Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([O:14][CH3:15])(=[O:13])[CH3:12].[CH:16]1(/[CH:19]=[N:20]/[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:18][CH2:17]1.C1C[O:30][CH2:29][CH2:28]1>CCOC(C)=O>[CH:16]1([C@@H:19]([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:28][C:29](=[O:30])[CH2:12][C:11]([O:14][CH3:15])=[O:13])[CH2:17][CH2:18]1
Reactant: COC(C)=O
Reactant: C1CCOC1
Reactant: CC(C)(C)[S@@](=O)/N=C/C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)C[C@H](N[S@](=O)C(C)(C)C)C1CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
NaHMDS (428 mL, 1 M in hexane) was dissolved in THF (356 mL) and the resulting solution was cooled to −78° C. Methyl acetate (28.3 mL, 356 mmol) was added over 15 minutes and the reaction mixture was stirred at −78° C. for 1 h after which a solution (R,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (26) (12.3 g, 71.3 mmol) in THF (50 mL) was added over 15 minutes. The reaction mixture was warmed to −20° C. and stirred at this temperature for 3 h after which HPLC indicated that the reaction was complete. The resulting solution was diluted with EtOAc (400 mL) and washed with sat. aq. NaHCO3 (200 mL). The organic phase was dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc, 9/1 to 1/1 to give 16.3 g (79%) of (5S)-methyl 5-cyclopropyl-5-[(R)-1,1-dimethylethylsulfinamido]-3-oxopentanoate (27). Retention time (min)=1.397 method [1], MS (m/z) 290.2 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[O:34]=[C:35]1[N:43]([CH2:44][CH2:45][CH3:46])[C:42]2[NH:41][C:40]([C:47]34[CH2:54][CH2:53][C:50]([CH:55]=O)([CH2:51][CH2:52]3)[CH2:49][CH2:48]4)=[N:39][C:38]=2[C:37](=[O:57])[N:36]1[CH2:58][CH2:59][CH3:60]>C1COCC1>[O:34]=[C:35]1[N:43]([CH2:44][CH2:45][CH3:46])[C:42]2[NH:41][C:40]([C:47]34[CH2:54][CH2:53][C:50]([CH2:55][CH:2]=[O:3])([CH2:51][CH2:52]3)[CH2:49][CH2:48]4)=[N:39][C:38]=2[C:37](=[O:57])[N:36]1[CH2:58][CH2:59][CH3:60]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1c(=O)c2nc(C34CCC(C=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2nc(C34CCC(CC=O)(CC3)CC4)[nH]c2n(CCC)c1=O
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a stirred suspension of methoxymethyl triphenylphosphonium chloride (1.1 g, 3.2 mmol) in THF (60 ml) at −78° C. was added a solution of KHMDS (0.5 M in toluene, 10 ml, 5 mmol). The resulting yellow mixture was stirred at this temperature for 1.5 h and a solution of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (372 mg, 1.0 mmol) in THF (12 ml) was added over a period of 20 minutes. The mixture was held at −78° C. for 6 h and allowed to reach ambient temperature overnight (12 h). The reaction mixture was partitioned between saturated aqueous NH4Cl (100 ml) and EtOAc (100 ml) and the aqueous phase was extracted with EtOAc (50 ml). The combined organic extracts were washed with saturated aqueous NaCl (100 ml), concentrated in vacuo, redissolved in THF and concentrated to a volume of approx. 20 ml. To the solution was added an equal volume of 1 N HCl and the mixture was stirred overnight. The mixture was diluted with EtOAc (20 ml), the aqueous phase was separated and extracted with EtOAc (10 ml). The combined organic phases were then washed with saturated aqueous NaCl (2×, 25 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting orange oil was purified in batches by radial chromatography (2 mm plate) using 3% MeOH and 3% THF in CH2Cl2 as eluent. Product-containing fractions were combined and concentrated to afford 290 mg (75%) of a white solid. MS: 387 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]([F:24])([F:23])C([O-])=O.[Na+]>CN(C)C=O.O>[F:23][CH:19]([F:24])[O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
To a solution of 2-methyl-4-nitrophenol (14 g, 91.50 mmol) in dimethylformamide (120 mL) and water (25 mL) was added Cs2CO3 (41.8 g, 128.22 mmol), and sodium 2-chloro-2,2-difluoroacetate (32 g, 209.84 mmol). The resulting solution was stirred for 20 minutes at room temperature, then for an additional 3 hours at 100° C. The reaction solution was cooled to room temperature before the addition of 100 ml of H2O. The resulting solution was extracted with EtOAc (4×100 ml) and the combined organic layers were washed with H2O (2×150 mL), dried over Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography to provide 16 g (86%) of 1-(difluoromethoxy)-2-methyl-4-nitrobenzene.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]2[CH2:12][C:7]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)([CH2:8]2)[C:6]1=[O:22])[CH:2]([CH3:4])[CH3:3]>C(O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]23[CH2:8][CH:9]([CH2:12]2)[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]3=[O:22])=[CH:18][CH:17]=1
Reactant: CC(C)CN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1, 2.0 g of 3-isobutyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]-heptane-2,4-dione in 100 ml of ethanol are hydrogenated in the presence of 0.1 g of palladium-on-carbon and worked up. Melting point 158°-160° (from ethyl acetate/petroleum ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]#N)=[N:28][CH:29]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-:32].[Na+].Cl.[OH2:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:18])([F:19])[F:20])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([OH:35])=[O:32])=[N:28][CH:29]=4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [OH-]
