Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH3:11].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[C:7]#[N:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C#N)cc1C
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C#N)cc1CBr
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To 9.8 g of 4-methoxy-3-methylbenzonitrile, were added 150 ml of carbon tetrachloride, 10 g of NBS, and 0.4 g of BPO. The mixture was heated under reflux for 2.5 hours. The reaction mixture was cooled in ice, filtered from insolubles and concentrated under reduced pressure. The residue was admixed with n-hexane, stirred for 30 minutes, and collected by filtration to yield 9 g of 3-bromomethyl-4-methoxybenzonitrile; m.p. 102°-103° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[S:7].C(=O)([O-])[O-].[Na+].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:23]([CH2:33][C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[O:35])[N:22]=2)=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[N:23]([CH2:33][C:34]([N:36]3[CH2:37][CH2:38][N:39]([C:6]4[S:7][CH2:2][CH2:3][CH2:4][N:5]=4)[CH2:40][CH2:41]3)=[O:35])[N:22]=2)=[CH:19][CH:20]=1
Reactant: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCNCC1
Reactant: S=C=NCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(C2=NCCCS2)CC1
Temperature: 60 °C

Procedure:
0.08 mL 1-bromo-3-isothiocyanato-propane and 305 mg sodium carbonate were added to 250 mg 2-(3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-1-piperazin-1-yl-ethanone in 5 mL chloroform. The reaction was stirred over night at 60° C. The reaction was filtered over silicagel and the solvent was evaporated. The residue was crystallized from diethylether to yield 206 mg of the desired compound. Rt: 1.17 min (method B), (M+H)+: 483
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]([OH:16])=[O:15])([C:11](O)=[O:12])[CH2:10][CH2:9]1.S(Cl)(Cl)=O.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C1COCC1.C(OC(C)C)(=O)C>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:11]([C:8]2([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[O:12])=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)C1(C(=O)O)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reaction time: 0.5 h

Procedure:
Triethylamine (8.0 kg) was added to a cooled (approximately 4° C.) solution of commercially available cyclopropane-1,1-dicarboxylic acid (2 1, 10.0 kg) in THF (63.0 kg) at a rate such that the batch temperature did not exceed 10° C. The solution was stirred for approximately 30 minutes, and then thionyl chloride (9.0 kg) was added, keeping the batch temperature below 10° C. When the addition was complete, a solution of 4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such that the batch temperature did not exceed 10° C. The mixture was stirred for approximately 4 hours and then diluted with isopropyl acetate (87.0 kg). This solution was washed sequentially with aqueous sodium hydroxide (2.0 kg dissolved in 50.0 L of water), water (40.0 L), and aqueous sodium chloride (10.0 kg dissolved in 40.0 L of water). The organic solution was concentrated by vacuum distillation followed by the addition of heptane, which resulted in the precipitation of solid. The solid was recovered by centrifugation and then dried at approximately 35° C. under vacuum to afford the title compound. (10.0 kg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1>>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[CH:6][N:5]=2)[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1ccccc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Yield: 94.8 %

Procedure:
The same procedure was used as described in Example 9 starting from (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone (125.4 mg, 0.3902 mmol, Example 6) and 4-amino-1-Boc-piperidine (101.0 mg, 0.484 mmol, Astatech) to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (158.2 mg, 95% yield). HRMS, observed: 428.2296; Calcd for (M+H)+: 428.2293.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:32][C:33](=[NH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH3:16])[CH:10]([C:11]1[O:13][N:40]=[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:32]=1)[OH:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(NO)c1ccccc1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethane (10 mL) was added and then 4-methylmorpholine (1 mL). The reaction mixture was stirred at ambient temperature for 16 h. After dilution with ethyl acetate (200 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80° C. for 15 h. The pyridine was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (eluent:ethyl acetate) to yield 2(S)-tert-butoxycarbonylamino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)butan-1-ol (290 mg, 0.83 mmol). 2(S)-tert-butoxycarbonylamino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)butan-1-ol (145 mg, 0.41 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (4 mL) was added. After stirring for 1 h, the reaction mixture was evaporated to dryness to yield 2(S)-amino-1-(3-phenyl-[1.2.4]oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[C@@H:10]([OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:13][C@@H:11]1[C@@H:10]([OH:19])[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Temperature: 120 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
(3R,4R)-1-Benzyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine (835 mg), sodium azide (381 mg), and N,N-dimethylformamide (12 mL) were mixed with one another and the mixture was stirred at 120° C. for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure. To the resulting residue, water (10 mL) was added and the mixture was extracted with diethyl ether (2×30 mL). The diethyl ether extracts were combined and the combined extract was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate: methanol=20:1) to give 576 mg of (3R,4R)-3-azidomethyl-1-benzyl-4-hydroxypyrrolidine as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]([F:42])([F:41])[F:40])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:38])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:39]([F:42])([F:40])[F:41])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:29][CH:30]=3)=[O:16])[C:10](=[O:38])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2ccncc2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(NC(=O)C(Cc2ccncc2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1

