Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:16]2[CH:17]=[C:18](B(O)O)[C:19]([F:22])=[N:20][CH:21]=2)[CH3:15])[C@@H:10]([CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]1[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH:29]=1.CC([O-])=O.[K+]>>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:35]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:18]3[CH:17]=[C:16]([C@H:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH3:26])[CH3:15])[CH:21]=[N:20][C:19]=3[F:22])[CH:29]=2)=[CH:51][CH:50]=1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3F)nc(C)n2)cc1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
A glass microwave reaction vessel was charged with (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (Example 272, Step 2) (0.530 g, 1.443 mmol), 6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (Example 177) (0.554 g, 1.443 mmol), PdCl2 (AmPhos)2 (0.102 g, 0.144 mmol) and KOAc (0.425 g, 4.33 mmol). The tube was sealed and evacuated under vacuum and back-filled with nitrogen. Dioxane (3.75 mL) and water (0.375 mL) was added and Ar (g) was bubbled through the mixture for 5 minutes. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl (3S)-4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (0.240 g, 0.358 mmol, 24.79% yield) as a yellow oil. m/z (ESI, +ve) 671.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.40 (dd, J=9.39, 2.54 Hz, 1H); 8.13 (d, J=1.37 Hz, 1H); 7.18 (d, J=8.02Hz, 4H); 6.80-6.90 (m, 5H); 4.50-5.03 (m, 4H); 4.03 (d, J=5.28 Hz, 1H); 3.73-3.84 (m, 6H); 3.24-3.57 (m, 3H); 3.08-3.22 (m, 1H); 2.69-2.81 (m, 1H); 2.61 (s, 3H); 2.29-2.51 (m, 2H); 1.37-1.48 (m, 12H); 1.02 (d, J=6.26 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]=[O:15])[C:10](=[O:16])[N:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.[O-:23]Cl=O.[Na+]>C(O)CCC>[CH3:1][N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:15])=[O:23])[C:10](=[O:16])[N:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(C=O)c(=O)n(-c2ccccc2)n1Cc1ccccc1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CCCCO
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.3 %

Procedure:
To a mixture of 1-benzyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxaldehyde (1 g, 4.624 mmol) in butyl alcohol were added to NaClO2 (1.254 g, 13.873 mmol) in an aqueous solution and potassium phosphate monobasic monohydrate (3.146 g, 23.12 mmol) in an aqueous solution slowly at 0° C. The resulting reaction mixture was slowly heated to room temperature and stirred for 10 hours. NaClO3 (1 g) was further added while monitoring the reaction. Following the addition of sodium chlorite, the reaction mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with, dried with Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was washed with 20% ethyl acetate solution in small amount of hexane. The target compound was obtained as a white solid (808 mg, 3.48 mmol, 75% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][C@H:15]([CH3:17])[C@@H:14]([OH:18])[C@H:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35]1[N:40]=[C:39]([C:41](O)=[O:42])[CH:38]=[CH:37][C:36]=1[F:44].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>CN(C=O)C.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35]1[N:40]=[C:39]([C:41]([NH:1][C:2]2[C:3]([N:11]3[CH2:16][C@H:15]([CH3:17])[C@@H:14]([OH:18])[C@H:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12]3)=[C:4]3[CH2:10][CH2:9][CH2:8][C:5]3=[N:6][CH:7]=2)=[O:42])[CH:38]=[CH:37][C:36]=1[F:44]
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl [(3R,4R,5S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-4-hydroxy-5-methylpiperidin-3-yl]carbamate (6.0 mg, 0.017 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (5.0 mg, 0.02 mmol), HATU (15.7 mg, 0.041 mmol) in DMF (0.05 mL) and DIPEA (0.01 mL, 0.05 mmol) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and Na2CO3 (aq.). The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried, filtered and concentrated under vacuum. The resulting crude product was used directly in the next step. LCMS calc. for C31H35F3N5O4 (M+H)+: m/z=598.3. Found: 598.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:26])=[C:10]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[N:11]([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[O:27]1[C:31](B(O)O)=[CH:30][C:29]2[CH:35]=[CH:36][CH:37]=[CH:38][C:28]1=2>>[O:27]1[C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[CH:30]=[C:31]1[C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[C:9]([CH3:26])=[C:10]([C:14]([N:16]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]2)=[O:15])[N:11]([CH3:13])[N:12]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CCN(CC)C1CCN(C(=O)c2c(C)c(-c3cccc(Br)c3)nn2C)C1
Product: CCN(CC)C1CCN(C(=O)c2c(C)c(-c3ccccc3-c3cc4ccccc4o3)nn2C)C1
Yield: 36 %

