Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:23]3[C@@H:19]([CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22]3)[C:18](=[O:31])[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1.C(OCC)(=O)C>[C:1]1([C@:18]2([OH:31])[CH2:17][CH2:16][C:15]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C@@H:23]3[C@H:19]2[CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@H]2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1
Yield: 41.1 %

Procedure:
A suspension of 10.78 g of phenylmagnesium bromide in 65 cm3 of diethyl ether is added dropwise to a solution of 11.66 g of (3aS,7aS)-7,7-diphenyl-2-tert-butoxycarbonyl-perhydroisoindol-4-one in 70 cm3 of dry tetrahydrofuran at room temperature, while stirring. The reaction mixture is stirred at room temperature for 24 hours, refluxed for 5 hours and then treated with 250 cm3 of an aqueous saturated solution of ammonium chloride, diluted with 200 cm3 of ethyl acetate, washed with 200 cm3 of water (twice) and then with 200 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 5.3 cm, height 31.5 cm), by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting fractions of 100 cm3. Fractions 23 to 48 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 5.75 g of (3aS,4S,7aS)-4,7,7-triphenyl-2-tert-butoxycarbonyl-perhydroisoindol-4-ol are obtained in the form of a pale yellow foam.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:24]([OH:26])=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[C:29](O)[CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N+:33]([C:32]1[CH:27]=[CH:28][C:29]([O:25][C:24](=[O:26])[C@H:12]([CH:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([OH:16])=[O:15])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])=[CH:30][CH:31]=1)([O-:35])=[O:34]
Reactant: O=C(N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: O=C(N[C@H](C(=O)Oc1ccc([N+](=O)[O-])cc1)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
N-carbobenzoxy-β-benzyl-L-aspartic acid (12 Kg) and p-nitrophenol (5.1 Kg) are dissolved in ethyl acetate (20-30 L) and the solution is cooled to below 5° C. Dicyclohexyl-carbodiimide (7.6 Kg) is dissolved in ethyl acetate (8-12 L) and added, maintaining the temperature below 5° C. The solution is stirred at reduced temperature for two hours and then for three hours at 20°-30° C. The dicyclohexylurea byproduct is removed by filtration and washed with ethyl acetate (20-30 L). The filtrate is concentrated in vacuo below 60° C. The concentrate is dissolved in a mixture of hot isopropyl alcohol (25-40 L) and distilled water (2-5 L) and cooled below 25° C. The solids are collected on a filter, rinsed with isopropyl alcohol and dried below 40° C. Melting point=76°-79° C.; specific rotation=-15° to 18° (C=1, DMF).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH2:39]([NH2:42])[CH2:40][NH2:41].CS(C)(=O)=O>O1CCOCC1>[NH2:41][CH2:40][CH2:39][NH:42][C:14]1[N:13]=[C:12]([NH:11][C@H:7]2[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]2)[C:17]([C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:16][N:15]=1
Reactant: NCCN
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(NCCN)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, ethylenediamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give N*2*-(2-amino-ethyl)-N*4*-((S)-1-methanesulfonyl-piperidin-3-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2,4-diamine. MS: (ES+): 432.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([N:8]=[C:9]=[O:10])[CH:7]=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][NH:18]2>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([NH:8][C:9]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)=[O:10])[CH:7]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: COc1ccc(Cl)cc1N=C=O
Solvent: ClCCl
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc2[nH]ccc12
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 5-chloro-2-methoxyphenyl isocyanate (Int-4, 5.5 g, 30 mmol) in DCM (20 mL) was added dropwise to the 4-amino-1H-indole in DCM (30 mL) from Step A, and the resulting mixture was stirred overnight, then filtered to give the crude product 1-(5-chloro-2-methoxyphenyl)-3-(1H-indol-4-yl)urea (6.6 g, 70%), which was used directly in the next step without purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1cccc2ccccc12
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3ccccc23)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.68 g, 3.74 mmol) in acetonitrile (9.35 mL) was treated with N,N-diisopropylethylamine (0.60 mL, 3.67 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.60 mL, 3.67 mmol) and acetonitrile (9.35 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (1.14 g, 3.4 mmol) in acetonitrile (8.5 mL). After the addition was complete, the reaction mixture was heated to 100° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 30% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[4-(naphthalen-1-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.38 g, 32%) as a light orange oil: HR-ES-MS m/z calculated for C21H23NO4 [M+H]+ 354.1700, observed 354.1700; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.3 Hz, 3H), 0.95 (d, J=6.3 Hz, 3H), 1.42-1.72 (m, 2H), 1.74-1.90 (m, 1H), 3.67 (s, 3H), 4.38 (s, 2H), 4.69-4.77 (m, 1H), 4.75 (s, 1H), 7.51 (d, J=6.9 Hz, 1H), 7.54-7.67 (m, 3H), 7.91 (d, J=8.2 Hz, 1H), 7.98-8.08 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([B:11]3[O:19]C(C)(C)C(C)(C)[O:12]3)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.O.Cl.CCOC(C)=O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([B:11]([OH:19])[OH:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccc3nccnc3c2)OC1(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccc2nccnc2c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To 6-quinoxaline boronic acid pinacol ester (S50) (256 mg, 1.00 mmol, 1.00 equiv) in THF (2.0 mL) at 23° C. was added H2O (8.0 mL) and NaIO4 (321 mg, 1.50 mmol, 1.50 equiv). After stirring for 1.0 hr at 23° C., the reaction mixture was added to 1N HCl aq (20 mL) and was further stirred for 1.0 hr. To the reaction mixture was added EtOAc (20 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases are washed with brine (20 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was triturated with Et2O to afford 121 mg of the title compound as a colorless solid (70% yield).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])C=C.[CH2:20]1[CH:29]2C(CCCC2)CC[CH2:21]1>>[CH2:29]([C:10]1[CH:9]=[C:8]([F:11])[CH:7]=[C:6]([C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:5]=1[OH:4])[CH:20]=[CH2:21]
Reactant: C1CCC2CCCCC2C1
Reactant: C=CCOc1ccc(F)cc1-c1c(Cl)cccc1Cl
Product: C=CCc1cc(F)cc(-c2c(Cl)cccc2Cl)c1O
Yield: 84 %

