Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:31]1([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:31]1([C:41]2[CH:46]=[CH:45][C:44]([C:2]3[C:3]4[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=4)[C:9]([C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]6[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=6[N:26]=5)=[CH:20][CH:21]=4)=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:43][CH:42]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(-c2cccc3ccccc23)cc1
Reactant: Brc1c2ccccc2c(-c2ccc(-c3nc4ccccc4o3)cc2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc2c(-c3ccc(-c4c5ccccc5c(-c5ccc(-c6nc7ccccc7o6)cc5)c5ccccc45)cc3)cccc2c1
Yield: 95.1 %

Procedure:
In a 50 mL three-neck flask, 0.97 g (2.2 mmol) of 2-[4-(10-bromo-9-anthryl)phenyl]benzoxazole, 0.57 g (2.3 mmol) of 4-(1-naphthyl)phenylboronic acid, 0.46 g (4.3 mmol) of sodium carbonate, 15 mL of toluene, 3 mL of ethanol, and 3 mL of water were placed. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 35 mg (0.030 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred under nitrogen stream at 100° C. for 18 hours. After a certain period, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a solid. The solid was purified by silica gel column chromatograghy (toluene:hexane=2:1) and recrystallized with toluene/hexane, giving 1.2 g of the target white powder in a yield of 94%.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[NH2:18][OH:19].Cl>O.C(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[CH:8]=[C:9]([NH2:10])[O:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#CCC(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C

Procedure:
(4-Fluorobenzoyl)acetonitrile (10 g., 0.063 mol) and 200 ml. of ethyl alcohol were placed in a 500 ml. 1-neck flask. To the reaction mixture was added in portionwise fashion a solution comprised of 24 g. of sodium acetate and 18.3 g. of hydroxylamine.HCl in 200 ml. of H2O. After refluxing for three days, the reaction mixture was cooled to room temperature. About half the solvent was removed and then an oily layer formed. The residue was extracted thoroughly in ether and then the combined ether extracts were washed in water, brine, and then dried over MgSO4. When the ether was removed orange crystals formed which were recrystallized from diethyl ether/hexane, m.p., 98°-99° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1.CC1(C)CCC(C)(C)C2C=C(COC3C=CC(C(O)=O)=CC=3C3C=CC=CC=3)C=CC1=2>>[CH3:21][C:17]1([CH3:22])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]2[CH:12]=[C:11]([CH2:10][O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH:20]=[CH:19][C:18]1=2
Reactant: Oc1ccccc1Br
Reactant: CC1(C)CCC(C)(C)c2cc(CCl)ccc21
Agent: CC1(C)CCC(C)(C)c2cc(COc3ccc(C(=O)O)cc3-c3ccccc3)ccc21
Product: CC1(C)CCC(C)(C)c2cc(COc3ccccc3Br)ccc21
Yield: 88.7 %

