Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([OH:25])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([O:12][C:13]1[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:46][CH2:47][N:48]4[CH2:52][CH2:51][CH2:50][CH2:49]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=1)=[CH:6][CH:5]=2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Reactant: OCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a suspension of 4-(2,3-dimethylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (124 mg, 0.32 mmol) in methylene chloride (2.5 ml) was added triphenylphosphine (179 mg, 0.628 mmol), 1-(2-hydroxyethyl)pyrrolidine (75 mg, 0.65 mmol) followed by diisopropyl azodicarboxylate (134 μl, 0.68 mmol) in portions. After stirring overnight at ambient temperature the mixture was poured onto a column of silica and eluted with ethyl acetate/methylene chloride (1/1) followed by ethyl acetate/methylene chloride/methanol (4/5/1) followed by methylene chloride/methanol (9/1). After removal of the solvent, the solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (51 mg, 37%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][CH3:20].[CH2:21]([C:23]([CH2:28][CH2:29][CH2:30][CH3:31])(CO)[CH2:24][OH:25])[CH3:22].[OH-].[K+]>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][CH2:20][C:23]([CH2:21][CH3:22])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][OH:25]
Reactant: CCCCC(CC)(CO)CO
Reactant: COc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O
Agent: [K+]
Agent: [OH-]
Product: CCCCC(CC)(CO)COc1cc(O)c2c(c1N)C(=O)c1ccccc1C2=O

Procedure:
15 parts of 1-amino-2-methoxy-4-hydroxyanthraquinone, 50 parts of 2-ethyl-2-butyl-1,3-propanediol, 2.5 parts of a polyethylene oxide of average moleclar weight 200 and 1.5 parts of potassium hydroxide are heated for 3.5 hours at 160°C under nitrogen. After working up, 13.5 parts of 1-amino-2-(2'-ethyl-2'-butyl-3'-hydroxypropanoxy)-4-hydroxyanthraquinone are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH3:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C:28](=[O:34])[C:29](OCC)=[O:30])[CH3:26].CC([O-])(C)C.[K+].C(O)C.Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH2:24][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:34])=[O:30])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 18.5 h

Procedure:
A solution of 4-(3-methyl-4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (example 43, step 1, 41.9 g, 1.0 eq.) and diethyloxalate (18.77 mL, 1.1 eq.) in tetrahydrofuran (241.7 mL) was dropped into a cold (0-5° C.) solution of potassium tert-butylate (28.54 g, 2.0 eq.) and ethanol (43.64 mL, 6.0 eq.) in tetrahydrofuran (1.022 L). The mixture was stirred for 3 h at 0-5° C. and for 18.5 h at room temperature, poured into 1M hydrochloric acid solution. The aqueous phase was extracted 3 times with tert-butylmethylether and the combined organic phases were washed with brine, dried over sodium sulfate, filtered, evaporated to dryness in vacuo and crystallized from ethanol to yield 44.09 g (81%) as white crystals. MS (m/e): 436.2 (M, 5%).
Reaction SMILES: Cl[CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].C(=O)(O)[O-:15].[Na+]>O1CCCC1>[OH:15][CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13]
Reactant: O=C([O-])O
Reactant: O=C1C(Cl)SCN1c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C(O)SCN1c1ccccc1

Procedure:
By a procedure similar to that described in Preparative Example 2, Step 3 above, but using 5-chloro-3-phenyl-4-thiazolidinone (prepared as in Step 2 above), tetrahydrofuran (10 ml) and saturated aqueous sodium bicarbonate (15 ml), the title compound was obtained as an oily solid, yield 0.24 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([OH:24])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][O:30][C:29]4=[O:33])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1OCCN1CCO
