Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:21])(C)C)=[O:16])[CH:8]([CH2:9][O:10][CH2:11]2)[C:7]1=[O:22])[CH3:2].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].C(N(CC)C(C)C)(C)C.ClC(OC[C:51]1[CH:56]=[CH:55]C=[CH:53][CH:52]=1)=O>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][CH2:18][C:21]3[CH:55]=[CH:56][CH:51]=[CH:52][CH:53]=3)=[O:16])[CH:8]([CH2:9][O:10][CH2:11]2)[C:7]1=[O:22])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CC1CC2COCC(C1=O)N2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1CC2COCC(C1=O)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Step II and III: a mixture of tert-butyl 7-(2-ethoxy-2-oxo-ethyl)-6-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 125b (654 mg, 2.0 mmol), trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated. The residue was dissolved in dimethylformamide (5.0 mL), followed by adding potassium carbonate (700 mg, 5.0 mmol) and N,N-diisopropylethylamine (0.3 mL). The result mixture was warmed to 40° C., then added dropwise benzyl chloroformate (311 μL, 2.2 mmol) in dimethylformamide (1.0 mL). The resulting mixture was stirred for another two hours. The reaction was quenched by adding ice-water, extracted with PE: EA=5:1 (30 mL) three times. The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel column to give benzyl 7-(2-ethoxy-2-oxo-ethyl)-6-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 125d (650 mg, yield: 90%).
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[S:12](=[O:17])(=[O:16])[CH2:11][CH2:10][CH2:9]2.C([Li])CCC.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:23]([CH:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH:2]=[O:3])[CH:7]=2)[S:12]1(=[O:16])=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=S1(=O)CCCc2cc(C3OCCO3)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCC(Cc1ccccc1)S2(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 254 mg (1.0 mmole) 6-(1,3-dioxolan-2-yl)-1,1-dioxothiachroman in 10 ml tetrahydrofuran was cooled to 0° C. and 1.15 mmole of 2.3M n-butyllithium was added dropwise. The resulting red solution was stirred for 30 minutes at 0° C., 137 microliters (1.15 mmole) benzyl bromide was added and stirring continued at 0° C. for one hour, then at room temperature for two hours. The reaction was quenched by addition of citric acid. The mixture was taken up in ethyl ether, washed with brine, dried (MgSO4) and the solvents evaporated. The residue was taken up in 15 ml tetrahydrofuran, 10 ml 3.5% aqueous perchloric acid added and the mixture stirred overnight. Extraction with ethyl ether, washing with brine, drying (MgSO4) and evaporation of solvent gave the title compound as an oil, Rf 0.6 on silica gel TLC (9:1 methylene chloride/ethyl ether).
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:32][CH3:33])=[C:25]([C:27]4OC=CC=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(NC2C3C(=CC=CC=3)C(CC3C=NC(OC)=C(Br)C=3)=NN=2)=CC=1)(C)(C)C.C([Sn](CCCC)(CCCC)C1[S:73][CH:74]=[CH:75][N:76]=1)CCC>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:32][CH3:33])=[C:25]([C:27]4[S:73][CH:74]=[CH:75][N:76]=4)[CH:26]=3)=[N:12][N:11]=2)=[CH:34][CH:35]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1-c1ccco1
Agent: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1Br
Product: COc1ncc(Cc2nnc(Nc3ccc(C(C)(C)C)cc3)c3ccccc23)cc1-c1nccs1

