Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CC#N>[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCCNCc1nc2ccccc2[nH]1
Yield: 43.6 %

Procedure:
2-Chloromethylbenzimidazole (19.81 g, 118.9 mmol) was added as a solid to a mechanically stirred and cooled (1.2° C. internal temperature) solution of (4-amino-butyl)-carbamic acid tert-butyl ester (56.0 g, 297.3 mmol) and DIPEA (51.8 mL, 297.3 mmol) in CH3CN (3 L) under N2. After 4.5 h at low temperature the cooling bath was removed and the mixture was concentrated in vacuo. The residue was taken up in CH2Cl2 (1.5 L) and washed with brine (1 L). The aqueous layer was extracted with CH2Cl2 (2×500 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford a yellow foamy solid. Purification by column chromatography on silica gel (CH2C2/MeOH/NH4OH (98:1:1) to CH2Cl2/MeOH/NH4OH (80:10:10)) afforded product containing mixed fractions. Repurification of these fractions by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH (98:3:3)) afforded the title compound as a yellow solid (16.5 g, 44%). 1H NMR (CDCl3) δ 1.50 (s, 9H), 1.60-1.64 (m, 4H), 2.70-2.74 (m, 2H), 3.10-3.18 (m, 2H), 4.13 (s, 2H), 4.86 (s, 1H), 7.19-7.25 (m, 2H), 7.50-7.95 (m, 2H), 10.4 (bs, 1H); 13C NMR (CDCl3) δ 26.1, 27.3, 28.1, 39.7, 41.2, 47.2, 47.7, 48.3, 49.4, 78.9, 121.7, 153.9, 155.9; ES-MS m/z 319 (M+H). Anal Calcd. For C17H26N4O2.0.2(H2O): C, 63.41; H, 8.26; N, 17.40. Found: C, 63.51; H, 8.19; N, 17.33.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC(O)=O.[C:18]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]([CH3:13])=[C:2]([NH:1][CH:28]2[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 23 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1.40 g, 7.04 mmol) in CH2Cl2 (30 mL) and AcOH (2.50 g, 42.2 mmol) was added N-Boc piperidinone (1.96 g, 9.85 mmol) and sodium triacetoxyborohydride (4.40 g, 21.1 mmol). The reaction mixture was stirred at 23° C. for 18 hours and then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×20 mL) and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 heptane/ethylacetate=10/1 to 1/1) to give the titled compound as oil (2.40 g, 89% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.09 (s, 1H), 6.69 (s, 1H), 4.05 (m, 2H), 3.88 (s, 3H), 3.63 (m, 1H), 3.42 (m, 1H), 2.97 (m, 2H), 2.23 (s, 3H), 2.05 (m, 2H), 1.45 (s, 9H), 1.27 (m, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[S:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1>ClCCl>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([OH:10])=[O:15])=[O:9]
Reactant: c1ccsc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (58.7 g, 440 mmol, 2.2 equiv.) and dichloromethane (150 mL) were added to a round bottom flask. A solution of phthalic anhydride (29.6 g, 200 mmol, 1.0 equiv.) in dichloromethane (150 mL) was then added, and the mixture was stirred at room temperature for 30 minutes. Thiophene (15.8 mL, 200 mL, 1.0 equiv.) was added over 1 hour, after which the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was cautiously quenched with hydrochloric acid (0.2 M, 1 L), extracted with dichloromethane, and extracted with aqueous NaOH (1 N, 3×200 mL). The aqueous layer was acidified with concentrated hydrochloric acid; the solids were collected by filtration, and stirred in refluxing methanol. The suspension was filtered, and water was added to the filtrate to crystallize 1 as a colorless solid (20.7 g, 45%). 1H NMR (500 MHz, CDCl3) δ8.09 (dd, J=7.8, 0.85 Hz, 1H), 7.70 (dd, J=4.9, 1.1 Hz, 1H), 7.67 (td, J=7.5, 1.3 Hz, 1H), 7.58 (td, J=7.8, 1.3 Hz, 1H), 7.47 (dd, J=7.5, 0.90, 1H), 7.27-7.26 (m, 1H), 7.07-7.06 (m, 1H). m.p 144-145° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[O:19]1[C:23]2([CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:26]2([OH:29])[CH2:27][CH2:28][C:23]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:24][CH2:25]2)=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCCCOc1cccc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(F)c1F
Reaction time: 2 h
Yield: 99.7 %

