Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([CH3:33])[CH3:32]>C(#N)C>[CH:31]([N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]2[CH2:15][C@H:14]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)([CH3:33])[CH3:32]
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 40.1 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (200 mg, 0.613 mmol) in acetonitrile (10 mL) was added potassium carbonate (254 mg, 1.838 mmol) followed by 2-bromopropane (98 mg, 0.797 mmol). The reaction mixture was heated in a sealed tube at 80° C. for 4 hours. The reaction mixture was filtered and evaporated. The resulting oil was purified by preparatory HPLC (5 to 40% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected. The solution was neutralized with 1 M NaOH, concentrated and extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and evaporated. The oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 min, and then it was concentrated. The concentrated solution was then partitioned between 2 ml of water and 5 mL of EtOAc. The organic layer was separated and evaporated. The resulting oil was dissolved in 3 mL of acetonitrile. 0.5 mL of 4 M HCl in dioxane was added. 3 mL of diethylether was added and the formed solid product was filtered. trans-N-((1-Isopropylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine (80 mg, 0.246 mmol, 40.1% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.40 (m, 2H), 7.13-7.28 (m, 3H), 3.43-3.63 (m, 3H), 3.21 (d, J=6.57 Hz, 2H), 3.11 (t, 2H), 3.04 (dt, J=3.98, 7.71 Hz, 1H), 2.49-2.69 (m, 1H), 2.17 (d, J=12.63 Hz, 3H), 1.56-1.86 (m, 3H), 1.34-1.48 (m, 7H); LC-MS Rt=0.42 min; MS (ESI): 273.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:25]1[C:26]([CH3:48])=[C:27]([C:34]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]=[C:41]([CH3:46])[NH:40][C:39]3=[O:47])=[O:35])[N:28]2[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]2>O.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:48][C:26]1[C:25]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])=[C:33]2[N:28]([C:27]=1[C:34]([C:36]1[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=1)[N:42]=[C:41]([CH3:46])[NH:40][C:39]3=[O:47])=[O:35])[CH:29]=[CH:30][CH:31]=[CH:32]2
Reactant: Cc1nc2ccc(C(=O)c3c(C)c(Br)c4ccccn34)cc2c(=O)[nH]1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-c2c(C)c(C(=O)c3ccc4nc(C)[nH]c(=O)c4c3)n3ccccc23)c1
Temperature: 150 °C
Yield: 58.6 %

Procedure:
0.139 g (0.78 mmol) of [3-(methoxycarbonyl)phenyl]boronic acid, 0.321 g (1.29 mmol) of potassium phosphate dihydrate dissolved in 0.81 ml of water, and 0.0149 g (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added, under an argon atmosphere at ambient temperature, to 0.256 g (0.65 mmol) of 6-[(1-bromo-2-methylindolizin-3-yl)carbonyl]-2-methylquinazolin-4(3H)-one in 9 ml of DMF. The reaction medium is microwave-heated at 150° C. for 15 minutes. After dilution with ethyl acetate, the organic phase is washed with a 1N aqueous solution of hydrochloric acid and then a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/2) mixture. 172 mg of a yellow solid are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[C:5](/[CH:20]=C/C3C=CC=CC=3)[CH:6]=[CH:7][C:8]=2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:29].[K+].[K+].[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH:20]([C:5]1[CH:6]=[CH:7][C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[C:9]2[C:4]=1[CH2:3][N:2]([CH3:1])[C:10]2=[O:11])=[O:29]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CN1Cc2c(/C=C/c3ccccc3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2c(C=O)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl {2-methyl-3-oxo-7-[(E)-2-phenylethenyl]-2,3-dihydro-1H-isoindol-4-yl}carbamate (Compound 109D, 1.0E2 mg, 0.27 mmol) was added in one portion to a pre-stirred mixture (room temperature, 45 min) of potassium osmate dihydrate (1.0 mg, 0.0027 mmol) and potassium monopersulfate (170 mg, 1.1 mmol) in DMF (1.35 mL). After stirring overnight at room temperature, the reaction mixture was treated with 1.35 mL of saturated aqueous Na2SO3. The resulting slurry was extracted with EtOAc (3×) and the combined organic layers were washed with 1N HCl (3×) and brine and concentrated in vacuo. The desired product was obtained after chromatography using an ISCO Combiflash unit (0-15% EtOAc in Heptane) as 23 mg of a tan solid (29% yield). 1H NMR (400 MHz, DMSO-d6) δ=1.51 (s, 9H), 3.08 (s, 3H), 4.74 (s, 2H), 8.12 (d, J=8.6 Hz, 1H), 8.21 (d, J=8.6 Hz, 1H), 9.95 (s, 1H), 10.01 (s, 1H). MS (ES+): m/z 291.28 (100) [MH+]; HPLC: tR=1.27 min (UPLC, Analytical).
Reaction SMILES: [CH2:1]([O:5][Zr:6](OCCCC)(OCCCC)[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].C(CC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:8]([O:7][Zr:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCO[Zr](OCCCC)(OCCCC)OCCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)CC(C)=O
Product: CCCCO[Zr]OCCCC

