Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.[Cl:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][C@@H:19]([NH:21][C:22]([C:24]3[NH:28][N:27]=[C:26]([C:29]4[N:30]=[CH:31][N:32](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:33]=4)[CH:25]=3)=[O:23])[CH3:20])[N:14]=2)[CH:8]=[CH:9][C:10]=1[C:11]#[N:12]>O.C1COCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][C@@H:19]([NH:21][C:22]([C:24]3[NH:28][N:27]=[C:26]([C:29]4[N:30]=[CH:31][NH:32][CH:33]=4)[CH:25]=3)=[O:23])[CH3:20])[N:14]=2)[CH:8]=[CH:9][C:10]=1[C:11]#[N:12]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Solvent: O=CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2c[nH]cn2)n[nH]1
Temperature: 50 °C
Reaction time: 48 h
Yield: 58.5 %

Procedure:
Formic acid (452 mmol, 20.82 g) was dissolved in a mixture of water (2 ml) and THF (40 ml). (S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide (1.508 mmol, 1 g) was added and the resulting mixture was heated to 50° C. for 3 h. The stirring continued for 2 days at RT. The mixture was concentrated. ACN was added and evaporated. This was repeated once more. The crude product was purified by flash chromatography. 0.371 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.14 (d, 3H), 4.23-4.56 (m, 3H), 6.76 (bs, 1H), 6.94 (d, 1H), 7.53 (bs, 1H), 7.76 (s, 1H), 7.83 (d, 1H), 7.95-8.04 (m, 2H), 8.07-8.10 (m, 1H), 8.27 (d, 1H), 12.30 (bs, 1H), 13.40 (bs, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[NH2:35][CH:36]([C:38]1[NH:39][C:40]([C:46]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:47]=2[N:48]=[C:49]([NH:57][C:58]([CH3:62])([CH3:61])[CH2:59][OH:60])[C:50]([CH3:56])=[N:51]3)=[CH:41][C:42]=1[C:43](O)=[O:44])[CH3:37].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[OH:60][CH2:59][C:58]([NH:57][C:49]1[C:50]([CH3:56])=[N:51][C:52]2[C:47]([N:48]=1)=[C:46]([C:40]1[NH:39][C:38]3[CH:36]([CH3:37])[NH:35][C:43](=[O:44])[C:42]=3[CH:41]=1)[CH:55]=[CH:54][CH:53]=2)([CH3:62])[CH3:61]
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(C(C)N)[nH]3)c2nc1NC(C)(C)CO
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)NC4=O)c2nc1NC(C)(C)CO
Yield: 29.1 %

Procedure:
Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (AK Scientific, Inc., Union City, Calif.) (226 mg, 0.43 mmol) was added to a solution of 2-(1-aminoethyl)-5-(3-((1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (302d) (140 mg, 0.33 mmol) and DIPEA (0.23 mL, 1.33 mmol) in CH2Cl2 (8 mL) and DMF (8 mL) at RT. After 30 min the reaction mixture was concentrated. The residue was put into solution with EtOAc and the organic layer was washed with water, saturated NaHCO3 (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to provide 2-(3-((1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (302e) (35 mg, 0.096 mmol, 28% yield) as a yellow foam. The mixture of enantiomers was separated by chiral SFC (Chiralcel OJ (Sepax) (21×250, 5 μm); additive in supercritical fluid CO2 was 15% MeOH with 20 mM NH3; 75 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give Example 302: (R)-2-(34(1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (22 mg, 0.06 mmol, 18% yield, >99% ee). 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (dd, J=7.63, 1.56 Hz, 1H), 7.69 (dd, J=8.02, 1.56 Hz, 1H), 7.39 (t, J=7.82 Hz, 1H), 6.87 (d, J=1.56 Hz, 1H), 4.60-4.69 (m, 1H), 3.80-3.91 (m, 2H), 2.59 (s, 3H), 1.63-1.64 (m, 3H), 1.61-1.62 (m, 3H), 1.53 (d, J=6.65 Hz, 3H). m/z (ESI, +ve) 366.2 (M+H)+.
Reaction SMILES: S(=O)(=O)=[O:2].[F:5][C:6]1([F:15])[S:10][C:9](F)(F)[C:8]([F:13])=[C:7]1[F:14].[F-].FC1(F)SC(F)(F)C=C1>>[F:5][C:6]1([F:15])[S:10][C:9](=[O:2])[C:8]([F:13])=[C:7]1[F:14]
Reactant: FC1=C(F)C(F)(F)SC1(F)F
Reactant: O=S(=O)=O
Agent: FC1(F)C=CC(F)(F)S1
Agent: [F-]
Product: O=C1SC(F)(F)C(F)=C1F
Yield: 24.5 %