Procedure:
383 mg (0.62 mmol) of tert-butyl 4-{[2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoyl]amino}benzoate (racemate) (Example 10.1C) were hydrolysed with TFA according to General Method 2. Yield: 180 mg (53% of theory)
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][C:10]1([CH3:32])[CH2:15][CH:14]([NH:16][CH2:17][CH2:18][NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[CH2:13][C:12]([CH3:31])([CH3:30])[NH:11]1>O>[CH2:3]([O:2][C:1]([N:16]([CH:14]1[CH2:15][C:10]([CH3:32])([CH3:9])[NH:11][C:12]([CH3:31])([CH3:30])[CH2:13]1)[CH2:17][CH2:18][N:19]([C:1]([O:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:7])[CH:20]1[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOC(=O)Cl
Reactant: CC1(C)CC(NCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Solvent: O
Product: CCCCOC(=O)N(CCN(C(=O)OCCCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1

Procedure:
120.2 g (0.88 mol) of butyl chlorocarbonate are reacted as described in Example 1 with 135.4 g (0.4 mol) of N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,2-ethanediamine dissolved in 410 ml of water.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:5]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:4][NH:3]1.[Li+].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.IC.[Cl-].[NH4+]>C1COCC1>[CH3:27][N:3]1[CH2:4][CH:5]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[C:2]1=[O:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ccc(C2CNC(=O)C23CCCN(C(=O)OC(C)(C)C)C3)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(C2CN(C)C(=O)C23CCCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 1-oxo-4-p-tolyl-2,7-diazaspiro[4.5]decane-7-carboxylate (333 mg, 0.967 mmol) in dry THF (6 ml) at −60° C. under nitrogen was added LiHMDS 1M in THF (1.26 ml, 1.257 mmol) dropwise and the mixture was left to stir at −60° C. for 1 hr. After this time a solution of iodomethane (79 ul, 1.257 mmol) in dry THF (1 ml) was added dropwise at −60° C. and the reaction mixture was allowed to warm from −60° C. to room temperature over 1 hr. After a further 3 hrs at room temperature the reaction mixture was added to sat. ammonium chloride (25 ml), extracted with EtOAc (3×25 ml) and the combined organics were washed with brine (25 ml), dried (MgSO4) and concentrated under reduced pressure to give the crude product as an orange oil. The crude material was purified via silica chromatography eluting with 20-80% iso-hexane/EtOAc. The appropriate fractions were combined and concentrated to give the product as a yellow solid (270 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[OH-].[Na+:23]>CO>[CH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([O-:19])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[Na+:23]
Reactant: C=Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)[O-])cc1

Procedure:
To a solution of 300 mg of 5-(4-vinylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in pb 5 ml of methanol is added 1 molar equivalent of sodium hydroxide, in the form of a 0.1 N solution. The solvent is taken up in 2 ml of methanol, followed by precipitation with ether, to yield crude sodium 5-(4-vinylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylate which can be crystallized from ethyl acetate-hexane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]([CH3:18])[CH2:10][O:11]C2CCCCO2)[C:3]=1[F:19].O.C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]([CH3:18])[CH2:10][OH:11])[C:3]=1[F:19]
Reactant: CC(COC1CCCCO1)c1ncc(F)c(Cl)c1F
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(CO)c1ncc(F)c(Cl)c1F
Temperature: 45 °C

