Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][N:32]1[C:36]([CH:37]=[O:38])=[CH:35][N:34]=[C:33]1[CH3:39]>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:37]([C:36]3[N:32]([CH3:31])[C:33]([CH3:39])=[N:34][CH:35]=3)[OH:38])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ncc(C=O)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2.0 g, 4.64 mmol, Intermediate 5: step d) was added THF (25 mL). The solution was cooled to −70° C. and then n-BuLi (2.5 M in hexanes, 1.8 mL, 4.5 mmol) was added dropwise. After 2 minutes, 1,2-dimethyl-1H-imidazole-5-carbaldehyde (720 mg, 5.8 mmol in 5 mL THF) was introduced. The reaction mixture was allowed to warm to 0° C. over 60 minutes at which time it was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc:THF (10:1, 5×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with EtOAc:Et2O (1:1), collected by filtration, rinsed with additional Et2O and dried to afford the title compound. The mother liquors were concentrated and chromatographed on silica gel (3% MeOH-DCM increasing to 10% MeOH) to provide additional title compound.
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:3]=1[O:4][CH:5]1[CH2:11][CH:10]2[NH:12][CH:7]([CH2:8][CH2:9]2)[CH2:6]1.[N+]([NH:24][C:25](N)=[O:26])([O-])=O.C(O)C>CO.CC(O)C.C(O)CC>[NH2:24][C:25]([N:12]1[CH:10]2[CH2:9][CH2:8][CH:7]1[CH2:6][CH:5]([O:4][C:3]1[C:13]([F:20])=[C:14]([F:19])[C:15]([F:18])=[C:16]([F:17])[C:2]=1[F:1])[CH2:11]2)=[O:26]
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Fc1c(F)c(F)c(OC2CC3CCC(C2)N3)c(F)c1F
Solvent: CCCO
Solvent: CC(C)O
Solvent: CO
Product: NC(=O)N1C2CCC1CC(Oc1c(F)c(F)c(F)c(F)c1F)C2

Procedure:
The reaction of 3-(2,3,4,5,6-pentafluorophenoxy)-8-azabicyclo[3.2.1]octane 5 and nitrourea in an alkanol (e.g. methanol, ethanol, 1-propanol, 2-propanol, and the like; methanol being preferred) at a temperature of from about 20° C. to about 100° C., preferably from about 50° C. to about 80° C., provides a means of a furnishing an 8-aminocarbonyl-3-(2,3,4,5,6-pentafluorophenoxy)-8-azabicyclo[3.2.1]octane 6.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[C:6]([Cl:12])[CH:5]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([Cl:22])[CH:15]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][C:16]=2[Cl:22])=[C:6]([Cl:12])[CH:5]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: OCc1ccc(Br)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Clc1cc(Br)ccc1COCc1ccc(Br)cc1Cl
Yield: 87.8 %

Procedure:
To a solution of 271 mg (6.78 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (25 ml) was added 1.00 g (4.52 mmol) of 4-bromo-2-chlorobenzyl alcohol in an atmosphere of argon, and the mixture was allowed to react at 40°-50° C. for 30 min. Then, 1.54 g (5.42 mmol) of 4-bromo-2-chlorobenzyl bromide was added, and the mixture was reacted at room temperature for 18 hours. To the reaction mixture at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with ethyl acetate-hexane (1:4) yielded 1.69 g (3.97 mmol) of bis(4-bromo-2-chlorobenzyl) ether.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.ClC1C=CC=CC=1C(O)=O.C(OC1C=CC(N)=CC=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccccc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Agent: Nc1ccc(OCc2ccccc2)cc1
Solvent: CCO
Product: O=C(O)c1ccccc1Nc1ccc(O)cc1

Procedure:
The corresponding free acid, 2-(4-hydroxyphenylamino)benzoic acid, yellow solid m.p. 233° C.(decompn.) was prepared by hydrogenation of 5 g of 2-(4-benzyloxyphenylamino)benzoic acid in 250 ml of ethanol containing 2 ml of concentrated hydrochloric acid and 2 g of palladium-on-carbon catalyst. The benzyloxy compound was in turn prepared by reaction of 2-chlorobenzoic acid and 4-benzyloxyaniline.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[CH:8]=1)=[O:6])=[N+]=[N-].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.CO>C1COCC1.[Pd]>[C:23]([O:22][C:20](=[O:19])[NH:1][CH2:4][C:5]([C:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[CH:8]=1)=[O:6])([CH3:26])([CH3:25])[CH3:24]
Reactant: [N-]=[N+]=NCC(=O)c1cn2c3c(cccc13)CCC2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)c1cn2c3c(cccc13)CCC2