Procedure:
Sulfur trioxide (128.0 g, 1.60 mol) was added rapidly to 77.6 g (0.40 mol) of hexafluoro-2,5-dihydrothiophene. After an initial exotherm, the mixture was refluxed for 30 min. and fractionated to give 121.9 g, bp 42°-55° C., shown to be mainly pyrosulfuryl fluoride by 19F NMR, and 29.5 g of crude tetrafluoro-2,5-dihydrothiophene, bp 77°-85° C. Redistillation of this product afforded 16.9 g (25%) of tetrafluoro-2,5-dihydrothiophene-2-one, bp 83° C. IR (CCl4): 1755 (C=O) and 1740 cm-1 (C=C). NMR (CCl4): 19F.0. -92.0 (d of d, JFF 14.7, 5.5 Hz, 2F, CF2), -133.5 (q, JFF 14.3 Hz, 1F, CF), -144.3 (d of t, JFF 13.9, 5.5 Hz, 1F, CF). MS: m/e 171.9615 (M+ ; calcd for C4F4OS, 171.9606), 3.9664 (M+ -CO; cald, 143,9657), 121.9641 (M+ -CF2 ; calcd, 121.9638). Anal. Calcd for C4F4OS: C, 27.91; S, 18.63 Found: C, 28.27; S, 19.16.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=3)[C:10]2=S)=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[OH:33]O>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([NH:23][CH3:24])=[O:22])=[C:19]([F:27])[CH:18]=3)[C:10]2=[O:33])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2]
Reactant: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F
Reactant: OO
Solvent: CCO
Product: CNC(=O)c1ccc(N2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F

Procedure:
To a solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (1.52 g, 3.4 mmol) in ethanol (60 mL) was added 30% aqueous H2O2 (30 mL) at room temperature. The solution was heated to reflux for 1 h. After removal of ethanol, brine (100 mL) was added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product that was purified by silica gel chromatography. MS (m/z), 449 (M+1). HPLC: Column, YMC ODS A, 4.6×150 mm, 5 μm, Mobile Phase A:10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, 10% B up to 2 min, 10% to 90% B in 3 min, hold for 3 min, 90% to 10% B in 5 min, Retention time, 8.976 min, HPLC Purity, 98.46%, Flow Rate, 1 mL/min. 1H NMR (CDCl3, Freebase): δ (ppm) 8.22 (t, 1H), 8.18 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 6.70 (m, 1H), 3.05 (d, 3H), 1.65 (s, 6H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:12][CH2:13][CH2:14]Br>O.CCOC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(OCCBr)c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated at reflux for 1 h and was cooled to room temperature. 1,2-Dibromoethane (11.52 g, 61.3 mmol) was added and the reaction was heated at reflux for 24 h. The cooled solution was diluted with EtOAc and the organic solution was washed sequentially with HCl (1N, 1×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 5% EtOAc in hexanes) provided the title compound (3.79 g). 1H NMR (400 MHz, CDCl3) δ 6.98 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)(=[O:6])[CH3:5]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1.C(OCC)(=O)C>[OH:6][C:4]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)([CH3:1])[CH3:5]
Reactant: CC(=O)c1cccc2c1CCC2
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cccc2c1CCC2
Reaction time: 0.5 h

