Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2](=[C:4]1[C:9](=O)[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:6][C:5]1=[O:18])[CH3:3].O.[NH2:20][NH2:21]>C(O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:7]1[CH2:8][C:9]2[NH:21][N:20]=[C:2]([CH3:3])[C:4]=2[C:5](=[O:18])[CH2:6]1
Reactant: NN
Reactant: CC(O)=C1C(=O)CC(c2ccccc2Cl)CC1=O
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 85.2 %

Procedure:
A solution of 2-(1-hydroxyethylidene)-5-(2-chlorophenyl)cyclohexane-1,3-dione (0.31 g) and hydrazine hydrate (0.065 g) in ethanol (10 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.26 g).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[N:38]1[C:42]([CH2:43][O:44][C:45]2[CH:50]=[CH:49][C:48]([C:51](=O)[CH3:52])=[C:47]([CH3:54])[CH:46]=2)=[C:41]([CH:55]([CH3:57])[CH3:56])[CH:40]=[N:39]1>C1COCC1>[Cl:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[C:32]=1[N:38]1[C:42]([CH2:43][O:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([CH3:52])=[CH:8][O:9][CH3:10])=[C:47]([CH3:54])[CH:46]=2)=[C:41]([CH:55]([CH3:57])[CH3:56])[CH:40]=[N:39]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C(C)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.9 %

Procedure:
To a room temperature suspension of potassium tert-butoxide (1.36 g, 12.12 mmol) in THF (30 mL) is added (methoxymethyl)triphenyl phosphonium chloride (4.14 g, 12.12 mmol). The reaction mixture is stirred at room temperature for 20 minutes. Solid 1-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-ethanone (843 mg, 2.02 mmol) is added and the reaction is stirred at room temperature overnight. The reaction is quenched with saturated aqueous NH4Cl and is concentrated under reduced pressure. The residue is partitioned between Et2O and water. The aqueous layer is extracted with Et2O and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure, and chromatographed (0% to 30% EtOAc/Hex) to yield the title compound (836 mg, 93%) as a mix of E/Z isomers. (Major Isomer) 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.41 (d, 2H, J=7.9 Hz), 7.33-7.28 (m, 1H), 6.93 (d, 1H, J=8.4 Hz), 6.64-6.52 (m, 2H), 5.83 (q, 1H, J=1.3 Hz), 4.78 (s, 2H), 3.63 (s, 3H), 3.00 (sept, 1H, J=7.0 Hz), 2.22 (s, 3H), 1.83 (d, 3H, J=1.3 Hz), 1.30 (d, 6H, J=7.0 Hz).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([NH:14]C(=O)C)=[CH:7][C:6]=1[F:18])(=O)C.Cl.N>O>[NH2:14][C:8]1[CH:7]=[C:6]([F:18])[C:5]([NH2:4])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(NC(C)=O)cc1F
Agent: Cl
Agent: N
Solvent: O
Product: Nc1cc([N+](=O)[O-])c(N)cc1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
166 g (0.65 mol) of the 1,4-bisacetylamino-2-fluoro-5-nitrobenzene prepared according to C. are heated at 98° C. together with 812 ml of water and 240 g of concentrated hydrochloric acid (36% strength), and the reaction mixture is stirred at this temperature for one hour. The mixture is then first cooled to 60° C., the pH is brought to 7.5 with 25% strength aqueous ammonia solution and the mixture is further cooled to 5° C. The product is now filtered off, washed twice with 75 ml of water each time and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[O:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[CH:17]=[C:18]([NH:22][C:8](=[O:10])[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(-c2nnco2)c1
Reactant: O=C(O)c1cc(Br)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2nnco2)c1)c1cc(Br)ccn1
Yield: 80.6 %

Procedure:
A solution of 4-bromopyridine-2-carboxylic acid (3.76 g, 18.6 mmol), 3-[1,3,4]oxadiazol-2-yl-phenylamine (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (7.1 g, 18.7 mmol), and diisopropylethylamine (15 mL) in N,N-dimethylformamide was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was stirred with acetonitrile (40 mL) and water (40 mL). The solid thus obtained was isolated by filtration, washed with water (20 mL), acetonitrile (20 mL) and diethyl ether (40 mL), and dried under reduced pressure to give N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-4-bromopicolinamide as a white powder (5.2 g, 15.0 mmol, 81% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:18]=1[CH3:24]>ClCC(Cl)(Cl)Cl.C(OCC)(=O)C.ClCCl>[OH:16][C:17]1[C:18]([CH3:24])=[C:19]([OH:23])[CH:20]=[CH:21][C:22]=1[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([OH:10])=[O:15])=[O:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1c(O)cccc1O
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(O)ccc(C(=O)c2ccccc2C(=O)O)c1O
Reaction time: 1 h

Procedure:
Aluminum chloride (21.4 g, 161 mmol) was added to a stirring suspension of phthalic anhydride (6 g, 40 mmol) in tetrachloroethane (200 mL) under nitrogen. 1,3-Dihydroxy-2-methylbenzene (5 g, 40 mmol) was added and the mixture quickly thickened. After the precipitates were broken up with a spatula the reaction continued for 1 hour. The solution was diluted with ethyl acetate (˜600 mL) and washed with 1 M hydrochloric acid (2×200 mL). The product was extracted from the organic layer into a saturated solution of sodium bicarbonate in water (600 mL). The basic aqueous phase was acidified with 3M hydrochloric acid to a pH of 5. The product was extracted from the aqueous phase into ethyl acetate (400 mL), washed with brine (2×100 mL), dried over magnesium sulfate and concentrated to give a brownish solid. The solid was slurried in dichloromethane (20 mL) and filtered to give 2-(2,4-dihydroxy-3-methylbenzoyl)benzoic acid as an off white powder (4.6 g, 16.9 mmol, 42% yield).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[C:11]([CH2:13][S:14][CH2:15][C:16]([CH3:21])([S:18][S:19][CH3:20])[CH3:17])[CH:10]=[C:9]([CH2:22][O:23]S(C)(=O)=O)[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:21][C:16]([S:18][S:19][CH3:20])([CH3:17])[CH2:15][S:14][CH2:13][C:11]1[CH:10]=[C:9]([CH2:22][OH:23])[CH:8]=[C:7]([CH2:6][OH:5])[CH:12]=1
Reactant: CSSC(C)(C)CSCc1cc(COS(C)(=O)=O)cc(COS(C)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSSC(C)(C)CSCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.5 %

Procedure:
IBD monomer (177 mg, 0.602 mmol) in anhydrous N,N-dimethylformamide (1.75 mL) was added to (5-((2-methyl-2-(methyldisulfanyl)propylthio)methyl)-1,3-phenylene)bis(methylene) dimethanesulfonate (119 mg, 0.251 mmol) at ambient temperature. Potassium carbonate (173 mg, 1.253 mmol) was added and the reaction was allowed to stir at ambient temperature for 20 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The extracts were washed with brine and then dried with anhydrous sodium sulfate, filtered and concentrated on high vacuum. The crude product was purified by flash silica gel chromatography (neat DCM→2% MeOH/DCM). Fractions containing product were combined, concentrated and purified by semi-prep RP-HPLC (C18, A=DI water B=ACN, 20 mL/min). Fractions containing desired product were combined, extracted with dichloromethane, dried with anhydrous magnesium sulfate, filtered and concentrated to yield the desired product (46 mg, 21%). 