Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:26])[C:13]([N:23]([CH3:25])[CH3:24])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1.C([O-])(=[S:29])C.[K+].O>CC(N(C)C)=O>[SH:29][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:26])[C:13]([N:23]([CH3:25])[CH3:24])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCI)cc1)N(C)C
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCS)cc1)N(C)C
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
6.4 g (0.014 mol) of 1-[4-(3-Iodopropylamino)phenyl]-2-dimethylamino-2-benzyl-butan-1-one are dissolved in 50 ml of dimethylacetamide. To the solution are added 2.28 g of potassium thioacetate and heated up to 50° C. After the reaction mixture is stirred at 50° C. for 15 min, it is poured into 150 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is dissolved in 50 ml of ethanol and the solution is bubbled by nitrogen for 30 min. to remove oxygen. To the solution are added 7 ml of 2 N sodium hydroxide solution and stirred at 0° C. for 15 min. After the reaction mixture is neutralized by adding 2% hydrochloric acid solution, the resulting solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:3) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 0.68 (t, 3H), 1.41 (t, 1H), 1.83-2.08 (m, 4H), 2.35 (s, 6H), 2.66 (q, 2H), 3.17 (d, 1H), 3.20 (d, 1H), 3.34 (br, 2H), 4.15 (br, 1H), 6.52 (d, 2H), 7.14-7.28 (m, 5H), 8.32 (d, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C@H:19]1[CH2:31][CH2:32][CH2:33]OS(C)(=O)=O)=[O:17])[CH:13]=[CH2:14].O>CN(C)C=O>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:20][C@H:19]1[CH2:31][CH2:32][CH2:33][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:17])[CH:13]=[CH2:14]
Reactant: c1c[nH]cn1
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCOS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCn1ccnc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
To a solution of imidazole (3.57 g) in dimethylformamide (100 ml) was added potassium t-butoxide (5.89 g) portionwise at room temperature and the mixture was stirred at the same temperature for 10 minutes. Then a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(3-methanesulfonyloxypropyl)pyrrolidine (20.1 g), in dimethylformamide (20 ml) was added and the mixture was heated at 60° C. After stirring for 1 hour, water (200 ml) was added and the mixture was extracted with hexane-ethyl acetate (2:1) (200 ml×5). The combined extract was washed with water (1 l), brine (1 l), and dried over magnesium sulfate. Evaporation of the solvent gave (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-[3-(imidazol-1-yl)propyl]pyrrolidine (18.1 g) as a yellow paste.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23]Br>CC(CC)=O.O>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: NC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: NC(=O)CCc1ccc(OCc2ccc(F)c(F)c2)cc1
Reaction time: 24 h
Yield: 41.3 %

Procedure:
A mixture of 106 mg (0.64 mmol) 3-(4-hydroxy-phenyl)-propionamide, 178 mg (1.29 mmol) potassium carbonate and 140 mg (0.68 mmol) 3,4-difluorobenzyl bromide in 5 ml ethyl methyl ketone is hold at 50° C. for 24 hours. The reaction mixture is cooled, diluted with water and extracted with diethyl ether. Crystallization from n-hexane yields 77 mg (41%) of a colorless solid. MS: m/e=291.3 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N+:12]([O-])=O)=[CH:5][C:4]=1[O:15][CH3:16].[O:17]=[CH:18][C:19](OCC)=O>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[O:15][CH3:16])[NH:12][C:18](=[O:17])[CH:19]=[N:9]2
Reactant: CCOC(=O)C=O
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2ncc(=O)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
A mixture of 1,2-dimethoxy-4,5-dinitrobenzene (5.7 g, 25.0 mmol) in ethanol/acetic acid (140 mL, 1:1) was hydrogenated over palladium on carbon (10%, 1 g) at normal pressure and room temperature for 3 hours, then filtered through a pad of celite. The filtrate containing the crude diamine was treated with ethyl oxoacetate (50 wt % in toluene, 10 mL, 50 mmol) and the reaction was stirred at room temperature overnight. The resulting precipitate was collected by filtration. This material was suspended in a mixture of methanol/dichloromethane and solvent was removed under reduced pressure to remove traces of acetic acid to give 2.0 g (38%) of product as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(N(CC)CC)C>C(O)C>[OH:16][C:9]1[CH:10]=[CH:11][C:12]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:14]=1
Reactant: CNc1ccccc1
Reactant: O=C1CCC(=O)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(c1ccccc1)c1ccc(O)cc1
Yield: 32.2 %