Procedure:
In 87 g of toluene was dissolved 38.3 g (0.1M) of tetra-n-butoxyzirconium, and 20.0 g (0.2M) of acetylacetone was gradually added to the resulting solution with stirring. An exothermic reaction of the mixture took place to give di-n-butoxyzirconium bisacetylacetonato.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([F:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:28]1[C:29]([CH3:31])=[CH:30][C:26]([O:25][C:15]2[C:16]([F:24])=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:14]=2[Cl:13])=[N:27]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
Triethylamine (2.02 g, 20.0 mmol) and ethyl isocyanate (1.42 g, 20.0 mmol) were added to an ethyl acetate (50 mL) solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (5.33 g, 18.0 mmol), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2 mol/L hydrochloric acid, followed by extraction with ethyl acetate (50 mL×3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, the desiccant was removed by filtering and the solvent was distilled off the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane= 1/10) to give a white solid of N-ethyl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (5.37 g, yield: 81.6%). Melting point: 84˜86° C., 1H-NMR (Acetone-d6, Acetone, ppm): δ1.10 (t, J=7.2 Hz, 3H), 2.55 (d, J=0.9 Hz, 3H), 3.26 (dq, J=6.1 and 7.2 Hz, 2H), 5.98 (q, J=0.9 Hz, 1H), 7.39˜7.48 (brt, J=6.1 Hz, 1H), 7.75 (ddq, J=2.1 and JHF=0.7 and 9.7 Hz, 1H), 7.82 (dq, 1H, J=2.1 and JHF=0.7 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([C:27]([F:28])([F:29])[F:30])[CH:16]=2)=[N:22]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2ccc(N)c(C(F)(F)F)c2)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc(N)c(C(F)(F)F)c2)cc1C
Reaction time: 6 h
Yield: 48.2 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and ethyl isocyanate (0.09 g, 1.3 mmol) were added to a solution of 3-(4-amino-3-trifluoromethylphenyloxy)-5-methylpyrazole (0.30 g, 1.2 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellowish solid of N-ethyl-3-(4-amino-3-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.19 g, yield: 50.5%). mp: 102-104° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.3 Hz, 3H), 2.56 (d, J=0.8 Hz, 3H), 3.37 (dq, J=5.9 and 7.3 Hz, 2H), 4.11 (br s, 2H), 5.61 (q, J=0.8 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.93 (br s, 1H), 7.14 (dd, J=2.7 and 8.8 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[N:13]=2)=[O:9])[CH:5]=[C:4]([C:27]2[O:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[N:3]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:27]2[O:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[N:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)NCc3cccc(CO[Si](C)(C)C(C)(C)C)n3)nc(N)n2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(-c2cc(C(=O)NCc3cccc(CO)n3)nc(N)n2)o1
Yield: 116.1 %

Procedure:
A solution of 2-amino-6-(5-methyl-2-furyl)-N-(6-(tert-butyldimethylsilyloxymethyl)pyridin-2-ylmethyl)pyrimidine-4-carboxamide (614 mg, 1.36 mmol) in acetic acid (9 mL) water (3 mL) and THF (3 mL) was stirred at room temperature for 4 days, neutralised with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic phase was dried (MgSO4), concentrated in vacuo, and the resulting solid triturated with MeOH and filtered to give the title compound (536 mg, 49%) as a cream solid.
Reaction SMILES: C[O:2][CH:3]=[C:4]1C(=O)OC(C)(C)O[C:5]1=O.[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18].C(OCC)C>C1C(Cl)=CC=C(Cl)C=1>[Br:14][C:15]1[CH:16]=[C:17]2[C:19]([C:3]([OH:2])=[CH:4][CH:5]=[N:18]2)=[CH:20][C:21]=1[F:22]
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: Nc1ccc(F)c(Br)c1
Solvent: Clc1ccc(Cl)cc1
Solvent: CCOCC
Product: Oc1ccnc2cc(Br)c(F)cc12
Temperature: 200 °C
Yield: 47.9 %

