Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[NH2:14][N:15]1[C:19]([NH2:20])=[N:18][N:17]=[C:16]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(O)C(F)(F)F.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1[C:5]([NH:6]2)=[N:20][C:19]2=[N:18][N:17]=[C:16]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:15]2[N:14]=1
Reactant: O=C1Nc2c(Cl)ccc(Cl)c2C1=O
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Solvent: O
Solvent: OCC(F)(F)F
Product: Oc1ccc(Cc2nnc3nc4[nH]c5c(Cl)ccc(Cl)c5c4nn23)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
In a pressure tube, 0.60 mmol of 4,7-dichloro-1H-indole-2,3-dione (130 mg) and 0.65 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (133.5 mg) in a mixture of trifluoroethanol (8 mL) and water (4 mL) was stirred at 125° C. overnight (16 hr). The mixture was cooled to room temperature, allowed to crystallize for 2 hours. The precipitated product was collected by filtration, washed with MeOH+water 1:1, then with chilled MeOH. Dried on high vacuum.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[O:17]1[CH2:18][CH2:19][N:14]([C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C1CCCCCCCCCCC1
Product: C1=C(N2CCOCC2)CCCCCCCCCC1

Procedure:
There is disclosed a process for the preparation of long-chain carbon compounds characterized by: (a) reacting cyclododecanone with morpholine in the presence of a catalyst to form 1-morpholino-1-cyclododecene; (b) separating the 1-morpholino-1-cyclododecene and reacting it with an organic acid halide of 15-20 carbon atoms in the presence of a tertiary amine in an organic solvent while maintaining the reaction temperature at 0°-10° C. followed by (c) hydrolysis under acidic conditions, thereafter (d) separating the 2-n-alkyl-cyclotetradecanedione and reacting with a solution of alkali metal hydroxide and diethylene glycol at 90°-110° C. followed by (e) addition of hydrazine hydrate and the reaction mixture is refluxed at 125°-135° C. thereafter (f) the distillate is removed until the temperature of the reaction mixture climbs to 190°-210° C. where it is refluxed for 3 to 20 hours with slow stirring, and then (g) cooled to 110°-125° C. followed by addition of hot (80°-95° C.) water with rapid stirring followed by (h) neutralization with aqueous acid to a pH of 2 to yield the carboxylic acid which is separated and purified by recrystallization which is then (i) dissolved in tetrahydrofuran under an inert atmosphere and has added thereto the reducing agent, borane-methyl sulfide complex with stirring and heated to 40°-65° C. for 2 to 3 hours before cooling to ambient temperature followed by the sequential addition of methanol and water to quench excess borane reagent followed by (k) separation and purification of the long chain alcohol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.Cl>C(OCC)C.O>[F:8][C:4]1[CH:3]=[C:2]([C:13]2([OH:17])[CH2:14][CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC1CCCC(=O)C1
Reactant: Fc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CC1CCCC(O)(c2cccc(F)c2)C1
Temperature: 5 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
A solution of 50.0 g (0.28 mole) of 3-bromofluorobenzene in 100 ml of diethyl ether was added dropwise with stirring to a cooled reaction vessel containing 7.0 g (0.29 mole) of freshly dried magnesium turnings. The reaction began after 10-20% of the 3-bromofluorobenzene-ether solution had been added. The remainder of the addition was done at a rate sufficient to promote gentle reflux. Upon complete addition an additional 210 ml of diethyl ether was added and the reaction mixture was heated under reflux for 1 hour. The reaction mixture was cooled to 5° C. and 32.5 g (0.29 mole) of 3-methylcyclohexanone in 100 ml of diethyl ether was added dropwise during 30 minutes. Upon complete addition the reaction mixture was stirred for 1 hour at 5° C., heated to reflux temperature for 30 minutes, then allowed to cool to ambient temperature and stand for 16 hours. The reaction mixture was slurried in 450 ml of water and made acidic with aqueous 10% hydrochloric acid. The two phases were separated and the aqueous phase was extracted with three portions of diethyl ether. The combined ether extracts and organic phase were washed with two portions of a saturated aqueous solution of sodium bicarbonate, then one portion of water. The organic layer was dried with sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 58.0 g of 1-(3-fluorophenyl)-3-methyl-1-cyclohexanol as a solid. The compound was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].C(O[CH2:39][CH3:40])(=O)C.[C:41](OCC)(=O)[CH3:42]>>[ClH:34].[CH2:1]([O:8][C:9](=[O:33])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]3[C:30](=[CH:41][CH:42]=[CH:39][CH:40]=3)[CH:31]=2)=[CH:22][CH:21]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)C(=O)OCc1ccccc1
Agent: Cl
Product: N[C@@H](Cc1ccc(-c2ccc3ccccc3c2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 82 %