Procedure:
A solution of 2-allyloxy-2′,6′-dichloro-5-fluorobiphenyl (11.02 g, 37 mmol) in decahydronaphthalene (100 mL) was refluxed for 38 h. The solvent was removed under vacuum. Chromatography with 0–20% ethyl acetate in hexanes afforded 9.26 g (84%) of 3-ally-2′,6′-dichloro-5-fluorobiphenyl-2-ol as a light yellow oil. MS (ES) m/z 295.0 ([M−H]−).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[C:16]([NH2:18])=[O:17])[CH:13]=2)OC1.Br[C:26]1[N:30]2[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:23][C:11]1[CH:10]=[CH:9][C:8]([C:26]2[N:30]3[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:36])[CH3:37])=[N:34][C:29]3=[N:28][CH:27]=2)=[CH:13][C:12]=1[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cnccc3C(N)=O)c2)OC1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cnccc4C(N)=O)c3)cnc2n1

Procedure:
3-[5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]isonicotinamide (100 mg, 0.41 mmol) was coupled to 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (106 mg, 0.41 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 8% methanol then trituration with diethyl ether gave 3-{2-fluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]phenyl}isonicotinamide as a white solid: δH (400 MHz, CDCl3) 1.58 (6H, s), 4.42 (1H, s), 5.68 (1H, s), 5.82 (1H, s), 7.08 (1H, d, J 7), 7.36 (1H, t, J 7), 7.57-7.61 (3H, m), 7.86 (1H, s), 8.71 (1H, d, J 7), 8.74 (1H, s), 8.78 (1H, d, J 5); m/z (ES+) 392 (M++H).
Reaction SMILES: [CH2:1]([OH:5])[C@H:2]([OH:4])[CH3:3].C(N(CC)CC)C.Cl[C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:15]1([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:5][CH2:1][C@H:2]([OH:4])[CH3:3])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of (2R)-1,2-propanediol (1.9 mL) in toluene (20 mL) was added triethylamine (8.3 mL) and 4-dimethylaminopyridine (32 mg). The mixture was ice-cooled and 1,1′,1″-(chloromethylidyne)tris-benzene (6.6 g) was added and the mixture stirred at ambient temperature for 20 h. The reaction mixture was diluted with toluene then extracted with ammonium chloride solution (×2), then brine (×1) and the organic layer was dried (MgSO4), filtered and evaporated. The resulting oil was triturated with iso-hexane to give subtitle compound as a white solid. Yield: 4 g
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1.[H-].C([Al+]CC(C)C)C(C)C.CC(C[AlH]CC(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([OH:11])[CH2:8][CH:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1
Reactant: Cc1ccc2c(c1)C(c1ccccc1)CC(=O)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Reaction time: 1 h

