Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:33][C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:41]([C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH2:45]Br)#[N:42]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:33]([CH2:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[C:41]#[N:42])[C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCC(c2nc3ccn(Cc4ccccc4)c(=O)c3[nH]2)C1)OCc1ccccc1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Cn1c(C2CCCC(NC(=O)OCc3ccccc3)C2)nc2ccn(Cc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 66 %

Procedure:
To a solution of [3-(5-benzyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.1 g, 0.22 mmol) in DMF (3 mL) were added Cs2CO3 (0.14 g, 0.44 mmol) and a solution of 2-cyanobenzyl bromide (52 mg, 0.26 mmol) in 3 mL DMF. After stirring for 17 h at room temperature, the reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2. The combined extracts were dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 1% MeOH in CH2Cl2 to give {3-[5-benzyl-3-(2-cyano-benzyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (83 mg, 66% yield). 1H-NMR (CDCl3): δ 7.73 (m, 1H), 7.48 (m, 1H), 7.32 (m, 1H), 7.15 (d, 1H, J=7.2 Hz), 6.90 (d, 1H, J=8.0 Hz), 6.68 (d, 1H, J=7.6 Hz), 6.21 (m, 1H), 5.92 (m, 1H), 5.05 (s, 2H), 4.70 (m, 1H), 3.58 (m, 1H), 2.80 (m, 1H), 2.01 (m, 2H), 1.85 (m, 1H), 1.70 (m, 2H), 1.51 (m, 2H), 1.17 (m, 1H). MS: calculated for C35H33N5O3+H 572.3; found: 572.5.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15](=[O:17])[NH2:16])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.O>CO.[Pd]>[C:15]([C@H:13]1[NH:12][C@@H:11]([C:9]([OH:10])=[O:8])[CH2:14]1)(=[O:17])[NH2:16]
Reactant: NC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NC(=O)[C@@H]1C[C@H](C(=O)O)N1
Yield: 96.2 %

Procedure:
53 mg (163 umol) of cis-1-benzyl-4-carbamoylazetidine-2-carboxylic acid benzyl ester (II) in 10 ml of methanol are hydrogenated in a Parr shaker over 18 mg of 10% Pd/C under a hydrogen pressure of 3.3 atm for 3 hours. 10 ml of water is added, the mixture filtered through a fluted filter, and the catalyst washed with several portions of methanol. Evaporation and drying in vacuo (0.1 torr, 4 hours) affords 22.6 mg (96%) of a colorless glass. 1H NMR (D2O): δ 5.00 (t, 1H, J=9), 4.75 (t, 1H, J=9), 3.14 (dt, 1H, J=10 (t), 12 (d)), 2.52 (dt, 1H, J=8(t), 12 (d)). IR (nujol): 3399, 3141, 3141, 3019, 2537, 2409, 1688, 1615, 1563, 1391, 1294, 1217, 1165, 1115, 1048, 968, 887, 810, 762, 696, 637 cm-1. Mass Spectra: El: m/z 142(M-2H, 40%), 100 (100), 91 (14), 82 (27), 68 (28), 54 (50), 44 (95); CI (isobutane): m/z 145 (M+ H, 100%), 126 (7), 100 (24), 99 (15), 84 (15), 72 (22).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][CH3:21])[C:3]=1[CH3:22].OOS([O-])=O.[K+].[O-2:29].[Al+3].[O-2:31].[O-2].[Al+3]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:21])(=[O:31])=[O:29])[C:3]=1[CH3:22]
Reactant: [O-2]
Reactant: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Agent: O=S([O-])OO
Agent: [Al+3]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Temperature: 65 °C

