Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:17])([O-])=O.[CH2:18](OC(OCC)N(C)C)C.N1CCCC1>CN(C)C=O>[O:10]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[NH:1][CH:18]=[CH:17]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(OCC)N(C)C
Reactant: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc3[nH]ccc3c2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A solution of 2-nitro-5-phenoxytoluene (2.06 g) in dimethylformamide (30 ml) containing dimethylformamide diethylacetal (1.57 g) and pyrrolidine (0.77 g) was heated at 120° C. for 2 hours. Solvent was removed at reduced pressure and the residue dissolved in methanol. Raney Nickel (one spatula measure) was added followed by hydrazine hydrate (3×0.5 ml portions, one portion every 30 minutes). The mixture was stirred for a further 1 hour after the final portion of hydrazine hydrate was added, the mixture filtered and solvent removed at reduced pressure. The residue was partitioned between water (100 ml) and diethyl ether (100 ml), the organic phase separated and dried (MgSO4), solvent removed at reduced pressure and the residue column chromatographed (silica gel, hexane →10% ethyl acetate/hexane eluant) to give 5-phenoxyindole (0.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([S:21][CH:22]([CH3:25])[CH2:23][CH3:24])=[CH:17][CH:16]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[O-:26]I(=O)(=O)=O.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH:22]([CH3:25])[CH2:23][CH3:24])=[O:26])=[CH:17][CH:16]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCC(C)Sc1ccc(OCC2COC(c3ccc(Cl)cc3)O2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(C)S(=O)c1ccc(OCC2COC(c3ccc(Cl)cc3)O2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-chlorophenyl)-4-[4-(1-methylpropylthio)phenoxymethyl]-1,3-dioxolane (7.1 mmol) in 10 ml of methanol at 0° is added, dropwise over 5 min., sodium m-periodate (1.67 g, 7.8 mmol) in 13 ml of water. The mixture is stirred for 3 hours while warming to RT. The reaction mixture is poured into water and extracted with ether. The combined organic extracts are washed with saturated sodium thiosulfate, with water and with brine, dried and rotoevaporated to give 2-(4-chlorophenyl)-4-[4-(1-methylpropylsulfinyl)phenoxymethyl]-1,3-dioxolane.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22](C)[CH:21]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)C.[OH-].[Na+].[CH2:31]1COCC1.CO>>[CH3:15][CH:13]([CH3:14])[CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:28])=[CH:6][CH:7]=1)[NH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:31]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C(CC(C)C)Nc2cnc3cc(C)ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc2cc(NC(CC(C)C)c3ccc(C(=O)O)cc3)cnc12
Yield: 100 %

Procedure:
A mixture of 4-[3-Methyl-1-(7-methyl-quinoline-3-ylamino)-butyl]-benzoic acid ethyl ester (48 mg, 0.13 mM) and 1N aqueous NaOH solution (0.318 mL, 0.318 mM) in THF-MeOH (1:1, 1.5 mL) was heated to 50° for 5 h. The reaction was cooled, concentrated to remove organic solvent. The aqueous solution was diluted with DCM (5 mL), acidified by 1N HCl solution to pH=3-4. The organic solution was separated and the aqueous solution was extracted with DCM (3×5 mL). The combined organic solution were dried (Na2SO4) and concentrated to give a yellow solid product (44 mg, ˜100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.97 (d, J=6.44 Hz, 3 H) 1.02 (d, J=6.44 Hz, 3 H) 1.54-1.67 (m, 1 H) 1.73-1.91 (m, 2 H) 2.43 (s, 3 H) 4.57-4.65 (m, 1 H) 7.14 (d, J=2.54 Hz, 1 H) 7.28 (dd, J=8.49, 1.27 Hz, 1 H) 7.46-7.58 (m, 4 H) 7.97 (d, 2 H) 8.44 (d, J=2.34 Hz, 1 H), two protons (COOH and NH) were exchanged. LC-MS: m/z 349.1 (M+1). This material will be used for the next step reaction without further work-up.
Reaction SMILES: O=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(Br)(Br)([Br:24])=O>CC#N>[Br:24][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(=O)[nH]c2c1
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Yield: 77.7 %