Reactant: O
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccc(C#N)nc4)cc3N2)cc1OC
Agent: Cl
Agent: [Na+]
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4ccc(C(=O)O)nc4)cc3N2)cc1OC
Yield: 74 %

Procedure:
To a suspension of 5-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)picolinonitrile (0.694 g, 1.62 mmol) was added 4.00 M sodium hydroxide solution in water (2.02 mL). The resulting mixture was heated at reflux for 3 h. 1.0 N hydrochloric acid solution (11.3 mL) was added and the light brown precipitate was filtered, rinsed with copious amounts of water, dried under air/vacuum for 30 min, and then under high vacuum 48 h to give a light brown solid (0.535 g, 74%). This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([OH:26])=O)[C:13]2=[O:27])=[O:10])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:56]([O:60][C:61](=[O:68])[NH:62][C@@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1)([CH3:59])([CH3:58])[CH3:57].CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:56]([O:60][C:61](=[O:68])[NH:62][C@@H:63]1[CH2:67][CH2:66][N:65]([C:24](=[O:26])[CH2:23][N:14]2[C:15](=[O:22])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:6]3[CH:7]=[C:2]([Cl:1])[C:3]([O:30][CH3:31])=[CH:4][C:5]=3[O:28][CH3:29])[C:13]2=[O:27])[CH2:64]1)([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial charged with {1-[(5-Chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (50.9 mg, 0.11 mmol), HATU (49.4 mg, 0.12 mmol), and (R)-Pyrrolidin-3-yl-carbamic acid tert butyl ester (25.7 mg, 0.12 mmol), DMF (3 ml) is added. The stirring mixture is treated with DIPEA (33 μL, 0.275 mmol) and stirred at RT for 1 hour. Water is added to the mixture with stirring giving rise to a solid. This is filtered off and washed with water to afford the title compound, [M+H]+ 616
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5](O)=[O:6].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Product: O=C(Cl)c1cc(Br)cc(Br)c1
Yield: 70.4 %

Procedure:
In a flask equipped with a reflux condenser, 84 g (0.3 mole) of 3,5-dibromobenzoic acid and 68 g (0.33 mole) of phosphorus pentachloride were reacted under reflux for one hour. After removal of phosphorus oxychloride under reduced pressure by means of an aspirator, the reaction product was subjected to vacuum distillation under 8 mm Hg to obtain 63 g of 3,5-dibromobenzoic acid chloride, melting at 125° to 130° C., in the form of a colorless transparent liquid (yield: 70%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(Cl)Cl>[F:8][C:7]1[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[N:3][C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:5][CH:6]=1
Reactant: Fc1ccc(Cc2ncc(F)c(Cl)n2)cc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(c2nc(Cc3ccc(F)cc3)ncc2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
A mixture of 0.48 g (2 mmol) of 4-chloro-5-fluoro-2-(4-fluorobenzyl)-pyrimidine from Step 2 and 1.53 mL (14 mmol) of 4-methylpiperazine in 10 mL of methylene chloride was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in methylene chloride. The resultant solution was washed with 4 X 30 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 0.59 g (95% yield) of the title compound as an oil; 1H NMR (CDCl3) d 2.32 (s, 3H), 2.47 (t, 4H), 3.78 (t, 4H), 3.99 (s, 2H), 6.97 (m, 2H), 7.29 (m, 2H), 7.97 (d, 1H). The product was carried on to the next step without purification.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[C:19]([C:26](O)=[O:27])=[CH:20][N:21]([CH3:25])[C:22](=[O:24])[CH:23]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>O.CO>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[C:19]([C:26]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:27])=[CH:20][N:21]([CH3:25])[C:22](=[O:24])[CH:23]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc3ccccc3c2Cl)cc1=O
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc3ccccc3c2Cl)cc1=O
Yield: 24 %

Procedure:
2-(Aminooxy)ethanol, 4-[(1-chloro-2-naphthyl)amino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid, DMT-MM and N-MM (2 eq) were reacted in 20% water/MeOH for 15 h according to the procedure outlined in example 33, step D. Further purification by flash chromatography on silica gel (EtOAc followed by 10% MeOH/CH2Cl2—100% MeOH gradient elution) gave 4-[(1-chloro-2-naphthyl)amino]-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (24%). 1H NMR [400 MHz, (CD3)2SO] δ 11.72 (br s, 1H), 9.89 (br s, 1H), 8.20-8.14 (m, 1H), 7.98 (t, J=9.6 Hz, 2H), 7.74-7.67 (m, 2H), 7.61-7.56 (m, 2H), 5.69 (s, 1H), 4.78 (br s, 1H), 3.94 (t, J=4.8 Hz, 2H), 3.67-3.61 (m, 2H), 3.38 (s, 3H). LCMS (ACPI−) 386 (100%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:42]3[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-hydroxypiperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H41Cl2N4O3 [(M+H)+] 623.255, observed 623.2551.