Procedure:
The 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline (300 mg, 0.893 mmol) was dissolved in chloroform (8 mL) and Oxone™ (1.65 g, 2.68 mmol) and wet aluminum(III) oxide (910 mg, 8.90 mmol) was added. The heterogeneous mixture was stirred vigorously at 65° C. and refluxed for five h. Another portion of Oxone™ (1.65 g, 2.68 mmol) and aluminum(III) oxide (910 mg, 8.90 mmol) was added and the reaction was stirred vigorously overnight at 65° C. The reaction was cooled to rt and slurried in DCM and filtered. The filtrate was concentrated and the crude product was purified by medium pressure chromatography (silica gel, 0 to 50% EtOAc:hexanes) to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline. Mass Spectrum (ESI) m/e=368.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11](=[O:35])[NH:12][C@H:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:14][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:16])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH3:37][O-:38].[Na+].O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11](=[O:35])[NH:12][C@H:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:14][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:16])[N:8]=[C:7]([O:38][CH3:37])[N:6]=1)=[O:4]
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(=O)OC)nc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(=O)OC)nc(OC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-2-chloro-pyrimidine-4-carboxylic acid methyl ester (74 mg, 0.145 mmol, from Example 42-1) in THF (5 mL) is added sodium methoxide (47 mg, 0.218 mmol) and the mixture is stirred at room temperature for 18 hours. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-2-methoxy-pyrimidine-4-carboxylic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[C:5]([CH3:16])=[CH:4][CH:3]=1.[C:17](O)(=[O:19])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH:17]([C:3]1[CH:4]=[C:5]([CH3:16])[C:6]2[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:13])[C:11]=2[C:2]=1[OH:1])=[O:19]
Reactant: Cc1ccc(O)c2c1C(C)(C)CCC2(C)C
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)c(O)c2c1C(C)(C)CCC2(C)C
Temperature: 20 °C
Reaction time: 2.5 h

Procedure:
Formylation. 1-Hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (78 g, 0.358 mol) was stirred with glacial acetic acid (632 mL) and hexamethylenetetramine (93.6 g, 0.669 mol). The mixture was heated at 105°-110° C. for 10 h. Hot water (632 mL) was added and the heating was continued for an additional 2.5 h at 100° C. The mixture was cooled to 20° C., toluene (250 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (2×50 mL), then neutralized with 5% NaHCO3 solution, and finally washed with brine (50 mL). The solvent was removed by distillation and the residue distilled to yield 2-formyl-1-hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (45 g), bp 138°-146° C./1 mm, GLC purity 95%. 1H-NMR (CDCl3) δ11.63 (1H, s), 9.73 (1H, s), 7.09 (1H, s), 2.52 (3H, s), 1.66 (3H, s), 1.47 (6H, s), 1.42 (6H, s). 13C-NMR (CDCl3) δ196 (1C, d), 159 (1C, s), 155 (1C, s), 134.7 (1C, d), 134.1 (1C, s), 128 (1C, s), 118.1 (1C, s), 39.3 (1C, t), 37.8 (1C, t), 36.5 (1C, s), 35.2 (1C, s), 28.7 (2C, q), 27.9 (2C, q), 23.5 (1C, q). IR (KBr) 1637 cm- 1, MS (m/e) 246.2 (M+, 36.1), 231.2 (100.0), 161.2 (41.6), 189.1 (27.9).
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1[N:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.[Cl:20][C:21]1[C:26]([CH3:27])=[C:25](Cl)[N:24]=[CH:23][N:22]=1>C1COCC1>[Cl:20][C:21]1[C:26]([CH3:27])=[C:25]([O:19][CH:16]2[CH2:15][CH2:14][N:13]([C:8]3[N:9]=[CH:10][CH:11]=[CH:12][N:7]=3)[CH2:18][CH2:17]2)[N:24]=[CH:23][N:22]=1
Reactant: OC1CCN(c2ncccn2)CC1
Reactant: Cc1c(Cl)ncnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(Cl)ncnc1OC1CCN(c2ncccn2)CC1
Temperature: 30 °C
Reaction time: 5 h
Yield: 3.3 %

Procedure:
Potassium tert-butoxide (2.86 gm, 0.01397 moles) was added to an ice-cold solution of 1-(pyrimidin-2-yl)piperidin-4-ol (2.50 gm, 0.01397 moles) and 4,6-dichloro-5-methylpyrimidine (2.27 mg, 0.01397 moles) in dry THF (15 ml) and the reaction mixture was stirred for 5 hours at 30° C. The reaction mixture was poured into ice cold water, solid precipitated was filtered and dried under vacuum to obtain 140 mg of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:31])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1ccc(Br)cc1
Reaction time: 4 h
Yield: 39.9 %