Procedure:
10 ml (14 mmol) of a 1.4 M methylmagnesium bromide solution in toluene-THF (3:1) is added in drops at 0° C. to a solution of 1.6 g (10 mmol) of 4-acetylindan (F. Dallacker, J. Van Wersch, Chem. Ber. 1972, 105, 2565) in 40 ml of THF. After 30 minutes at 0° C. and 1.5 hours at room temperature, the batch is diluted with 200 ml of ethyl acetate, washed with 1 M hydrochloric acid and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 0.64 g of product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[CH2:10]([N:17]=[C:18]=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[CH2:10]([N:17]1[C:18]([S:19][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[N:9][N:8]=[C:6]1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(CBr)cc1
Reactant: S=C=NCc1ccccc1
Reactant: NNC(=O)c1ccco1
Product: COc1ccc(CSc2nnc(-c3ccco3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-furancarboxylic acid hydrazide, benzyl isothiocyanate and 4-methoxybenzyl bromide as the starting materials. (M+H)+−378.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[CH2:16]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:27]=O)[CH3:17].[CH:29]([C:31]1[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[CH:32]=1)=O>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:27][C:21]4[C:20]5[C:24](=[CH:25][CH:26]=[C:18]([CH2:16][CH3:17])[CH:19]=5)[NH:23][CH:22]=4)[C:29]([C:31]4[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[CH:32]=4)=[C:9]3[C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: CCc1ccc2[nH]cc(C=O)c2c1
Reactant: COC(=O)c1cc(C=O)n(C)c1
Product: CCc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)OC)cn3C)c(=O)n(C)c(=O)n4CC3CC3)c2c1