Procedure:
A solution of methyl 3-oxo-2-phenyl-3,4-dihydroquinoxaline-6-carboxylate (2.1 g, 7.50 mmol, 1.00 equiv) and POBr3 (21.5 g, 74.91 mmol, 10.00 equiv) in CH3CN (120 mL) in a 1000-mL round-bottom flask was heated under reflux overnight in an oil bath. The resulting mixture was concentrated under vacuum; the pH value was adjusted to 7-8 with aqueous sodium bicarbonate (saturated), and the solution extracted with 4×100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum, giving 2 g (78%) of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate as a white solid. LC-MS (ES, m/z): 343 [M+M]+. 1H-NMR (300 MHz, DMSO-d6) 8.620-8.615 (d, J=1.5 Hz, 1H), 8.38-8.35 (q, J=3.3 Hz, 1H), 8.28-8.25 (d, J=8.7 Hz, 1H), 7.85-7.82 (q, J=6 Hz, 2H), 7.60-7.58 (t, J=2.4 Hz, 3H), 3.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][C:14]([O-])(C)[CH3:15].[K+].IC(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:14]([CH3:15])[CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: COC(=O)C(c1ccc(Br)cc1)C(C)C
Temperature: 0 °C
Yield: 48 %

Procedure:
To a solution of methyl 2-(4-bromophenyl)acetate, 13-a, (2.29 g, 10 mmol) in DMF (40 ml) was added dropwise a mixture of t-BuOK (1.12 g, 10 mmol) in DMF (20 mL) with stirring at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 30 min, 2-iodopropane (1.70 g, 10 mmol) was added dropwise. Then the resulting solution was stirred overnight and ice-water was added. The aqueous layer was extracted by EA. The combined organic layers were washed by brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to afford the title compound, 13-b, (1.3 g, 48%). 1H NMR (300 MHz, CDCl3) δ 0.70-0.72 (m, 3H), 1.02-1.04 (m, 3H), 2.27-2.32 (m, 1H), 3.10-3.14 (m, 1H), 3.65 (s, 3H), 7.19-7.24 (m, 2H), 7.42-7.45 (m, 2H). LC-MS: (M+H)+ 254, 256.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15](Br)[CH:16]=[C:11]2[N:10]=[N:9]1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)CCC>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: Cn1ncnc1COc1nc2c(cc1Br)nnn2-c1ccccc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1-c1ccccc1)nnn2-c1ccccc1F
Temperature: 100 °C
Yield: 51.8 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.15 g, 0.37 mmol), tributylphenyltin (0.14 ml, 0.44 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.02 g, 5 mol %) in dry DMF (2 ml) was purged with nitrogen and heated in a sealed tube at 100° C. for 24 h. The mixture was cooled, diluted with water (50 ml) and extracted with 10% methanol-dichloromethane (2×25 ml). The extracts were washed with brine (20 ml), dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 2% methanol-dichloromethane, gave a yellow oil that solidified on trituration and washing with diethyl ether (2 ml). The material was recrystallised from ethyl acetate-hexane to give 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-phenyl-1,2,3-triazolo[4,5-b]pyridine (0.077 g, 52%) as a cream-coloured solid, m.p. 144-146° C. (EtOAc-hexane). Found: C, 62.00; H, 4.00; N, 24.01. C21H16N7OF.0.33(H2O) requires C, 61.91; H, 4.12; N, 24.07%. δH (360 MHz; CDCl3) 3.64 (3H, s), 5.56 (2H, s), 7.38-7.47 (5H, m), 7.53 (2H, dd, J=8 and 1), 7.56-7.62 (1H, m), 7.71 (1H, dd, J=8 and 8), 7.82 (1H, s) and 8.32 (1H, s); m/z (ES+) 402 (M+H+).
Reaction SMILES: [CH2:1]=O.[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([C:9]([NH:11][C:12](=[O:20])[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:10])=[CH:7][CH:6]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.N>C(O)(=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12](=[O:20])[NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:1][C:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:23][CH:24]=3)[CH2:16][CH2:15]2)=[O:10])=[CH:21][CH:22]=1
Reactant: C=O
Reactant: COc1ccc(C(=O)NC(=O)NC2CCNCC2)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)NC(=O)NC2CCN(Cc3c[nH]c4ccccc34)CC2)cc1
Reaction time: 5 h
Yield: 95 %