Procedure:
3-Butoxy-1,2-difluorobenzene (7) (30.0 g) and THF (500 ml) were added to a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.66 M in n-hexane solution; 120 ml) was added dropwise in the temperature range of −74° C. to −70° C. and the stirring was continued for another 2 hours. Successively, 1,4-dioxaspiro[4.5]decan-8-one (8) (30.2 g) in THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The resulting reaction mixture was poured into a 1N—HCl aqueous solution (500 ml) and ethyl acetate (500 ml) in a vessel and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to leave 8-(4-butoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (9) (55.0 g). The resulting compound (9) was a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:16]=3[O:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]([O:44][C:45]([NH:47][CH:48](P(OC)(OC)=O)[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:52][O:51][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:41]([CH3:42])([CH3:40])[CH3:43])=[O:46])=[CH:23][C:21]1[CH:20]=[CH:19][C:17]2[O:18][C@@H:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)[CH2:14][O:15][C:16]=2[CH:22]=1
Reactant: O=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.7 %

Procedure:
(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6 carbaldehyde (2.1 g) was dissolved in 8 mL dry DCM under nitrogen at rt and DBU (1.61 g) was added by syringe. A solutuion of Boc-phosphonoglycine trimethyl ester (1.58 g) in 4 mL of dry DCM was added to the reaction mixture and stirred at rt. for 12 hours. Reaction mixture was directly loaded on to silica gel column (40% hexanes in DCM to DCM) gave 1.8 g pure product. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H), 7.46 (d, 1H), 7.32-7.38 (m, 1H), 7.18-7.28 (m, 3H), 7.10-7.15 (m, 1H), 6.94-7.06 (m, 4H), 5.13 (m, 1H), 5.03 (s, 2H), 4.36 (m, 1H), 4.01 (m, 1H), 3.84 (s, 3H), 1.44 (s, 9H). LCMS (m/z): 587.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:26][CH:25]=1.[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=2)[C:32](=[O:34])[CH3:33])=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Reactant: CC(=O)NCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2ccncc2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.6 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 2.55 g of product from Example 20, 0.999 g of product from Example 15, 0.319 g of washed 50% sodium hydride and 30 ml of tetrahydrofuran. The reaction is stirred at room temperature for 18 hours, heated at reflux temperature for 24 hours; followed by stirring at room temperature for an additional 48 hours. The residue is purified by column chromatography (silica gel: 5% methyl alcohol/ethyl acetate) to give 0.862 g of the desired product. The spectral data indicates the presence of 2 rotomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]2[C:6]([C@@:7]3([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)=[C:5]([OH:25])[CH:4]=1.N1C=CC=CC=1.[O:32](S(C(F)(F)F)(=O)=O)[S:33]([C:36]([F:39])([F:38])[F:37])(=O)=[O:34]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[S:33]([O:25][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[C:19]2[C:6]=1[C@@:7]1([CH3:24])[C@H:16]([CH2:17][S:18]2)[C@:15]2([CH3:21])[C@H:10]([C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]1)(=[O:34])=[O:32]
Reactant: COc1cc(O)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(OS(=O)(=O)C(F)(F)F)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a solution of (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 29) (0.61 g, 1.69 mmol) in CH2Cl2 (40 mL), pyridine (0.20 g, 2.54 mmol) was added and the mixture was cooled to 0° C. Tf2O (0.62 g, 2.20 mmol) was added dropwise to the reaction mixture and stirred for 1.5 h. The reaction was diluted with CH2Cl2 and washed with water (2×40 mL). The organic layer was separated, dried (Na2SO4) and concentrated giving (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl trifluoromethanesulfonate (Compound No. 32) (0.825 g, 98%) as a yellow foam. 1H NMR (CDCl3): δ 6.58 (d, 2H), 3.75 (s, 3H), 2.90 (m, 3H), 1.80-1.40 (m, 8H), 1.38 (s, 3H), 1.25-1.00 (m, 2H), 0.95 (s, 3H), 0.90 (m, 1H), 0.85 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Yield: 85.1 %

