Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[NH2:50][CH:51]1[CH2:56][C:55]([CH3:58])([CH3:57])[NH:54][C:53]([CH3:60])([CH3:59])[CH2:52]1>C1COCC1>[Cl:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[Cl:28])[NH:19][C:18]([C:17]1[CH:16]=[CH:15][C:11]([C:12]([NH:50][CH:51]3[CH2:52][C:53]([CH3:60])([CH3:59])[NH:54][C:55]([CH3:58])([CH3:57])[CH2:56]3)=[O:14])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:26]2
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: O=C(O)c1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)c(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC1(C)CC(NC(=O)c2ccc(-c3cc4cc(Cl)c(Cl)cc4[nH]3)c(OCc3ccccc3)c2)CC(C)(C)N1
Yield: 50.2 %

Procedure:
To a solution of 3-benzyloxy-4-(5,6-dichloro-1H-indol-2-yl)benzoic acid (0.14 g, 0.34 mmol), prepared as in Description 19, in THF (14 ml), WSC (N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride) (0.078 g, 0.408 mmol) and 1-hydroxybenzotriazole (0.0551 g, 0.408 mmol) was refluxed for 6 h. A solution of 4-amino-2,2,6,6-tetramethylpiperidine (0.064 g, 0.408 mmol) in THF (2 ml) was added dropwise and refluxed for additional 2 h. The solvent was removed under vacuum and the residue suspended in water. The solid was filtrated and dried under vacuum. The solid was triturated with CH3CN (5 ml) to give 0.094 g (yield 45%) of the title compound as a white powder, mp=220° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.Cl.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[OH:32].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]5[OH:32])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Reactant: N[C@@H]1CCCC[C@@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 110 °C
Yield: 7.5 %

Procedure:
To a suspension of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (1.0 g, 3.0 mmol) and (1S,2R)-2-aminocyclohexanol hydrochloride (916 mg, 6 mmol) in anhydrous DMA (12 mL) was added DIEA (1.6 mL, 9.0 mmol). The mixture was heated in a sealed tube at 110° C. for 12 h. The mixture was cooled to rt and additional (1S,2R)-2-aminocyclohexanol hydrochloride (458 mg, 3 mmol) and DIEA (530 μL, 3 mmol) were added. The mixture was further heated in a sealed tube at 120° C. for 12 h. The mixture was cooled to rt and partitioned between EtOAc (200 mL) and 0.5 M aq K2CO3 (100 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 5% MeOH in CH2Cl2, then by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (89 mg, 7%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.41 (s, 1H), 8.06 (dd, J=2.5, 9.5 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.21 (dd, J=1.3, 8.3 Hz, 1H), 5.47 (s, 2H), 4.67 (m, 1H), 3.90 (m, 1H), 3.84 (m, 1H), 1.64-1.74 (m, 2H), 1.43-1.63 (m, 4H), 1.25-1.34 (m, 2H); LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)O[C:6](=[O:7])[C:5]2=[CH:12][CH:13]=1.CSC(=N)[NH:17][S:18]([CH2:21]Cl)(=[O:20])=[O:19].C(#[N:26])C>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[N:26]3[CH2:21][S:18](=[O:19])(=[O:20])[NH:17][C:9]3=[N:10]2)=[CH:12][CH:13]=1
Reactant: CSC(=N)NS(=O)(=O)CCl
Reactant: CC#N
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Agent: CN(C)c1ccncc1
Product: O=c1c2ccc(Cl)cc2nc2n1CS(=O)(=O)N2