Procedure:
2-Bromophenol (1.50 g., 8.70 mmol) is alkylated with 2-chloromethyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene) (18a) (2.05 g., 8.70 mmol) in a similar manner as described in Example 26 (for the synthesis of 44) to afford 2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy-bromobenzene (50) (2.88 g., 7.72 mmol, 89%): chromatographed on silica gel using EtOAc/hexane to afford a clear oil; 1H NMR (300 MHz, CDCl3) δ 7.57 (dd, J=2, 8 Hz, 1H, ArH), 7.45 (d, J=2 Hz, 1H, ArH), 7.32 (d, J=8 Hz, 1H, ArH), 7.25 (m, 2H, ArH, 6.98 (dd, J=2, 8 Hz, 1H, ArH), 6.83 (dd, J=8, 8 Hz, 1H, ArH), 5.09 (s, 2H, ArCH2O), 1.70 (s, 4H, CH2CH2), 1.29 (s, 6H, 2×CH3), 1.28 (s, 6H, 2×CH3) .
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:21][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
To a solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (150 mg, 0.47 mmol) in ethanol (20 mL) was added 10% palladium-on-carbon (100 mg). The reaction mixture was stirred under a hydrogen atmosphere using a balloon filled with hydrogen gas for 2 h at room temperature. The reaction mixture was filtered through Celite and the residue was rinsed with ethanol under a nitrogen atmosphere. The filtrate was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH:22]([NH:32]C(=O)OC(C)(C)C)[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[N:19][N:18]=4)=[C:13]([NH:40][CH:41]([CH3:43])[CH3:42])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C>C(Cl)Cl>[NH2:32][CH:22]([C:20]1[O:21][C:17]([C:14]2[C:13]([NH:40][CH:41]([CH3:43])[CH3:42])=[CH:12][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[N:16][CH:15]=2)=[N:18][N:19]=1)[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27]
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)o1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(C(N)CO[Si](C)(C)C(C)(C)C)o1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
tert-butyl (1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (56) (200 mg, 0.3 mmol) was dissolved in DCM (10 mL), cooled to −10° C. Added 2,6-lutidine (1.9 mmol, 6 equiv.) and stirred for 15 min. Added TBDMS-Triflate (1.6 mmol, 5 equiv.) in portions, dropwise to the reaction mixture and stirred at −10° C. for 30 min. Gradually, the reaction temperature was raised to room temperature and stirred for 30 min. Diluted the reaction mixture using DCM and quenched by addition of 5% citric acid solution. Extracted the reaction mixture in DCM. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography through silica gel and MeOH: DCM as eluent to provide the desired compound, 5-(5-(1-amino-2-((tert-butyldimethylsilyl)oxy)ethyl)-1,3,4-oxadiazol-2-yl)-N2-(benzo[d]thiazol-6-yl)-N4-isopropylpyridine-2,4-diamine LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.79 min; LCMS (ES-API), m/z 526.9 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.F[C:39](F)(F)C1C=C(S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=CC=1>>[F:37][C:17]([F:16])([F:36])[C:18]1[CH:19]=[C:20]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH:35][C:13]([C@@H:9]4[CH2:39][CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and (3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step D of Example 252D for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 266: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.37-8.38 (bs, 1H), 8.32 (d, J=5.2 Hz, 1H), 8.19 (d, J=7.9 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 4.07-4.23 (m, 2H), 3.84 (dd, J=9.9, 2.2 Hz, 1H), 3.46 (td, J=12.9, 2.8 Hz, 1H), 3.16 (d, J=9.2 Hz, 1H), 3.12 (dd, J=9.5, 7.6 Hz, 1H), 2.90-2.94 (m, 1H), 2.41-2.57 (bs, 2H), 2.24-2.29 (m, 1H), 1.75-1.97 (m, 2H), 1.53-1.65 (m, 3H), 1.49-1.55 (m, 2H), 1.48 (s, 9H), 1.42-1.51 (m, 1H), 1.29-1.39 (m, 1H), 1.17-1.29 (m, 1H); MS (ESI+) m/z 563 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:24]=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].C[NH3+].[C:29]([BH3-])#[N:30].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:24][NH:30][CH3:29])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(C=O)cn2S(=O)(=O)c2ccc(F)cc2)cc1
Reactant: [BH3-]C#N
Agent: C[NH3+]
Agent: [Cl-]
Agent: [Na+]
Product: CNCc1cc(-c2ccc(OC)cc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Yield: 44.6 %

Procedure:
Using 1-(4-fluorophenylsulfonyl)-5-(4-methoxyphenyl)-1H-pyrrole-3-carbaldehyde (0.28 g), methylammonium chloride (0.62 g) and sodium cyanoborohydride (0.15 g), a procedure as in Example 6 was performed to give the title compound as a colorless oil (yield 0.13 g, 44%).
Reaction SMILES: [NH:1]1C2[C:5](=[CH:6][CH:7]=[CH:8]C=2)[CH2:4][CH2:3][C:2]1=[O:11].Cl[CH2:13][CH2:14][Cl:15].[Cl:16]Cl.[OH-].[NH4+]>C(O)=O.Cl>[Cl:16][C:7]1[CH:6]=[C:5]2[C:13](=[C:14]([Cl:15])[CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2
Reactant: O=C1CCc2ccccc2N1
Reactant: ClCl
Reactant: ClCCCl
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O=CO
Product: O=C1CCc2cc(Cl)cc(Cl)c2N1
Reaction time: 0.5 h