Procedure:
Can be obtained analogously to Ex. 18a from 1-(4-tert-butyl-anilino)-4-[5-bromo-6-methoxy-(pyridin-3-yl)-methyl]phthalazine and 2-tributylstannyl-thiazol (supplier: Frontier Scientific; Logan/USA). MS: (M+H)+=482; HPLC(Grad20-100) tRet=14.6.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].C(N(CC)CC)C>ClCCl>[CH:31]([O:30][C:28]([N:23]1[CH2:24][CH2:25][CH:20]([C@@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:29])([CH3:33])[CH3:32]
Reactant: CC(C)OC(=O)Cl
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC([C@]2(C)Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine by treatment with isopropyl chloroformate in the presence of triethylamine using dichloromethane as a solvent. LC (method 6): tR=1.33 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:68])[C@H:10]([CH2:62][CH:63]1[CH2:67][CH2:66][CH2:65][CH2:64]1)[NH:11]C(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC1C=CC=CC=1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:68])[C@H:10]([CH2:62][CH:63]1[CH2:64][CH2:65][CH2:66][CH2:67]1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 520 mg (0.56 mmol) of N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester in 3 ml of piperidine and 12 ml of dichloromethane was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly ethyl acetate/petrol (1:1) and then methanol/dichloromethane (1:9) for the elution. The resulting amine was added to a solution of 207 mg (0.504 mmol) of N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-α-aspartic acid, 78 mg (0.51 mmol) of 1-hydroxybenzotriazole and 134 mg (0.7 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of dichloromethane and stirred at room temperature for 18 hours. The solutionwas then extracted with 2M hydrochloric acid and saturated sodium bicarbonate solution and dried over anhydrous magnesium sulphate. Evaporation, trituration with diethyl ether and filtration gave 440 mg of N-[N-[N-[N-O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester as a white solid; MS: m/e 1101 [M+H].
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.CN(C)CCN(C)C.CN([CH:31]=[O:32])C>CCCCCC.CCOCC>[CH3:19][O:18][C:17]1[C:8]([O:7][CH3:6])=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: COc1cc2ccccc2cc1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc2ccccc2c(C=O)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
n-Butyl lithium in hexane (1.6 N, 31.3 ml) was gradually added to a solution of 2,3-dimethoxynaphthalene (9.4 g) and N,N,N′,N′-tetramethylethylenediamine (7.4 ml) in ether (150 ml) under argon at 0° C. The reaction mixture was stirred at room temperature for two hours, cooled to 0° C. and DMF (7.3 g) in ether (20 ml) added. The reaction mixture was stirred at room temperature overnight and poured in ice water. The product was extracted with ether, washed with water, dried, evaporated and recrystallized from ether. Yield: 4.2 g.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.[C:17]([CH2:19][C:20]([OH:22])=O)#[N:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:1])[C:20](=[O:22])[CH2:19][C:17]#[N:18])[CH2:4]2)=[N:13][CH:12]=1
Reactant: N#CCC(=O)O
Reactant: CN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)CC#N)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.9 %

Procedure:
To a solution of (R)—N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (75 mg, 0.345 mmol) and 2-cyanoacetic acid (35 mg, 0.414 mmol) in THF (5 mL) were added HATU (157 mg, 0.414 mmol) and DIPEA (0.12 mL, 0.69 mmol). The reaction mixture was stirred at room temperature for 20 hours. The precipitate was filtered, washed with EtOAc, and dried under reduced pressure to give the title compound (45 mg, 46%). MS (m/z): 285 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5]
Reactant: CCCCCCCCCCCCCC(O)CC(=O)O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-hydroxyhexadecanoic acid (1.90 g) and triethylamine (0.97 ml) in DMF (20 ml) was added benzyl bromide (0.83 ml) and the mixture was stirred at room temperature for 3 days. After the solvent was removed in vacuo, ethyl acetate and water were added to the residue. The separated ethyl acetate layer was washed twice with water and then dried over anhydrous sodium sulfate. After concentration, the residue was purified by a silica gel column chromatography (silica gel 15 g, chloroform: methanol=100:0-8) to afford 1.22 g of benzyl 3-hydroxyhexadecanoate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=2)=[CH:16][CH:15]=1.O>CN(C=O)C>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(-c2ccc(Cn3ccc4ccccc43)cc2)no1
Reaction time: 0.33 h
Yield: 17.7 %

Procedure:
To a mixture of indole (13 mg, 0.11 mmol) in DMF (1 mL) was added NaH (60% dispersion; 5 mg, 0.125 mmol). The mixture was stirred for 20 min and then a solution of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. H2O was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed three times with H2O/brine, dried (Na2SO4), evaporated, and purified by chromatography (10-25% acetone/CH2Cl2) to give 3-(4-indol-1-ylmethyl-phenyl)-isoxazole-5-carboxylic acid amide (6 mg, 18%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.34 (br. s., 1H), 7.97 (br. s., 1H), 7.82 (d, J=8.2 Hz, 2H), 7.48-7.61 (m, 3H), 7.43 (d, J=7.8 Hz, 1H), 7.30 (d, J=8.2 Hz, 2H), 6.94-7.14 (m, 2H), 6.49 (d, J=3.0 Hz, 1H), 5.49 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([CH:19]1[CH2:23][O:22]C(C)(C)[O:20]1)[CH2:3][NH:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[C:7]=1[OH:17].O>CO>[OH:1][CH:2]([CH:19]([OH:20])[CH2:23][OH:22])[CH2:3][NH:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([C:13]([F:15])([F:16])[F:14])[C:7]=1[OH:17]
Reactant: CC1(C)OCC(C(O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2O)O1
Solvent: CO
Solvent: O
Product: O=C(NCC(O)C(O)CO)c1cc(F)cc(C(F)(F)F)c1O