Procedure:
To a stirred slurry of 4-chloroisatoic anhydride (4.95 g, 25 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (5.07 g, 25 mmol) in acetonitrile (25 ml) under nitrogen is added 4-(N,N-dimethylamino)pyridine (3.97 g, 33 mmol). The mixture is refluxed under nitrogen for 24 hr, concentrated, then worked up as in Example 4 above. The resulting gummy solid is triturated with hot ethanol, then recrystallized from DMF to provide the title compound as a white solid, mp >300° C. (1.65 g, 24%)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH3:23].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:24][C:25]1[N:26]=[C:27]([C:32]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH3:23])=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CC
Yield: 79.5 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (110c) (0.35 g, 1.45 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.11 g, 0.6 mmol), WSC hydrochloride (0.38 g, 2 mmol), HOBt (0.13 g, 1 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 3/2, 2/1) to obtain 0.23 g of the title compound as a colorless solid (80%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:18])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36]Br)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.O>[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][C:14]([CH3:16])([CH3:15])[C:13]([OH:18])=[O:17])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C(=O)O
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(CCCOc1ccc(OCc2ccccc2)cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
To a solution of 15 g of diisopropylamine in 75 ml of dry tetrahydrofuran was dropwise added 100 ml of n-butyl lithium (15 w/w, n-hexane solution) at -5° to 0° C. After stirring at the same temperature for 30 minutes, 6.7 g of isobutyric acid was added dropwise to the mixture. After stirring was continued at the same temperature for 1 hour, a solution of 20 g of p-(3-bromopropoxy)phenyl benzyl ether in 60 ml of dry tetrahydrofuran was added dropwise to the solution. Thirty minutes after, the mixture was stirred at room temperature for 16 hours. The mixture was cooled and 250 ml of water was added thereto. After the aqueous layer was washed with ether, the aqueous layer was acidified with 6N hydrochloric acid and extracted twice with 70 ml of methylene chloride. The extract was washed with an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure and the residue was recrystallized from ethyl acetate to give the desired product, 5-(p-benzyloxyphenoxy)-2,2-dimethylpentanoic acid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]OS(C)(=O)=O)(=O)=O.Cl.[NH2:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][SH:21].[OH-:25].[Na+].Cl>O.C(O)C>[CH2:11]([S:21][CH2:20][C@@H:19]([C:22]([OH:23])=[O:25])[NH2:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][S:21][CH2:20][C@@H:19]([C:22]([OH:24])=[O:23])[NH2:18]
Reactant: CS(=O)(=O)OCCCCCCOS(C)(=O)=O
Reactant: N[C@@H](CS)C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N[C@@H](CSCCCCCCSC[C@H](N)C(=O)O)C(=O)O

Procedure:
At 70° C., under nitrogen, a mixture of 137 g of 1,6-hexanediyl dimethanesulfonate and 175.5 g of cysteine-hydrochloride monohydrated in 1.5 l of water containing a little ethanol is agitated. There is then slowly added a solution of 5 N NaOH so that the pH of the reaction mixture is maintained between 8.5 and 9.5. At the end of the reaction the mixture is acidified to pH 5.2 with a solution of HCl. The precipitate is filtered, washed thoroughly with water, then dried and analyzed.
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>N1C(C)=CC(C)=CC=1C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: COc1ccc(O)cc1
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc1

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (1.751 g, 5.40 mmol), 4-methoxy phenol (715 mg, 5.76 mmol) and cuprous oxide (390 mg, 2.73 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 81.73° C. (DSC)
Reaction SMILES: [Cl:1]CCCCC=O.Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([Cl:15])=O.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1.C(O)(C)C>C1(C)C(C)=CC=CC=1>[ClH:1].[Cl:15][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:21]2[NH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20]=2[CH2:19][CH2:18][NH:17]1
Reactant: O=CCCCCCl
Reactant: O=C(Cl)CCCCCl
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Solvent: CC(C)O
Solvent: Cc1ccccc1C
Product: ClCCCCC1NCCc2c1[nH]c1ccccc21
Yield: 62.8 %

Procedure:
435 parts of a 13.7% strength by weight solution of δ-chlorovaleraldehyde in xylene (prepared by catalytic hydrogenation of a solution of δ-chlorovaleryl chloride in xylene) were stirred with 96 parts of 3-(β-aminoethyl)-indole hydrochloride in 500 parts of isopropanol for 6 hours at 85° C., and the mixture was cooled and then filtered under suction to give 92 parts (62.8%) of 1-(δ-chlorobutyl)-1,2,3,4-tetrahydro-β-carboline hydrochloride. After recrystallization, the substance had a melting point of 245°-247° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:22]([N+:23]([O-])=O)=[C:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:20]=[C:19]([CH3:33])[C:18]=1[CH3:34].C(O)C.O1CCCC1>O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:18]([CH3:34])=[C:19]([CH3:33])[N:20]=[C:21]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:22]=1[NH2:23]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCCl)c1C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCCCl)c1C
Yield: 126.3 %