Procedure:
A solution of 2-azido-1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethanone (4.70 g, 19.58 mmol), (BOC)2O (4.48 g, 20.56 mmol), Pd/C (10%) in THF (30 mL)/MeOH (20 mL) was shaken under H2 (60 psi) overnight. The mixture was filtered through a pad of Celite and concentrated to give a residue that was purified by silica gel column chromatography (eluent, 2/1 hex/EtOAc). [2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was obtained as a white solid (2.82 g, 46%). M.p.=175-177° C.; 1H NMR (400 MHz, DMSO-d6) δ: 8.35 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.99 (m, 2H), 4.27 (d, J=6.0 Hz, 2H), 4.23 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.4 Hz, 2H), 2.14 (m, 2H), 1.41 (s, 9H). LCMS: m/e 315.21 [M+H], 259.17 [M-56].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:12]([O:26]CC3C=CC(OC)=CC=3)=[N:11]2)=[CH:5][CH:4]=1.O1CCOCC1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[C:12](=[O:26])[NH:11]2)=[CH:5][CH:4]=1
Reactant: CCCCOC(=O)/C=C/c1cc(=O)n(Cc2ccc(OC)cc2)nc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCOC(=O)CCc1cc(=O)n(Cc2ccc(OC)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
A solution of butyl (2E)-3-[1-{[4-(methyloxy)phenyl]methyl}-3-({[4-(methyloxy)phenyl]methyl}oxy)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-propenoate (580 mg) in ethanol (15 ml)/1,4-dioxane (5 ml) was treated with 10% Pd/C (400 mg) and stirred under hydrogen at atmospheric pressure and RT for 2 hours. The catalyst was filtered off using kieselguhr and the filtrate was evaporated and redissolved in 1,4-dioxane and the solution evaporated to dryness to give the product (0.43 g, 98%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13].ClS(N=C=O)(=O)=O>O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([O:11][S:12](=[O:15])(=[O:14])[NH2:13])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: NS(=O)(=O)Cl
Agent: O=C=NS(=O)(=O)Cl
Solvent: O
Product: CC(=O)Nc1cccc(OS(N)(=O)=O)c1