Procedure:
In analogy to the procedure described in Example 14C], [5-(3-bromo-phenyl)-2,4-dimethyl-2H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and benzo[b]furan-2-boronic acid gave the title compound in 36% yield as yellow foam. MS: 457.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]C(OCC)=O)[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.[CH3:24][Mg]Br.[NH4+].[Cl-].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C1COCC1.CCOCC.O.CCOC(C)=O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([CH3:31])([OH:34])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:32]([OH:34])([CH3:31])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Reactant: C[Mg]Br
Agent: O=C(O)/C=C/C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a stirred solution, under N2, of ethyl 3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionate (3.1 g, 9 mmol), in THF (100 ml) was added, dropwise, methylmagnesium bromide (9.0 ml, 27 mmol of a 3M solution in ether). The reaction was stirred at ambient temperature for 16 hours and then a saturated solution NH4Cl was added dropwise, with cooling. The reaction was further diluted with H2O, and after extractive workup of the aqueous mixture with EtOAc, 2.8 g of a waxy solid resulted. The solid was dissolved in EtOAc and 3.0 g of fumaric acid was added, and 5.0 g of a fumarate salt was collected, which was contaminated with unreacted fumaric acid. The crude salt was recrystallized from MeOH-Et2O, and then from DMF to afford 1.6 g (45.7%) of the desired compound as a hemifumarate, m.p.=237°-239° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[CH:19]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]3[CH:15]=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[CH:19]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1ccc2c(c1)oc1ccccc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2oc3cc(Br)ccc3c2c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Chlorosulfonic acid (3.75 mL, 56 mmoles) was added dropwise to a solution of 3-bromo-dibenzofuran (9.21 g, 37.3 mmoles) in 150 mL of chloroform at room temperature. The reaction was stirred for 5 hours, cooled to 0° C., filtered, and washed the solid with cold dichloromethane. This solid (6.12 g, 18.7 mmoles) was mixed with phosphorous pentachloride (12.9 g, 61.7 mmoles) and the mixture was heated to 110° C. for 4 hours. The mixture was cooled to room temperature and quenched with ice water. Filtered the resulting suspension to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:5]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH:2]([CH3:4])[CH3:3].[H][H]>[Pd].CO>[CH2:1]([CH:5]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: COC(=O)CC(CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(CC(C)C)C(=O)O
Yield: 86.1 %

Procedure:
A mixture of 8.01 g (0.029 mol) of (2) and 1 g of 10% palladium on carbon in 50 mL of methanol was hydrogenated at room temperature under 4 atmospheres of hydrogen gas for 8 hr. After removal of the catalyst by filtration the filtrate was evaporated to dryness under reduced pressure to give 4.7 g (86% yield) of 2-isobutyl-3-(methoxycarbonyl)-propionic acid (3) as a colorless oil.
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(O)(=O)CC.S(=O)(=O)(O)O.O.CC1C(C)=C2C(CC[C@](CCC[C@H](CCC[C@H](CCCC(C)C)C)C)(C)O2)=C(C)C=1O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@@H](C)CCC[C@@H](C)CCCC(C)C)O2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Yield: 99 %