Reaction SMILES: ClC1N=C(Cl)N=CN=1.CN(C=O)C.C(N(C(C)C)C(C)C)C.NC1C(C)=C(C=CC=1)C(N)=O.Cl[C:35]1[N:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]2[C:43]([CH3:51])=[C:44]([CH:48]=[CH:49][CH:50]=2)[C:45]([NH2:47])=[O:46])[N:36]=1.[CH3:52][C:53]1[CH:54]=[C:55]([N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH:56]=[CH:57][C:58]=1[CH3:59]>O>[CH3:52][C:53]1[CH:54]=[C:55]([N:60]2[CH2:61][CH2:62][N:63]([C:35]3[N:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]4[C:43]([CH3:51])=[C:44]([CH:48]=[CH:49][CH:50]=4)[C:45]([NH2:47])=[O:46])[N:36]=3)[CH2:64][CH2:65]2)[CH:56]=[CH:57][C:58]=1[CH3:59]
Reactant: Cc1c(Nc2ncnc(Cl)n2)cccc1C(N)=O
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: Cc1c(N)cccc1C(N)=O
Agent: Clc1ncnc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(c3ncnc(Nc4cccc(C(N)=O)c4C)n3)CC2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (50.0 mg, 0.333 mmol) in DMF (1334 μL, 0.333 mmol) was added N-ethyl-N-isopropylpropan-2-amine (174 μL, 1.000 mmol). The reaction mixture was cooled in an ice-water bath prior to the addition of 3-amino-2-methylbenzamide (50.1 mg, 0.333 mmol). The reaction mixture was stirred for 1 h at 0° C. at which time LC-MS revealed complete conversion to 3-(4-chloro-1,3,5-triazin-2-ylamino)-2-methylbenzamide. To this yellow solution was added 1-(3,4-dimethylphenyl)piperazine (63.4 mg, 0.333 mmol). The reaction mixture was allowed to stir and warm slowly to RT over 3 h. Water was added yielding a precipitate, which was filtered off, washed with water, and then purified further by reverse phase liquid chromatography using TFA as a modifier. Fractions containing the product were combined and washed with sat. NaHCO3. The product was extracted with CH2Cl2. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to afford 3-(4-(4-(3,4-dimethyl-phenyl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-2-methylbenzamide (78 mg, 0.187 mmol, 56.0% yield) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cn3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Absolute ethanol was degassed by applying a vacuum while simultaneously bubbling nitrogen through it. A solution of 188 mg (0.5201 mmol) ethyl 6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronapth-2-yl)ethynyl]-nicotinoate in 2 ml absolute ethanol was treated with 800 ml of a 1.65M (1.32 mmol) solution of potassium hydroxide in ethanol and water. The mixture was stirred at room temperature for 18 hours and then the solvent removed in vacuo. The residue was dissolved in water and extracted with 50 ml ether, which was discarded. The aqueous layer was then acidified with glacial acetic acid and extracted with 4×50 ml ether. The ether extracts were combined, washed with water, saturated NaCl solution and then dried (MgSO4). Solvent was removed in vacuo to give the title compound as a pale yellow solid. PMR (CDCl3): δ 1.31 (12H, s), 1.71(4H, s), 7.34 (1H, d, J~7.8 Hz), 7.40 (1H, d, J~7.8 Hz), 7.62 (1H, s), 8.39 (1H, dd, J~7.3 Hz, 2.1 Hz), 9.33 (1H, d, J~2.1 Hz).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31][OH:32]>CC(C)=O>[CH3:14][C:15]1[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH3:23])[C:17](=[O:24])[C:16]=1[CH:25]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:26][CH2:27][CH2:28][C:29]#[C:30][C:31]([OH:3])=[O:32]
Reactant: CC1=C(C)C(=O)C(C(CCCC#CCO)c2ccccc2)=C(C)C1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC1=C(C)C(=O)C(C(CCCC#CC(=O)O)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Jones' reagent (2.25 ml) was added dropwise to a solution of 7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-7-phenyl-2-heptyne-1-ol (1.01 g, 3.0 mmole) in acetone (15 ml) at room temperature over the 15-minutes period. The mixture was stirred at room temperature for another 30 minutes and the acetone was distilled off under reduced pressure. Isopropyl ether and water were added to the residue, and extraction was effected. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was recrystallized from isopropyl ether to give 7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-7-phenyl-2-heptynoic acid (0.71 g, 68%).