Procedure:
By the same method described for Example 53, the title compound was prepared from m-acetamidophenol (12.10 g, 0.08 m), reacting with the sulfamoyl chloride generated from water and chlorosulfonyl isocyanate. The crude product contained desired product and starting material. The product was isolated by chromatography on 100 g silica gel, eluted first with 7:3 methylene chloride/acetonitrile and then increasing the proportion of acetonitrile in the eluting solvent. The main fraction was evaporated and triturated with isopropyl alcohol/isopropyl ether to give 4 g of white solid, recrystallized from acetonitrile/isopropyl ether, and dried in vacuum at 60° C. overnight to give 3.73 g of solid, mp 148°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13](I)[N:14]=[CH:15][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[NH2:26][C:27]1[O:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][N:31]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:35]([O:34][C:32]([C:29]1[O:28][C:27]([NH:26][C:13]2[N:14]=[CH:15][C:10]3[CH2:9][N:8]=[C:7]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[C:6]4[CH:25]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]=3[N:12]=2)=[N:31][CH:30]=1)=[O:33])[CH3:36]
Reactant: Fc1cccc(F)c1C1=NCc2cnc(I)nc2-c2ccc(Cl)cc21
Reactant: CCOC(=O)c1cnc(N)o1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1cnc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2F)=NC3)o1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A mixture of 9-Chloro-7-(2,6-difluoro-phenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine (200 mg, 0.43 mmol), ethyl 2-aminooxazole-5-carboxylate (81.2 mg, 0.52 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (935 mg, 0.034 mmol), Xantphos (30 mg, 0.052 mmol), powdered K3PO4 (183 mg, 0.86 mmol), and degassed toluene were submitted to microwave irradiation (300 W) for 20 minutes at 145° C. The mixture was cooled to room temperature and then evaporated to leave a brown solid which was purified by column chromatography (silica gel, CH2Cl2 to 50% diethyl ether in CH2Cl2) to yield 2-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-oxazole-5-carboxylic acid ethyl ester as a yellow powder (103 mg, 48%) MS m/z=496 (M+H). 2-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-oxazole-5-carboxylic acid ethyl ester (91 mg, 0.18 mmol), methanol (1 mL), tetrahydrofuran (3 mL), and 1N LiOH (3.7 mL, 3.7 mmol) were stirred at room temperature for 3 hours. Water (50 mL) was added with stirring, and the resulting clear yellow solution was acidified by slowly adding 1N HCl. A yellow precipitate formed. Diethyl ether (10 mL) was added and the precipitate was collected by filtration, washed with water, diethyl ether and then dried in vacuo to yield I-364 as a yellow powder (78 mg, 93% yield) MS m/z=468 (M+H).
Reaction SMILES: N[C@H:2]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[Br-:16].[K+].N([O-])=O.[Na+]>O>[Br:16][CH:2]([CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: [Br-]
Reactant: CC(C)(C)C[C@@H](N)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CC(C)(C)CC(Br)C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of (R)-2-amino-4,4-dimethylpentanoic acid (950 mg, 6.55 mmol) in 2.5N aqueous sulfuric acid (13 ml, 33 mmol) was cooled to -5° C. and treated with potassium bromide (2.72 g, 22.9 mmol) in one portion. The colorless solution was treated with sodium nitrite (680 mg, 9.86 mmol) portionwise, keeping the temperature between 0° and 3° C. over a period of 25 minutes. The reaction mixture was stirred at 0° C. for one hour and at room temperature for 1.5 hours. The reaction mixture was poured into water (10 ml). The product was extracted with ether (60 ml), washed with water (20 ml) and brine (20 ml), dried (magnesium sulfate), and concentrated in vacuo to give the title product as a colorless liquid.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[C:25]2[O:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[C:26]3[CH2:32][CH:31]4[N:33]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH:28]([CH2:29][CH2:30]4)[CH2:27]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C1COCC1.C(Cl)Cl>[F:38][C:35]([F:36])([F:37])[C:34]([N:33]1[CH:31]2[CH2:30][CH2:29][CH:28]1[CH2:27][C:26](=[C:17]1[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][CH:8]=[O:10])[C:25]=3[O:24][C:23]3[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:32]2)=[O:39]
Reactant: Nc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Reactant: O=CO
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CNc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2C(=O)C(F)(F)F
Temperature: 50 °C

Procedure:
Into a flask was placed acetic anhydride (4 mL) and the reaction was cooled in an ice bath. Upon cooling, formic acid (2 mL) was added and the mixture was heated to 50° C. for 15 min, and then cooled to rt. Upon cooling, the resulting solution (0.6 mL) was added to an ice bath-cooled solution of compound 4k (0.300 g, 6.0 mmol) in THF (2 mL), and the reaction was heated to 50° C. for 1 h. The mixture was cooled to rt, diluted with methylene chloride, and the organic phase was washed sequentially with saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over MgSO4, filtered, and concentrated to yield 0.42 g of the title compound 5k.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:23]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C.O>[NH2:23][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Reactant: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(4-iodophenyl)propanoic acid (35.1 g) was dissolved in DMF (200 mL) and to the resulting solution was added N-ethylmorpholine (17.0 mL) followed by TBTU (28.8 g). The mixture was stirred at room temperature for 0.5 h and then cooled to 0° C. 0.880 Ammonia (11.1 mL) was added and the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 16 h and was then to poured into water and the resulting precipitate removed by filtration. The solid was dried in vacuo to give the sub-titled compound (34.2 g).
Reaction SMILES: F[C:2]1C=C([C@H]2N(CC(OCC)=O)C(=O)C3(CCCC3)NC2)C=C(F)C=1.[ClH:26].[NH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.NC1(C(O)=O)CCCCC1>>[ClH:26].[NH2:27][C:28]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:2]1
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)NC[C@H]1c1cc(F)cc(F)c1
Reactant: COC(=O)C1(N)CCCC1
Agent: Cl
Agent: NC1(C(=O)O)CCCCC1
Product: COC(=O)C1(N)CCCCC1