Procedure:
Formaldehyde (0.4 cm3, 40% aqueous solution) was added to a stirred solution of 4-(4-methoxybenzoylureido)piperidine (1.39 g, 0.005 mol) and indole (0.6 g, 0.005 mol) in acetic acid (3 cm3). The solution was allowed to stand for 5 hours and the diluted with water (50 cm3). The turbid solution was then basified by addition of ammonia solution and the precipitated solid collected by filtration washed with water and ether to give 2.1 g (95%) of the title compound as the free base. The base was suspended in warm ethanol (20 cm3) and acidified with ethanolic hydrogen chloride. After stirring at room temperature for 1 hour and 0° C. for 0.5 hours the suspension was filtered to remove the hydrochloride. The hydrochloride was recrystallised from aqueous methanol (80% methanol, 20 cm3) to give (1.8 g, 82%) of the hydrochloride of the title compound m.p. 220°-22° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][CH2:8][CH2:9][N:10]=[C:11]1[CH:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH:12]1[CH3:18].C(N(CC)CC)C>CCCCCC>[CH3:18][C:12]1[CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[C:11]=1[N:10]([CH2:9][CH2:8][O:7][CH3:6])[C:3](=[O:4])[CH2:2][Cl:1]
Reactant: COCCN=C1C(C)CCCC1C
Reactant: O=C(Cl)CCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COCCN(C(=O)CCl)C1=C(C)CCCC1C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
Over a period of 3 hours and at 20°-30° C. 37.5 g of chloroacetylchloride are added dropwise while stirring to a solution of 57 g of N-(2-methoxy-ethyl)-2,6-dimethylcyclohexylideneamine in 200 ml of hexane. Afterwards during 2 hours 48 ml of triethylamine are added dropwise in the course of which the temperature of the mixture rises to ca. 50° C. Subsequently the mixture is heated under reflux for 30 minutes and poured onto ice. The organic layer is washed with water and dried over sodium sulfate. The solvent is distilled off and the residue is fractionally distilled: 54.5 g of N-(2,6-dimethyl-1-cyclohexene-1-yl)-N-(2-methoxyethyl)-α-chloro-acetamide are obtained, b.p. 136°-139° C./0.1 Torr.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>C(O)C>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:17][CH:18]=1
Reactant: BrCCCCCBr
Reactant: COC(=O)C(C)(C)CCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)C(C)(C)CCCOc1ccc(OCCCCCBr)cc1

Procedure:
To 2.52 g of methyl 5-(p-hydroxyphenoxy)-2,2-dimethylpentanoate and 1.38 g of anhydrous potassium carbonate was added 30 ml of ethanol and the mixture was heated under reflux for 30 minutes while stirring. After cooling, 2.53 g of 1,5-dibromopentane was added thereto and the mixture was reacted overnight with heating under reflux. After the solvent was removed by distillation under reduced pressure, water was added to the resulting residue followed by extracting with chloroform. After the chloroform layer was successively washed with an aqueous saturated hydrogen sodium carbonate solution and then an aqueous saturated sodium chloride solution, the chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue was subjected to silica gel column chromatography. The product was eluted using an n-hexane-ethyl acetate mixture (8:1 in a volume ratio). The solvent was removed by distillation to give the desired product, methyl 5-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylpentanoate as an oily substance.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[C:2]([F:1])[N:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCC1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Product: Cc1cnc2[nH]cc(Cc3ccc(NC4CCCCC4)nc3F)c2c1

