Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:17]O>>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CBr)cc1

Procedure:
Intermediate 1 was prepared as shown in Scheme 2. Esterification of 4-bromomethylbenzoic acid 4 (25 grams) was carried out in refluxing methanol (500 ml) in the presence of concentrated H2SO4 (5 ml) to yield methyl 4-bromomethylbenzoate 5. TLC (thin layer chromatography) monitoring of the reaction mixture showed formation, over time, of a side-product (about 15-20%), which according to 1H-NMR analysis, was identified as methyl 4-methoxymethylbenzoate. The mixture of methyl 4-bromomethylbenzoate 5 and the side-product (4.56 grams; 1 equiv) was reacted with commercially available 4-boc-aminopiperidine 6 (Aldrich™) (4.0 grams) in 100 ml of DCM or 100 ml of methanol in the presence of potassium carbonate (4.14 grams; 1.5 equiv) at room temperature to yield compound 7. Reaction in methanol afforded compound 7, as identified by 1H NMR, in 72% yield compared to 57% obtained with DCM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH:17]1([CH2:20][NH2:21])[CH2:19][CH2:18]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:21][CH2:20][CH:17]2[CH2:19][CH2:18]2)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: NCC1CC1
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)cc1OC(F)(F)F
Yield: 90.8 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and cyclopropylmethylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)-2-(trifluoromethoxy)benzenesulfonamide (0.35 g, 91%) was provided after purification. MS (ESI) m/z 374. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO.O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36]#[N:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(N)n3)[C@H]2SC1
Yield: 64.2 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.05 g.) and conc. hydrochloric acid (1.52 g.) in methanol (30 ml.) and tetrahydrofuran (20 ml.) was stirred at room temperature for 2 hours. After the solvent was evaporated in vacuo, the residue was dissolved in 10% aqueous solution of sodium hydroxide. After filtration, the filtrate was adjusted to pH 3.0 with 10% hydrochloric acid and stirred under ice-cooling for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.25 g.).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[N:13][C:12](C(OCC)=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].O.NN>C(O)C>[CH2:1]([N:3]1[C:15]2[CH:14]=[N:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCOC(=O)c1cc2c3ccccc3n(CC)c2cn1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCn1c2ccccc2c2ccncc21
Yield: 101.9 %

Procedure:
Compound 31 (2.7 g, 10 mmol) was dissolved into ethanol (50 ml). 85% Hydrazine hydrate (15 ml) was added. The mixture was refluxed by heating for 6 h and concentrated to 30 ml in reduced pressure. After cooling, filtration, wash with ethanol, and natural drying in the air, white solids (2.0 g, 83%) were obtained. Samples for analysis could be recrystallized by 90% ethanol to obtain white flaring sheet-like crystals, mp 195-196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19]>O1CCCC1>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH:10]=2)[CH:6]=[N:7]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2cn[nH]c2c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 59.6 %

Procedure:
A mixture of 6-amino-1H-indazole (2.00 g) and pyridine (2.67 ml) in tetrahydrofuran was stirred at 0° C. and then p-nitrophenyl chloroformate (3.18 g) was added and stirred at the same temperature for 2 hours. The reaction mixture was evaporated and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The pale yellow powder was washed with isopropyl ether and diethyl ether, and vacuumed to afford 4-nitrophenyl N-(lH-indazol-6-yl)carbamate (2.67 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[C:16](OC)=[S:17])=[CH:5][CH:4]=1.[H-].[Na+].[C:22]([OH:25])(=[O:24])[CH3:23]>O1CCCC1.CN(C)C=O>[C:22]([O:25][C:10]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:16]=2[S:17][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)O
Reactant: COC(=S)c1ccncc1Cc1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cnccc3c2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 0.200 g (.69 mmol) of methyl 3-(4-methoxyphenyl)methylthiopyridine-4-carboxylate in 2 mL of dry tetrahydrofuran was added to a suspension of 83 mg (2.1 mmol) of 60% dispersion of sodium hydride in 2 mL of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 3 hours, then poured onto ice water and acidified with glacial acetic acid. The solid material (product) was collected by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate extract was dried, concentrated and combined with the solid precipitate that had been collected. This material was heated at reflux with 100 mg sodium acetate in 2 mL of acetic anhydride for 2 hours, then was partitioned between ethyl acetate and water. The aqueous layer was washed with two portions of ethyl acetate and the combined extracts were dried and concentrated. The residue was crystallized from methanol to afford 100 mg (48%) of white crystalline material, m.p. 141-142° C.