Procedure:
Essentially following the procedures described in Intermediate 25 for methyl 1-aminocyclopentanecarboxylate hydrochloride, but using 1-aminocyclohexanecarboxylic acid in place of 1-aminocyclopentanecarboxylic acid, the title compound was obtained. MS: m/z=158 (M+1).
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.[CH:8]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[C:12](=[CH2:13])[C:9]2([CH3:11])[CH3:10].C(OOC(C)(C)C)(C)(C)C.[OH-].[Na+]>>[CH3:10][C:9]1([CH3:11])[CH:8]2[CH2:17][CH:14]([CH2:15][CH2:16]2)[CH:12]1[CH2:13][CH2:6][C:5]([OH:4])=[O:7]
Reactant: C=C1C2CCC(C2)C1(C)C
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)OOC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)C2CCC(C2)C1CCC(=O)O

Procedure:
To refluxing acetic anhydride (1050 g., 10 moles), there is added dropwise over six hours a solution of camphene (136 g., 1 mole) and di-tert-butyl peroxide (0.1 mole, 14.6 g.). After complete addition, the mixture is heated at reflux for five hours. The cooled reaction mixture is concentrated under reduced pressure to leave a yellow-orange residual oil, 750 ml. of 2.5N NaOH is added to the residue which is then heated on the steam bath for one hour. The cooled solution is extracted once with ether, made acidic with concentrated HCl, and extracted thoroughly with ether. The dried (Na2SO4) ether extracts are concentrated under reduced pressure and the residue distilled under vacuum.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][C:12]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](OCC4C=CC=CC=4)=O)[CH2:23][CH2:22]3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][C:12]([CH:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[CH:13][C:14]=2[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2cc(-c3ccncc3)c(-c3cccc(C(F)(F)F)c3)nn2)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCC(c2cc(-c3ccncc3)c(-c3cccc(C(F)(F)F)c3)nn2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
Under Ar, a solution of 15 (0.73 g, 1.4 mmol) in THF (175 mL) was treated with LAH (0.37 g, 9.7 mmol). After addition, the reaction was heated at 60° C. After 2 h, the reaction was cooled to room temperature and treated with saturated Na2SO4 until a suspension results. The reaction mixture was filtered and the filtrate washed with EtOAc. The organic was washed with H2O, brine, dried, filtered and concentrated to dryness. The residue was treated with Et2O-hexanes, filtered and dried to yield 0.3 g of 16; mp 188-9° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([CH3:29])([CH3:28])[CH2:9][NH:10][C:11](=[O:27])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[O:20][N:19]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.[Pd+2].ClC1C=C[C-](P(C(C)(C)C)C(C)(C)C)C=1Cl.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:2]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:29])([CH3:28])[CH2:9][NH:10][C:11](=[O:27])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[O:20][N:19]=3)[CH:13]=2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1cccc(Br)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P([c-]1ccc(Cl)c1Cl)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1cccc(-c2ccccc2)c1
Temperature: 60 °C
Yield: 20.1 %

Procedure:
A solution of N-(2-(3-bromophenyl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (30 mg, 0.064 mmol) and phenyl boronic acid (39 mgs, 0.32 mmol) in THF (1.2 mL) was degassed with nitrogen. Dichloro[1,1′ bis(di-tert-butylphosphino)]ferrocene palladium (II) (5 mgs, 0.006 mmol) and 1 M potassium carbonate (1.2 mL) were added. The reaction was heated overnight at 60° C. The reaction was extracted with ethyl acetate and dried over sodium sulfate. The crude was purified by prep TLC using 30% EA/hexanes to yield N-(2-([1,1′-biphenyl]-3-yl)-2-methylpropyl)-3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (6 mgs, yield 18%). 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H) 8.18 (d, J=7.2 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.64-7.30 (m, 10H) 5.88 (s, 1H), 3.73 (d, J=7.2 Hz, 2H), 1.48 (s, 6H). MS (ESI) m/z: Calculated for C26H22F3N3O2: 465.17. found: 466.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:39])[C@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:12][C:13](=[O:31])[C@H:14]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:15][C:16](=[O:23])[C@H:17]([CH2:19][C:20](=[O:22])[NH2:21])[NH2:18].ClC1C=CC([O:47][C:48](=O)[CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=C(Cl)C=1Cl.C(N1CCOCC1)C>CN(C)C=O>[CH3:8][O:9][C:10](=[O:39])[C@H:11]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH:12][C:13](=[O:31])[C@H:14]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:15][C:16](=[O:23])[C@H:17]([CH2:19][C:20](=[O:22])[NH2:21])[NH:18][C:48](=[O:47])[CH2:49][NH:50][C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52]
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: CCN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OC(C)(C)C