Procedure:
Cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine P-3008 is prepared in one step from 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 49 and cyclohexanone 67 as shown in Scheme 10.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21]3)=[O:19])=[CH:13][C:12]=2[Cl:33])=[CH:5][CH:4]=1)=[O:2].CC(C)=[O:37].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21]3)=[O:19])=[CH:13][C:12]=2[Cl:33])=[CH:7][CH:8]=1)([OH:37])=[O:2]
Reactant: CC(C)=O
Reactant: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C=O)cc3)c(Cl)c2)CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C(=O)O)cc3)c(Cl)c2)CC1
Reaction time: 0.67 h

Procedure:
The crude 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-formylphenyl ester (19.1 g) obtained was dissolved in 800 ml of acetone. 30 ml of Jones' reagent were added dropwise to this solution within 15 minutes, the mixture warming slightly. The mixture was stirred for a further 40 minutes, then the separated inorganic material was filtered off under suction and the filtrate was concentrated. The residue was suspended in water and the suspension obtained was suction filtered. The residue was washed neutral with water on the suction filter and recrystallized from acetone, there being obtained 14.6 g of 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-carboxyphenyl ester; m.p. (C-S) 135°-136° C., transition S-N 156° C., cl.p. (N-I) >300° C.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.[F:13][C:14]([F:34])([F:33])[C:15]1[CH:32]=[CH:31][CH:30]=[CH:29][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])=[O:18]>O1CCCC1.CCCCCC>[OH:18][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28])([C:16]1[CH:29]=[CH:30][CH:31]=[CH:32][C:15]=1[C:14]([F:33])([F:34])[F:13])[CH2:2][C:1]#[N:4]
Reactant: O=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(O)(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of diisopropylamine (4.02 mL) in dry tetrahydrofurane (30 mL) under argon was treated dropwise with 1.6M n-butyl lithium in hexane (18 mL). The reaction was kept at -5° C. during the addition and for 15 minutes thereafter, then it was cooled to -78° C. and a solution of 2,2'-bis(trifluoromethyl)benzophenone (8.0 g) in tetrahydrofurane was added at such a rate that the reaction temperature did not exceed -65° C. The mixture was stirred at -78° C. for 10 minutes, then it was allowed to slowly equilibrate to room temperature over 30 minutes. After the solvents were removed under reduced pressure, the residue was treated with water (100 mL) and the resulting solid was filtered off, washed with water and dried. Crystallization of the solid from dichloromethanehexane furnished 7.72 g of 3-hydroxy-3,3-bis[2-(trifluoromethyl)phenyl]-propanenitrile, mp 168°-170° C. A sample was recrystallized from the same solvent system to give the analytical specimen, mp 171°-172° C. Anal. Calculated for C17H11F6NO: 56.83: H, 3.08: F, 31.73: N, 3.80. Found: C. 56.87; H, 2.81: F, 31.88: N, 4.14.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:8][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: NC(=O)c1ccc(N)cc1
Product: Cc1cc(C)cc(NC(=O)c2ccc(N)cc2)c1
Yield: 98.4 %