Procedure:
A glass microwave vial was charged with 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (Bionet; 0.102 g, 0.552 mmol) and 3-bromo-4-fluoroaniline (Matrix Scientific; 0.100 g, 0.526 mmol) in dichlorobenzene (1.00 ml). The reaction mixture was stirred and heated under microwave irradiation (Biotage AB, Inc., Upssala, Sweden) at 200° C. for 10 min. Diethyl ether was added to the reaction and the solids were filtered, washing well with ether (some product passed through with the filtrate) to yield 61 mg of crude 7-bromo-6-fluoroquinolin-4-ol. Material carried forward without further purification. m/z (ESI) 243.9 (M+H)+.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[C:14]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH2:26][CH2:27][CH2:28][CH3:29])=CC=1)([O-])=O.[N:31]1[CH:36]=[C:35]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=[N:33][CH:32]=1>O1CCCC1>[CH2:26]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([O:24][CH3:25])=[CH:23][C:14]=1/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C:35]1[CH:36]=[N:31][CH:32]=[N:33][CH:34]=1)=[O:10])[CH2:27][CH2:28][CH3:29]
Reactant: NCCCCCCc1cncnc1
Reactant: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)cc(OC)c2ccccc12
Solvent: C1CCOC1
Product: CCCCc1c(/C=C/C(=O)NCCCCCCc2cncnc2)cc(OC)c2ccccc12
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
As in Example 114, (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester (1.21 g) was reacted with 5-pyrimidinehexanamine (0.505 g) in tetrahydrofuran (20 mL) at room temperature overnight and then at 50° C. for 1.5 hour. The product was isolated in the usual manner then was purified by HPLC (ethyl acetate) and twice crystallized from ethyl acetate-hexane to provide 0.86 g of (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-N-[6-(5-pyrimidinyl)hexyl]-2-propenamide, mp 128°-129° C. Anal. Calcd for C28H35N3O2 : C, 75.47; H, 7.92; N, 9.43 Found: C, 75.52; H, 7.95; N, 9.40
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9](=O)[CH:10]([CH3:12])[CH3:11].[NH2:14][NH2:15].O>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:9]([CH:10]([CH3:12])[CH3:11])=[N:14][NH:15]2
Reactant: NN
Reactant: CC(C)C(=O)c1c(F)cccc1Br
Solvent: OCCO
Solvent: O
Product: CC(C)c1n[nH]c2cccc(Br)c12
Temperature: 160 °C

Procedure:
A mixture of 1-(2-bromo-6-fluoro-phenyl)-2-methyl-propan-1-one (1.1 g, 4.5 mmol) and anhydrous hydrazine (0.17 mL, 5.4 mmol) in ethylene glycol (10 mL) is heated for 16 hours at 160° C. Water is added and the mixture is extracted with CH2Cl2. The combined extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography to yield 4-bromo-3-isopropyl-1H-indazole. 1H NMR (CDCl3) 10.1 (br s, 1H), 7.38 (d, 1H), 7.32 (d, 1H), 7.17 (t, 1H), 3.99 (m, 1H), 1.43 (d, 6H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5]Br.[CH3:8][Si:9]([CH3:39])([CH3:38])[CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:37]=[CH:36][C:22]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[N:29](CCO)[N:28]=[CH:27]4)=[CH:21][CH:20]=2)=[CH:17][CH:16]=[N:15]1>>[CH3:38][Si:9]([CH3:39])([CH3:8])[CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([O:23][C:24]3[CH:32]=[CH:31][C:30]4[C:26](=[CH:27][N:28]([CH2:5][CH2:4][CH2:3][OH:2])[N:29]=4)[CH:25]=3)=[CH:36][CH:37]=2)=[CH:17][CH:16]=[N:15]1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3c(cnn3CCO)c2)cc1
Reactant: COC(=O)CCBr
Product: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3nn(CCCO)cc3c2)cc1

Procedure:
The titled compound AB is synthesized from intermediate Y-1 and 3-bromo-propionic acid methyl ester according to the procedure described for the synthesis of intermediate Y.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(F)c(Br)c1

