Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[CH:6]=[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[O:8]2.C(OC([N:37](C(OC(C)(C)C)=O)[CH2:38][C:39](O)=[O:40])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:64]>ClCCl.C(OCC)(=O)C>[ClH:64].[CH2:19]([CH:16]([O:15][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:29])[CH:6]=[C:7]([S:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:39](=[O:40])[CH2:38][NH2:37])=[CH:24][CH:23]=3)[O:8]2)=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[CH2:17][CH3:18])[CH3:20]
Reactant: CCC(CC)Oc1cc2oc(Sc3ccc(O)cc3)cc(=O)c2c(OC)c1OC
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(CC)Oc1cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c2c(OC)c1OC
Reaction time: 3 h

Procedure:
300 ml in dichloromethane of 5.66 g of 5,6-dimethoxy-7-(1-ethylpropoxy)-2-(4-hydroxyphenylthio)chromone obtained in Example 25, 2.62 g of N-t-butoxycarbonyl(Boc)glycine, and 3.08 g of 1,3-dicyclohexylcarbodiimide (DCC) was stirred over 5.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that N-t-butoxycarbonyl(Boc)glycine ester was obtained. This product was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 3 hours. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and dried, whereby 6.44 g of 7-(1-ethylpropoxy)-5,6-dimethoxy-2-(4-glycyloxyphenylthio)chromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[CH:9]=2)[NH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1.O>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=3[F:17])[CH:9]=2)[N:4]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][O:30]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: Fc1cccc(F)c1-c1ccc2[nH]nc(Br)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 3-bromo-5-(2,6-difluoro-phenyl)-1H-indazole (30.0 g, 97.05 mmol) and p-toluene sulfonic acid (3.7 g, 19.4 mmol) in THF (776 ml) was added 3,4-dihydro-2H-pyran (18.2 ml, 194.1 mmol) at RT. The mixture was stirred at 70° C. for 8 h. The reaction mixture was cooled to RT. Water was added to the reaction mixture and extracted with EtOAc (2×200 ml). The organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The crude product was purified by column using (100-200 mesh) silica with 0-5% EtOAc in hexane to provide 3-bromo-5-(2,6-difluoro-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-indazole (18.5 g, 48.4% yield). MS (ESI, pos. ion) m/z: 393.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]([I:14])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]([I:14])[C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:7]=2[CH:6]=1)=[O:4].[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]([I:14])[C:8]2[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(I)c2nc[nH]c2c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c2c(c1)ncn2CC(C)C
Product: COC(=O)c1cc(I)c2ncn(CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %
Yield: 11 %

Procedure:
To a solution of 7-iodo-3H-benzoimidazole-5-carboxylic acid methyl ester (783 mg, 2.59 mmol) in DMF (50 mL) was added Cs2CO3 (1.69 g, 5.18 mmol), followed by isobutyl bromide ((0.338 mL, 3.11 mmol). The reaction mixture was stirred room temperature overnight, then partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography gave 805 mg (87%) of 7-iodo-3-isobutyl-3H-benzoimidazole-5-carboxylic acid methyl ester (the regioisomer 7-iodo-1-isobutyl-1H-benzoimidazole-5-carboxylic acid methyl ester (100 mg, 11%) was recovered as separate fraction).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([N:34]([CH3:36])[CH3:35])=C(C#N)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+].[CH3:41][C:42]([OH:44])=[O:43].CS(C)=O>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:28][CH2:29][C@H:30]([CH3:33])[CH2:31][CH2:32]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[C:11]([N:34]([CH3:35])[CH3:36])=[C:41]([C:42]([OH:44])=[O:43])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CN(C)c1c(C#N)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: CN(C)c1c(C(=O)O)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Temperature: 70 °C

Procedure:
To a suspension of 4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (31.8 mg, 0.06 mmol) in EtOH (1 mL) was added NaOH (0.2 mL of a 5M aq. solution, 1 mmol). The reaction was heated at 70° C. for 60 hours and then cooled to room temperature. HOAc (60 μL, 1 mmol) was added followed by DMSO (1.5 mL). After sonication and filtration to remove solids, the filtrate was purified by mass triggered reverse phase HPLC(C-18) eluting with acetonitrile/water+0.1% TFA to afford 4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (TFA salt). MS ESI calc'd for C29H37ClN6O3 [M+H]+=553. found=553. 1H NMR (600 MHz, DMSO-d6) δ 8.75-8.77 (m, 2H), 8.27 (m, 1H), 3.93 (dd, J=12.0, 1.8 Hz, 1H), 3.75-3.81 (m, 2H), 3.47-3.52 (m, 2H), 3.38 (m, 1H), 3.15 (s, 6H), 3.03 (m, 1H), 2.81 (m, 1H), 2.26 (m, 1H), 1.85 (m, 1H), 1.69 (m, 1H), 1.51-1.63 (m, 2H), 1.31-1.41 (m, 2H), 1.13 (m, 1H), 1.05 (m, 1H), 0.83 (m, 1H), 0.64-0.73 (m, 6H), 0.34-0.46 (m, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])[CH:2]=[CH2:3].[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:3]/[CH:2]=[CH:1]/[N:4]2[C:8](=[O:9])[C:7]3[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]2=[O:14])=[CH:18][CH:17]=1
Reactant: Fc1ccc(I)cc1
Reactant: C=CCN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1/C=C/Cc1ccc(F)cc1
Reaction time: 18 h