Procedure:
A solution of 6 g of 3,4-dihydro-2(1H)-quinolinone in 50 ml of formic acid and 50 ml of conc. hydrochloric acid was added to 75 ml of 1,2-dichloroethane which had been saturated with chlorine. The mixture was stirred over ice for 30 minutes. Chlorine was introduced for 5 minutes and stirring in the cold was continued for 2 hours. It was then poured onto ice, was made basic with ammonium hydroxide and was extracted with methylene chloride. The extracts were dried and evaporated and the residue was chromatographed over 300 g of silica gel using 8% (v/v) of ethyl acetate in methylene chloride. Crystallization of the combined clean fractions from ether gave colorless crystals of 6,8-dichloro-3,4-dihydro-2(1H) quinolinone with m.p. 145°-146°.
Reaction SMILES: [P:1]([O-:21])([O-:20])([O:3][CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5][CH2:6][CH3:7])=[O:2].[OH-].[Na+:23]>C(O)C>[P:1]([OH:21])([OH:20])([OH:3])=[O:2].[CH3:7][CH2:6][CH2:5][CH:4]([Na:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: [Na+]
Reactant: CCCCCCCCCCCCC(CCC)OP(=O)([O-])[O-]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCC([Na])CCC
Product: O=P(O)(O)O
Reaction time: 48 h
Yield: 93.5 %

Procedure:
4-Hexadecanyl phosphate (3.13 g, 0.0097 mol) was dissolved in ethanol (150 ml). NaOH (0.37 g, 0.0092 mol) was added and the mixture was stirred for 48 hrs and then evaporated. Ethanol (2×150 ml) was added and evaporated. Ether (2×100 ml) was added and evaporated. The obtained solid was triturated with acetone (100 ml) and dried under 1 mm. Hg atmosphere overnight. 2.98 g of final product was obtained. Yield 87%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19](N)=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)[CH3:2].[OH-:25].[Na+].O.Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH:18]([CH3:22])[C:19]([OH:25])=[O:20])=[CH:17][C:11]=3[C:10](=[O:23])[CH2:9][C:8]=2[CH:24]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCOc1ccc2c(c1)CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc2c(c1)CC(=O)c1cc(C(C)C(=O)O)ccc1S2
Temperature: 0 °C
Yield: 37 %