Procedure:
Compound 41-2 (3.63 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (4.88 g) and N-bromosuccinimide (3.31 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.87 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([OH:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([O:30][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Solvent: O
Product: CCCCCCCN(CCc1ccc(CC(OCc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution of 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester (0.59 mmol, 250 mg) was added anhydrous CsOH (0.885 mmol, 148.6 mg) and freshly dried powdered 4 Angstrom molecular sieves (300 mg) followed by benzyl bromide (4.72 mmol, 0.56 mL). The mixture was allowed to stir for 16 hours. The mixture was poured into water and extracted with diethyl ether (3×). The organic layers were combined, washed with water (2×), brine (2×), dried over Na2SO4, and concentrated to a crude oil. The oil was purified by chromatography on silica gel (Merck silica gel 60, art#9385-3) eluting with 20% ethyl acetate in hexanes to give 2-benzyloxy-3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-propionic acid ethyl ester as a clear oil (180 mg, 58%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5](OCC)=[O:6].[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[CH2:16][CH2:17][C:18]#[N:19])[CH3:13].O>O1CCCC1>[CH2:21]([O:20][CH:15]([O:14][CH2:12][CH3:13])[CH2:16][CH:17]([C:5](=[O:6])[C:4]([F:11])([F:10])[F:3])[C:18]#[N:19])[CH3:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCOC(CCC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CC(C#N)C(=O)C(F)(F)F)OCC
Yield: 32.3 %

Procedure:
To a 40°-45° C. stirring suspension of hexanewashed sodium hydride (5.5 g of a 60% dispersion, 0.14 mol) in 200 mL of dried tetrahydrofuran is added dropwise a solution of ethyl trifluoroacetate (15 g, 0.11 mol) and 3-cyanopropionaldehyde diethyl acetal (17 g, 0.11 mol) in 100 mL of dry tetrahydrofuran. The previously gray suspension slowly turns light brown in color. The reaction mixture is stirred at 50°-55° C. overnight before being quenched by slow addition of 2-propanol (15 mL). Rotary evaporation of the volatiles yields a dark oil, to which is added 150 mL of pH 7 water. Unreacted starting materials are conveniently removed by washing the aqueous layer with diethyl ether (3×30 mL). The basic aqueous phase is then acidified with 12 N hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed once with saturated sodium bicarbonate (40 mL) and once with brine (15 mL) before being dried over magnesium sulfate. Rotary evaporation yields a reddish oil which is flash chromatographed over silica gel using 4:1 hexane-ethyl acetate as eluent to provide the desired product (9 g, 32%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][O:4][N:3]=1.COC(=O)[C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[N:12][CH:11]=1.[OH-].[Li+].O1CCCC1>O1CCCC1.O>[N:12]1[CH:11]=[CH:10][CH:15]=[C:14]([O:16][C:2]2[CH2:6][CH2:5][O:4][N:3]=2)[CH:13]=1
Reactant: BrC1=NOCC1
Reactant: COC(=O)c1cncc(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: c1cncc(OC2=NOCC2)c1

Procedure:
The enantiomers of 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-74a and III-74b were prepared in 2 steps according to the following procedures: racemic 3-bromo 4,5-dihydroisoxazole III-66 was reacted with 5-hydroxynicotinic acid methyl ester using Method 5. The resulting ester (1.0 equiv) was dissolved in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room temperature for 1 h after which point the tetrahydrofuran was removed under a stream of nitrogen and the remaining solution was acidified to pH<2 with 1N HCl to provide the racemic desired acid III-74 as a white solid which was isolated via vacuum filtration. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=395.5 m/z. Activity: A
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].B(F)(F)F.[CH3:20]COCC>CO>[CH2:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH2:9][CH2:10][C:11]([O:13][CH3:20])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: CCOCC
Reactant: C=CCNc1ccc(CCC(=O)O)cc1
Agent: FB(F)F
Solvent: CO
Product: C=CCNc1ccc(CCC(=O)OC)cc1
Temperature: 0 °C

Procedure:
A solution of 50.5 g. of 4-(allylamino)hydrocinnamic acid and 34.4 ml. of boron trifluoride etherate in 200 ml. of methanol is stirred under reflux for 44 hours, allowed to cool, and poured into 1.20 liters of ice-cold 5% aqueous sodium carbonate solution. The white solid is collected by filtration and recrystallized from benzeneethanol to yield methyl 4-(allylamino)hydrocinnamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)[CH:6]=[CH:7][CH:8]=1.[C:17]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:25]2[CH2:26][CH2:27][CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24]2)=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2oncc2C(=O)O)c1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)c1
Temperature: 25 °C