Procedure:
6.86 g (15 mmol) of 5-fluoro-2-hydroxy-3-(trifluoromethyl)-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in 30 ml of methanol, 30 ml of water and 300 mg of cation exchanger Amberlyst 15 are added and refluxed for 2 hours. The ion exchanger is then filtered off, 250 mg of palladium-carbon (10%) is added to the filtrate and hydrogenated for 1 hour at normal pressure. The catalyst is then filtered off, the filtrate is evaporated to dryness in a vacuum and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane/methanol. 3.08 mg (9.41 mmol)=62.7% of the theoretical yield of the compound is obtained as an amorphous solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19](O)[CH2:20][CH3:21].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:19](/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Br:12])=[CH:20]\[CH3:21]
Reactant: CCC(O)c1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C/C=C/c1ccccc1Br
Yield: 803.4 %

Procedure:
p-Toluenesulfonic acid (30 mg) was added to a solution (50 mL) of 1-(2-bromophenyl)-1-propanol (5.55 g, 3.0 mmol) in toluene, followed by reflux for 5 hours. Next, the reaction solution was added to a saturated aqueous solution of sodium bicarbonate under ice-cooling to neutralize the reaction solution, and the mixture was then extracted with diethyl ether. After the extract was washed with a saturated brine and then dried over sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developed with diethyl ether/hexane=1/10) to give 2-((E)-1-propenyl)bromobenzene (4.75 g, yield 100%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH:23]([C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])#[N:22].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:21]([CH:23]([C:35]1[CH:36]=[CH:37][C:38]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:39][CH:40]=1)[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])#[N:22]
Reactant: CON=C(COc1ccc(CO)cc1)c1ccccc1
Reactant: N#CC(CC(=O)OCc1ccccc1)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)OCc3ccccc3)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged Toluene (20 mL). To the stirred solvent was added 2-(4-Hydroxymethyl-phenoxy)-1-phenyl-ethanone O-methyl-oxime (0.039 g, 0.14 mmol) and benzyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.04 g, 0.14 mmol) at 0° C. for 5 min. Then added tributylphosphine (0.043 g, 0.2 mmol) stirred at 0° C. for 15 min, was added 1,1′aza(dicarbonyl)dipiperidine (0.054 g, 0.2 mmol), this resulting mass stirred at RT for 16 h. The solvent removed, the residue was extracted with ethyl acetate. The organic layer washed with water and brine solution and dried by anhydrous sodium sulphate to and evaporated, purified by 100-200 silica column using pet-ether and ethylacetate. The product obtained as a colourless oily liquid (0.06 g, 79.00%)
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>>[CH2:1]([C:8]1[O:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][S:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=2)(=[O:32])=[O:31])=[C:17]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Product: Cc1oc(Cc2ccccc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 55 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.509 g, 1.36 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.645 g, 2.72 mmol). Purification on 2% H3PO4 /MeOH treated silica gel, eluting with 20% EtOAc/hexane gave 0.430 g (55%) of the title compound a pale yellow solid, mp 80-85° C. 1H NMR (DMSO-d6) δ 1.23-1.34 (m, 2 H), 1.45-1.59 (m, 2 H), 1.61-1.74 (m, 4 H), 1.76 (s, 3 H), 2.16 (s, 3 H), 2.95 (quintet, 1 H), 3.78 (s, 2 H), 6.98 (d, 2 H), 7.13-7.25 (m, 4 H), 7.36-7.38 (m, 2 H), 7.44-7.57 (m, 2 H), 7.97 (d, 1 H). IR (KBr) 3400, 2950, 1690, 1580, 1480 and 1190 cm-1. mass spectrum (-ESI) m/z 573 (M-H). Anal. Calcd. for C32H30O8S.0.2H2O: C, 66.88; H, 5.26; N, 0.00. Found: C, 66.53; H, 5.40; N, 0.07.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1F
Reaction time: 48 h

Procedure:
A solution of 2-fluoro-5-nitro-benzoic acid (3.702 g, 20 mmol) in anhydrous methanol (10.00 mL) was treated with 98% sulphuric acid and the solution was heated to reflux for 4 hours. The solvent was removed under vacuum and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with saturated aqueous sodium bicarbonate (3×10 mL), brine until neutrality ant then water, and dried over anhydrous sodium sulphate. The solvent was removed under vacuum to afford a thick oil that started to crystallize, After adding n-hexane (3 mL) the crude was stored for 2 days in the fridge. The crystalline compound was filtered and washed with n-hexane to yield 3.147 g of the pure compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH2:7][C:8]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=O.CSC>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH2:7][CH2:8][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(OC(=O)CNc2nccs2)cc1
Solvent: Cc1ccccc1
Solvent: CSC
Product: COC(=O)c1ccc(OCCNc2nccs2)cc1
Reaction time: 0.25 h