Procedure:
Using 4-bromo-3-fluorobenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4 g) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (7 g) was obtained.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4])[NH2:2].[OH-].[K+].[C:31](=S)=[S:32]>CCO>[S:32]=[C:31]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][N:8]3[C:11]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[O:22])[CH:17]=[CH:18][CH:19]=4)=[CH:12][N:13]=[C:7]3[CH:6]=2)=[N:1][NH:2]1
Reactant: NNC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4n[nH]c(=S)o4)ccn23)c1
Temperature: 65 °C
Yield: 52.9 %

Procedure:
To a solution of 1-[3-(7-Hydrazinocarbonyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (120 mg, 0.30 mmol) and KOH (20 mg, 0.36 mmol) in EtOH (4 ml) was added carbon disulfide (241, 0.36 mmol). The reaction mixture was heated at 65° C. for 3 h, cooled and then placed in an ice bath upon which a precipitate was formed. The solid was filtered off, wash with EtOAc and Et2O, then dried to afford the title compound (69 mg). MS: [M+H]+=435.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:48])[CH:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[C:34]([C:36]([NH:38][C:39]4[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=4[F:46])=[O:37])[CH:33]=[CH:32][C:31]=3[F:47])[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:48])[CH:5]([NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[C:34]([C:36]([NH:38][C:39]4[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=4[F:46])=[O:37])[CH:33]=[CH:32][C:31]=3[F:47])[CH:26]=[CH:25][N:24]=2)[NH:20][CH:19]=1)=[O:17])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)C(CCC(=O)O)NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of tert-butyl 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoate (75 mg, 0.11 mmol) in 5 ml of methylene chloride was added 1 ml of TFA. The mixture was stirred at room temperature for 90 minutes, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 5 ml of methanol and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give 5-(ethylamino)-4-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-oxopentanoic acid as white solid. Yield: 60 mg, 87%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13](=O)[CH3:14].[OH:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[CH2:18][NH2:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]([NH:19][CH2:18][CH:17]([OH:16])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=1)[CH3:14]
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CC(C)=O)c(Cl)c1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2cccc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared as in Example 1b from 1-(2-chloro-4-carbomethoxyphenyl)propan-2-one (2.32 g) and 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine (2.1 g). The compound crystallised from hexane m.p. 82°-94° as a 40:60 mixture of diastereoisomers. τ(CDCl3) 8.85 (3H,d,J=6 Hz), 6.8-7.6 (5H,m+2H replaceable by D2O), 6.1 (3H,s), 5.3 (1H,m), 2.7 (1H,d,J=8 Hz), 2.3-2.6 (4H,m), 2.1 (2H,d,J=8 Hz), 1.95 (1H,s).
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][C:9]1[N:10]=[CH:11][N:12]([CH2:14][CH2:15][C:16]([NH:19]C(=O)OC(C)(C)C)([CH3:18])[CH3:17])[CH:13]=1>ClCCl>[I:8][C:9]1[N:10]=[CH:11][N:12]([CH2:14][CH2:15][C:16]([NH2:19])([CH3:17])[CH3:18])[CH:13]=1
Reactant: CC(C)(CCn1cnc(I)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)CCn1cnc(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
10 mL (130 mmol) trifluoroacetic acid were added to a solution of 1.90 g (5.00 mmol) tert-butyl [3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propyl]-carbamate in 90 mL dichloromethane at ambient temperature with vigorous stirring. The reaction mixture was stirred for 16 h at ambient temperature and the solvent was eliminated using the rotary evaporator. The residue was taken up in 100 mL sodium hydroxide solution (1M) and 100 mL dichloromethane. The phases were separated and the aqueous phase was extracted three times with 100 mL dichloromethane. The combined organic phases were dried over magnesium sulphate and the solvent was eliminated using the rotary evaporator. 1.37 g (4.91 mmol, 98%) 3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamine were obtained as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ccccc2)cc1
Yield: 78 %

Procedure:
Bromobenzene (80 mg, 0.51 mmol) reacted with 4-chlorophenylboronic acid (103 mg, 0.66 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and K3PO4 (318 mg, 1.50 mmol) in toluene at 100° C. to give the title compound (75 mg, 78%) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 7.41-7.62 (m, 9H). 13C{1H}-NMR (100 MHz, CDCl3): δ 139.95, 139.62, 133.33, 128.88, 128.86, 128.36, 127.56, 126.96. GC/MS(EI): m/z 188 (M+), 152
Reaction SMILES: [C:1]1(=[O:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2]1.[C:9]1(=O)N[C:12](=O)[CH2:11][CH2:10]1>>[CH2:9]([N:6]1[C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[CH2:10][CH2:11][CH2:12][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C1CCCC(=O)N1
Reactant: O=C1CCC(=O)N1
Product: CCCCCCCCCN1C(=O)CCCC1=O