Procedure:
1.07 g of N-methylaniline, 2.24 g of 1,4-cyclohexanedione and 1.4 ml of triethylamine were heated with stirring in 15 ml of ethanol at 50° C. to 60° C. and reacted in air for 8 hours. During the reaction, ethanol was added as needed. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resultant was separated by silica gel column chromatography (n-hexane:ethyl acetate=3:1) and 0.64 g of N-(4-hydroxyphenyl)-N-methylaniline was obtained (yield 32.1%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1F
Yield: 85.9 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (4.8 g), triethylamine (3.3 mL), 2-fluorocinnamic acid (3.9 g), WSC.HCl (4.5 g), and methylene chloride (150 mL), to give the captioned compound (6.0 g, 86%) as crystals.
Reaction SMILES: O=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.CO>O1CCCC1.[Rh]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(Cl)cc1
Agent: [Rh]
Agent: O=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)[C@H](C(=O)O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
Rhodium-catalyzed hydrogenation. --A catalyst solution was prepared in a glove box (O2 content <1 ppm) by dissolving 0.0482 g (0.1 19 mmol) of [Rh(COD)2 ]BF4 and 0.0858 g (0.1 19 mmol) of (R,S)-BPPFA-EPIP in 20 ml of tetrahydrofuran and stirring at 20° for 15 minutes. Then, 5.0 g (23.74 mmol) of 2-(p-chlorophenyl)-3-methylcrotonic acid, 13 ml of methanol, 33 ml of tetrahydrofuran were placed in a 185 ml autoclave and the catalyst solution prepared above was added. The autoclave was sealed and the hydrogenation was carried out at 20° while stirring and under a constant pressure of 50 bar. The conversion was 100% after 18 hours. The hydrogenation solution was evaporated at 50°/20 mbar and the residue was distilled in a bulb tube oven at 150°/0.2 mbar. There were obtained 4.8 g (96%) of (S)-2-(p-chlorophenyl)-3-methylbutyric acid as a colorless oil which crystallized out at RT; chemical purity 99.9 GC area %; 97.6% ee.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:17]2[N:22]=[C:21]([Br:23])[CH:20]=[CH:19][CH:18]=2)([C:10]2[N:15]=[C:14]([Br:16])[CH:13]=[CH:12][CH:11]=2)O)[N:3]=1.C(N(S(F)(F)[F:30])CC)C.[OH-].[Na+]>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:17]2[N:22]=[C:21]([Br:23])[CH:20]=[CH:19][CH:18]=2)([C:10]2[N:15]=[C:14]([Br:16])[CH:13]=[CH:12][CH:11]=2)[F:30])[N:3]=1
Reactant: OC(c1cccc(Br)n1)(c1cccc(Br)n1)c1cccc(Br)n1
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: FC(c1cccc(Br)n1)(c1cccc(Br)n1)c1cccc(Br)n1
Temperature: 5 °C

Procedure:
A solution of 50.0 g (100 mmol) of tris(2-bromo-6-pyridyl)methanol in 750 ml of dichloromethane was admixed with good stirring dropwise with 47.3 ml (400 mmol) of diethylaminosulfur trifluoride. Subsequently, the reaction mixture was heated under reflux for 30 min, then cooled to 5° C., and admixed with good stirring (highly exothermic!!!) with 300 ml of water and then with a solution of 64.0 g (1600 mmol) of sodium hydroxide in 600 ml of water (highly exothermic!!!). The organic phase was removed, the aqueous phase was washed twice with 200 ml of dichloromethane, and the combined organic phases were dried over calcium chloride and subsequently freed of dichloromethane. The remaining red-brown crystal slurry was taken up in 100 ml of methanol and filtered off. After washing with methanol, the colorless to beige crystals were dried under reduced pressure. The yield was 47.4 g (91.3%) at a purity of greater than 99.0% by 1H NMR.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=1>C(#N)C>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)[CH:12]=[N:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCc1cncn1Cc1ccc(C#N)cc1

Procedure:
A solution of 4-(tert-butyldimethylsilyloxymethyl)-1-triphenylmethylimidazole (4.66 g, 10.26 mmol) and 1-bromomethyl-4-cyanobenzene (2.01 g, 10.26 mmol) in acetonitrile (50 mL) was refluxed 4 h. The reaction was cooled, acetonitrile removed in vacuo, and the residue dissolved in methanol (30 mL). This solution was refluxed for 2 h, cooled and methanol evaporated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The crude product was chromatographed on silica with 3% methanol in chloroform. The title compound was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15]I)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:28])[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][N:25]3[CH2:26][CH2:27][CH:22]([CH2:21][C:20]([O:19][CH3:18])=[O:28])[CH2:23][CH2:24]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCC(CI)CC2)cc1
Reactant: COC(=O)CC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC1CCN(CC2CCN(c3ccc(C#N)cc3)CC2)CC1
Temperature: 130 °C