Procedure:
Amide 24-3 (1.0 g, 3.4 mmol) was dissolved in 7 mL toluene at 0°, and BH3.DMS (341 μL, 3.6 mmol) was added. After 15 min, the reaction was heated to reflux for 16 h, cooled to 0°, and quenched with 10% Na2CO3. The mixture was extracted with EtOAc, the organic phase was washed with water and brine, dried (MgSO4), concentrated, and purified by flash chromatography (silica, 70% EtOAc/hexane) providing 24-4 as a white solid. Rf 0.64 (silica, EtOAc).
Reaction SMILES: C(O)(=O)C(O)=O.C([N:14]1[CH2:20][CH:19]2[O:21][CH:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=32)[CH2:15]1)C1C=CC=CC=1.[OH-].[Na+]>CO.[Pd]>[N:14]1[C:15]2[CH:16]=[CH:17][CH:25]=[CH:24][C:23]=2[CH:22]=[CH:18][CH:19]2[O:21][C:20]=12
Reactant: c1ccc(CN2CC3OC(C2)c2ccccc23)cc1
Agent: [Pd]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: C1=CC2OC2=Nc2ccccc21
Yield: 69.4 %

Procedure:
A solution of the compound prepared in Example 18 (6.1 g, 0.018M) in methanol (300 ml) was hydrogenated (0.61 g, 10% Pd-C) in a Parr apparatus at an initial pressure of 30 psi for 3.5 hours. The resulting solution of the product in methanol was made basic with aqueous NaOH, filtered through Celite and evaporated. The residue was partitioned between H2O and CH2Cl2 ; the organic layer was dried (Na2SO4) to give 3-H-epoxybenzazepin (1.95 g, 68% yield). This compound was treated with acetic anhydride (6 ml) and allowed to stir for two hours. Excess acetic anhydride was removed in vacuo to give 3-acetylepoxybenzazepin as a white solid (2.2 g), mp 126°-128° C. NMR (CDCl3) δ 1.80 ppm (s, 3H, --CH3), 3.10-4.45 (m, 4H, --CH2 --N--CH2), 5.20 [m, 2H, (2x), ArCHO], 7.30 (s, 4H, aromatic H). MS: 203 (M+).
Reaction SMILES: C(=O)([O:7][CH2:8][C:9]([C:12]1[CH:16]=[C:15]([N:17]2[CH2:21][C@@:20]3([CH2:26][CH2:25][CH2:24][C@@:23]([CH2:28][N:29]4[C:33]5[CH:34]=[C:35]([C:38]#[N:39])[CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)([CH3:27])[CH2:22]3)[O:19][C:18]2=[O:40])[O:14][N:13]=1)([CH3:11])[CH3:10])OC(C)(C)C.C([O-])([O-])=O.[K+].[K+].O.CO>CC#N.O>[OH:7][CH2:8][C:9]([C:12]1[CH:16]=[C:15]([N:17]2[CH2:21][C@@:20]3([CH2:26][CH2:25][CH2:24][C@@:23]([CH2:28][N:29]4[C:33]5[CH:34]=[C:35]([C:38]#[N:39])[CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)([CH3:27])[CH2:22]3)[O:19][C:18]2=[O:40])[O:14][N:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)OCC(C)(C)c1cc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CC(C)(CO)c1cc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)on1
Temperature: 110 °C
Yield: 25.2 %

Procedure:
To a 2 mL microwave vial was added tert-butyl (2-(5-((5S,7S)-7-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)isoxazol-3-yl)-2-methylpropyl) carbonate (30 mg, 0.053 mmol), K2CO3 (5.15 μg, 0.037 μmol), water (0.500 mL) and MeOH (0.5 mL). The vial was capped and heated to 110° C. for 3 h. The mixture was then filtered through paper, and the paper washed with MeOH (2 mL), then concentrated. This mixture was purified on reverse phase Gilson HPLC: 30 mm×150 mm Waters Sunfire column, neutral conditions 10-100% MeCN/H2O, 14 min, 40 mL/min to give 1-(((5S,7S)-3-(3-(1-hydroxy-2-methylpropan-2-yl)isoxazol-5-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (6.2 mg, 24% yield). MS (m/z) 464.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:25])[NH:15][C:16]1[N:17]=[C:18]2[N:22]([CH:23]=1)[CH:21]=[C:20](Br)[S:19]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14](=[O:25])[NH:15][C:16]1[N:17]=[C:18]2[N:22]([CH:23]=1)[CH:21]=[C:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:19]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1
Reactant: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)Nc1cn2cc(-c3ccccc3)sc2n1

Procedure:
Compound 15 was synthesized from compound 14 (0.155 mmol) and phenylboronic acid (0.492 mmol), following the procedure as described for compound A1 to give compound 15 as a yellow gum in 38% yield. MS (ESI, EI+) m/z=429 (MH+).