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=S)[CH2:2]1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C>[OH:15][N:14]=[C:3]1[NH:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2]1
Reactant: NO
Reactant: S=C1CSc2ccccc2CN1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CSc2ccccc2CN1

Procedure:
A mixture of 4,5-dihydro-1,4-benzothiazepin-3(2H)-thione (1.56 g), hydroxylamine hydrochloride (0.83 g) and sodium acetate (0.98 g) in dry ethanol (100 ml) was heated under reflux for three hours. The mixture was cooled, and the precipitated solid was collected by filtration and washed with water. Purification of the precipitate by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 3-hydroxyimino-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethanol. Yield 1.2 g (m.p. 208°-210° C.).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].CI.[C:25](=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH3:25][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[CH:21][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccc(O)cc2)CC1
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CI
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(OC)cc2)CC1

Procedure:
A mixture of 0.3 g of 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]phenol, 0.14 g of methyl iodide, 0.6 g of potassium carbonate and 50 ml of absolute butanone was heated to reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave pure 1-methoxy-4-[4-(trans-4-pentylcyclohexyl)-1-butyl]benzene with m.p. (C-I) 27° C. and cl.p. (SB -I) 16° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:31](=[O:32])[CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)Cc3ccccc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10 mL), was added phenyl acetyl chloride (0.22 mL, 1.7 mmol) and N,N-diisopropyl ethylamine (0.57 mL, 3.5 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-phenyl-acetamide as a light yellow solid (254 mg, 40% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.70 min (98.5%); mp, 275-277° C.; 1HNMR (DMSO-d6)2.11-2.18 (m, 1H, CHH), 2.58-2.86 (m, 6H, CHCH2, CH3), 3.53 (s, 2H, CH2), 4.74-4.78 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.21-7.71 (m, 8H, Ar), 8.35 (t, J=6 Hz, 1H, CH2NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.27, 30.58, 41.69, 42.41, 56.48, 117.69, 124.70, 125.56, 126.34, 128.20, 129.03, 133.80, 136.30, 140.74, 148.44, 154.79, 160.91, 169.48, 170.23, 172.58. LCMS MH=419; Anal Calcd For C23H22N4O4+0.2H2O: C, 65.45; H, 5.35; N, 13.27. Found: C, 65.32; H, 5.04; N, 13.10.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([SH:7])[CH3:6].Cl[C:9]1[C:10]([C:15](=[O:18])[CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][N:14]=1.O>C(O)C>[CH2:5]([S:7][C:9]1[C:10]([C:15](=[O:18])[CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][N:14]=1)[CH3:6]
Reactant: CCC(=O)c1nccnc1Cl
Reactant: CCS
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCSc1nccnc1C(=O)CC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
A mixture of sodium ethoxide (100 mg, 1.47 mmoles) and ethanethiol (110 mg, 1.77 mmoles) in 7 ml of absolute ethanol is stirred under nitrogen at room temperature for 10 minutes. 1-(3-Chloro-2-pyrazinyl)-1-propanone (250 mg, 1.47 mmoles) in 5 ml absolute ethanol is added to the above mixture, and the reaction mixture is stirred for 4 hours at which time thin layer chromatography indicates that all of the starting materials have reacted. The mixture is poured into water (100 ml) and extracted with methylene chloride (3×10 ml), and the extracts are combined and washed with water (1×50 ml) and saturated NaCl solution (1×50 ml). After drying (MgSO4), the solvent is removed under reduced pressure to give an 87% yield of 1-(3-ethylthio-2-pyrazinyl)-1-propanone (m.p. 45°-48° C.).