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-ethyl-1H-indole-3-carbaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 515.25 (M+H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>CCO>[CH3:7][N:6]1[C:2]([NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1NCCCNC(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 86.9 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.81 g, 5 mmol), tert-butyl 3-aminopropylcarbamate (0.85 g, 4.88 mmol) and DIPEA (1.8 mL, 10.5 mmol) in EtOH (5 mL) was heated at 130° C. in the microwave for 90 min. On cooling the reaction mixture was concentrated under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane) to afford tert-butyl 3-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)propylcarbamate as a yellow gum (1.27 g, 85%). A mixture of this gum (0.3 g, 1 mmol), K2CO3 (0.41 g, 3 mmol) and methyl iodide (0.1 mL, 1.58 mmol) in DMF (5 mL) was stirred at 60° C. for 18 hr. More methyl iodide (0.1 mL, 1.58 mmol) was added and stirring at 60° C. was continued for 24 hr. The reaction mixture was cooled and concentrated under reduced pressure. The residue was triturated in DCM (100 mL), filtered and the filtrate concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 3-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)propylcarbamate as a pale yellow gum (0.122 g, 38%). 1H-NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 4.60 (s, 1H), 3.77 (s, 3H), 3.20-3.14 (m, 4H), 2.86 (s, 3H), 1.72-1.61 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]([CH2:19][C:20]([NH:22][CH:23]1[C:40](=[O:41])[N:25]2[C:26]([C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])=[C:27]([CH3:31])[CH2:28][S:29](=[O:30])[C@H:24]12)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.COP(OC)OC>CC(C)=O.C(OCC)(=O)C.O.O.O.[Ru](Cl)(Cl)Cl>[O:12]([CH2:19][C:20]([NH:22][CH:23]1[C:40](=[O:41])[N:25]2[C:26]([C:32]([O:34][CH2:35][C:36]([Cl:38])([Cl:39])[Cl:37])=[O:33])=[C:27]([CH3:31])[CH2:28][S:29](=[O:9])(=[O:30])[C@H:24]12)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)C1
Agent: Cl[Ru](Cl)Cl
Agent: COP(OC)OC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A solution of 0.026 g (0.1 mM) of ruthenium trichloride trihydrate in 25 ml of acetone containing 0.5 mM of m-chloroperbenzoic acid was stirred for 10 minutes at 0° to -10° C. under a nitrogen atmosphere. To the stirred reaction mixture were added 4.94 g (10 mM) of 2,2,2-trichloroethyl 7-phenoxyacetamido-1-oxo-3-methyl-3-cephem-4-carboxylate in one portion, followed by the portion-wise addition over ten minutes of a solution of 8.0 g (40 mM) of m-chloroperbenzoic acid in 40 ml of acetone. Following the complete addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. Thin-layer chromatographic analysis indicated that no starting material remained in the reaction mixture. Trimethylphosphite was added to the reaction mixture until a negative starch iodide test was obtained. The solvent was removed from the reaction mixture by evaporation under reduced pressure to provide a solid. The solid was dissolved in 100 ml of ethyl acetate and washed twice with 100 ml portions of dilute sodium carbonate and then with water and finally with brine. The solution was dried and the solvent was removed by evaporation under reduced pressure to provide an oil. Crystallization of the oil from 50 ml of methanol afforded 2.91 g of 2,2,2-trichloroethyl 7-phenoxyacetamido-1,1-dioxo-3-methyl-3-cephem-4-carboxylate. Yield 57%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12](Cl)=[O:13].[NH2:15][C:16](=[N:22]O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)C(C)C)(C)C.O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[O:13][N:22]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2cc(OC)ccc2OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
2-(2,5-dimethoxyphenyl)acetyl chloride (0.662 mL; 3.78 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.500 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (18 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.414 g (37%) of ethyl 5-(2,5-dimethoxybenzyl)-1,2,4-oxadiazole-3-carboxylate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][CH2:11][OH:12])=[CH:7][C:6]=2[CH:13]=1.C(N(CC)CC)C.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:12][CH2:11][CH2:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: OCCc1cc2cc(Br)ccc2s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
The product from Example 165C (0.5 g) in methylene chloride (10 mL) was added triethylamine (0.3 g, 1.5 eq) followed by tosyl chloride (0.37 g, 1.0 ea). The solution was stirred at RT overnight and washed with 3×20 mL of water. The methylene chloride layer was concentrated to viscous oil (0.98 g, 68.1% potency, 83.5% yield). The crude product can be purified by crystallization from 20:80 EtOAc:hexane to give crystalline solid (0.48 g). 1H NMR(CDCl3, δ) 2.38 (s, 3H), 3.21 (t, 2H), 4.30 (t, 2H), 6.87 (s, 1H), 7.18 (d, 2H), 7.36 (d of d, 1H), 7.55 (d, 1H), 7.63 (d, 2H), 7.75 (d, 1H). MS(m/z): 428, 430 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([Cl:17])=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5](Br)=[CH:4][C:3]=1[Br:20].B(O)(O)[OH:22].S(=O)(=O)(O)O.NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C(Br)=CC=1Br>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([Cl:17])=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([OH:22])=[CH:4][C:3]=1[Br:20]
Reactant: OB(O)O
Reactant: Nc1c(Br)cc(Br)c2c1C(=O)c1ccc(Cl)cc1C2=O
Agent: Nc1c(Br)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(O)O
Product: Nc1c(Br)cc(O)c2c1C(=O)c1ccc(Cl)cc1C2=O

Procedure:
When 104 g of 1-amino-2,4-dibromo-6-chloroanthraquinone (preparation see Example 467a) are treated with boric acid/sulphuric acid according to the procedure for 1-amino-2,4-dibromoanthraquinone in BIOS 1484, page 5, then 83.9 g, corresponding to 95% of theory, of 1-amino-2-bromo-4-hydroxy-6-chloroanthraquinone are obtained.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C)C=O>[C:1]([Cl:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)Cl
Reaction time: 16 h
Yield: 39.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 5.0 grams (0.027 mole) of undecanoic acid in 75 mL of methylene chloride was stirred and 2.8 ml (0.032 mole) of oxalyl chloride and 5 drops of N,N-dimethylformamide were added. Upon completion of addition, the reaction mixture was stirred for about 16 hours, then it was concentrated under reduced pressure, yielding 2.2 grams of undecanoyl chloride.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]=[CH:9][CH2:10][CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1>CO>[CH:1]1([CH2:7][CH:8]=[CH:9][CH2:10][C@H:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C(CC=CCC1CCCCC1)C(=O)O
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: CO
Product: CC(C)[C@@H](CC=CCC1CCCCC1)C(=O)O

