Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)#[N:25].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]#[N:25])[CH:27]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg (0.50 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 6 ml of DMF. 24 mg (0.60 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 137 mg (0.70 mmol) of 3-cyanobenzyl bromide was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11]OS(C)(=O)=O)[CH:5]=[CH:4][N:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C>COCCOC>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:11][C:10]2[CH:17]=[CH:18][CH:19]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:29][C@@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCc1cccc(-c2ccnc(Cl)n2)c1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 64 %

Procedure:
Intermediate 125 Methanesulfonic acid 3-(2-chloro-pyrimidin-4-yl)-benzyl ester (0.70 g) and Intermediate 126 2-(S)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (0.61 g) with diisopropylethylamine (0.70 mL) in ethylene glycol dimethyl ether (20 mL) was refluxed for 3 hours, cooled to room temperature, evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water (3×), brine, dried over dried over Na2SO4, chromatographed on silica gel (dichloromethane:methanol=98:2) to give 0.60 g of oily product with yield 64%. LC-MS showed the product had the expected M+H+ of 403. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.6 (s, 1H) 8.0 (s, 1H) 7.9 (d, 1H) 7.6 (d, 1H) 7.5 (m, 2H) 4.2 (S, 1 h) 3.8 (d, 1H) 3.4 (m, 2H) 3.0 (m, 1H) 2.7 (d, 1H), 2.6 (d, 1H) 2.1 (m, 2H) 1.5 (s, 9H) 1.2 (d, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:49])[C@@H:26]([C@@H:45]([CH3:48])[CH2:46][CH3:47])[C@H:27]([O:43][CH3:44])[CH2:28][C:29](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:72])[C@H:62]([CH3:71])[C@@H:63]([O:69][CH3:70])[C@@H:64]2[CH2:68][CH2:67][CH2:66][NH:65]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=[CH:52]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:72])[C@H:62]([CH3:71])[C@H:63]([C@@H:64]2[CH2:68][CH2:67][CH2:66][N:65]2[C:29](=[O:30])[CH2:28][C@@H:27]([O:43][CH3:44])[C@@H:26]([N:25]([CH3:49])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[C@@H:45]([CH3:48])[CH2:46][CH3:47])[O:69][CH3:70])[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=[CH:57]1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCCC1C=CC=CC=C1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a solution of #174 (706 mg, 1.02 mmol, 1 eq.) and #64 (311 mg, 1.02 mmol, 1 eq.) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (400 mg, 3.07 mmol, 3 eq.). After 18 hours of stirring at room temperature, the reaction was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #175 (560 mg, 68%) as a white solid. LC-MS (Protocol Q1): m/z 611.8 [M+H+], retention time=1.15 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[OH:13][CH:14]([CH2:18][CH2:19]Br)[CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[OH:13][CH:14]1[CH2:18][CH2:19][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)[CH2:16][CH2:15]1
Reactant: OC(CCBr)CCBr
Reactant: Nc1ccc2[nH]c(=O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2cc(N3CCC(O)CC3)ccc2[nH]1
Temperature: 100 °C

Procedure:
A mixture of 6-aminocarbostyril, 1.6 g (0.01 mole), crude bromopentanes from step c, 3.1 g, anhydrous sodium carbonate, 2.0 g (0.020 mole), and dimethylformamide, 15 mL, was heated for 4.5 hours at 100° C. with occasional stirring. The mixture was then cooled and diluted with water, 150 mL, to give a pasty precipitate which was filtered off and washed with water to give a sticky solid (2.9 g). The solid was taken up in hot methanol and the insoluble material filtered off (0.6 g, mp 270°-280° C.). Further treatment with hot methanol gave 0.4 g of the desired product, mp 280°-283° C.
Reaction SMILES: C(O[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6])C.[N+:10]([CH:13]([CH3:15])[CH3:14])([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:14][C:13]([N+:10]([O-:12])=[O:11])([CH3:15])[CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8]
Reactant: CCOC(O)C(F)(F)F
Reactant: CC(C)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 6 h