Procedure:
Methyl oleate (100 grams, 0.338 moles), propionic acid (250.3 grams, 3.38 moles), concentrated sulfuric acid (12 grams, 0.12 moles), distilled water (100 grams, 5.56 moles), and Covi-Ox T-50 antioxidant (0.087 grams) are charged to a mantle-heated round bottom flask connected to a 30 cm. distillation column fitted with a take-off head. The bottom 8 cm. of the distillation column is packed with approximately 10 grams of XN1010 ion exchange resin (described in Example III) in pellet form. The distillation column is designed to allow vapor flow upward through the resin packing but liquid downflow is returned without passing through the resin packing. The flask is heated to between 105° C. and 110° C. for three hours. Methanol is taken off at the take-off head during reaction. Sample workup and analysis indicates a 99% yield of oleic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:11][CH3:12])[C:8]=1[CH2:9]O)[CH3:2].[Br:13]P(Br)Br>C(Cl)(Cl)Cl>[Br:13][CH2:9][C:8]1[C:3]([CH2:1][CH3:2])=[CH:4][N:5]=[CH:6][C:7]=1[CH2:11][CH3:12]
Reactant: CCc1cncc(CC)c1CO
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: CCc1cncc(CC)c1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,5-diethylpyridin-4-yl)methanol (1.50 g, 9.07 mmol) in anhydrous chloroform (40 mL) at 0° C. was added dropwise tribromophosphane (2.48 g, 0.861 mL, 9.16 mmol). The reaction mixture was allowed to stir overnight at room temperature. The solvent was evaporated to provide crude 4-(bromomethyl)-3,5-diethylpyridine, which was used for the next step without any further purification; M+ 229.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[OH-].[K+].[CH3:11]I.O>CS(C)=O>[CH3:11][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CI
Reactant: Cc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C)nc1
Reaction time: 1 h
Yield: 58.6 %

Procedure:
5-Hydroxy-2-methylpyridine (15 g, 0.14 mol) was added to a stirred suspension of KOH (31 g, 0.55 mol) in DMSO (150 mL). The mixture was stirred for 1 hour and then treated with methyl iodide (9.8 mL, 0.15 mol). After 20 mins the reaction mixture was poured into H2O and extracted with ether. The ether extracts were dried over MgSO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 50% EtOAc in hexanes) gave the product as a clear oil (10.1 g, 59%). 1H NMR (400 MHz, CDCl3): δ 2.49 (s, 3H), 3.83 (s, 3H), 7.06 (d, J=8.6 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 8.19 (d, J=2.8 Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11]N2C(=O)CCC2=O)=O)=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3].Cl.[C:23]([NH:31][CH2:32][C@@H:33]([C:35]([O:37][CH3:38])=[O:36])[NH2:34])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>>[N:1]([CH2:4][C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:34][C@H:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32][NH:31][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])=[C:7]([Cl:21])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Reactant: [N-]=[N+]=NCc1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Yield: 69.6 %

Procedure:
A solution of 1-[[4-(azidomethyl)-2-chlorobenzoyl]oxy]-2,5-pyrrolidinedione (4.64 g, 15.0 mmol), 3-(benzoyl)amino-L-alanine, methyl ester hydrochloride (4.00 g, 15.5 mmol), and triethylamine (4.00 g, 39.5 mmol) in N,N-dimethylformnamide (50 mL) was stirred at room temperature for 3 h. The solvent was evaporated, and 1 M HCl (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried (MgSO4), filtered, evaporated, and chromatographed (50-75% ethyl acetate/hexanes) to give N-[4-(azidomethyl)-2-chlorobenzoyl]-3-(benzoyl)amino-L-alanine, methyl ester (4.34 g, 69%) as a colorless oil that solidified on standing, mp 112-114° C.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]2[CH:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=3/[CH:17]=[CH:18]/[CH3:19])[CH2:7][CH2:8][C:2]=12.C1COCC1>[Pd].CCO>[CH:1]1[N:5]=[CH:4][N:3]2[CH:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=3[CH2:17][CH2:18][CH3:19])[CH2:7][CH2:8][C:2]=12
Reactant: C/C=C/c1cc(C#N)ccc1C1CCc2cncn21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1cc(C#N)ccc1C1CCc2cncn21
Reaction time: 60 h