Procedure:
Using general procedure A, 4-aminobenzamide (170 mg, 1.25 mmol) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 2:3; 15 in L fractions). Fractions 9–18 provided 246 mg (98% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.74–7.69 (m, 2H), 7.66 (br s, 1H), 7.28 (s, 2H), 6.78 (s, 1H), 6.74–6.69 (m, 2H), 4.05 (br s, 2H), 2.33 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 165.7, 150.3, 139.1, 138.6, 129.2, 126.2, 124.8, 118.2, 114.6, 21.8.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][CH:11](C)[CH2:12][CH2:13][CH2:14][C:15]#N.Cl.C([O:21]CC)C>>[CH3:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:21]
Reactant: COC(C)CCCC#N
Reactant: CCOCC
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Product: COCCCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of phenylmagnesium bromide (16.0 g, 88 mmol) in anhydrous diethylether (55 ml) under an atmosphere of nitrogen was dropwise added a solution of the above nitrile (10.0 g, 88 mmol) in anhydrous diethylether while the temperature was allowed to raise to reflux. The reaction mixture was heated at reflux for 5 h and then stirred at room temperature for 16 h. A 4N hydrochloric acid solution (50 ml) was carefully added and the mixture stirred at ambient temperature for 4 h. The phases were separated and the aqueous phase extracted with diethylether (2×50 ml). The combined organic phases were washed with 5% sodium hydrogencarbonate (25 ml) and dried (Na2SO4). The solvent was evaporated in vacuo and the residue submitted to fractional distillation to give 9.1 g of 5-methoxy-1-phenyl-1-pentanone. B.p. 127°-130° C./5 mmHg.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:5]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1[CH3:8])#[N:2].[CH2:19]([N:22]=[C:23]=[S:24])[CH2:20][CH3:21]>>[C:1]([C:3]1[C:4]([S:15]([NH:18][C:23]([NH:22][CH2:19][CH2:20][CH3:21])=[S:24])(=[O:16])=[O:17])=[C:5]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1[CH3:8])#[N:2]
Reactant: CCCN=C=S
Reactant: CCOC(=O)Nc1sc(C)c(C#N)c1S(N)(=O)=O
Product: CCCNC(=S)NS(=O)(=O)c1c(NC(=O)OCC)sc(C)c1C#N

Procedure:
The title compound was prepared from 4-cyano-2-ethoxycarbonylamino-5-methyl-thiophene-3-sulfonamide and propyl isothiocyanate in analogy with the synthesis described in Example 1-d; m.p. 167-168° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH2:8])=[N:4][CH:3]=1.C[N+]1([O-])CC[O:24]CC1.C1COCC1.[OH2:33]>S([O-])([O-])(=O)=S.[Na+].[Na+].[Os](=O)(=O)(=O)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)([OH:24])[CH2:8][OH:33])=[N:4][CH:3]=1
Reactant: C=C(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)OCC)CC1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(CO)c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)ethenyl]cyclohexanecarboxylate (40 mg, 0.12 mmol), 4-methylmorpholine N-oxide (31 mg, 0.27 mmol), THF (0.8 ml), water (0.4 ml) and osmium tetroxide (0.22 ml, 0.028 mmol) were combined and the mixture was stirred at room temperature for 40 min. The mixture was then diluted with saturated sodium thiosulfate and extracted with EtOAc. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (EtOAc/hexane=1/1) to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-1,2-dihydroxyethyl]cyclohexane-carboxylate. MS ESI calc'd. for C14H20BrNO4S [M+H]+ 378, 380. found 378, 380. 1H NMR (500 MHz, CDCl3) δ 7.55 (s, 1H), 4.15 (dd, J=5.7, 11.1, 1H), 4.07 (q, J=7.1, 2H), 3.74 (dd, J=7.0, 11.1, 1H), 2.61 (t, J=6.4, 1H), 2.20-2.10 (m, 1H), 2.05-1.84 (m, 3H), 1.85-1.70 (m, 1H), 1.60 (d, J=12.8, 1H), 1.46-1.13 (m, 5H), 1.13-1.05 (m, 1H).
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[C:22]([C:24]3[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>C(Cl)Cl.CCCCCCC>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[C:22]([C:24]3[NH:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)[N:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Agent: FB(F)F
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: FC(F)(F)c1c[nH]c(-c2cc(-c3ccc(Cl)c(Cl)c3)ncn2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.1 %

Procedure:
Boron trifluoride diethyl etherate (0.16 ml, 1.3 mmol) was added dropwise to a cool (0° C.), stirred solution of 4-(3,4-dichloro-phenyl)-6-[4-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrimidine (0.064 g, 0.13 mmol) in DCM (2 ml) under a nitrogen atmosphere. The mixture was stirred at this temperature for 10 minutes before being allowed to warm to room temperature and stirred overnight. The solution was diluted with heptane (5 ml) and the resulting precipitate was collected by filtration and dried under vacuum before being purified by prep HPLC to give the title compound (0.05 g, 15% yield) as a white powder.