Procedure:
A mixture of triflouroacetaldehyde ethyl hemiacetal (2.58 ml), 2-nitropropane (1.81 ml) and potassium carbonate (111 mg) is stirred at 65° C. (oil bath temperature) for 6 hours followed by 2.5 days at room temperature. The reaction mixture is diluted with water (100 ml) and extracted with methylene chloride (100 ml+5×50 ml). The combined organic layers are dried over sodium sulphate and the solvent is evaporated under reduced pressure. Purification of the liquid residue by flash chromatography on silica gel (eluant n-hexane/ethylacetate 85:15) affords 3-methyl-3-nitro-1,1,1-trifluorobutan-2-ol as an oil (2.005 g)
Reaction SMILES: [CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[NH:10]/[C:9](=[N:15]\[NH2:16])/[N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:22](OCC)(OCC)(OCC)[CH3:23]>>[CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[N:10]4[C:22]([CH3:23])=[N:16][N:15]=[C:9]4[N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=3[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Product: CCCCCn1c2nc(C3CCC3)[nH]c2c(=O)n2c(C)nnc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
(2E)-8-cyclobutyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (100 mg, 0.0003 mol) was mixed with triethyl orthoacetate (10 mL, 0.05 mol) and then stirred at 100° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by preparative LCMS to yield the desired product (10 mg, 9.2%). 1HNMR (300 MHz, CD3OD): δ 4.35 (m, 2H), 3.72 (m, 1H), 2.84 (s, 3H), 2.44 (m, 4H), 2.05 (m, 2H), 1.90 (m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMS calculated for C16H23N6O(M+H): 315.2; found: 315.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2-].[Na+].N.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][N:11]=1>O1CCOCC1>[N:1]1([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1ncc(C2CCCCC2)c2ccccc12
Reactant: c1c[nH]cn1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc2c(-n3ccnc3)ncc(C3CCCCC3)c2c1

Procedure:
3.4 g (50 mmoles) of imidazole were allowed to react with 1.9 g (49 mmoles) of sodium amide in 50 ml of absolute dioxane until the evolution of ammonia was finished. Then 9 g (37 mmoles) of 1-chloro-4-cyclohexyl-isoquinoline were added and the solvent was evaporated. The reaction mixture was heated for 3 hours to 140° C, distributed between methylene chloride and water and the organic phase was evaporated after having been dried over magnesium sulfate. The oily crude product was taken up in 30 ml of ether and crystallized upon trituration. M.p. 92° to 93° C, hydrochloride M.p. 228° to 229° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>C(OC(=O)C)(=O)C>[F:1][C:2]1[N:7]=[C:6]([N+:15]([O-:17])=[O:16])[C:5]([NH:8][C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(Nc1ccc(F)nc1)C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=C(Nc1ccc(F)nc1[N+](=O)[O-])C1CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
[step 2] N-(6-fluoropyridin-3-yl)cyclobutanecarboxamide (800 mg, 4.12 mmol) obtained in step 1 was dissolved in acetic anhydride (4 mL), fuming nitric acid (0.7 mL, 15.7 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Under ice-cooling, 5 mol/L aqueous sodium hydroxide solution was added dropwise to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 v/v) to give N-(6-fluoro-2-nitropyridin-3-yl)cyclobutanecarboxamide (348 mg, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[N:6][CH:7]=1.[OH:11]S(O)(=O)=O>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH2:10])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: N#CCc1cncc(Br)c1
Reactant: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: NC(=O)Cc1cncc(Br)c1
Temperature: 110 °C

Procedure:
(5-Bromo-pyridin-3-yl)-acetonitrile (1 g, 5.1 mmol) was dissolved in a mixture of EtOH (20 ml) and water (1.2 ml). H2SO4 (6.8 ml) was then added to the mixture and the mixture was heated at ˜110° C. for 24 hrs. Solvent was removed under vacuo, taken up in EtOAc and washed with 2N Na2CO3 solution. Drying and evaporation gave a crude oil which was sufficiently pure for the next step. Alternatively, the above crude was dissolved in 7N NH3— MeOH (20 ml) and stirred at R.T over the weekend. Solvent was evaporated and purified by flash column eluting with DCM-MeOH (95:5) to obtain a yellow colored material (0.9 g).
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(F)cccc1C(=O)OCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOP(=O)(OCC=C)OCc1c(F)cccc1C(=O)O