Procedure:
To a solution of N-tert.-butoxycarbonyl-4-(4-fluorophenyl)-L-phenylalanine benzyl ester (700 mg) in ethyl acetate (3.2 ml) was added 4.1N hydrogen chloride/ethyl acetate (3.8 ml). The mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo to give 3.1 g (82%) of the titled compound (reference compound No. 1-1).
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C@H:13]([C:15]([N:17]1[C:23](=[O:24])[CH:22]([CH3:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[C:19]2[C:30]([NH2:34])=[CH:31][CH:32]=[CH:33][C:18]1=2)=[O:16])[CH3:14]>>[CH2:1]([NH:12][C@H:13]([C:15]([N:17]1[C:23](=[O:24])[CH:22]([CH3:25])[C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[C:19]2[C:30]([NH2:34])=[CH:31][CH:32]=[CH:33][C:18]1=2)=[O:16])[CH3:14])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: O=C(O)/C=C/c1ccccc1
Product: CC1C(=O)N(C(=O)[C@H](C)NC/C=C/c2ccccc2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure C-P above using trans-cinnamic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 440 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11](OCC)(=[O:14])[C:12]#[CH:13]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:11](=[O:14])[CH:12]=[CH:13][C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: C#CC(=O)OCC
Product: CC1(C)CC(=O)c2ccc(=O)[nH]c2C1
Yield: 78.5 %

Procedure:
In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092.), 3-amino-5,5-dimethylcyclohex-2-en-1-one was reacted with ethyl propio-late to give the title compound as a light brown solid in 78.5% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1C1=CCNCC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
4-(2-Nitrophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.45 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 4 mL). After stirring for 0.5 hour at 50° C., the solvent was removed by evaporation and the residue triturated with diethyl ether to give the title compound as a white solid (0.29 g). LCMS m/z 205.2 [M+H]+. R.T.=3.80 min (Analytical Method 4).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-:5])=O.[O-]CC.[Mg+2].[O-]CC.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>CO.O1CCCC1>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])=[O:5]
Reactant: O=C(O)c1ccco1
Reactant: COC(=O)CC(=O)[O-]
Agent: CC[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
In 100 mL of methanol, was dissolved 5.90 g (50.0 mmol) of monomethyl malonate, and the resulting solution was mixed with 2.86 g (25 mmol) of magnesium ethoxide followed by stirring at room temperature for 4 hours. The reaction solution was concentrated and the residue was dried under reduced pressure. In 100 mL of tetrahydrofuran, was dissolved 2.80 g (25 mmol) of 2-furancarboxylic acid and the resulting solution was mixed with 4.45 g (27.4 mmol) of carbonyldiimidazole, followed by stirring for 1 hour. The reaction solution was added to a dry magnesium salt and stirred at room temperature for 19 hours. The reaction solution was concentrated; the residue was mixed with 100 mL of 1.5 N hydrochloric acid, extracted with ethyl acetate, and washed with an aqueous sodium hydrogencarbonate solution and saturated sodium chloride water. The resultant was dried over sodium sulfate anhydride, filtered, and concentrated. The residue was distilled (0.06 mmHg, 69 to 75) to give 2.93 g (17.4 mmol, 69.6%) of methyl 2-furancarbonylacetate as an anhydrous liquid. Similarly to Example 133, 65 mg (1.34 mmol, 58.1%) of dark yellow crystals were obtained from 2.93 g (17.4 mmol) of methyl 2-furancarbonylacetate.
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:5]=1[CH2:6][C:7]1[NH:8][CH2:9][CH2:10][N:11]=1)([CH3:3])[CH3:2].C1(N(Cl)C(=O)N(Cl)C(=O)N1Cl)=O.C1CCN2C(=NCCC2)CC1>>[CH:1]([C:4]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:5]=1[CH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1CC1=NCCN1
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)c1cccc(C(C)C)c1Cc1ncc[nH]1