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(O)c3)cnc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(OCCN4CCOC4=O)c3)cnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(5-Hydroxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.305 mmol) is dissolved in 2 mL DMF and added to 3-(2-hydroxy-ethyl)-oxazolidin-2-one (48 mg, 0.37 mmol). Triphenylphosphine (192 mg, 0.733 mmol) in 1 mL DMF is added followed by di-t-butyl azodicarboxylate (168 mg, 0.733 mmol) in 1 mL DMF. The solution is shaken at room temperature for 16 hrs. The reaction mixture is evaporated to dryness to afford the crude product. Purification by HPLC chromatography affords 6-{5-[2-(2-oxo-oxazolidin-3-yl)-ethoxy]-pyridin-3-yl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([O-:18])(=O)=[O:16])[CH:7]=[CH:6]2.[Na+].S(Cl)([Cl:22])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([S:15]([Cl:22])(=[O:18])=[O:16])[CH:7]=[CH:6]2
Reactant: COc1cc2ccc(S(=O)(=O)[O-])cc2cc1OC
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 50 g of finely divided sodium 6,7-dimethoxy-2-naphthalenesulfonate in 100 ml of dimethylformamide was added dropwise 62.2 ml of thionyl chloride at room temperature. After 30 minutes, the reaction mixture was poured into 1 l of ice water, and the precipitate filtered and then dissolved into 250 ml of benzene. The benzene solution was repeatedly washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness in vacuo, and the residue was recrystallized from benzene-n-hexane (1 : 1) to give 32 g of 6,7-dimethoxy-2-naphthalenesulfonyl chloride, M.P. 127.5° - 129.5° C
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[OH:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2occc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1cccc2c1CCO2
Yield: 101 %

Procedure:
At ambient temperature a rapidly stirred solution of 4-hydroxybenzofuran (2.0 g) (prepared by the method of G. Keen & P. Maddocks Syn. Comm., 16(13), 1635-1640 (1986)) in glacial acetic acid (30 ml) containing 30% palladium on carbon (0.2 g) was exposed to an atmosphere of hydrogen. When uptake of hydrogen had ceased the solution was filtered and the filter cake washed with glacial acetic acid. The combined filtrates were evaporated to dryness to give of 4-hydroxy-dihyrobenzofuran (2.05 g) 1H NMR (DMSO-d6, 300 MHz, ppm): 3.0(2H,t), 4.5(2H,t), 6.2(1H.d), 6.3(1H,d), 6.8(1H,t), 9.5(1H,b) m/Z 135 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br-]>CN(C=O)C.C(OCC)(=O)C>[CH2:8]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(OCc3ccccc3)c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 5,6-dihydro-4-(3-hydroxyphenyl)pyridine-1(2H)-carboxylate (crude, 100 mg) and potassium carbonate (300 mg) in DMF was added bnezyl bromide (60 μL) at room temperature. The resulting mixture was stirred at 80° C. for 16 h. The mixture was cooled down, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The product (60 mg) was purified by combiflash using hexane/ethyl acetate (max. EtOAc 10%) to afford tert-butyl 4-(3-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate which was then converted to the final compound using procedures analogous to those for example 1. MS(ESI): (M+H)+=462.2
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15][C:16]([CH3:18])=[O:17].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:8])[CH2:15][C:16](=[O:17])[CH3:18])=[CH:11][CH:12]=1
Reactant: CC(C)=O
Reactant: CCOC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
A mixture containing 45 g of ethyl 4-chlorobenzoate in 235 ml of anhydrous THF and 19.50 g of NaH (60% in mineral oil) in 235 ml of anhydrous TBF is placed under nitrogen. 36 ml of acetone and 750 ml of additional anhydrous THF are added dropwise at 0° C., and it is heated under reflux for 3 hours. The mixture is acidified to pH=5 by addition of 2N HCl then it is extracted with ether and washed with water and then with saturated NaHCO3 solution; it is dried over MgSO4 and concentrated. The raw product is dissolved in a minimum of toluene, the insoluble matter is filtered then it is purified by chromatography on silica, eluting with cyclohexane/AcOEt mixture (95/5; v/v). 47.9 g of the expected compound is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[I:22]I>C1COCC1>[I:22][C:11]1[O:10][C:9]([CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][CH:12]=1
