
Reactant: COC(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CNc1cccc(OC)c1

Procedure:
A mixture of 3-methoxyaniline (61.6 g), methyl chloroacetate (44 ml), sodium acetate trihydrate (114 g) and methanol (70 ml) was heated under reflux for 18 h. The mixture was poured into water (500 ml) and extracted with dichloromethane (3×250 ml). The combined, dried organic extracts were evaporated and the residue was treated with a 10% concentrated sulphuric acid in methanol (250 ml). After 3 h the solution was poured carefully into 8% sodium bicarbonate (1200 ml) and partitioned with ether (4×500 ml). The combined organic extracts were washed successively with 0.5M citric solution (5×200 ml) and brine (500 ml), dried and evaporated to give an oil. Purification by FCC eluting initially with ether:petroleum ether 60°-80° (2:3) and then with ether:petroleum ether 60°-80° (1:1) give the title compound (52 g) as an oil, t.l.c (System A, 1:1) Rf 0.31.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:19]2([CH3:20])[C:6]([CH2:7][C@@H:8]([CH3:22])[C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C:13]2=[O:21])=[CH:5][C:4](=[O:23])[CH2:3]1.[CH3:24][C@H:25]1[C@@:42]2([CH3:43])[C:29]([C@@H:30]([CH3:45])[CH2:31][C@@H:32]3[C@@H:41]2[CH2:40][CH2:39][C@@:37]2([CH3:38])[C@H:33]3[CH2:34][CH2:35][C:36]2=[O:44])=[CH:28][C:27](=[O:46])[CH2:26]1.C[C@H]1[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[CH2:58][C:59]2=[O:67])=CC(=O)C1>>[C:36]([O:23][C@H:4]1[CH2:3][C@@H:2]([CH3:1])[C@@:19]2([CH3:20])[C:6](=[CH:7][C@@H:8]([CH3:22])[C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:21][C:59](=[O:67])[CH3:58])[CH2:5]1)(=[O:44])[CH3:35].[C:13]([O:46][C@H:27]1[CH2:26][C@@H:25]([CH3:24])[C@@:42]2([CH3:43])[C:29](=[C:30]([CH3:45])[CH2:31][C@@H:32]3[C@@H:41]2[CH2:40][CH2:39][C@@:37]2([CH3:38])[C@H:33]3[CH2:34][CH2:35][C@@H:36]2[O:44][C:59](=[O:67])[CH3:58])[CH2:28]1)(=[O:21])[CH3:12]
Reactant: C[C@@H]1CC2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reactant: C[C@@H]1CC(=O)C=C2[C@@H](C)C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Product: CC(=O)O[C@@H]1CC2=C(C)C[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H](C)C1
Product: CC(=O)O[C@@H]1CC2=C[C@@H](C)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H](C)C1

Procedure:
Substituting 1β,7α-dimethyl-4-androstene-3,17-dione and 1β,6α-dimethyl-4-androstene-3,17-dione for the 1β-methyl-4-androstene-3,17-dione above results in the preparation of 1β,7α-dimethyl-5-androstene-3β,17β-diol diacetate and 1β,6-dimethyl-5-androstene-3β,17β-diol diacetate.
Reaction SMILES: [CH3:1][Mg]Br.C1(=O)[O:9][CH2:8][CH2:7]CC1.[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][C:8]([OH:9])([CH3:7])[CH2:15][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: O=C1CCCCO1
Reactant: C1CCOC1
Reactant: C[Mg]Br
Product: CC(C)(O)CCCCO
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 84 %