Procedure:
A suspension of 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-((E)-propenyl)benzonitrile (0.150 g, 0.602 mmol), 20% (w/w) palladium on carbon (0.040 g), THF (15 mL), and EtOH (15 mL) is stirred under an atmosphere of hydrogen (1 atm) for 60 h. The suspension is the filtered and the filtrate concentrated. The residue is then purified by flash chromatography (Hexane/EtOAc, and then 10% MeOH/EtOAc) to give 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-(n-propyl)benzonitrile as a white solid. MS (ESI) m/z 252.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.04 (t, J=7.3 Hz, 3 H), 1.63-1.77 (m, 2 H), 2.33-2.45 (m, 1 H), 2.62-2.80 (m, 2 H), 2.92 (app t, J=7.1 Hz, 2 H), 3.04-3.19 (m, 1 H), 5.58 (dd, J=7.8, 5.6 Hz, 1 H), 6.73 (d, J=8.1 Hz, 1 H), 6.81 (s, 1 H), 7.25 (s, 1 H), 7.41 (d, J=8.1 Hz, 1 H), 7.51 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.[Cl-].[Na+].O>[CH3:13][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][C:7]1=[O:12]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1)CC(=O)N2
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)CC(=O)N2C
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.8 %

Procedure:
5-methoxy oxindole (450 mg, 2.76 mmol) and potassium carbonate (585 mg, 4.23 mmol) were combined in 45 ml of acetone under an inert atmosphere. To this white, heterogenous mixture was added 0.33 ml of methyl iodide (5.30 mmol) via syringe. The reaction mixture was stirred at room temperature for 10 hours and then at 75° C. for 3 hours. Additional potassium carbonate and methyl iodide were added (290 mg and 0.11 ml, respectively), and the reaction mixture was stirred at 75° C. for 6 more hours. The reaction mixture was then poured into 300 ml of saturated brine solution and extracted with 3×200 ml ether. The combined organic layers were dried over MgSO4, filtered, and stripped to a yellow oil. This was purified via flash chromatography (3:1 ethyl ether/hexane) to provide the title compound (307 mg, 63% yield) as white crystals: m.p. 93°-94° C. M/z calculated for C10H11NO2 : 177.0790, Found: 177.08066.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]([CH3:21])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:8][CH:7]=1.[OH-].[K+]>CO>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([CH:5]=[C:4]([CH3:21])[C:3]([OH:22])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)C(C)=Cc1ccc(OCc2cccc(F)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=Cc1ccc(OCc2cccc(F)c2)cc1)C(=O)O
Temperature: 65 °C
Reaction time: 3 h