Procedure:
2-(2,6-Diisopropyl-benzyl)-1H-imidazole was prepared from 2-(2,6-diisopropyl-benzyl)-4,5-dihydro-1H-imidazole (Example 4), TCCA and DBU in analogy to Example 194e): yellow crystals; MS (ISP): 243.4 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([C:32]#[CH:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][CH:35]([CH3:40])[CH2:36][CH2:37][CH2:38]O.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:38]([O:30][C:29](=[O:31])[CH2:28][C@@H:27]([C:32]#[CH:33])[NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:25])[CH2:37][CH2:36][CH:35]([CH3:40])[CH3:34]
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CC(C)CCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C#C[C@H](CC(=O)OCCCC(C)C)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (0.5 g), 4-methyl-1-pentanol 0.15 ml) and N,N-dimethylaminopyridine (13 mg) in dichloromethane (5 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g) at 0° C. After stirring at an ambient temperature overnight, the solution was evaporated in vacuo. The residue was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate, water and brine, dried over magnesium sulfate, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with CHCl3:MeOH (100:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine isohexyl ester (0.59 g) as an oil.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:22][C:21]=2[F:34])[CH2:16][CH2:15]1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:31]([CH:28]([CH2:29][CH3:30])[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][CH:14]([C:6]([OH:13])([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:19][CH2:18]2)=[C:21]([F:34])[CH:22]=1)=[O:33])[CH3:32]
Reactant: [Li]CCCC
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCC(C(=O)c3ccccc3)CC2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(O)(c1ccccc1)C1CCN(c2ccc(NC(=O)C(CC)CC)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of n-BuLi (1 mL, 2.5 M in hexanes) in THF (10 mL) at −78° C., N-[4-(4-benzoyl-piperidin-1-yl)-3-fluoro-phenyl]-2-ethyl-butyramide (200 mg, 0.50 mmol) in THF (10 mL) was added. After 10 min, the mixture was warmed to 25° C. and diluted with satd. aq. NaHCO3 (10 mL). The mixture was extracted with EtOAc, and the organic layer was concentrated and purified by PTLC to provide the title compound (130 mg, 57%). MS: 455.4. 1H NMR (CDCl3): 7.42-7.15 (m, 7H), 6.84 (t, J=9.1, 1H), 3.42 (d, J=11.7, 1H), 3.32 (d, J=11.7, 1H), 2.61-2.45 (m, 2H), 2.01-1.82 (m, 4H), 1.78-1.62 (m, 3H), 1.61-1.41 (m, 6H), 1.32-1.15 (m, 4H), 0.98-0.80 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:21])[CH:3]=1.[Br-].[CH:23]1([Zn+])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>C1COCC1.CN1C(=O)CCC1.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]>[Cl:21][C:4]1[CH:3]=[C:2]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=[CH:19][C:5]=1[CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]1=[O:18]
Reactant: [Zn+]C1CCCCC1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(C3CCCCC3)cc2Cl)CCN1C1CCCCC1
Yield: 83 %