Procedure:
The procedure of Example 1 was repeated except that glutarimide replaced the succinimide.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]([CH3:29])[C:26]([OH:28])=[O:27])[CH:19]=[CH:18]2>>[CH3:29][CH:25]([C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[CH:16]=2)[CH:21]=1)[C:26]([OH:28])=[O:27]
Reactant: CCCCCCCCCCCCI
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Product: CCCCCCCCCCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodododecane and racemic 6-hydroxy-α-methyl-2-naphthalene acetic acid. White crystals are obtained having a melting point of 96°-97° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Yield: 33.9 %

Procedure:
A procedure similar to that described in Preparation 66 was repeated, except that 15 g of 2-chloro-3-nitro-pyridine, 13.22 g of aniline and 25.07 g of sodium carbonate were reacted in 180 ml of toluene. After working up the product as described in Preparation 66, the resulting crude product was purified by column chromatography through silica gel, using a 1:5 by volume mixture of ethyl acetate and hexane, to give 6.9 g of the title compound, melting at 66°-68° C.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][C:2]=1/[C:12](/[CH3:25])=[CH:13]/[C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C.O>[CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][C:2]=1/[C:12](/[CH3:25])=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)CCCCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)CCCCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.8 %

Procedure:
300 mg of ethyl p-[(E)-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten -2-yl)propenyl]benzoate are treated in 20 ml of ethanol with 2 ml of 2.5M sodium hydroxide solution. The mixture is stirred at room temperature for 48 hours, diluted with water and extracted with diethyl ether. The aqueous phase is acidified, extracted with ether. The ethereal phase is washed with water, dried and evaporated. There are obtained 200 mg of p-[(E)-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)propenyl]benzoic acid of m.p. 198°.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>ClCCl>[CH3:18][S:19]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([O:13][C:14]([F:16])([F:15])[F:17])=[CH:12][C:2]=1[Cl:1])(=[O:21])=[O:20]
Reactant: OCCCOc1ccc(OC(F)(F)F)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCOc1ccc(OC(F)(F)F)cc1Cl
Yield: 98.4 %

Procedure:
To a solution of 3-(2-chloro-4-trifluoromethoxyphenoxy)-propanol (20 g, 0.074 mole) in 100 mL of dichloromethane at 0° C. was added methanesulfonyl chloride (6.83 mL, 0.089 mole) and triethylamine (20.5 mL, 0.148 mole). The resulting solution was stored in a refrigerator overnight. The solution was then washed with 100 mL of cooled, diluted HCl-H2O solution. The organic layer was separated, dried over MgSO4, filtered and evaporated of solvent to yield 25.4 g of the product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][OH:45])=[O:38])([CH3:35])([CH3:34])[CH3:33].[CH3:46][C:47]1[C:52](O)=[CH:51][CH:50]=[CH:49][N:48]=1>C1COCC1>[CH3:46][C:47]1[C:52]([O:45][CH2:44][C@@H:40]2[CH2:41][CH2:42][CH2:43][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:51][CH:50]=[CH:49][N:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Cc1ncccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncccc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of triphenylphosphine (3.83 g, 14.6 mmol) in 40 mL of anhydrous THF at 0° C. was added diethyl azodicarboxylate (2.30 mL, 14.6 mmol) dropwise. The mixture was stirred at 0° C. for 30 minutes, then brought to room temperature. (S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.96 g, 9.75 mmol, Aldrich Chemical Co.) and 2-methyl-3-hydroxypyridine (Aldrich Chemical Co., 1.60 g, 14.6 mmol) were added to the reaction vessel, and the mixture was stirred for 16 hours. Solvent was removed in vacuo, and the residue was diluted with hexane and sonicated for 30 minutes. The resulting precipitate was filtered and washed with hexane. The hexane was removed in vacuo. The residue was purified by silica gel flash chromatography (ethyl acetate) to give 1.42 g (50% yield) of the title compound as a pale yellow oil. TLC Rf =0.50 (EtOAc). MS (DCI/NH3) m/e: 293 (M+H)+.