Procedure:
383 mg (1.28 mmol) of 3-[4-(3-fluoro-benzyloxy)-phenyl]-2-methyl-acrylic acid methyl ester is added to a solution of 143 mg (2.55 mmol) potassium hydroxide in 7 ml methanol. The solution is stirred at 65° C. for about 3 h, evaporated to dryness, treated with aqueous 0.1 molar hydrochloric acid and extracted 3 times with ethyl acetate. Evaporation of the solvent leaves the pure acid. 305 mg (84%) of a colorless solid. MS (neg.ions): m/e=285.0 (M−H).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:12])=[N:6][CH:7]=[N:8][C:9]=1[CH2:10]Br)[CH2:2][CH3:3].C(C1C(Cl)=NC=NC=1CCl)CC.[F:25][C:26]1[N:31]=[C:30]([C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:25][C:26]1[N:31]=[C:30]([C:32]2[NH:36][CH:35]=[CH:34][N:33]=2)[CH:29]=[CH:28][CH:27]=1.[Cl:12][C:5]1[N:6]=[CH:7][N:8]=[C:9]([CH2:10][N:36]2[CH:35]=[CH:34][N:33]=[C:32]2[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[N:31]=2)[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1c(Cl)ncnc1CBr
Agent: CCCc1c(Cl)ncnc1CCl
Agent: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCc1c(Cl)ncnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Fluoro-2-(1H-imidazol-2-yl)-pyridine is prepared as described in Example 16 of U.S. patent application Ser. No. 10/038,069, filed Dec. 12, 2001 and published as US 2003/0069257 on Apr. 10, 2003, which is hereby incorporated by reference at page 31 for its teaching regarding the synthesis of this compound. A mixture of 102 or 5-propyl-6-chloromethyl-4-chloro-pyrimidine (1 mmol of either), 6-fluoro-2-(1H-imidazol-2-yl)-pyridine (163 mg, 1 mmol) and K2CO3 (552 mg, 4 mmol) in DMF (6 ml) is stirred at room temperature overnight. The solvent is removed in vacuo and EtOAc (10 ml) and water (10 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (10 ml). The combined extracts are washed with brine (10 ml), dried (Na2SO4) and evaporated. PTLC separation of the residue with 5% MeOH in CH2Cl2 provides the product (103) as a white solid.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]1[C:9]([CH:10]=[O:11])=[CH:8][CH:7]=[N:6]1)[CH3:4]>CO>[CH2:3]([N:5]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[N:6]1)[CH3:4]
Reactant: CCn1nccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCn1nccc1CO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of sodium borohydride (686 mg, 18.1 mmol) in methanol (40 mL) was added a solution of 1-ethyl-1H-pyrazole-5-carbaldehyde (1.5 g, 12.1 mmol) in methanol (10 mL) at 0° C. The mixture was stirred for 2.5 hours at room temperature. The solvent was evaporated, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. After evaporation of solvent, (1-ethyl-1H-pyrazol-5-yl)methanol was obtained as a colorless oil (1.07 g, 70% yield) and used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6): δ 1.31 (t, J=7.2 Hz, 3H), 4.10 (q, J=7.2 Hz, 2H), 4.49 (d, J=5.5 Hz, 2H), 5.25 (t, J=5.5 Hz, 1H), 6.12 (d, J=1.5 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([CH3:24])=[C:22]([F:25])[CH:21]=[C:20]([C:26]([NH:28][CH:29]4[CH2:31][CH2:30]4)=[O:27])[CH:19]=3)=[CH:14][CH:13]=2)=[N:9][N:8]=1>O.CN(C=O)C.C(O)C>[N:1]([CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([CH3:24])=[C:22]([F:25])[CH:21]=[C:20]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31]4)=[O:27])[CH:19]=3)=[CH:14][CH:13]=2)=[N:9][N:8]=1)=[N+:2]=[N-:3]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN=[N+]=[N-])o2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A solution of sodium azide (40 mg) in water (3.5 ml) was added to (4′-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 34) (200 mg) in DMF (1.5 ml) and ethanol (7 ml) and the reaction mixture stirred for 5 hours at 90° C. The reaction was concentrated under vacuum and the residue partitioned between water (15 ml) and chloroform (15 ml) and the aqueous extracted with chloroform (2×15 ml). The combined organic extracts were dried (magnesium sulphate), and the solvent evaporated under vacuum to give 4′-[5-(azidomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: O=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:23])C=CC.[CH3:24][OH:25]>ClCCl>[O:25]=[CH:24][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:23]
Reactant: CC=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Reactant: CO
Agent: O=[O+][O-]
Solvent: ClCCl
Product: O=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Reaction time: 1.25 h
Yield: 97 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 75 minutes while stirring through a solution, cooled to -70°, of 12.0 g of (RS)-2-(2-buten-1-yl)-6-phenyl-1-indanone in 180 ml of anhydrous dichloromethane and 40 ml of anhydrous methanol. Subsequently, the mixture was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5.04 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 120 ml of dichoromethane and, after the addition of 30 ml of water and 30 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 1.2 g (97%) of (RS)-2-(2-oxoethyl)-6-phenyl-1-indanone were obtained as a light yellow oil.