Procedure:
Dissolve 3-(4-bromo-2-chlorobenzyl)-1-cyclohexylpyrrolidin-2-one (Example 55) (0.20 g, 0.54 mmol) in THF/NMP (10 mL/10 mL) under N2. Add Pd(dppf)Cl2 (0.04 g, 0.054 mmol) and cyclohexylzinc(II) bromide (1.08 mL, 0.5 M in THF) with stiring. Heat the reaction mixture to reflux for 4 hours until LC-MS shows the starting material has gone. Cool the reaction to room temperature and add water (20 mL). Extract the aqueous with EtOAc (3×50 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 10-50% of EtOAc-Hexane) to give 0.20 g (83%) of the title compound as a colorless oil: MS (APCI-pos mode) m/z (rel intensity) 374.3 (100), 376.3 (30).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35](O)=[O:36])[CH2:29][CH2:28]2)=[CH:22][C:21]=1[C:38]([F:41])([F:40])[F:39])([O-:19])=[O:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:28][CH2:29][CH:30]([O:33][CH2:34][C:35]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:16]=[CH:15][C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[N:8]=4)[CH2:6][CH2:5]3)=[O:36])[CH2:31][CH2:32]2)=[CH:22][C:21]=1[C:38]([F:39])([F:40])[F:41])([O-:19])=[O:18]
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of 2-(piperazin-1-yl)quinoline (150 mg, 0.70 mmol) in dichloromethane (30 ml) was added 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (300 mg, 0.83 mmol, 1.2 eq), EDAC.HCl (201 mg, 1.05 mmol, 1.5 eq), HOBt (142.6 mg, 1.06 mmol, 1.5 eq) and triethylamine (213 mg, 2.10 mmol, 3 eq). The resulting solution was stirred overnight at room temperature, quenched by the addition of water (50 ml), and then extracted with dichloromethane (3×50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to give a residue. The crude material was purified by Pre-TLC using 5% methanol in dichloromethane to elute. The product-containing fractions were combined and then concentrated under vacuum to afford 229 mg (580) of 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-(quinolin-2-yl)piperazin-1-yl]ethan-1-one as a yellow solid. (ES, m/z): [M+H]+ 558.40; 1H NMR (300 MHz, CDCl3): δ 7.94-8.03 (1, 2H), 7.71 (s, 1H), 7.55-7.65 (1, 2H), 7.28-7.30 (t, J=5.4 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.65 (m, 1H), 4.51 (d, J=7.5 Hz, 1H), 4.27 (s, 2H), 3.74-3.96 (1, 8H), 3.34-3.51 (1, 2H), 2.14-2.17 (1, 4H), 1.50-1.60 (m, 2H), 1.36-1.47 (m, 2H).
Reaction SMILES: C(OC([NH:8][CH:9]1[C:42](=[O:43])[N:11]2[C:12]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH:23]([CH3:25])[CH3:24])[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[NH2:8][CH:9]1[C:42](=[O:43])[N:11]2[C:12]([C:26]([O:28][CH:29]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[O:22][CH:23]([CH3:24])[CH3:25])[CH2:14][S:15][C@H:10]12
Reactant: CC(C)Oc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)[C@H]3SC2)c(=O)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Yield: 58.3 %