Procedure:
5-(3-methoxyphenyl)-isoxazole-4-carboxylic acid (50.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1482.
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:14]([F:36])=[CH:13][N:12]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([S:26]([CH:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:15]2[C:14]([F:36])=[CH:13][N:12]=[C:11]([NH2:10])[CH:16]=2)(=[O:27])=[O:28])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To an ethanol (5 ml) solution of t-butyl[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]carbamate (170 mg, 0.331 mmol) was added concentrated hydrochloric acid (5 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was recrystallized from hexane:ethyl acetate to give the title compound (110 mg, 0.266 mmol, 81%) as a pale violet powder.
Reaction SMILES: [CH2:1]([C:13]1[NH:17][N:16]=[N:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1NN=NN=1)CCCCCCCCC.[CH2:33]([O:35][C:36](=[O:51])[CH:37](Br)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH3:34].BrC1C=CC=CC=1CC(OCC)=O>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:36]([O:35][CH2:33][CH3:34])=[O:51])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Reactant: CCCCCCCCCCCCc1nnn[nH]1
Agent: CCCCCCCCCCc1nnn[nH]1
Agent: CCOC(=O)Cc1ccccc1Br
Product: CCCCCCCCCCCCc1nnn(C(CCCCCCCCCCCC)C(=O)OCC)n1

Procedure:
When in the general procedure of Example 71 an appropriate amount of 5-dodecyl-1H-tetrazole was substituted for 5-decyl-1H-tetrazole and an appropriate amount of ethyl-2-bromomyristate was substituted for ethyl 2-bromophenylacetate, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2,5-dibromopyridine (4.10 g, 17 mmol) in anhydrous toluene (250 mL) at −78° C. was dropwise added n-BuLi (1.6 M, 12 mL). After stirred at −78° C. for 2.5 hours, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (2.73 g, 17 mmol) in methylene chloride (25 mL) was added into the reaction mixture, and the resulting mixture was stirred for additional one hour and allowed to warm up to room temperature slowly. The reaction mixture was poured into aqueous NaHCO3 (200 mL) and then extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over MgSO4, and concentrated in vacuo. The resulting solid was triturated with ether and the solid was collected by filtration. The ether solution was concentrated and the solid was chromatographed on silica gel, eluting with hexane/ethyl acetate (2 to 1) to give a pale yellow solid. Weight of combined solids: 4.26 g. LCMS: 316.10/314.10 (M+H+, 100%). 1HNMR: δ 8.6 (s, 1H), 7.82 (d, 1H), 7.38 (d, 1H), 4.6 (s, 1H), 4.0 (m, 4H), 2.2 (m, 4H), 1.7 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].O>[N+](C)([O-])=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:7]([CH3:10])[C:6]=2[CH:11]=1
Reactant: Cc1coc2ccc(F)cc12
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cc1c(C(=O)C(C)C)oc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5-fluoro-3-methyl-1-benzofuran (2.0 g) synthesized in Example A67(2) and isobutyryl chloride (1.56 g) in nitromethane (40 mL) was added aluminum chloride (anhydrous) (2.66 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr, and at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (1.933 g, 66%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CCN(CC)CC.[CH2:22]([C:30]1[O:34][C:33]([C:35](ON2C(=O)CCC2=O)=[O:36])=[CH:32][CH:31]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH3:8][N:5]1[CH2:4][CH2:3][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([NH:1][C:35]([C:33]2[O:34][C:30]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:31][CH:32]=2)=[O:36])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CC1(N)CCN(C)CC1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(CCc2ccccc2)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1(NC(=O)c2ccc(CCc3ccccc3)o2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A stirred solution of ethyl 2-(4-amino-1-methylpiperidin-4-yl)acetate (16 mg, 0.077 mmol) in CH2Cl2 (1 mL) was treated with NEt3 (31 uL, 0.219 mmol), and 2,5-dioxopyrrolidin-1-yl 5-phenethylfuran-2-carboxylate, prepared as described in Preparation 5 (23 mg, 0.073 mmol). The reaction was stirred overnight, at room temperature, then the solvent removed in vacuo and the crude product purified by column chromatography to obtain the title compound (25 mg, 86%). 1H NMR (400 MHz, CD3OD) δ 7.29-7.16 (m, 5H), 7.00 (s, 1H), 6.17 (s, 1H), 4.06 (q, 2H, J=7.2 Hz), 3.05 (s, 4H), 2.88 (s, 2H), 2.75-2.69 (m, 2H), 2.54-2.48 (m, 2H), 2.41-2.31 (m, 5H), 1.87-1.81 (m, 2H), 1.15 (t, 3H, J=7.2 Hz); MS ESI 399.2 [M+H]+, calcd for [C23H30N2O4+H]+ 399.50.