Procedure:
A solution of 5 g (24.6 mmol) 3-bromo-4-fluoro-benzaldehyde in 20 ml anhydrous methanol is mixed in portions with 1.38 g (36.58 mmol) sodium borohydride while stirring and stirred for another hour at room temperature. After adding water, an extraction is carried out using diethyl ether, and the organic phase is dried over sodium sulfate. After the solvent is removed under vacuum, the appropriate alcohol is obtained. The product is obtained in pure form and can be used for further reactions.
Reaction SMILES: I[C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]([CH3:11])[N:3]=1.C([Mg]Cl)(C)C.[CH2:17]([Sn:21]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:11][N:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:2]([Sn:21]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][CH2:19][CH3:20])=[N:3]1
Reactant: Cn1nc(I)c2c1CCCC2
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2c1CCCC2
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a 25 mL round-bottomed flask, 3-iodo-1-methyl-4,5,6,7-tetrahydro-1H-indazole (62 mg, 237 μmol) was dissolved in THF (3 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride 2 M in THF (132 μL, 265 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Then, tributylchlorostannane (88.6 mg, 73.8 μL, 272 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to an off-white waxy solid. The residue was dried under high vacuum yielding 1-methyl-3-(tributylstannyl)-4,5,6,7-tetrahydro-1H-indazole assumed quantitative and taken into next step without further treatment.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[C:8]([Br:20])[CH:7]=1.CN(C)C1C=CC=CC=1>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Br:20])[CH:7]=1
Reactant: Brc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Oc1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Aluminium chloride (11.7 g, 87.6 mmol) was added in portions to a solution of 1,3-dibromo-5-benzyloxybenzene (10.0 g, 29.2 mmol; see step (i) above) and N,N-dimethylaniline (35.4 g, 292 mmol) in CH2Cl2 (100 mL) at room temperature under a nitrogen atmosphere. After 30 min, the mixture was partitioned with 1N HCl (300 mL) and EtOAc (5× 150 mL). The combined organic extracts were washed with saturated NaHCO3 (150 mL) and brine (150 mL) then, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with Hex:EtOAc (9:1) afforded the sub-title compound (6.1 g, 82%) as a white solid.
Reaction SMILES: O1CC[CH2:3][CH2:2]1.C([Li])CCC.[CH3:11][C@H:12]([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13][CH:14]=O>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CC)C=CC=CC=1.O>[CH3:11][C@H:12]([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13][CH:14]=[CH:2][CH3:3]
Reactant: C[C@@H](CC=O)CCO[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Product: CC=CC[C@H](C)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a slurry of 80 g. (0.2155 m) of triphenyl-ethyl phosphonium bromide in 800 ml. of dry tetrahydrofuran cooled to 0° C. was added 165.7 ml. of 1.3M solution of n-butyl lithium (0.2155 m) in the same solvent. After 2 hours, 45 g. (0.196 m) 3-(R)-methyl-5-(t-butyldimethylsilyloxy)-1-pentanal in 200 ml. of dry tetrahydrofuran was added dropwise to the reaction mixture. The reaction was allowed to stir 2 hours at room temperature and was then poured into water and extracted with ether. The combined extracts were washed with water and a brine solution and dried over magnesium sulfate. Removal of the solvent in vacuo gave a yellow oil which, on distillation gave 37.4 g. of product, b.p. 74°-79° C./0.2-0.1 torr.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].[OH-].[Na+].Cl>C(Cl)(Cl)Cl.O>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: NCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CCCCCCCCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
Compound I (50 g, 0.204 mol), prepared according to the general method described in Example 1, was dissolved in 2500 ml of chloroform, followed by the addition of a solution of 43.1 g (0.214 mol) of 11-aminoundecanoic acid and 60.0 g (1.5 mmol) of sodium hydroxide in 1500 ml of water. The mixture was stirred vigorously for one hour in a 5 liter Morton flask to insure thorough mixing of the two layers. The mixture was acidified with 250 ml of concentrated hydrochloric acid and stirred an additional 30 minutes. The organic layer was separated and the aqueous was extracted with 3×500 ml of chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give a solid. The product was recrystallized from toluene to give 68.37 g (82%) of 11-(4-benzoylbenzamido)undecanoic acid with a melting point of 107-109° C. Analysis on an NMR spectrometer was consistent with the desired product: 1H NMR (CDCl3) aromatic protons 7.20-7.80 (m, 9H), amide NH 6.30 (broad t, 1H), methylene adjacent to amide N 3.35 (in, 2H), methylene adjacent to carbonyl 2.25 (t, 2H), and remaining methylenes 1.00-1.80 (m, 16H).
Reaction SMILES: [C:1]1([CH3:48])[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:29](OS(C)(=O)=O)[CH3:30])[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:36])[C@H:12]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([CH3:48])[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:29]=[CH2:30])[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:36])[C@H:12]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 4-nitrobenzyl 2-[(3R,4R)-4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methanesulfonyloxy-2-butenoate (XVc, 0.0714 g, 0.00010 mole) in chloroform (1 mL) was treated with triethylamine (0.014 mL, 0.00010 mole) at room temperature. After a period of 1 h, reverse-phase C-18 HPLC indicated consumption of the starting material with formation of a single new peak (eluting phase: 65% acetonitrile and 35% 0.01M phosphate pH 6.5 buffer). Dilute hydrochloric acid (chilled at 0° C.) and ethyl acetate were added. The organic layer was washed with cold water, dried (sodium sulfate) and concentrated to give 0.0615 g (ca. 100%) of the title compound as a foam. The product was characterized by its 1H-NMR spectrum.