Procedure:
A mixture of 70 mg of 2-(10,11-dihydro-8-ethoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 800 mg of sodium hydroxide, 5 ml of water and 5 ml of ethanol was refluxed for 3 hours. After the completion of the reaction, the solvent was removed by distillation to obtain a residue, to which was added ice water, and the mixture was acidified with 10% hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was chromatographed over silica gel and eluted with chloroform/benzene (4/1), thereby obtaining 26 mg (yield: 37%) of 2-(10,11-dihydro-8-ethoxy-11-oxodibenzo-[b,f]thiepin-2-yl)-propionic acid as an oil.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH:7]1([O:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([CH2:21][OH:22])[CH:14]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[K+].C([OH:28])(C)C>O>[CH:7]1([O:12][C:13]2[C:18]([O:19][CH3:20])=[CH:17][N:16]=[C:15]([C:21]([OH:28])=[O:22])[CH:14]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cnc(CO)cc1OC1CCCC1
Reactant: CC(C)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cnc(C(=O)O)cc1OC1CCCC1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Solid potassium permanganate (5.87 g) is added portionwise during 30 minutes to a suspension of 4-cyclopentyloxy-2-hydroxymethyl-5-methoxypyridine (4.0 g) in water (100 mL) at 50±5° C. When the addition is complete the mixture is heated at 70±5° C. for 45 min and then cooled to room temperature. A solution of potassium hydroxide (1.95 g) in water (50 mL) is added followed by sufficient isopropanol to react with excess potassium permanganate. After stirring for 10 minutes the mixture is filtered through diatomaceous earth and the filtrate concentrated to ˜70 mL. The solution is acidified to pH 2 with concentrated aqueous hydrochloric acid and extracted with chloroform. After drying (MgSO4) the extracts are evaporated to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (2.5 g) as a white solid, m.p. 184-5° C. [1Hnmr in D6-DMSO shifts relative to Me4Si:— 1.55-1.79, 6H, m; 1.95, 2H, m; 3.92, 3H, s; 5.00, 1H, m; 7.59, 1H, s; 8.24, 1H, s.].
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[NH2:30].CC1C=CC(C)=CC=1>C(Cl)Cl>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:30][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Reactant: COc1cc(N)cc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: Cc1ccc(C)cc1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (700 mg, 1.92 mmol), 3-methoxy-5-nitroaniline (645 mg, 3.84 mmol) and p-xylene (7 mL) were combined and heated to 140° C., then stirred for 16 hours at 130° C. The reaction was allowed to cool, placed in a sep. funnel, diluted with DCM, and washed with 2M HCl and brine and concentrated in vacuo. The resulting solid was washed with Et2O to give N-(3-(3-methoxy-5-nitro-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide (400 mg, 42%). MS (EI) m/z for C21H16N6O7S: 496.94 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([C:20]#[N:21])=[CH:17][NH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][C:27]=1[O:33][CH2:34][O:35][CH3:36])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([N:18]2[CH:19]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]([C:20]#[N:21])=[CH:17]2)=[CH:28][C:27]=1[O:33][CH2:34][O:35][CH3:36])[CH3:23]
Reactant: CCOC(=O)c1ccc(F)cc1OCOC
Reactant: N#Cc1c[nH]cc1-c1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCc3ccccc3)c2)cc1OCOC
Temperature: 65 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
To a solution of 4-(2-benzyloxyphenyl)-1H-pyrrole-3-carbonitrile (1.5 g), 4-fluoro-2-methoxymethoxybenzoic acid ethyl ester (1.4 g) in N,N-dimethylformamide (25 mL) was added cesium carbonate, and this mixture was stirred at 65° C. for 15 hours. This reaction mixture was poured into water, the precipitated solid was collected by filtration, and washed with water and n-hexane, dried under reduced pressure at 50° C. to give the title compound (2.3 g).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1([S:25][CH3:26])[CH2:16][N:15]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:14]1=[O:24].C(N(CC)CC)C.[N+:34]([C:37]1[CH:55]=[CH:54][C:40]([CH2:41][O:42][C:43]([CH:45]([C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[C:46](Cl)=[O:47])=[O:44])=[CH:39][CH:38]=1)([O-:36])=[O:35]>ClCCl>[Si:17]([N:15]1[CH2:16][C:13]([S:25][CH3:26])([NH:12][C:46](=[O:47])[CH:45]([C:43]([O:42][CH2:41][C:40]2[CH:54]=[CH:55][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=2)=[O:44])[C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[C:14]1=[O:24])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CSC1(N)CN([Si](C)(C)C(C)(C)C)C1=O
Reactant: O=C(Cl)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)c1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1(NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccsc2)CN([Si](C)(C)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
A solution of (23) (418 mg) in dry dichloromethane (10 ml) containing triethylamine (222 mg) at 0° C. was treated with a solution of 2-(p-nitrobenzyloxycarbonyl)-2-thien-3-ylacetylchloride (407 mg) in dry dichloromethane (5 ml). The mixture was stirred at 0° C. for 15 minutes, then allowed to warm to room temperature. After 1 hour the mixture was washed successively with sat. NaHCO3, water, dilute HCl, water and brine. The organic phase was dried (MgSO4), filtered and evaporated. Chromatography of the residue on silica gel gave the product (39) (496 mg) as a foam.
Reaction SMILES: [NH3:1].[F:2][C:3]1([F:10])[CH2:5][C:4]1([CH3:9])[C:6](Cl)=[O:7]>O1CCOCC1>[F:2][C:3]1([F:10])[CH2:5][C:4]1([C:6]([NH2:1])=[O:7])[CH3:9]
Reactant: CC1(C(=O)Cl)CC1(F)F
Reactant: N
Solvent: C1COCCO1
Product: CC1(C(N)=O)CC1(F)F
Yield: 81 %