Procedure:
A solution of sodium dithionite (24.01 g, 137.9 mmol) in water (90 mL) was added to a mixture of N-(6-chlorohexyl)-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine (10.42 g, 27.58 mmol) and ethanol (276 mL). After about 4 hours sodium dithionite (6.71 g) in water (20 mL) was added to the reaction mixture. About 1 hour later tetrahydrofuran (100 mL) was added. When analysis by thin layer chromatography indicated that the reaction was complete, the reaction mixture was filtered to remove solids. The solids were rinsed with ethanol. The rinses and the filtrate were concentrated under reduced pressure. The residue was diluted with toluene (200 mL) and then concentrated under reduced pressure to remove the bulk of the solvent. The residue was partitioned between ethyl acetate (200 mL) and water (50 mL). The aqueous layer was separated, combined with saturated aqueous sodium bicarbonate to adjust to pH 8 and then extracted with ethyl acetate. The combined organics were washed with brine (100 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was combined with toluene and then concentrated under reduced pressure to provide 12.12 g of N4-(6-chlorohexyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:20].[CH3:21][C:22](C)(C)C([O-])([O-])[O-].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:21][C:22]1[O:20][C:3]2[CH:4]=[CH:5][C:6]3[NH:7][C:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9][S:10](=[O:13])(=[O:12])[C:11]=3[C:2]=2[N:1]=1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc(O)c2N)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc3oc(C)nc23)N1
Yield: 79 %

Procedure:
A solution of the product of Example 352E (56.3 mg, 0.188 mmol) in anhydrous N,N-dimethylformamide (2 mL) was treated with trimethylorthoacetate (0.098 mL, 0.752 mmol) and p-toluenesulfonic acid monohydrate (1Mg) at room temperature for 3 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with 4% methanol/dichloromethane to give the title compound as a white crystalline solid (48 mg, 79%). MS (ESI−) m/z 322 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (t, J=7.17 Hz, 3 H) 2.69 (s, 3 H) 3.71 (s, 2 H) 4.17 (q, J=7.11 Hz, 2 H) 7.27 (d, J=8.82 Hz, 1 H) 8.02 (d, J=8.82 Hz, 1 H) 12.33 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:19]=[N+:20]([O-:30])[CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(c1cccnc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Product: CC(c1ccc[n+]([O-])c1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 88.7 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-3-(pyridin-3-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (diastereoisomeric pair B from Example 14) (1.00 g) and 85% w/w 3-chloroperoxybenzoic acid (1.30 g) in dichloromethane (20 ml) was stirred at room temperature for 18 hours and then evaporated. The residue was stirred with ether and the solid was filtered off and dried to give the title compound (0.93 g), m.p. 190°-193°. (ii) 2-(2,4-Difluorophenyl)-3-(2-cyanopyridin-3-yl)-1-(1H-1,2,4-triazol-yl)butan-2-ol and 2-(2,4-difluorophenyl)-3-(2-cyanopyridin-5-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:12]([O:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:11][C@H:9]2[NH:10][C@@H:6]1[CH2:7][CH2:8]2)=[O:4].Cl.[CH2:23](N(CC)CC)C.C1(=O)OC(=O)CC1.C(Cl)CCl>C(Cl)Cl.O>[CH3:23][N:10]1[C@H:6]2[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:12]([O:13][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:11][C@@H:9]1[CH2:8][CH2:7]2
Reactant: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C1CCC(=O)O1
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Temperature: 25 °C

Procedure:
A solution of norcocaine hydrochloride (1 g, 3.07 mmol), triethylamine (0.86 ml, 6.14 mmol) in methylene chloride (20 ml) is treated with succinic anhydride (614 mg, 6.14 mmol) and the mixture heated at 45.degree. C. overnight, as described in U.S. Pat. No. 5,876,727. The solvents are removed under reduced pressure and the residue purified using silica gel flash chromatography (2:1 chloroform:methanol as the eluent). This gives succinylated norcocaine (1.0 g, 84%) as a thick syrup (3.beta.-(Benzoyloxy)-8-succinoyl-8-azabicyclo[3.2.1]octane-2.beta.-carboxylic acid methyl ester). To a solution of the acid (14 mg, 0.036 mmol) in distilled water (1 ml) at 0.degree. C., EDC (10.4 mg, 0.055 mmol) was added. After 5 minutes a solution of Qβ VLP in PBS (1 ml) is added dropwise and the mixture is allowed to warm to ambient temperature overnight. The conjugate is purified by dialysis against PBS and the degree of conjugation analyzed by mass spectral analysis. The resultant conjugate is used to immunize individuals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:27][CH:26]=2)[CH:5]=[C:6]([F:24])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1.CI.[C:38]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:24][C:6]1[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:35]([CH3:38])[N:34]=[N:33][N:32]=3)=[CH:27][CH:26]=2)[CH:3]=[C:2]([F:1])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][N:21]=2)[CH2:12][CH2:11]1
Reactant: CCc1cnc(N2CCC(COc3c(F)cc(-c4ccc(-c5nnn[nH]5)cc4)cc3F)CC2)nc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCc1cnc(N2CCC(COc3c(F)cc(-c4ccc(-c5nnnn5C)cc4)cc3F)CC2)nc1
Temperature: 80 °C