Procedure:
3,4-Dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one (III, EXAMPLE 1, 100.0 g, 420.2 mmol) is added to toluene (500 mL). The mixture is degassed by purging alternately with vacuum and nitrogen and then cooled to -21°. Diisobutylaluminumhydride in toluene solution (DIBAL, 1.5M, 290 mL, 435 mmol) is then slowly added over 2 hr via add funnel while maintaining the reaction temperature at -20 to -25°. The reduction is usually done when the DIBAL add is completed. If the reaction is not done additional DIBAL can be added in increments. When the reaction is done (<1% lactone) ethyl acetate (45 mL) is added at -20° to -25° via add funnel. Very little exotherm is observed. Next, citric acid (23%, 500 mL) is added. The mixture is stirred at 45-50° for 1 hr (or stirred overnight at 20-25°), the phases are separated, the organic phase is washed with water (2×300 mL). The organic phase is concentrated to 250 mL under reduced pressure. Methanol (500 mL) is added, and the mixture is concentrated to 250 mL. The methanol addition and distillation is repeated to give the title compound in methanol solution. This solution is concentrated to a thick oil which crystallizes on standing to give the title compound (as a mixture of diastereomers), IR (neat) 3410, 3020, 2925, 1605, 1498, 1447, 1205 and 1010 cm-1 ; MS (m/z, EI)=240 (parent). Rather then isolating and characterizing the title compound, it is normally taken directly into the next step.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:13])[CH2:9][CH:8]([CH2:10][CH:11]=[O:12])[CH2:7][CH2:6][O:5]1>C(O)C>[CH3:3][C:4]1([CH3:13])[CH2:9][CH:8]([CH2:10][CH2:11][OH:12])[CH2:7][CH2:6][O:5]1
Reactant: CC1(C)CC(CC=O)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CC(CCO)CCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred suspension of sodium borohydride (0.620 g, 16.39 mmol) in dry ethanol (20 ml) was cooled to 0° C. (ice bath) under nitrogen and a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)acetaldehyde (2.56 g, 16.39 mmol) in ethanol (20 ml) was added dropwise over a period of 20 mins. The mixture was then stirred in the cold for a further 1 hour then allowed to warm to ambient and stirred for 72 hours. The solvent was removed by evaporation and the residual oil was poured into ice and extracted with DCM (3×30 ml). Combined the organic extracts and dried by passing through a hydrophobic frit and evaporated in vacuo to give a colourless oil which contained the title compound.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=3[CH:16]=2)[OH:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([NH:3][S:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]([C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:27])([CH3:28])[C:17]=3[CH:16]=2)=[O:14])=[CH:11][CH:12]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(C(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCNS(=O)(=O)c1ccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 75.4 %

Procedure:
To a solution, stirred at ambient temperature, of 2 g of N-ethyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) hydroxymethyl] phenyl sulfonamide, prepared in Example III, in 100 cm3 of acetone, there is added the Jones reagent prepared in accordance with Example II. The reaction mixture is then treated under the same conditions. The carbonyl derivative is purified by passage through a silica gel chromatography column. It is eluted with a 4/1 hexane/ethyl acetate mixture and recrystallized in a hexane/isopropyl ether mixture. 1.5 g of N-ethyl 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) carbonyl]phenylsulfonamide are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.C(Cl)Cl.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:29](=[O:32])[CH2:30][CH3:31])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)CC)n2oc(=O)nc2n1
Reaction time: 1.5 h