Procedure:
A solution of asparaginyl-phenylalanyl-phenylalanine methyl ester trifluoroacetate (0.88 g, 1.59 mmole, described by H. U. Immer et al., U.S. Pat. No. 3,917,578, issued Nov. 4, 1975), t-butoxycarbonyl-glycine trichlorophenyl ester (0.56 g, 1.59 mmole) and N-ethylmorpholine (0.203 ml, 1.59 mmole) in dimethylformamide (9 ml) is stirred at 0° C. for 1 hour and at 25° C. for 20 hours. The solution is evaporated and the residue is crystallized from methanol to give the title compound, mp 211°-214° C.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35]4)[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH:34]4[CH2:38][O:37][C:36]([CH3:39])([CH3:40])[O:35]4)[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[C:26]([NH2:46])=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Reaction time: 2 h

Procedure:
3-Chloroperoxybenozic acid (mCPBA) (75% pure, 11.57 g, 50.27 mmol, 1.5 eq) was added to a solution of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (15.00 g, 33.52 mmol, 1 eq) in dichloromethane (200 mL), and the reaction mixture was stirred for two hours. Analysis by thin layer chromatography indicated the reaction was incomplete and additional mCPBA (1.2 g) was added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane (300 mL), washed sequentially with 4% aqueous sodium carbonate solution (2×300 mL) and brine (300 mL), and concentrated under reduced pressure to afford a residue. Concentrated ammonium hydroxide (75 mL) was then added to a mixture of the residue in dichloromethane (200 mL) and cooled to 4° C. p-Toluenesulfonyl chloride (2.75 g, 14.44 mmol, 1.1 eq) was added in portions to the reaction mixture and stirred at ambient temperature for 16 hours. The reaction mixture was then diluted with dichloromethane (200 mL), washed with 4M aqueous sodium carbonate solution and separated. The aqueous layer was re-extracted with dichloromethane (200 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a brown solid. The crude material was purified by crystallization from diethyl ether to provide 9.8 g of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-ylamine as white plates of solid, mp 186-187° C. 1H-NMR (300 MHz, CDCl3) δ 7.89 (d, J=9.1 Hz, 1H), 7.53-7.29 (m, 6H), 7.05 (dd, J=9.0, 2.6 Hz, 1H), 5.42 (br s, 2H), 5.18 (s, 2H), 4.94 (d, J=12.6 Hz, 1H), 4.83-4.69 (m, 3H), 4.68-4.58 (m, 1H), 4.15 (dd, J=8.6, 6.2 Hz, 1H), 3.86 (dd, J=8.6, 6.1 Hz, 1H), 3.62 (q, J=7.0 Hz, 2H), 1.45 (s, 3H), 1.29 (s, 3H), 1.25 (t, J=7.0 Hz, 3H); 13C-NMR (75 MHz, CDCl3) δ 158.3, 151.7, 149.0, 147.1, 136.8, 134.7, 128.6, 128.0, 127.6, 125.4, 120.9, 113.8, 110.2, 109.7, 108.9, 74.6, 70.0, 66.7, 66.3, 65.3, 48.2, 26.7, 25.1, 15.0; MS (APCI) m/z 463.1 (M+H)+; Anal. calcd for C26H30N4O4: C, 67.51; H, 6.54; N, 12.11. Found: C, 67.29; H, 6.33; N, 12.03.