Procedure:
154.65 g (0.65 mol) of racemic 6-cyclohexyl-2-isopropyl-4-hexenoic acid and 210.5 g (0.65 mol) of anhydrous quinine are dissolved in 1 liter of methanol. The mixture is concentrated by evaporation and the residue is recrystallised from ether hexane. The crystallisate is filtered with suction and thoroughly washed with cold hexane. The salt is treated with 1N HCl and the acid is extracted with ether. Concentration by evaporation yields 6-cyclohexyl-2(R)-isopropyl-4-hexenoic acid of 90% ee. If the quinine salt is recrystallised a second time from ether/hexane before the treatment with HCl, the (R)-acid obtainable therefrom has a purity of more than 95% ee.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([Br:18])=[C:13]([F:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23]C)=[O:22])[C:6]=1[Cl:25])(=O)C.[OH-].[Na+].Cl>C1COCC1.CO.O>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[C:16]([F:17])=[CH:15][C:14]([Br:18])=[C:13]([F:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([OH:23])=[O:22])[C:6]=1[Cl:25]
Reactant: COC(=O)c1nc(-c2c(F)cc(Br)c(F)c2F)cc(NC(C)=O)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(-c2c(F)cc(Br)c(F)c2F)nc(C(=O)O)c1Cl
Yield: 64.5 %

Procedure:
A solution of methyl 4-acetamido-6-(4-bromo-2,3,6-trifluorophenyl)-3-chloropicolinate (50 mg, 0.122 mmol, 1.0 eq) and sodium hydroxide (14 mg, 0.366 mmol, 3.0 eq) in THF:MeOH:H2O (1:1:0.5, 2.5 mL) was stirred at 20° C. for 2 h. The reaction mixture was acidified to pH 4-5 using 1.5 N HCl and extracted with EtOAc (2×). The combined organic extract was dried over anhydrous Na2SO4 and evaporated to dryness under reduced pressure to provide the title compound as a pale brown solid (30 mg, 65%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.O1C2=CC3C(=O)C(=O)NC=3C=C2OCC1.Br[CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Br:42]CC1OC(C(F)(F)F)=CC=1>>[Br:42][C:33]1[CH:34]=[CH:35][C:30]([CH:29]([N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[C:4](=[O:12])[C:5]2=[O:11])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH:32]=1
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cc3c(cc2C1=O)OCCO3
Product: O=C1C(=O)N(C(c2ccccc2)c2ccc(Br)cc2)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 26A and making non-critical variations using 4-bromoisatin to replace 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, and bromodiphenylmethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 4-bromo-benzhydrylindoline-2,3-dione was obtained (78%) as a red solid: MS (ES+) m/z 413.8 (M+23), 415.8 (M+23).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][C:11]([OH:13])=O)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][C:20]=1[O:31][CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:11](=[O:13])[CH2:10][N:6]3[C:5]4[CH:14]=[CH:15][C:2]([OH:1])=[CH:3][C:4]=4[O:8][C:7]3=[O:9])[CH2:29][CH2:30]2)=[CH:21][C:20]=1[O:31][CH3:32]
Reactant: O=C(O)Cn1c(=O)oc2cc(O)ccc21
Reactant: COc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(O)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (6-hydroxy-2-oxo-benzooxazol-3-yl)-acetic acid (53) (800 mg, 1 equiv), 1-(4-chloro-3-methoxy-phenyl)-piperazine dihydrochloride (1.16 g, 1 equiv), BOP (1.7 g, 1 equiv), triethylamine (5 mL, 5 equiv) in 10 ml of DMF was stirred at room temperature for overnight. The resultant solution was then diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide a crude residue which was purified by flash chromatography to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-hydroxy-3H-benzooxazol-2-one (54).