Reactant: C(=Cc1ccco1)c1cccnc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Ic1ccc(C=Cc2cccnc2)o1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a stirred -78° C. solution of 2-[2-{3-pyridyl}ethenyl]furan (0.95 g, 5.5 mmol), prepared as in step 4, in THF (25 mL) was added lithium diisopropylamide (4 mL, 6 mmol, 1.5M in hexanes). The cold reaction mixture was stirred 1 hour, followed by the addition of a THF (3 mL) solution of iodine (1.39 g, 5.5 mmol). The ice bath was removed and the reaction mixture allowed to stir at ambient temperature overnight. Saturated NH4Cl was added and the mixture diluted with ether. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel eluting with 40% ethyl acetate-hexanes to afford 1.1 g of 2-iodo-5-[2-{3-pyridyl}ethenyl]furan.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:40]4[CH2:39][CH2:38][C:37]5[C:42](=[CH:43][CH:44]=[CH:45][C:36]=5[Cl:35])[CH2:41]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc2c1CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(Cl)cccc5C4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (245 mg, 0.517 mmol), 5-chloro-1,2,3,4-tetrahydroisoquinoline (175 mg, 1.03 mmol), cupric acetate (94.8 mg, 0.517 mmol), pyridine (84 μL, 1.0 mmol), 4 Å molecular sieves (139 mg, 264 mg/mmol SM), and DCM (9 mL, 100 mmol) was stirred at rt under an atmosphere of air for 3 d. The mixture was diluted with DCM (50 ml), washed with EDTA solution (2%, 3×50 ml), water (3×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark black oil that was purified by MDPS to give the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ=1.48 (s, 9H), 1.88-1.99 (m, 2H), 2.12-2.19 (m, 2H), 2.84-2.98 (m, 2H), 3.04 (t, J=6.0 Hz, 2H), 3.36 (t, J=6.0 Hz, 2H), 4.16 (s, 2H), 4.22-4.36 (m, 3H), 7.02 (d, J=7.6 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.62 (s, 1H), 7.66 (s, 1H), 7.69 (s, 1H). MS(ES+): m/z=508.77/511.16 (52/20) [MH+]. HPLC: tR=3.00 min (ZQ2, polar—5 min).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[C:5]1([N:11]=[C:12]=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([NH:11][C:12]([NH:4][CH2:1][C:2]#[CH:3])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#CCN
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: C#CCNC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
25 g (0.45 mol) of propargylamine dissolved in 80 ml of toluene are added dropwise to a suspension of 50 ml (0.45 mol) of phenyl isocyanate in 160 ml of toluene. The mixture is stirred for 1 h 30 min, the precipitate is filtered, washed with a small amount of toluene and then dried in a vacuum oven at 40° C. 70.7 g of product are obtained. (m.p.=133° C.).
Reaction SMILES: [CH2:1]([C@@H:5]([C:22](=[O:29])[NH:23][CH2:24][C:25]([O:27]C)=[O:26])[NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:2]([CH3:4])[CH3:3].O[Li].O>C1COCC1.O>[CH2:1]([C@@H:5]([C:22](=[O:29])[NH:23][CH2:24][C:25]([OH:27])=[O:26])[NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CCCCCNC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)CCCCCNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 3 h

Procedure:
To a solution of (S)-methyl 13-isobutyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oate (6w) in THF was added a solution of LiOH.H2O in water at room temperature. After 3 h, the reaction mixture was concentrated, diluted with water and acidified with a 1N aqueous solution of HCl to about pH 4-5. The mixture was stirred for 15 min and the white precipitate formed was filtered off, rinsed with water, and dried to afford (S)-13-isobutyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oic acid (7w).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([F:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccc(F)cc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
Pyridine (500 μL, 6.19 mmol) was added to a solution of 4-fluoro-3-nitro-phenylamine (1 g, 6.41 mmol) and 4-fluoro-benzenesulfonyl chloride (1.2 g, 6.19 mmol) in DCM (20 mL) and the reaction was stirred at room temperature overnight. The reaction was then partitioned between water and DCM. The organic layer was washed several times with water and concentrated. Recrystalization from ethanol/water gave 1.57 g of the sub-title compound as tan crystals.