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][C@H:10]1[C:13]([O:15]C)=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.C(C(CCCC)C(O)=O)C>CCCCCCC>[CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][C@H:10]1[C:13]([OH:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1CCN1[C@@H](C)c1ccccc1
Agent: CCCCC(CC)C(=O)O
Solvent: O
Solvent: CCCCCCC
Product: C[C@@H](c1ccccc1)N1CC[C@H]1C(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 400.8 %

Procedure:
To a mixture of methyl N-[(S)-methylbenzyl]azetidine-2-(s)-carboxylate (161.6 g) and water (323 g) was added 2-ethylhexanoic acid (116.9 g) and resulting mixture was stirred at 60° C. for about 12 hours. Heptane (161 g) was added to the reaction mixture and separated. The organic layer was extracted with water (80 g). Combined water layer was washed with heptane (161.6 g×3) to give aqueous N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylic acid solution (606.2 g). Yield 94%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([OH:35])[CH:31]=[C:32]([F:34])[CH:33]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:30]2[CH:29]=[C:28]([F:27])[CH:33]=[C:32]([F:34])[CH:31]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cc(F)cc(F)c1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 3,5-difluorophenol: 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.6 Hz), 8.18 (1H, d, J=2.6 Hz), 7.95 (1H, dd, J=6.8, 1.8 Hz), 7.38 (2H, d, J=8.1 Hz), 6.83–6.69 (2H, m), 6.40–6.32 (2H, m), 6.25 (1H, br.s), 5.39–5.30 (1H, m), 1.60 (3H, d, J=6.2 Hz), 1.59 (9H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[C:14]3[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=3)[C:43]2=[O:57])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:54])([CH3:53])[CH3:55])[CH:48]=3)[C:43]2=[O:57])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[C:14]3[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CC(C)(C)OC3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(C)(C)OC4)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 50.2 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 139e (177 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (207 mg, 0.50 mmol), Pd(dppf)Cl2 (41 mg, 0.050 mmol), sodium acetate (82 mg, 1.0 mmol), K3PO4.trihydrate (266 mg, 1.0 mmol), water (6 drops), and acetonitrile (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 139f (161 mg, 50%) as a brown solid. MS-ESI: [M+H]+ 642.3
Reaction SMILES: [N+]([O-])([O-])=O.[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([NH2:17])=[NH2+:16])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[C:18]([O:22][C:23]([NH:25][C:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35](=O)[C:36]([C:41]#N)=[CH:37][N:38](C)C)=[CH:31][CH:30]=1)([CH3:28])[CH3:27])=[O:24])([CH3:21])([CH3:20])[CH3:19].[OH-].[Na+]>CC(O)C>[C:18]([O:22][C:23]([NH:25][C:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([C:37]#[N:38])=[CH:41][N:17]=[C:15]([NH:14][C:10]3[CH:9]=[C:8]4[C:13](=[CH:12][CH:11]=3)[NH:5][N:6]=[CH:7]4)[N:16]=2)=[CH:31][CH:30]=1)([CH3:28])[CH3:27])=[O:24])([CH3:20])([CH3:19])[CH3:21]
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(C(C)(C)NC(=O)OC(C)(C)C)cc1
Reactant: NC(=[NH2+])Nc1ccc2[nH]ncc2c1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc4[nH]ncc4c3)ncc2C#N)cc1
Yield: 90.5 %

Procedure:
A mixture of indazol-5-ylguanidinium nitrate (524 mg, 2.2 mmol), 1-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-2-cyano-3-dimethylaminopropen-1-one (714 mg, 2.0 mmol) and powdered sodium hydroxide (96 mg, 2.4 mmol) in propan-2-ol (30 ml) was heated at reflux for 6 h. The reaction was concentrated in vacuo and the residue purified by column chromatography (silica, 60% ethyl acetate in hexane, loading the crude material in dichloromethane) to give 4-[4-(1-tert-butoxycarbonylamino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)-pyrimidine-2-amine as a yellow solid (850 mg). δH (CDCl3) 8.69 (1H, s), 8.18 (1H, s), 8.11 (1H, s), 8.05 (2H, d, J 8.4 Hz), 7.93 (1H, bs), 7.57 (2H, d, J 8.4 Hz), 7.50 (2H, m), 5.10 (1H, bs), 1.66 (6H, s), 1.40 (9H, bs). MS (ESI) 492 (MNa+, 61%), 470 (MH+, 100%), 414 (19%). This product was dissolved in a mixture of TFA acid (20 ml) and CH2Cl2 (20 ml) and was stirred for 30 mins at room temperature before concentrating the reaction in vacuo. The residue was dissolved in 10% MeOH in CH2Cl2 (200 ml) and the organic phase washed with sat. Na2CO3 (aq) (50 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a bright yellow solid (541 mg) m.p. 267-271° (dec.). δH (d6DMSO) 13.03 (1H, bs), 10.46 (1H, s), 8.91 (1H, s), 8.16 (1H, s), 8.04 (1H, s), 7.94 (2H, d, J 8.4 Hz), 7.74 (2H, d, J 8.4 Hz), 7.61 (1H, m), 7.52 (1H, d, J 8.9 Hz), 3.44 (2H, bs), 1.48 (6H, s). MS (ESI) 392 (MNa+, 11%), 370 (MH+, 23%), 353 (100%).