Procedure:
To a solution of Example B1 (20 mg, 0.04 mmol) and methyl iodide (10 μL, 0.16 mmol) in DMF (3 mL) is added Cs2CO3 (40 mg, 0.12 mmol). The resulting suspension is heated to 80° C. for 1 h, cooled to rt, and diluted with H2O (20 mL). The mixture is extracted with EtOAc (2×20 mL), and the combined organics are washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by flash chromatography (EtOAc/hexanes gradient) afford the title compounds (Example C1) and (Example C2) as white solids.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([OH:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:41](C(OC(C)(C)C)=O)[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:45]([O:44][C:42](=[O:41])[N:15]([CH2:14][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:39])([F:40])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1)[OH:38])[CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=1[C:27]1[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=1[O:36][CH3:37])([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol (Example 6 Step B, 325.0 mg, 0.561 mmol) in CH2Cl2 (15 mL) was added BOC2O (122 mg, 0.561 mmol) and DIPEA (98 μL, 0.561 mmol). The reaction was stirred at room temperature. After 5 hours, additional BOC2O (50 mg, 0.229 mmol) and DIPEA (50 μL, 0.287 mmol) were added. The reaction was stirred at room temperature for 48 hours. The reaction was then concentrated to ˜2 mL, diluted with hexanes (8 mL) and purified by flash chromatography with 10 to 20% EtOAc/hexanes to afford tert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.38 (25% EtOAc/hexanes). LCMS=580.3 (M+1−BOC)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.78 (s, 1H), 7.54-7.67 (m, 4H), 7.23-7.33 (m, 2H), 6.90-6.95 (m, 2H), 3.15-4.82 (m, 9H), 2.87 (m, 1H), 1.19-1.43 (m, 15 H).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][O:17]/[N:18]=[C:19](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)\[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[CH2:4]([O:11][C:12]1[CH:33]=[CH:32][C:15]([CH2:16][O:17]/[N:18]=[C:19](/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)\[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2ccccc2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
Lithium hydroxide monohydrate (70.7 mg) was added to a solution of methyl E-4-(4-benzyloxybenzyloxyimino)-4-phenylbutyrate (340 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-(4-benzyloxybenzyloxyimino)-4-phenylbutyric acid (238 mg, yield 72%) as colorless crystals. m.p. 86-87° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[C:4]([F:13])[CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][O:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:13])([CH3:11])[CH3:12]
Reactant: CC(C)(CO)c1ccc(Br)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(C)(C)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a DMF (4 ml) solution of 2-(4-bromo-2-fluorophenyl)-2-methylpropan-1-ol (199 mg, 0.8 mmol, WO2004074270A2) was added 60% sodium hydride (35 mg, 0.88 mmol) at 0° C. and the mixture was stirred at 0° C. for 15 minutes followed by additional stirring for 1 hour at room temperature. After the mixture was cooled to 0° C., methyliodide (342 mg, 2.4 mmol) was added and the mixture was stirred for 30 minutes at 0° C. followed by additional stirring for 16 hours at room temperature. Then, the reaction was quenched with water and the whole was extracted with EtOAc, which was dried over sodium sulfate. Then, filtration, evaporation and purification by silica gel column chromatography, eluting with hexane/EtOAc (20:1), gave the title compound (174 mg, 83% yield) as a colorless oil.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][CH3:9])=[S:7])([CH3:4])([CH3:3])[CH3:2].[Br:10][CH2:11][C:12](=[O:26])[CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[BrH:10].[C:1]([N:5]=[C:6]1[N:8]([CH3:9])[C:12]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([OH:26])[CH2:11][S:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Reactant: CNC(=S)NC(C)(C)C
Solvent: CC(C)=O
Product: Br
Product: CN1C(=NC(C)(C)C)SCC1(O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A 1.48 g. portion of 1-tert.-butyl-3-methyl-2-thiourea in 75 ml. of acetone is treated with a clarified solution of 2.89 g. of 3-bromo-1,1-diphenyl-2-propanone in 75 ml. of acetone. The mixture is stirred at room temperature for 17 hours. The solid is collected by filtration, washed with acetone and dried at 60° C. in vacuo, giving 2.8 g. of the desired product, m.p. 170°-172° C. (dec.).