Procedure:
N-Allylphthalimide (13.9 g, 74.3 mmol), 1-fluoro-4-iodobenzene (15.0 g, 67.6 mmol) triethylamine (15.0 g, 148 mmol) and Pd(OAc)2 (152 mg) were heated at 104° in a glass bomb with shaking for 18 h under an inert atmosphere. The reaction mixture was dissolved in hot acetonitrile. The catalyst was removed by filtration and the filtrate cooled to 0°. The precipitated white solid product was filtered off and dried under vacuum. This title material (12.55 g) was used without further purification.
Reaction SMILES: [NH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([O:11][CH3:12])[N:4]=1)[NH2:2].CC(O)C.[N:17]#[C:18]Br>C(#N)C>[NH2:17][C:18]1[N:4]2[C:5]([O:11][CH3:12])=[N:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]2=[N:1][N:2]=1
Reactant: COc1ncc(OC)c(NN)n1
Reactant: N#CBr
Solvent: CC(C)O
Solvent: CC#N
Product: COc1cnc(OC)n2c(N)nnc12
Temperature: 42 °C
Yield: 87.3 %

Procedure:
4-Hydrazino-2, 5-dimethoxypyrimidine (8.522 g, 0.050 mole) was loaded into a 500 mL three necked flask equipped with an overhead stirrer, condenser, and thermocouple temperature probe. IPA (100 mL) was added and the mixture was stirred to form a slurry. A solution of cyanogen bromide (8.546 g, 0.081 mole) in acetonitrile (15 mL) was added, resulting in a 3° C. endotherm, followed by a 6° C. exotherm. The mixture wash heated to 42° C. for 3.5 h, then cooled to room temperature. A solution of sodium carbonate (5.92 g) in water (100 mL) was added, and the resulting mixture was stirred for 3.3 h. The product precipitated from the solution an d was recovered by filtration through Whatman #54 paper using a Buchner funnel and aspirator vacuum. The solids w ere dried overnight in vacuo at room temperature to give 8.516 g of 3-amino-5,8-dimethoxy[1,2,4]triazolo[4,3-c]pyrimidine (yield=87.1%): mp=232-235° C. 1H NMR (300 MHz, DMSO-d6) 3.83 (s, 3H), 3.97 (s, 3H), 6.45 (br s, 2H), 6.84 (s, 1H); 13C NMR (75.47 MHz, DMSO-d6) 55.4, 56.4, 115.5, 139.7, 142.0, 142.5, 148.3.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[H-].[Na+].[CH2:10](Br)[C:11]#[CH:12].O>O1CCCC1>[CH:10]([N:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1)=[C:11]=[CH2:12]
Reactant: C#CCBr
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C=Cn1ccc(C=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1 g of pyrrole-3-carboxaldehyde was dissolved in 25 ml of tetrahydrofuran with stirring at the ambient temperature for 15 minutes and after cooling to 0° to 5° C., 528 mg of sodium hydride as 50% in oil were added with stirring for 10 minutes cold. The temperature was allowed to return to the ambient with stirring for 40 minutes under nitrogen and 1 ml of propargyl bromide was added with stirring for a further 2 hours at 40° to 50° C. Then, the reaction mixture was poured into 15 ml of water, and was extracted with methylene chloride. The extracts were dried and concentrated by distilling off the solvent. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (7-3) to obtain 1.166 g of 1-propadienyl-1H-pyrrole-3-carboxaldehyde.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([OH:14])=O)[CH:4]=[CH:3][N:2]=1.[Br:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH2:21])[S:19][CH:20]=1>>[Br:15][C:16]1[C:17]([C:22]2[NH:26][N:25]=[CH:24][N:23]=2)=[C:18]([NH:21][C:12](=[O:14])[CH2:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[CH:1]=[N:2][CH:3]=[CH:4]3)[S:19][CH:20]=1
Reactant: O=C(O)Cc1cccc2ccncc12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cc1cccc2ccncc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
N-(4-Bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-8-yl)acetamide was prepared from 2-(isoquinolin-8-yl)acetic acid (53 mg, 0.286 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (35 mg, 0.143 mmol) according to protocol A. Retention time (min)=1.769, method [7], MS(ESI) 414.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 9.84 (bs, 1H), 8.55 (bs, 1H), 8.41 (d, J=6.0 Hz, 1H), 8.26-8.23 (m, 2H), 8.18 (dd, J=8.1, 7.2 Hz, 1H), 7.99 (d, J=4.0 Hz, 1H), 7.09 (s, 1H), 4.61 (s, 2H).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].N12CCCN=C1CCCCC2.[C:16]([O:23][CH3:24])(=[O:22])/[CH:17]=[CH:18]/[CH2:19][CH2:20][CH3:21].Cl>C(#N)C>[N+:1]([CH2:4][CH:18]([CH2:19][CH2:20][CH3:21])[CH2:17][C:16]([O:23][CH3:24])=[O:22])([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: CCC/C=C/C(=O)OC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCC(CC(=O)OC)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.4 %