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.[N:11]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[N:11]1([CH2:17][CH2:18][C:19]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[NH:1][CH:2]=[CH:3][C:4]2=3)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)CCN1CCCCC1
Reactant: c1cc2c([nH]1)CCCCN2
Solvent: ClCCl
Product: O=C(CCN1CCCCC1)N1CCCCc2[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-piperidin-1-yl-propionic acid (472 mg, 3 mmol) in DCM (15 mL) at 0° C. was added oxalyl chloride (4.5 mmol) followed by one drop of DMF. After stirring for 2 hours at rt, the solvent was removed to give 3-piperidin-1-yl-propionyl chloride as a white solid. To a solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (347 mg, 2.55 mmol) in DCM (10 mL) was added TEA (1 eq.) and 1-piperidinepropionic acid chloride. The mixture was stirred at rt for overnight. The reaction was diluted with DCM, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 230 mg of 3-piperidin-1-yl-1-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepin-4-yl)-propan-1-one as a light brown gel.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:21])[CH2:4][C:5]([O:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[N:22]([O-])=[O:23].[Na+].[Cl-].[Na+]>C(O)(=O)C.O>[Br:1][CH2:2][C:3](=[O:21])[C:4](=[N:22][OH:23])[C:5]([O:7][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:6]
Reactant: O=C(CBr)CC(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(CBr)C(=NO)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
In 30 ml of acetic acid there were dissolved 6.94 g of benzhydryl 4-bromo-3-oxobutyrate and, under ice-cooling and stirring, a solution of 1.588 g of sodium nitrite in 6 ml of water was added dropwise. The mixture was further stirred at that temperature for 20 minutes and, following addition of 60 ml of a saturated aqueous solution of sodium chloride, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed under reduced pressure to recover 7.56 g of the captioned compound.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH:8]12[O:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]2[C:15]([O:17]C)=O.[Cl-].[NH4+]>O1CCCC1>[CH:8]12[O:14][CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]2[C:15]1([OH:17])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCCCCBr
Reactant: COC(=O)C1CC2CCC1O2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(C2CC3CCC2O3)CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A flask was charged with 14.6 g of magnesium and 270 ml of tetrahydrofuran, to which 64.8 g of 1,4-dibromobutane was added dropwise at 50° C. After the completion of dropwise addition, the solution was stirred at 60° C. for one hour. To the solution below 40° C., 39.0 g of methyl 7-oxa-2-norbornanecarboxylate was added dropwise. The solution was stirred at room temperature for one hour, after which an aqueous solution of ammonium chloride was added for hydrolysis. Ordinary post-treatment yielded 43.7 g of 1-(7-oxanorbornan-2-yl)cyclopentanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:23]1COCC1>>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[O:11][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
Alcohol Compound 40 (48.8 g, 0.16 mmol) was added to a mixture of NaH (4.0 g, 0.17 mol) in dry THF (500 mL). After 5 min, Mel (10 mL, 0.17 mol) was added and, after another 3 hours, the mixture was quenched with H2O (150 mL), extracted into diethyl ether (500 mL), dried (MgSO4) and concentrated. Purification of the residue by silica-gel column chromatography [eluent: hexane/ethyl acetate, 90/10, v/v] yielded 1-O-benzyl-3-O-t-butyldimethylsilyl-2-O-methyl-rac-glycerol (Compound 41) (37 g, 74%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O:26]1[CH:28]([C:29]2[N:34]=[C:33]([CH3:35])[CH:32]=[CH:31][CH:30]=2)[CH2:27]1>CN(C)C=O>[OH:26][CH:28]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([CH3:35])[N:34]=1)[CH2:27][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: Cc1cccc(C2CO2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C(O)Cn2c(NC3CCN(C(=O)OC(C)(C)C)CC3)nc3ccccc32)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