Procedure:
According to a similar procedure to that described in Example 4-(6), 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-fluorobenzoate (1.40 g, 3.12 mmol) obtained in Example 6-(1) was reacted with anisole (1.4 g, 12.9 mmol) and trifluoroacetic acid (5 ml), and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-fluorobenzoic acid as a crude product. According to a similar procedure to that described in Example 4-(6), the crude product obtained above, oxalyl chloride (1.98 g, 15.6 mmol), and N,N-dimethylformamide (15 μl) were reacted, and the reaction mixture was worked up to afford 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-fluorobenzoyl chloride as a crude product.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:8]=[CH:9][CH:10]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CC(C)([O-])C.[K+]>CC(N(C)C)=O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: COCOc1cccc(CCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCOc1cccc(CCc2ccccc2OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 68.4 %

Procedure:
Following a procedure similar to that described in Example: 40(a), 1.58 g of 2-[2-(3-methoxymethoxyphenyl)ethyl]phenol, 2.34 g of 1-t-butoxycarbonyl-4-[2-(p-toluenesulfonyloxy) ethyl]piperidine and 0.686 g of potassium t-butoxide were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.96 g (yield 68%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.C(O)(=O)C.[C-:14]#[N:15].[K+]>CS(C)=O>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:14]#[N:15]
Reactant: OCc1ccccc1O
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: N#CCc1ccccc1O
Temperature: 125 °C
Reaction time: 2 h

Procedure:
29.8g of 2-hydroxybenzyl alcohol are dissolved in 250 ml of dimethylsulfoxide, together with 18g of potassium cyanide, and the mixture is heated to 125°C. 16g of glacial acetic acid are then added dropwise over the course of 1 hour and the mixture is stirred for a further 2 hours at 125°C. The dimethylsulfoxide is removed in vacuo and the residue is stirred with 200 ml of water and 150 ml of chloroform. The chloroform phase is separated off and the aqueous phase is re-extracted with 150 ml of chloroform. The combined chloroform phases are extracted by shaking with water and dried with sodium sulfate. After distilling off the chloroform, an oil remains, which solidifies on cooling. Yield: 19.8g = 60.5% of theory. Recrystallization from benzene/ligroin: melting point 118°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A solution of tert-butyl-4-[4-(methoxycarbonyl)phenyl]-1-piperidinecarboxylate (3.95 g) in a mixture of methanol (80 ml), THF (40 ml) and 4N sodium hydroxide (30 ml) was stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo. To a residue was added water (100 ml) and adjusted to pH 3 with 1N hydrochloric acid. The solution was extracted twice with a mixture of ethyl acetate (100 ml) and THF (50 ml). The extracts was dried over magnesium sulfate and evaporated in vacuo to give 4-[1-(tert-butoxycarbonyl)-4-piperidyl]benzoic acid (3.64 g).
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[Br:11][CH2:12][CH2:13][CH2:14]Br.[OH-].[Na+]>>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH2:14][CH2:13][CH2:12][Br:11])([CH3:1])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)C(=O)OC
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C(C)(CCCBr)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
NaH at 60% in mineral oil (1.63 g, 40.8 mmol. 1.3 eq) was washed three times with hexane and subsequently dried. After addition of dried THF (30 mL) the suspension was cooled to 0° C. Dimethyl methylmalonate (4.7 g, 32.3 mmol, 1.0 eq) was slowly and carefully added and gas development was observed. The mixture was stirred for 15 minutes and subsequently 1,3-dibromopropane (24 g, 119.0 mmol, 3.7 eq) was added in one portion. The mixture was allowed to reach room temperature and was then stirred for further 16 hours. NaOH 1.0 M solution was added, the crude was extracted with ethyl acetate; the organic layers were collected and dried, the obtained oil was purified by SiO2 column (elution: cyclohexane followed by EtOAc). The title product (6.6 g, 76% yield) was obtained.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:18])[CH2:9][NH:10]C(=O)OC(C)(C)C)#[N:2].C(#N)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:10][CH2:9][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[C:1]#[N:2])=[O:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N#C[C@@H]1CCCN1C(=O)CN
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The nitrile obtained from step 4 (1.21 g, 4.78 mmol) was dissolved in acetonitrile (9.95 mL, 191.3 mmol) and cooled to 0° C. Trifluoroacetic acid (7.1 mL, 96.63 mmol) was added dropwise. The solution was stirred overnight, concentrated and washed with ether (2×15 mL) to yield the crude product as an orange oily substance Yield: 2.00 g, 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:17])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Yield: 99.6 %