1H NMR (400 Hz, CDCl3): δ 8.19 (d, J=8.0 Hz, 2H), 7.77 (m, d, J=4.4 Hz, 2H), 7.50 (s, 2H), 7.34 (s, 1H), 7.31 (s, 2H), 7.19 (m, 4H), 7.03 (t, J=7.2, 7.6 Hz, 2H), 6.77 (s, 2H), 5.14 (m, 4H), 4.40 (m, 2H), 3.91 (s, 6H), 3.70 (m, 2H), 3.63 (m, 2H), 3.41 (m, 2H), 2.65 (s, 2H), 2.29 (s, 3H), 1.26 (s, 6H). MS (m/z), Calcd. 893.2 (M+Na)+. found 893.2 (M+Na)+, 911.2 (M+H2O+Na)+, 929.2 (M+2H2O+Na)+, 945.1 (M+2H2O+K)+. See FIG. 30.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:33]=[CH:32][C:23](/[CH:24]=[CH:25]/[C:26]3[O:30][C:29](=[O:31])[NH:28][N:27]=3)=[CH:22][CH:21]=2)=[C:4]([CH3:34])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:24]=[CH:25]/[C:26]3[O:30][C:29](=[O:31])[NH:28][N:27]=3)=[CH:32][CH:33]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/c4n[nH]c(=O)o4)cc3)c(-c3ccc(F)cc3C)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/c2n[nH]c(=O)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a 30 mL screw cap vial, (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one (15 mg, 0.032 mmol) was dissolved in DCM (1 mL). The vial was charged with BBr3 (1.0 M in hexanes, 0.095 ml, 0.095 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with 4 mL MeOH and stirred for 10 min. The mixture was concentrated onto silica gel and the crude material was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH3CN/H2O) to afford (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one (6 mg, 0.013 mmol, 41% yield) as a white solid. LC/MS (m/z, MH−): 459.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
(2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS Reg. No. 74844-91-0) (1.10 g, 4.08 mmol) was dissolved in THF (25 ml) and 4-chlorophenol (0.78 g, 6.12 mmol) and triphenylphosphine (1.6 g, 6.12 mmol) were added. The solution was cooled in and ice bath and DIAD (0.96 ml, 4.88 mmol) added dropwise. The reaction was stirred at room temperature overnight. After evaporation of the solvent, the residue was dissolved in diethylether (20 ml) and pentane added until solution was only just maintained. The solution was seeded with triphenylphosphine oxide and cooled in ice. The resultant precipitate was filtered and the filtrate evaporated. The residue was purified by flash chromatography on silica (100 g), loading with pentane:diethylether (2:1 by volume) and eluting with pentane : diethylether (1: 1 by volume) to give the title compound as a colourless oil (1.35 g, 69%) containing a small impurity of diisopropylbicarbamate (CAS Reg. No.19740-72-8) by NMR.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1.CI.[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:24])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cncc(Cl)n2)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(c1cncc(Cl)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 4-[(6-chloropyrazin-2-yl)amino]piperidine-1-carboxylate (0.165 g, 0.528 mmol) in THF (2.6 ml) was added methyl iodide (0.165 ml, 2.64 mmol). The solution was cooled to 0° C., and a solution of NaHMDS in THF (1M; 1.06 ml, 1.06 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with saturated aqueous ammonium chloride (50 mL, and extracted with EtOAc (2×50 mL). The combined EtOAc layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 4-[(6-chloropyrazin-2-yl)(methyl)amino]piperidine-1-carboxylate as a yellow oil. LRMS calculated for C15H23ClN4O2 [M+Na]+, 349.2; found 349.0.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)=O.C(C1C=CC(S([N:33]2[C:37]3=[N:38][CH:39]=[C:40]([NH:42][NH2:43])[N:41]=[C:36]3[CH:35]=[CH:34]2)(=O)=O)=CC=1)(C)(C)C.CCN(C(C)C)C(C)C.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:2]1([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[N:41]2[C:36]3[CH:35]=[CH:34][NH:33][C:37]=3[N:38]=[CH:39][C:40]2=[N:42][N:43]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(c2nnc3cnc4[nH]ccc4n23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
Benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate (0.41 g, 1.4 mmol, Preparation #5) was added to a solution of 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (0.50 g, 1.4 mmol, Preparation #3) and DIEA (0.25 mL, 1.4 mmol) in 1,4-dioxane (15 mL) at about 0° C. After the complete addition, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After about 1 h, SOCl2 (0.53 mL, 7.2 mmol) was added and the reaction was heated at about 90° C. for about 1 h. The reaction was allowed to cool to ambient temperature then aqueous Na2CO3 (2 M, 14.5 mL, 29.0 mmol) was added and the reaction was heated at about 90° C. for about 3 days. The reaction was partitioned with EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified over silica gel (12 g) eluting with 50-100% EtOAc in heptane to afford benzyl 4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)piperidine-1-carboxylate as a yellow solid (0.34 g, 61%): LC/MS (Table 2, Method a) Rt=1.89 min; MS m/z: 377 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[O:11])[O:9][C:8](=[O:12])[C:5]2=[N:6][CH:7]=1.[CH:13]([OH:16])([CH3:15])[CH3:14]>C1COCC1>[CH:13]([O:16][C:8]([C:5]1[C:4]([C:10]([OH:9])=[O:11])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:12])([CH3:15])[CH3:14]
Reactant: CC(C)O
Reactant: O=C1OC(=O)c2ncc(Br)cc21
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ncc(Br)cc1C(=O)O
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
To a solution of 3-bromo-furo[3,4-b]pyridine-5,7-dione (200 mg, 0.877 mmol) in THF (3 ml) at −10° C. was added Mg(ClO4)2 (235 mg, 1.053 mmol, 1.2 equiv.) and the reaction mixture was stirred for 5 min at that temperature. Then isopropanol (6 ml) was added and the reaction mixture was stirred at 25° C. for 16 hours. The volatilities were removed in vacuo and the resultant residue was dissolved in EtOAc (30 ml). The organic layer was washed with water (15 ml) and brine (15 ml), dried over anhydrous Na2SO4, filtered and evaporated off in vacuo. The crude material thus obtained was purified by column chromatography over normal silica gel (30-50% EtOAc/hexane) to afford 5-bromo-pyridine-2,3-dicarboxylic acid 2-isopropyl ester (210 mg, 83.1%) as light brown solid, MS: m/e=286.0 (M−H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)=[N+]=[N-].[OH2:19]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:9]([Cl:17])[CH:8]=1)[O:19][CH:12]1[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: O
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(OC1C=CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of (3-chloro-4-methanesulfonyl-phenyl)-diazo-acetic acid methyl ester (Example 6; 489 mg, 1.69 mmol) in dichloromethane (10 mL) at 25° C. was treated with 2-cyclohexen-1I-ol (0.42 mL, 4.23 mmol) followed by rhodium (11) acetate dimer (15 mg, 0.034 mmol) and the resulting solution was stirred at 25° C. for 1 h. The reaction mixture was diluted with dichloromethane (10 mL), then was poured into water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 40S column, 75/25 hexanes/ethyl acetate) provided rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid methyl ester (350 mg, 58% yield) as a colorless oil: EI-HRMS m/e calcd for C16H19ClS O5 (M+) 358.0642, found 358.0640.