Procedure:
To 67 mL of a 3.0M solution of methylmagnesium bromide (201 mmol in ether) stirring at 0° C. under argon, was added dropwise a solution of valerolactone (5.0 g, 50 mmol) in 25 mL dry THF. A white precipitate was formed. After 30 minutes the reaction mixture was warmed up to room temperature. After 4.5 hours, the reaction was quenched with 12 mL of water and concentrated on a rotoevaporator. The residue was stirred with 50 mL EtOAc and 20 mL saturated aqueous NH4Cl. The 2 layers were separated. The aqueous layer was extracted twice more with EtOAc (50 mL each). The organic layers were combined and washed with brine, dried over MgSO4, and concentrated on a rotoevaporator to obtain 5.57 g (84%) of the title product. Rf is 0.35 in EtOAc; UV, Ce(SO4)2.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([O:7][CH2:8][CH2:9][CH3:10])[NH:4][C:3]=1[CH:11]=[O:12].[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][C:27]=2[F:34])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:4]3[C:3]([CH:11]=[O:12])=[C:2]([Br:1])[N:6]=[C:5]3[O:7][CH2:8][CH2:9][CH3:10])=[CH:28][C:27]=2[F:34])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCOc1nc(Br)c(C=O)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
5-Bromo-2-propoxy-3H-imidazole-4-carbaldehyde (3.7 g, 15.7 mmol), 4′-bromomethyl-2′-fluorobiphenyl-2-carboxylic acid t-butyl ester (5.7 g, 15.7 mmol) and potassium carbonate (6.5 g, 47.0 mmol) were dissolved in DMF (50 mL, 646 mmol), and stirred at room temperature until the reaction was complete, as determined by HPLC. Water (100 mL) was added and the mixture was extracted with EtOAc (2×), washed with saturated aqueous NaCl (2×), dried over MgSO4, filtered and concentrated to yield a yellow oil. The oil was purified by flash chromatography (2-20% EtOAc/hexanes) to yield compound A (4.8 g) as a colorless oil.
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.[CH3:32][N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Br.[NH:66]1[C:70](NC)=[N:69][N:68]=[N:67]1>C(Cl)Cl>[NH:69]1[C:70]([CH2:32][NH:33][C:28]([CH:9]2[CH: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])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])=[N:66][N:67]=[N:68]1
Reactant: CNc1nnn[nH]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCc2nnn[nH]2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a stirred solution 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 (100 mg, 0.22 mmol) in methylene chloride (10 mL), HATU (Aldrich, 83 mg, 0.22 mmol) was added followed by the addition of DIPEA (0.20 mL) and 1H-tetrazol-5-yl-methylamine hydrobromide (Aldrich, 54 mg, 0.3 mmol). The mixture was stirred at rt 4.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC to give a white solid. 47 mg.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].O[C:9]1([CH:18]=[CH:17][CH:16]=[CH:15][CH2:14]1)[C:10]([O:12][CH3:13])=[O:11].C1N2CN3CN(C2)CN1C3.[OH2:29]>>[CH:3]([C:15]1[CH:14]=[C:9]([CH:18]=[CH:17][C:16]=1[OH:29])[C:10]([O:12][CH3:13])=[O:11])=[O:4]
Reactant: COC(=O)C1(O)C=CC=CC1
Reactant: O=C(O)C(F)(F)F
Reactant: O
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)c1ccc(O)c(C=O)c1
Reaction time: 2 h
Yield: 37 %

Procedure:
24 ml of trifluoroacetic acid are added at 0° C. to a mixture of 4.56 g (30 mmol) of methyl 1-hydroxybenzoate and 8.64 g (60 mmol) of hexamethylenetetramine. The solution is brought to reflux and is stirred for 2 hours. After cooling, the solution is diluted with water to 50 ml. The solution is stirred overnight at ambient temperature and is then extracted with ether. The combined organic phases are then washed with water and then with brine. After drying over sodium sulfate and concentrating under vacuum, the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 10/90) to give 2 g (37%) of methyl 3-formyl-4-hydroxybenzoate in the form of a white solid; 1H NMR (300 MHz, CDCl3): 11.30 (broad s, 1H), 9.90 (s, 1H), 8.26 (d, J=2.1 Hz, 1H), 8.12 (dd, J=2.1 Hz and 8.7 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]([O:34][CH2:35][CH2:36][CH2:37]Br)(=[O:33])[CH3:32]>CN(C=O)C>[C:31]([O:34][CH2:35][CH2:36][CH2:37][O:19][C:15]1[CH:14]=[C:13]([C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)c1cc(-c2cccc(O)c2)n(-c2cccc(Cl)c2)n1
Reactant: CC(=O)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccc(OCCCOC(C)=O)c2)n(-c2cccc(Cl)c2)n1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
100 mg (0.292 mmol) of the compound of Example 44A are provided in 1 ml of dry DMF, 242 mg (1.75 mmol) of potassium carbonate and 158 mg (0.875 mmol) of 1-acetoxy-3-bromopropane are added, and the mixture is stirred at 90° C. for 4 h. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid) and 109 mg (84% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=O.[Br:8][CH2:9][CH2:10]Br.C([O-])([O-])=O.[K+].[K+].CC#[N:20]>>[Br:8][CH2:9][CH2:10][N:20]1[C:2](=[O:1])[CH2:3][CH2:4][C:5]1=[O:6]
Reactant: CC#N
Reactant: O=C1CCC(=O)O1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CCC(=O)N1CCBr

Procedure:
To a mixture of dihydro-furan-2,5-dione (396 mg, 4.00 mmol) and 1,2-dibromo-ethane (1.50 g, 8.00 mmol) in CH3CN (20 ml) was added K2CO3 (829 mg, 6.00 mmol) at room temperature. The mixture was stirred at reflux overnight and the solvent was evaporated. The mixture was diluted with EtOAc (150 mL), washed with water, sat. Na2CO3aq., brine, and dried over MgSO4. The solvent was evaporated to give 1-(2-bromo-ethyl)-pyrrolidine-2,5-dione that was used for next step without further purification (580 mg, 70.4%).
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](I)[CH:26]=[CH2:27].Cl>CN(C=O)C.O>[CH2:27]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:26]=[CH2:25]
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: C=CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (3 g, 0.011M) in DMF (30 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.5 g, 0.012M). The mixture was stirred at room temperature for 0.5 hours, and then allyl iodide (1.8 g, 0.01M) was added dropwise. The reaction mixture was warmed to 60° C. and stirred for 2 hours. The mixture was then diluted with water (50 ml), neutralized with 10% HCl and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate and the methylene chloride removed under vacuum to afford N-allyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.