Procedure:
A heterogeneous mixture comprising 3-methoxy-4-nitrobenzoic acid (15.42 g, 78.2 mmol) and thionyl chloride (70 mL, 391 mmol) was heated at reflux for one hour. The excess thionyl chloride was removed by distillation and the residue was concentrated in vacuo to provide 3-methoxy-4-nitrobenzoyl chloride (16.8 g, 99% yield) as a light yellow solid; MS (PB-PCI) C8H6CINO4 m/e calc 215.59; found 216 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][C:20](=[O:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][C:10]21OCC[O:11]2.Cl>>[CH3:26][CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[C:20](=[O:27])[CH:19]=[CH:18][CH:17]1[CH2:16][CH2:15][C:10](=[O:11])[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CCCCC(C)C(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Agent: Cl
Product: CCCCC(C)C(=O)C=CC1CCC(=O)C1CCCCCCCO
Temperature: 60 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixture of 6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (1.0 g.) and hydrochloric acid (25 ml; 1N) was stirred at 60° C. for 2 hours, cooled to ambient temperature and extracted with diethyl ether. The ether extract was washed with 2N aqueous sodium carbonate solution and water respectively then dried over magnesium sulphate. Removal of the solvent under reduced pressure gave a crude product (0.7 g.) which was purified by preparative thin layer chromatography on silica gel, using a mixture of diethyl ether, ethyl acetate and hexane (2:1:1 v/v) as eluant, to give 7-[2-(4-methyl-3-oxooct-1-enyl)-5-oxocyclopentyl]heptanol (0.38 g.), νmax (liquid film) 3450 cm-1, 1730 cm-1, 1690 cm-1, 1660 cm-1, 1380 cm-1, 995 cm-1 ; λmax. (ethanol) 230 nm (ε = 13,600); Elemental analysis: Found: C, 74.9; H, 11.0%; C21H36O3 requires C, 74.95; H, 10.8%; N.M.R. (approximately 10% solution in deuterochloroform): Triplets at 3.57 δ (J = 6 cycles/sec.) and 0.88 δ, doublet of doublets at 6.81 δ (J = 15.5 cycles/sec. and J = 7 cycles/sec.), doublets at 6.20 δ (J = 15.5 cycles/sec.) and 1.11 δ (J = 7 cycles/sec.), broad singlet 2.0 δ.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.C1COCC1.O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[CH2:7][OH:8]
Reactant: O=C(O)c1cc(Br)ccc1I
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-Bromo-2-iodobenzoic acid (100 g, 0.306 mol) is dissolved in THF (350 mL) and cooled in an ice bath. Borane-THF complex (460 mL of 1 M in THF, 0.460 mol) is added dropwise. After addition is complete, the reaction is warmed to room temp and stirred for 14 hours. The mixture is transferred a large erlenmeyer flask (4 L), cooled in an ice bath and carefully quenched with water (250 mL). Evaporation of the THF by rotary evaporator gives a white suspension which is treated with additional water (1 L) and then filtered and dried in a vacuum dessicator over P2O5 to give 5-bromo-2-iodobenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[H-].[Na+].Br[CH2:15][C:16]([CH3:18])=[CH2:17]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([I:9])[C:7]=1[O:8][CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: C=C(C)CBr
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)COc1c(I)cc(CO)nc1Cl
Reaction time: 0.5 h
Yield: 86 %

Procedure:
2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2) (6.3 g, 22 mmol) is dissolved in 30 mL DMF in a dry flask under N2. The flask is placed in an ice bath, and 60% sodium hydride in mineral oil (880 mg, 22 mmol) is added. The reaction is stirred 30 min while the flask is kept in an ice bath. The ice bath is removed for 30 min and then the flask is placed back into the ice bath to cool the reaction. 3-Bromo-2-methylpropene (23.1 mmol) is added, and the reaction is stirred overnight at rt. The reaction is diluted with 150 mL EtOAc and is washed with 4×50 mL 50% saturated 1:1 NaCl/NaHCO3. The organic layer is dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo to a pale oil which is crystallized from hexanes to afford (6-chloro-4-iodo-5-[(2-methyl-2-propenyl)oxy]-2-pyridinyl)methanol (C19) (86% yield). HRMS (FAB) calculated for C10H11C11NO2+H: 339.9603, found 339.9604 (M+H).