Procedure:
5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 80 ml. of methylene chloride and 5 ml. of triethylamine. 2.2 ml. of propionyl chloride in 20 ml. of methylene chloride are added dropwise at 0° C. The mixture is stirred for 90 minutes, then diluted with water, adjusted to pH 4 and extracted with methylene chloride. The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed over silica gel using chloroform for the elution. Recrystallization from methylene chloride and diethyl ether yields pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}propionamide having a melting point of 157°-159° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:29])[CH2:22][S:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:30]1CCC[CH2:31]1>CCOCC>[CH2:1]([O:8][C:9]1[C:14]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:20][CH:21]([OH:29])[CH2:22][S:23][CH2:24][CH:25]1[CH2:26][O:27][C:31](=[O:30])[O:28]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: OCC(O)CSCC(O)Cc1cccc(C2CCCC2)c1OCc1ccccc1
Solvent: CCOCC
Product: O=C1OCC(CSCC(O)Cc2cccc(C3CCCC3)c2OCc2ccccc2)O1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
200 mg (0.48 mmol) of 7-(2-benzyloxy-3-cyclopentylphenyl)-4-thiaheptane-1,2,6-triol (Example 11) are dissolved in 3 ml of tetrahydrofuran, and 150 mg (0.93 mmol) of N,N'-carbonyldiimidazole are added. The solution is stirred at 70° C. with exclusion of moisture for 5 h and then diluted with ether and washed once with 1N sodium hydroxide solution and twice with saturated brine. Drying over sodium sulfate, removal of the solvent by distillation in vacuo and chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 1:1) yields 133 mg of 4-[5-(2-benzyloxy-3-cyclopentylphenyl)-4-hydroxy-2-thiapentyl]-1,3-dioxolan-2-one.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>>[CH2:1]([CH:3]1[N:12]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2]
Reactant: CCC1Nc2cc(F)ccc2-n2cccc21
Reactant: COc1cccc(C(=O)Cl)c1
Product: CCC1c2cccn2-c2ccc(F)cc2N1C(=O)c1cccc(OC)c1

Procedure:
4-Ethyl-7-fluoro-5-(3-methoxybenzoyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 17 and m-anisoyl chloride according to the procedure of Example 106, Step 2 mp 70-74° C. MS (ESI) m/z 351; Anal. Calcd for C21H19FN2O2: C, 71.99; H, 5.47; N, 7.99. Found: C, 70.08; H, 5.55; N, 7.14.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)=[CH:5]1)([CH3:3])[CH3:2].FC1C=CC=C(F)C=1F.O1CCCC1.[BH4-].[Na+]>C(OCC)(=O)C.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C.CO>[NH2:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=3)=[CH:5][N:4]2[CH:1]([CH3:3])[CH3:2])=[CH:8][CH:9]=1
Reactant: CC(C)n1cc(-c2cc(F)c(F)c(F)c2)c2ccc([N+](=O)[O-])cc21
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: Fc1cccc(F)c1F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1cc(-c2cc(F)c(F)c(F)c2)c2ccc(N)cc21

Procedure:
Method H Combine 1-isopropyl-6-nitro-3-(3,4,5-trifluoro-phenyl)-1H-indole (4, R1=i-Pr, R3=3,4,5-trifluoro-benzene) (136.1 mg, 0.41 mmol), nickel(II) acetate tetrahydrate (204 mg, 0.82 mmol), tetrahydrofuran (2.5 mL) and methanol (2.5 mL) in a 50 mL flask. Add sodium borohydride (62 mg, 1.64 mmol) in small portions. Once gas evolution is complete quench the reaction with saturated aqueous ammonium chloride (5 mL), dilute with ethyl acetate (10 mL), and separate the layers. Wash the organic layer with saturated aqueous sodium bicarbonate (5 mL), water (5 mL), brine (5 mL), dry (Na2SO4), filter and concentrate. This material may be used without further purification in the following preparation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1c(F)cc(N2CCOCC2)cc1F
Temperature: 10 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
2,4,6-Trifluoronitrobenzene (4.95 g) and potassium carbonate (4.63 g) were mixed in dry dimethyl sulfoxide (40 mL) and cooled to 10° C. under argon. Morpholine (2.56 mL) was added and the reaction mixture was allowed to warm to 25° C. and stirred under argon for 16 hours. The reaction mixture was concentrated in vacuo. Brine (50 mL) was added and the product was extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography to furnish 2.49 g (37% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 3.43 (t, 4H), 3.69 (t, 4H), 6.87 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: COC(=O)Cc1cc(O)cc(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(F)cc(OC)c1
Reaction time: 8 h
Yield: 15.9 %

Procedure:
To a stirred mixture of methyl 5-fluoro-3-hydroxyphenylacetate (3.3 g, 15.7 mmol) and potassium carbonate (1.82 g, 50 mmol) in DMF (30 ml) was added methyl iodide (1.82 g, 50 mmol) at room temperature and the reaction mixture was stirred overnight. Then the mixture was diluted with water (50 ml) and extracted with ether. The combined extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 150 g; hexane/ethyl acetate (10/1)) afforded 495 mg (55%) of methyl 5-fluoro-3-methoxyphenylacetate as a colorless oil.