Procedure:
Nitromethane (2.54 ml, 46 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.4 ml, 36 mmol) were added to a solution of methyl (E)-2-hexenoate (4.62 g, 36 mmol) in acetonitrile (20 ml) and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was acidified by addition of a 1N HCl aqueous solution and then extracted with ethyl acetate. After washing the organic layer with brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (3.64 g) as a light yellow oil. 1H-NMR (CDCl3) δ(ppm) 0.92 (3H, t, J=0.8 Hz), 1.29-1.48 (4H, m), 2.45 (2H, d, J=6.4 Hz), 2.57-2.68 (1H, m), 3.69 (3H, s), 4.43 (1H, dd, J=14.0 Hz, 6.0 Hz), 4.50 (1H, dd, J=14.0, 6.8 Hz)
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8](O)=[O:9])[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[N:4]1)[CH3:2].[CH3:35][CH2:36][N:37]=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.Cl.C(N)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:36]([NH:37][C:8]([C:6]1[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)(=[O:13])=[O:14])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)=[O:9])[CH3:35]
Reactant: CCn1cc(C(=O)O)c(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCNC(=O)c1cn(CC)nc1NS(=O)(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 16 h

Procedure:
To a solution of the title compound of Example 3 (0.15 g, 0.31 mmol), EDCl (0.12 g, 0.62 mmol), 1-hydroxybenzotriazole (0.42 g, 0.31 mmol) and TEA (0.2 g, 1.5 mmol) in DCM, is added ethylamine hydrochloride (0.5 g, 0.62 mmol) at RT. The reaction mixture is stirred for 16 h. The reaction mixture is diluted with ethyl acetate, washed with 1N hydrochloric acid, water and brine. The organic filtrate is concentrated, the crude is chromatographed using 25% ethyl acetate in hexanes to provide 1-ethyl-3-{4-[5-methyl-2-phenyl-oxazol-4-ylmethoxy]-benzenesulfonylamino}-1H-pyrazole-4-carboxylic acid ethyl amide as a crystalline solid: MS [m/z] 508.1 [M-1]−.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][O:25][C:26]3[C:35]4[C:30](=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([C:40]([F:43])([F:42])[F:41])[CH:27]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].CO.[OH-].[Na+]>C1COCC1>[F:43][C:40]([F:41])([F:42])[C:28]1[CH:27]=[C:26]([O:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:15]3[CH:14]=[CH:13][C:12]([S:9]([NH:8][CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:44])=[O:2])(=[O:11])=[O:10])=[CH:17][CH:16]=3)=[CH:19][CH:20]=2)[C:35]2[C:30](=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:32]=[CH:33][CH:34]=2)[N:29]=1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc(C(F)(F)F)nc4c(C(F)(F)F)cccc34)cc2)cc1)C(=O)O
Reaction time: 72 h
Yield: 45.9 %

Procedure:
2-[4′-(2,8-Bis-trifluoromethyl-quinolin-4-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid methyl ester (1.026 g, 1.6 mmol, 1 equiv.) was dissolved in THF (15 mL) and MeOH (6 mL) and 1N NaOH (17.6 mL, 11 equiv.) was added. The reaction was monitored by TLC. It was complete in 3 days. Solvent was removed by rotovap and the residue was dissolved in H2O. The mixture was then acidified to pH 3 with 1N HCl. The resulting precipitate was collected by filtration and washed with cold water and dried overnight. 460 mg of white solid was obtained in 46% yield.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C:12]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:33]I>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C:12]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:33])[CH:21]=[CH:20]3)=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3[nH]ccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C(=O)C3(Cc4ccccc4)CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.6 %