Procedure:
A solution of diphenylmethyl 7-(t-butoxycarbonylamino)-3-(3,4-dioxo-2-(2-propoxy)-1-cyclobutenyl)-3-cephem-4-carboxylate (300 mg, 0.496 mmol) and p-toluenesulfonic acid monohydrate (189 mg, 0.992 mmol) in acetonitrile (1.5 mL) was stirred for 1 hr at 22° C. The solution was applied to the Michel-Miller HPLPLC column. The column was eluted with acetonitrile-H2O (45:55, v/v) to remove the toluenesulfonic acid and then with acetonitrile-H2O (70:30, v/v) to elute the deblocked amine. The acetonitrile was removed on a rotary evaporator and the resulting mixture extracted twice with ethyl acetate. The combined extracts were washed (saturated NaCl), dried (Na2SO4), and concentrated to leave the title compound (146 mg, 58% yield) as a yellow powder.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Br[CH2:42][C:43]([N:45]1[C:50]([CH3:52])([CH3:51])[CH2:49][CH2:48][CH2:47][C:46]1([CH3:54])[CH3:53])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[C:50]([CH3:52])([CH3:51])[CH2:49][CH2:48][CH2:47][C:46]2([CH3:54])[CH3:53])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 6.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.4 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][C:13]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:14]=1[CH2:15][C:16]1[CH:27]=[C:26](Cl)[CH:25]=[CH:24][C:17]=1[O:18][CH:19]([CH3:23])[C:20]([OH:22])=[O:21])=[O:10])C1C=CC=CC=1.COC(=O)COC1C=CC(Cl)=CC=1CC1C=CC=CC=1O>>[Cl:33][C:30]1[CH:31]=[CH:32][C:13]([O:12][CH2:11][C:9]([O:8][CH3:1])=[O:10])=[C:14]([CH:29]=1)[CH2:15][C:16]1[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=1[O:18][CH:19]([CH3:23])[C:20]([OH:22])=[O:21]
Reactant: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)O
Agent: COC(=O)COc1ccc(Cl)cc1Cc1ccccc1O
Product: COC(=O)COc1ccc(Cl)cc1Cc1ccccc1OC(C)C(=O)O

Procedure:
The titled compound is prepared analogously to 2-[2-(2-benzyloxycarbonylmethoxy-5-chloro-benzyl)-4-chloro-phenoxy]-propionic acid by replacing [4-chloro-2-(5-chloro-2-hydroxy-benzyl)-phenoxy]-acetic acid benzyl ester with [4-chloro-2-(2-hydroxy-benzyl)-phenoxy]-acetic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.B1([C:24]2[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=2)OCCCO1>>[CH2:14]([N:13]([CH2:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:10]=2)[CH:6]=[CH:7]1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCN(CC)CCn1ccc2ccc(Br)cc21
Reactant: c1cncc(B2OCCCO2)c1
Product: CCN(CC)CCn1ccc2ccc(-c3cccnc3)cc21

Procedure:
(16.6 mg , 56%); from 6-bromo-1-(2-(N,N-diethylamino)ethyl) indole (30.7 mg, 0.101 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (33.0 mg,0.202 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:18][C@H:17]2[C@H:15]([O:16]2)[CH2:14][C@@H:13]1[C:19]([O:21][CH3:22])=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:18][C@H:17]([OH:16])[CH2:15][CH2:14][C@@H:13]1[C:19]([O:21][CH3:22])=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1C[C@H]2O[C@H]2C[C@H]1NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](O)C[C@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 39.4 %

Procedure:
To a mixture of methyl (1R,3S,4R,6S)-4-{[(benzyloxy)carbonyl]amino}-7-oxabicyclo[4.1.0]heptane-3-carboxylate (1.9 g, 6.2 mmol) in ethanol (30.0 mL) was added sodium tetrahydroborate (0.471 g, 12.4 mmol). The resulting mixture was stirred overnight (22 h) at room temperature. The reaction was quenched with sat. NH4Cl, then most of the solvent evaporated. The residue was taken up in EtOAc and washed with water, dried (Na2SO4), filtered and concentrated. The crude was purified on silica gel, eluted with 40-100% EtOAc in hexanes to give 0.75 g (39%) of the desired product. LCMS calculated for C16H22NO5 (M+H)+: m/z=308.1. Found: 308.0. 1H NMR (300 MHz, CDCl3) δ 7.36-7.28 (m, 5H), 6.02 (d, J=9.0 Hz, 1H), 5.05 (s, 2H), 4.03 (s, 1H), 3.87 (s, 1H), 3.64 (s, 3H), 2.68 (s, 1H), 2.22-2.11 (m, 1H), 1.97-1.67 (m, 5H), 1.42 (s, 1H) ppm.