Procedure:
A suspension of 2.18 g of 1-(4-cyanophenyl)-4-iodomethyl-piperidine (mixture from Example XXV), 1.26 g of methyl-4-piperidyl-acetate-hydrochloride and 1.35 g of triethylamine in 150 ml of dimethylformamide is heated to 130° C. for 24 hours. After cooling, the solvent is removed under reduced pressure and the residue is chromatographed over silica gel with methylene chloride/methanol (30:1). The solvent is removed under reduced pressure and the crude product is used for the next stage of synthesis without any further purification.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN(C3SC=CN=3)C2)=NC=1CC.Br[C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1.[CH2:40]([O:42][C@H:43]1[CH2:47][NH:46][CH2:45][C@H:44]1[NH:48][C:49]1[C:54]([CH2:55][CH3:56])=[N:53][C:52]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=2[CH3:65])=[C:51]([CH2:66][CH3:67])[N:50]=1)[CH3:41]>>[CH2:40]([O:42][C@H:43]1[CH2:47][N:46]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:45][C@H:44]1[NH:48][C:49]1[C:54]([CH2:55][CH3:56])=[N:53][C:52]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=2[CH3:65])=[C:51]([CH2:66][CH3:67])[N:50]=1)[CH3:41]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC
Reactant: Brc1ncccn1
Agent: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but substituting 2-bromopyrimidine and starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.28, 2.13, 2.48, 2.74, 3.51, 3.77, 3.85, 3.98, 4.25, 4.90, 5.20, 6.56, 6.81, 7.12, 8.37; IR (diffuse reflectance) 2970, 2402 (w), 2350 (w), 2307 (w), 2212 (w), 2169 (w), 1583 (s), 1568, 1548 (s), 1508 (s), 1475 (s), 1393, 1383, 1242, 798 cm−1 HRMS (ESI) calcd for C26H34N6O2+H1 463.2821. found 463.2816.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.FC1C=CC([N:41]2C3C(=CC(C(C4C=CC=CC=4)C(C)(C)CN)=CC=3)C=N2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:19]([NH2:41])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: O=C(O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: NC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(c)(d) 3-(1-(4-Fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanoic acid (80, mg, 0.154 mmol) was converted into the acid fluoride using the identical procedure to that for Synthetic Intermediate I above. A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanoyl fluoride in anhydrous THF (5 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropan-amide.
Reaction SMILES: [CH2:1]([CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[Cr](Cl)([O-])(=O)=O.CCOCC>C(Cl)Cl>[CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of dilinoleyl methanol (2.0 g, 3.8 mmol) and anhydrous sodium carbonate (0.2 g) in 100 mL of CH2Cl2 was added pydimium chlorochromate (PCC, 2.0 g, 9.5 mmol). The resulting suspension was stirred at room temperature for 60 min. Ether (300 mL) was then added into the mixture, and the resulting brown suspension was filtered through a pad of silica gel (300 mL). The silica gel pad was further washed with ether (3×200 mL). The ether filtrate and washes were combined. Evaporation of the solvent gave 3.0 g of an oily residual as a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 250 mL) eluted with 0-3% ether in hexanes. This gave 1.8 g (90%) of dilinoleyl ketone (V). 1H NMR (400 MHz, CDCl3) δ: 5.25-5.45 (8H, m, 4×CH═CH), 2.78 (4H, t, 2×C═C—CH2-C═C), 2.39 (4H, t, 2×COCH2), 2.05 (8H, q, 4×allylic CH2), 1.45-1.7 (4H, m), 1.2-1.45 (32H, m), 0.90 (6H, t, 2×CH3) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][Si](C(C)C)(C(C)C)C(C)C)=[CH:11][CH:10]=2)=[CH:6][C:5]=1[C:28]([F:31])([F:30])[F:29])([O-:3])=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.O>[N+:1]([C:4]1[CH:27]=[CH:26][C:7]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[CH:6][C:5]=1[C:28]([F:29])([F:30])[F:31])([O-:3])=[O:2]
Reactant: CC(C)[Si](Oc1ccc(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Nc2ccc(O)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 4-nitro-3-(trifluoromethyl)-N-(4-[[tris(propan-2-yl)silyl]oxy]phenyl)aniline (3 g, 6.6 mmol) in tetrahydrofuran (60 ml) was added TBAF (2.59 g, 9.9 mmol) with stirring for 1 hour at room temperature. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with 30% ethyl acetate in petroleum ether to afford 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenol as a orange solid (1.5 g, 76%); (ES, m/z): [M+H]+ 299; 1H NMR (300 MHz, DMSO-d6): δ 9.53 (s, 1H), 9.28 (s, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 7.01-7.05 (m, 1H), 6.81 (d, J=8.7 Hz, 2H).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=O)[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:19])=O>>[CH2:1]([C:5]1[C:6]([Cl:19])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1c[nH]cc(C(=O)OCC)c1=O
Product: CCCCc1cncc(C(=O)OCC)c1Cl