Procedure:
Sodium hydride (60% in mineral oil, 12 mg, 0.296 mmol) was added at room temperature to a solution of 3-benzyl-3-(1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.247 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for 20 minutes, and then methyliodide (18 μL, 0.296 mmol) was added. The reaction mixture was then stirred for 30 minutes, then quenched by addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 105 mg of 3-benzyl-3-(1-methyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam that was used without further purification.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1F
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.95 g, 5.34 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.213 g, 5.34 mmol) dissolved in water (2.000 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.327 mL, 5.34 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to yield a slightly yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using two injections with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.09 g, 61%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.80-2.17 (m, 4H), 2.72-2.87 (m, 2H), 2.91-3.02 (m, 1H), 3.12-3.24 (m, 1H), 3.52 (s, 3H), 3.95-4.05 (m, 1H), 4.29-4.40 (m, 1H), 5.72 (s, 1H), 6.94-7.12 (m, 3H), 7.12-7.20 (m, 1H). MS m/z 335 (M+H)+
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[O:34]1[CH:38]=[CH:37][C:36]([CH:39]([OH:43])[CH2:40][NH:41][CH3:42])=[CH:35]1.O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:41]([CH2:40][CH:39]([C:36]4[CH:37]=[CH:38][O:34][CH:35]=4)[OH:43])[CH3:42])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: CNCC(O)c1ccoc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccoc1
Temperature: 90 °C
Yield: 52.8 %

Procedure:
N,N-Diisopropylethylamine (0.14 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) were added to a solution of rac-1-(3-furyl)-2-(methylamino)ethanol (Preparation 43, 0.116 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into water (25 mL). The suspension was filtered and the resulting solid was purified by column chromatography (CH2Cl2/methanol, 98/2) followed by recrystallization from ethyl acetate to yield 0.102 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 93-97° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.55, 7.54-7.53, 7.41-7.32, 6.87, 6.42, 4.97, 4.694.65, 4.55, 3.91, 3.74, 2.63-2.53, 2.30; 13C NMR (100 MHz, CDCl3) δ 173.7, 164.7, 153.2, 150.6, 143.4, 141.1, 139.4, 137.3, 132.8, 128.9, 126.0, 116.8, 114.7, 108.3, 106.6, 102.1, 63.2, 62.7, 54.1, 42.6, 41.8, 37.8; MS (ESI+) m/z 470 (M+H)+.
Reaction SMILES: [O:1]1[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[CH3:10][C:11]1[NH:15][C:14]([C:16]#[N:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C:3]1([CH2:2][N:15]2[C:11]([CH3:10])=[CH:12][CH:13]=[C:14]2[C:16]#[N:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1CCCC2(CC1)CO2
Reactant: Cc1ccc(C#N)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)n1CC1(O)CCCCCC1

Procedure:
1-Oxaspiro[2,6]nonane (2.5 g), 5-methyl-1H-pyrrole-2-carbonitrile (2.1 g) and Cs2CO3 (6.45 g) in N,N-dimethylformamide (15 mL) was heated at 120° C. in a Biotage Initiator microwave reactor for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and concentrated. The residue was purified by reverse phase chromatography, and was eluted with 30%-70% acetonitrile in 0.1% TFA water solution to provide the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[CH:30]=[CH:29][C:21]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:38]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Cl:76]CCl>CN(C)C=O>[ClH:76].[N:38]1([C:26](=[O:28])[CH2:25][NH:24][C:22](=[O:23])[C:21]2[CH:29]=[CH:30][C:18]([S:15](=[O:16])(=[O:17])[NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:19][CH:20]=2)[CH2:44][CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Reactant: ClCCl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cl
Product: O=C(NCC(=O)N1CCCNCC1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a stirred solution of [4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetic acid (Example 2.1/c) (36 mg, 0.085 mmol) in a mixture of dichloromethane (2 mL) and dimethylformamide (0.2 mL) and [1,4]diazepane-1-carboxylic acid tert-butyl ester (Fluka) (20 mg, 0.1 mmol), HBTU (46 mg, 0.12 mmol) and triethylamine (30 μL, 0.2 mmol) were added. The mixture was stirred at room temperature for 24 h, then purified by column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and gradient elution starting with 100% A eluent and processing to 100% B eluent over a period of 20 minutes (eluent A: n-hexane; eluent B: ethyl acetate). The purified compound was dissolved in ethyl acetate (0.5 mL) 2.5 M hydrogen chloride in ethyl acetate (2.0 mL) was added and the mixture was stirred at room temperature for 24 h. The precipitated product was filtered, washed with diethyl ether and dried in vacuum to yield 29 mg (62%) of the title compound. MS (EI) 509.2 (MH+).