Reaction under N2 flow. NaH 60% (0.02 mol) was added to a mixture of 1,1-dimethyl-ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate (0.02 mol) in N,N-di-methylformamide (100 ml). The mixture was stirred at 40° C. for 1 hour. 6-(Epoxyethyl)-2-picoline (0.02 mol) in a small amount of N,N-dimethylformamide was added. The mixture was stirred at 100° C. overnight. The solvent was evaporated. The residue was taken up in H2O and CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5 and 90/10). The pure fractions were collected and the solvent was evaporated, yielding 3.5 g of (±)-1,1-dimethylethyl 4-[[1-[2-hydroxy-2-(6-methyl-2-pyridinyl)ethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (interm. 16).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:24]=3[NH:23][CH:22]=[C:21]4[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:24]=3[NH:23][CH:22]=[C:21]4[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC)c(OC)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1OC
Temperature: 20 °C
Reaction time: 4 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 3-(7-{5-[3,4-bis(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D67) (100 mg) in tetrahydrofuran (10 mL) and methanol (10 mL) stirred at 20° C. was added a solution of sodium hydroxide (48 mg) in water (10 mL) in one charge. The reaction mixture was stirred at 20° C. for 4 h. The organic solvent was evaporated off and the mixture was acidified with HCl (1 M) solution to pH around 1. The solid was filtered and recrystallized from acetonitrile/EtOAc to afford 3-(7-{5-[3,4-bis(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E43) (72 mg). δH (DMSO-d6, 400 MHz): 2.61 (2H, t), 2.99 (2H, t), 3.90 (3H, s), 3.93 (3H, s), 7.21 (1H, t), 7.23 (1H, d), 7.26 (1H, d), 7.75 (1H, d), 7.81 (1H, d), 7.90 (1H, dd), 7.95 (1H, dd), 10.74 (1H, s). MS (ES): C21H19N3O6 requires 393; found 394.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1>>[F:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: FC1CCCNC1
Agent: Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)C1
Yield: 97 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 3-fluoropiperidine hydrochloride gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellow oil (0.27 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 4.88-4.71 (m, 1H), 3.79 (s, 3H), 3.47 (ddd, J=29.8, 12.8, 2.1 Hz, 1H), 3.32-3.15 (m, 2H), 3.07-2.99 (m, 1H), 2.11-1.99 (m, 2H), 1.95-1.76 (m, 1H), 1.74-1.62 (m, 1H)
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([CH:10]([C:11]([O:13]CC)=[O:12])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(C(OCC)=O)C2(CCCCC2)C1>>[C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([CH:10]([C:11]([OH:13])=[O:12])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CC12CCC(C(C)(C)C)CC2
Agent: CCOC(=O)C1CC12CCCCC2
Product: CC(C)(C)C1CCC2(CC1)CC2C(=O)O

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 24B for the product from Example 1A. MS m/z 228 (M+NH4)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=1)[C:5]([NH2:7])=[O:6].N([O-])=O.[Na+].[OH-].[Na+].[F:24][B-](F)(F)F.[H+]>O>[F:24][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: CCCCCCOc1cc(N)cc(C(N)=O)c1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CCCCCCOc1cc(F)cc(C(N)=O)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3-amino-5-hexyloxy benzamide (0.9 g, 3.8 mmol) in tetrafluoroboric acid (20 ml), a solution of sodium nitrite (0.315 mg, 4.6 mmol) in water (5 ml) was added at 0° C. and stirred for 1 hr. Later it was allowed to come to RT and stirred for 1 hr followed by heating at 60° C. for 2 hrs. It was then basify to pH=14 using saturated NaOH solution and extracted with dichloromethane (3×30 ml). The solvent was evaporated to yield crude product, which was purified by column chromatography using silica gel (230-400 mesh) and dichloromethane as an eluent (100 mg, 11%). 1H NMR (DMSO-d6, 400 MHz with D2O): δ 0.88 (t, J=7.2 Hz, 3H), 1.32 (m, 2H), 1.41 (m, 4H), 1.72 (m, 2H), 4.0 (t, J=7.2 Hz, 2H), 6.97 (m, 1H), 7.22 (m, 1H), 7.28 (m, 1H), 7.52 (br s, 1H), 8.03 (br s, 1H). MS ES+ (238.0, 239.0), HPLC (method 7) Rt=11.34 min.