Procedure:
Ethyl 5-n-butyl-4-oxo-1,4-dihydropyridine-3-carboxylate (prepared as described by M. Balogh, et al. in J. Heterocyclic Chem., 17, 359-368 (1980)) is refluxed in phosphorous oxychloride to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:5](=O)[CH2:6][C:7]#[N:8])[CH2:4][CH2:3]1.[CH3:10][NH:11][NH2:12]>CO>[CH3:10][N:11]1[C:7]([NH2:8])=[CH:6][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[N:12]1
Reactant: CC1(C(=O)CC#N)CC1
Reactant: CNN
Solvent: CO
Product: Cn1nc(C2(C)CC2)cc1N

Procedure:
A solution of 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile (1.0 g, 8.1 mmol), methylhydrazine (0.56 g, 12.2 mmol) and MeOH (40 mL) is heated at 80° C. for 16 h. The solution is then concentrated in vacuo and the residue is suspended in 5 mL DCM and 20 mL heptane, filtered to give product. MS (ESI) m/z 152.3 (M+1).
Reaction SMILES: [SH:1][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:10]1(=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]1=[O:20]>>[O:9]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2][S:1][C:12]2[C:11](=[O:20])[C:10](=[O:21])[C:19]3[C:14]([C:13]1=2)=[CH:15][CH:16]=[CH:17][CH:18]=3
Reactant: OC1(CS)CCCCC1
Reactant: O=C1C=Cc2ccccc2C1=O
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCCC1)O2

Procedure:
The crude 1-(mercaptomethyl)cyclohexanol was then reacted with naphthalene-1,2-dione as outlined in procedure F [both step (i) and (ii)] to afford crude spiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione. The crude spiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione was purified by flash column chromatography (SiO2, 100% dichloromethane) to afford the product (0.183 g) as a purple solid. M.p.=194-195° C., 400 MHz 1H NMR CDCl3 δ 8.05-8.0 (m, 1H), 7.8-7.72 (m, 1H), 7.68-7.6 (m, 1H), 7.5-7.4 (m, 1H), 2.91 (s, 2H), 2.15-2.0 (m, 2H), 1.8-1.53 (m, 7H), 1.5-1.35 (m, 1H); LCMS=301 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3(=[O:33])=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)S(=O)CC3)cc(C(C)(C)C)c1O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(-c2cn3c(n2)S(=O)(=O)CC3)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
In 10 ml of chloroform was dissolved 0.6 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole 1-oxide and then 0.4 g of m-chloroperbenzoic acid was added to the solution. After 30 minutes, 0.4 g of m-chloroperbenzoic acid was further added to the mixture and the resultant mixture was allowed to stand for one hour. The reaction mixture was washed with an aqueous 5% sodium hydrogen carbonate solution, dried, and then the solvent thereof was distilled off. The residue was purified by silica gel chromatography using chloroform as the eluent and further recrystallized from aqueous ethanol to provide 0.2 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole 1,1-dioxide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.Cl.[NH2:17][C@@H:18]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:39][C:37]1[CH:38]=[C:33]([CH:34]=[C:35]([F:40])[CH:36]=1)[CH2:32][C@H:18]([NH:17][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1ccc(-c2ncco2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(-c3ncco3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1,3-oxazol-2-yl)benzoic acid (105 mg, 0.6 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (220 mg, 0.6 mmol), and HATU (210 mg, 0.6 mmol) stirring in methylene chloride (5 mL) is added N,N-diisopropylethylamine (340 μL, 1.9 mmol). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is partitioned between methylene chloride and water. The organic layer is washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude solid. Purification by flash column chromatography (silica, gradient 96:4 to 93:7 methylene chloride/methanol) provided the title compound. ESI MS m/z 506.2 [M+H]+.