Reaction SMILES: [N:1]([CH2:4][C:5]12[CH2:12][CH2:11][C:8]([CH3:13])([CH2:9][CH2:10]1)[C:7](=[O:14])[O:6]2)=[N+]=[N-].[H][H]>C(O)C.[Pt](=O)=O>[NH2:1][CH2:4][C:5]12[CH2:12][CH2:11][C:8]([CH3:13])([CH2:9][CH2:10]1)[C:7](=[O:14])[O:6]2
Reactant: [H][H]
Reactant: CC12CCC(CN=[N+]=[N-])(CC1)OC2=O
Agent: O=[Pt]=O
Solvent: CCO
Product: CC12CCC(CN)(CC1)OC2=O
Yield: 84.6 %

Procedure:
0.025 g of platinum dioxide was added to a solution of 0.6 g of 1-azidomethyl-4-methyl-2-oxabicyclo[2.2.2]octan-3-one (Example 29) in 30 ml of ethanol. The resultant solution was reacted for 14 hours under 3.5 atom hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate. As a result, 0.44 g of 1-aminomethyl-4-methyl-2-oxabicyclo[2.2.2]-octan-3-one was obtained as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:3]=1.[H-].[Na+].[CH2:13]([N:23]=[C:24]=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>CN(C)C=O>[CH2:13]([NH:23][C:24]([NH:10][S:7]([C:4]1[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=1)(=[O:9])=[O:8])=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH:10][S:7]([C:4]1[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=1)(=[O:9])=[O:8])=[O:22]
Reactant: O=C=NCCCCCCCN=C=O
Reactant: Cc1cc(S(N)(=O)=O)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)NC(=O)NCCCCCCCNC(=O)NS(=O)(=O)c2csc(C)c2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of 0.35 g 5-methyl-thiophene-3-sulfonic acid amide (example 46a) in 10 ml dimethylformamide was added 0.080 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 30 min. To the resulting solution was added dropwise 0.180 g heptamethylene diisocyanate (CAS18020-78-5) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The phases were separated and the aqueous phase was washed with ethyl acetate and purified by chromatography on 100 ml MCl gel with a gradient (water 0-50% acetonitrile) The product fractions were collected and the product was precipitated by adjusting the pH to 2.00 by addition of 1N hydrochloric acid. The solid was collected by filtration and washed with water and dried to constant weight to yield 0.24 g of the title compound as white powder. MS (ISN) M−H+=536.0
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:42])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:38](=[O:41])[NH:39][CH3:40])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][NH:39][C:38]([N:25]1[CH2:26][CH:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)[CH:21]2[N:20]([C:18](=[O:19])[CH:13]([NH:12][C:11](=[O:42])[CH:9]([NH:7][CH3:6])[CH3:10])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:24][CH2:23][CH:22]12)=[O:41]
Reactant: CNC(=O)N1CC(COc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CC(COc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)NC)C(C)(C)C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
A solution of carbamate 90 (175 mg, 0.29 mmol) in DCM (10 mL) was treated with TFA (4 mL) at 0° C. After 1.5 h, the reaction mixture was concentrated, diluted with EtOAc, washed successively with saturated aqueous NaHCO3, and brine dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (2″ Dynamax® C18; 10% ACN/water to 70% ACN/water containing 0.1% HOAc, 30 min; Flow: 40 mL/min). The product-containing fractions were combined, frozen, and lyophilized to afford 91 (80 mg, 55%) as a white flocculent solid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=[O:16].[Na+]>S(=O)(=O)(O)O.O>[OH:16][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C2CCC(=O)CC2)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1CCC(c2ccc(O)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
200 ml of 4N sulfuric acid were heated to 80° C. in a sulfonation flask and then treated with about 5% of a solution of 37.9 g of 4-(4-aminophenyl)cyclohexanone in 200 ml of 4N sulfuric acid. Subsequently, the remaining solution of 4-(4-aminophenyl)cyclohexanone as well as a solution of 15.2 g of sodium nitrite in 45 ml of water were simultaneously added dropwise to the reaction mixture at 80° C. within 1.5 hours. Thereafter, the mixture was treated dropwise at 80° C. within 30 minutes with a solution of 9 g of sodium nitrite in 27 ml of water and stirred at 80° C. for a further 1 hour. After cooling the reaction mixture to 0° C. the separated crystals were removed by filtration under suction, washed with 200 ml of cold water and dried up to constant weight at 60° C. in a drying oven under a water-jet vacuum. The crystalline crude product (34.6 g) was suspended in 520 ml of ethyl acetate. The suspension was heated to reflux for 1 hour, then treated with 1.7 g of active carbon and then heated to reflux for a further 1 hour. The mixture was subsequently suction filtered (rinsing with 40 ml of warm ethyl acetate) and the filtrate was evaporated under a water-jet vacuum at a bath temperature of 40° C. Drying of the evaporation residue up to constant weight at 60° C. in a drying oven under a water-jet vacuum gave 32.2 g of 4-(4-hydroxyphenyl)cyclohexanone as yellow-brown crystals with m.p. 165°-166° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.O.NN>C1COCC1>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2nnnn2C)c1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: CSc1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a stirred solution of 2-(6-{[({[3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione (2.79 g, 5.75 mmol) in dry THF (70 mL) was added hydrazine hydrate (1.44 g, 28.7 mmol). The reaction mixture was stirred at room temperature for 4 h, then insolubles were removed by filtration and washed with dichloromethane. The filtrates were combined and concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with water (50 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo to afford 6-{[({[3-(methylsulfanyl)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine as a white solid [1.63 g, yield 77%; HPLC/MS: m/z=356 (M+H); logP(HCOOH)=1.42].