Procedure:
Gaseous ammonia is passed for 90 minutes into a stirred solution of 15.45 g (0.1 mol) of 2,2-difluoro-1-methyl-cyclopropane-carbonyl chloride in 80 ml of dioxane at 20° to 30° C. The resultant suspension is then evaporated to dryness under a waterpump vacuum. The residue remaining is stirred with 50 ml of water, filtered off with suction and dried. In this manner, 11 g (81% of theory) of 2,2-difluoro-1-methyl-cyclopropyl-carboxamide in form of a solid substance of melting point 125°-127° C. are obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH2:3][OH:4].[N:15]#[C:16]Br>>[C:9]1([CH:6]([CH2:7][CH3:8])[CH2:5][C@H:2]2[CH2:3][O:4][C:16]([NH2:15])=[N:1]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CBr
Reactant: CCC(C[C@H](N)CO)c1ccccc1
Product: CCC(C[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1b (S)-2-amino-4-phenyl-hexan-1-ol was reacted with cyanogen bromide to give (S)-4-(2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine (mainly one epimer). White crystalline solid. MS (ISP): 219.4 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16](Cl)[N:15]=2)[C@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.[CH3:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:17]=[C:16]([N:32]3[CH2:33][CH2:34][CH2:35][C@H:31]3[CH3:30])[N:15]=2)[C@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CCCN1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(Cl)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(N2CCC[C@H]2C)n1

Procedure:
Heat a mixture of 4-[2-chloro-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 12.3 mmol), 2-(R)-methyl-pyrrolidine hydrobromide (Nijhuis et. al. (1989) J. Org. Chem. 54:216-220) (3.0 g, 16.0 mmol), and K2CO3 (5.2 g, 37.8 mmol) in DMA at 120° C. for 16 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a white solid.
Reaction SMILES: [B-](F)(F)(F)F.[N+:6](=[O:8])=[O:7].N1C(C)=CC(C)=CC=1C.[CH3:18][C@H:19]([NH:22][C:23]([C@@H:25]1[CH2:29][S:28][C:27](=[O:30])[NH:26]1)=[O:24])[CH2:20][OH:21]>C(#N)C>[CH3:18][C@H:19]([NH:22][C:23]([C@@H:25]1[CH2:29][S:28][C:27](=[O:30])[NH:26]1)=[O:24])[CH2:20][O:21][N+:6]([O-:8])=[O:7]
Reactant: C[C@@H](CO)NC(=O)[C@@H]1CSC(=O)N1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: C[C@@H](CO[N+](=O)[O-])NC(=O)[C@@H]1CSC(=O)N1
Yield: 29.2 %

Procedure:
In 10 ml of dry acetonitrile were dissolved 478 mg of nitronium tetrafluoroboron (85% content), 0.43 ml of 2,4,6-collidine was added thereto with stirring under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes. To the resulting mixture were added 500 mg of (4R)-N-[(1S)-1-methyl-2-hydroxyethyl]-2-oxothiazolidin-4-yl-carboxamide, and the mixture was stirred at room temperature for 1 hour and 45 minutes. Then, the solvent was distilled off under reduced pressure and the thus obtained residue was purified by silica gel column chromatography employing cyclohexane-ethyl acetate (3:7) as an eluent to obtain 178 mg of the desired compound as colorless crystals.