Reaction SMILES: CO.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:14]([N+:25]([O-])=O)[CH:13]=3)=[CH:11][C:6]=2[O:5][CH2:4]1>[C].[Pd].C(OCC)(=O)C>[NH2:25][C:14]1[CH:13]=[C:12]([C:10]2[CH:9]=[CH:8][C:7]3[O:3][CH2:4][O:5][C:6]=3[CH:11]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.42 g of 10% palladium-carbon was added to a mixed solution of 14 mL of methanol and 14 mL of ethyl acetate containing 1.4 g of tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-nitrobenzoate and stirred under hydrogen atmosphere at room temperature for 2 hours. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=20:1] to obtain 0.52 g of tert-butyl 2-amino-4-(benzo[1,3]dioxol-5-yl)benzoate as pale red solid.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=[CH:9]2.Cl.[BrH:21]>O>[Br:21][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=[CH:9]2
Reactant: Br
Reactant: Nc1ccc2cc(S(=O)(=O)O)ccc2c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(Br)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of sodium nitrite (2.7 g) in water (5 ml) was added during 2 hours to a stirred mixture of 6-amino-2-naphthalene-sulphonic acid (8.8 g), dilute aqueous hydrochloric acid (2.8% weight/volume, 20 ml) and water (15 ml) which had been cooled to 0° C. The mixture was stirred at 0° C. for 30 minutes and poured onto a stirred suspension of cuprous bromide (5.34 g) in dilute aqueous hydrobromic acid (2.8%, 20 ml). The mixture was stored at ambient temperature for 18 hours. The mixture was evaporated to give 6-bromo-2-naphthalenesulphonic acid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[Cl:25][C:26]1[C:31]([C:32](O)=[O:33])=[CH:30][C:29]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[Cl:25][C:26]1[C:31]([C:32]([NH:1][C:2]2[CH:24]=[CH:23][C:5]3[CH2:6][CH2:7][C:8]4[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)[C:12]=4[C:4]=3[CH:3]=2)=[O:33])=[CH:30][C:29]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:28][CH:27]=1
Reactant: O=C(O)c1cc(N2CCOCC2)ncc1Cl
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(N4CCOCC4)ncc3Cl)cc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound of Example 244 (0.757 mmoles), 5-chloro-2-morpholin-4-ylisonicotinic acid, (1.38 mmoles), and HATU (1.57 mmoles) were dissolved in 5 mL DMF followed by the addition of 0.4 mL of triethylamine. The mixture was stirred at room temperature for 3 hrs and partially stripped of DMF. The reaction mixture was then added to water, filtered, and washed with water. The solid was dissolved in THF, decolorized with decolorizing carbon, and dried over anhydrous MgSO4. The THF was stripped and the solid triturated in diethyl ether three times, then triturated in ethanol, and twice more with acetonitrile, filtered and dried under vacuum. Mp: 309-313° C. 1H NMR (d6-DMSO, 400 MHz): δ 2.80-2.95 (m, 4H); 3.42 (t, 4H, J=5 Hz); 3.62 (t, 4H, J=5 Hz); 6.88 (s, 1H); 7.17-7.21 (m, 1H); 7.23-7.41 (m, 5H); 7.49-7.58 (m, 3H); 8.14 (s, 1H); 10.31 (s, 1H). 13C NMR (d6-DSMO, 100 MHz): δ 20.34, 29.70, 45.74, 66.50, 106.55, 114.97, 115.87, 117.09, 117.32, 120.05, 121.41, 126.67, 128.64, 128.73, 129.62, 133.47, 136.80, 136.82, 137.48, 139.64, 143.21, 145.28, 147.54, 158.30, 161.39, 163.85, 164.45. M+1=547.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][CH:12]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)[C:13](=[O:19])[NH:14]3)=[CH:9][C:8]=2[CH2:7][N:6]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:4].[OH-].[Li+].Cl>C1COCC1.CO>[C:39]([O:38][C:36]([N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][CH:12]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)[C:13](=[O:19])[NH:14]3)=[CH:9][C:8]=2[CH2:7]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)OC(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)C(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
(7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (1.6 g) was dissolved in THF-methanol (4:1, 20 mL), 2 N lithium hydroxide solution (2.5 mL) was added, and the resulting reaction mixture was stirred at 0° C. for 3 h when an additional equiv of LiOH (2N) was added. The resulting mixture stirred at 0° C. for 3 h. The reaction mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to afford 3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (1.5 g). LC-MS (m/z) 601.