Procedure:
The product of Step 1 is dissolved in 200 mL of 2:1 THF:water and to this solution is added 6 mL of acetic acid. The reaction mixture is heated at 45° C. for approximately 5 hours. The THF is removed under reduced pressure and the aqueous reaction mixture is adjusted to a pH in the range of 8 to 9 with 10% sodium carbonate and is then extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([O:11][C:12]([N:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][O:16][S:15]1=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].P([O-])([O-])(O)=[O:24].[Na+].[Na+].Cl>O.C(#N)C.O.[Ru](Cl)(Cl)Cl>[C:7]([O:11][C:12]([N:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][CH2:17][O:16][S:15]1(=[O:24])=[O:22])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=P([O-])([O-])O
Reactant: CC(C)(C)OC(=O)N1S(=O)OCCC1(C)C
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of ruthenium(III)chloride hydrate (440 mg, 2.12 mmol, 0.003 equiv) and sodium metaperiodate (132.2 g, 0.62 mol) in water (1.5 l) is stirred for 45 min and added at a temperature of 20-25° C. over a period of 35 min to a suspension of the crude product of Step b (140 g) in a mixture of acetonitrile (0.6 l) and saturated aqueous solution of disodium hydrogen phosphate (0.3 l). During the addition the pH of the suspension is kept between 6.9 and 7.3 by the continuous addition of additional saturated aqueous solution of disodium hydrogen phosphate (1.0 l). After the addition has ended the reaction mixture is stirred for 1 hour at 20° C., the pH is adjusted to 6.4 with 1 M hydrochloric acid and then stirring is continued for a further hour. The solid is collected by filtration, washed with water (3×100 ml) and lastly stirred for 2 hours with water (1.5 l). The crystals are isolated by filtration, washed with water (3×0.1 l) and dried at 50° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[F:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[O:24][CH2:25][CH2:26]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:26][CH2:25][O:24][C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[F:21])=[CH:7][CH:6]=1
Reactant: OCCOc1ccccc1F
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccccc2F)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(2-fiuorophenoxy)ethanol (1.17 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The dichloromethane extract was evaporated and the residue was purified by HPLC (dichloromethane-hexane; 4:1) and the resulting solids were crystallized from dichloromethane-diethyl ether to give 0.8 g of 4-[[2-(2-fiuorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 112°-113° C.
Reaction SMILES: [OH:1][CH:2]([C:28]([F:31])([F:30])[F:29])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:7][CH:6]=1>C(I)CCC.[Ag]=O>[CH2:28]([O:1][CH:2]([C:28]([F:30])([F:31])[F:29])[CH:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][N:12]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(O)C(F)(F)F)cc2)nc1
Agent: O=[Ag]
Solvent: CCCCI
Product: CCCCCCCCCCOc1cnc(-c2ccc(C=CC(OCCCC)C(F)(F)F)cc2)nc1
Reaction time: 96 h
Yield: 173.7 %

Procedure:
1.0 g of (-)-2-(4-(3-hydroxy-4,4,4-trifluoro-1-butenyl) phenyl)-5-decyloxypyrimidine was dissolved in 5 ml of butyl iodide. The solution was added with 3 g of silver oxide and stirred at 25°-30° C. for 4 days. The reaction mixture was cleared of silver oxide by filtration and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 0.98 g of (-)-2-(4-(3-butoxy-4,4,4-trifluoro-1-butenyl)phenyl)-5-decyloxypyrimidine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:2]1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][C:43](O)=[O:44])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[C:43](=[O:44])[CH2:42][CH:38]2[CH2:39][CH2:40][CH2:41][N:37]2[C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:36])=[N:2]1
Reactant: COc1ccc(-c2ccc(CNCCCNc3nsc4ccccc34)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CC(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(CN(CCCNc3nsc4ccccc34)C(=O)CC3CCCN3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
N1-(Benzo[d]isothiazol-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine (100 mg, 0.25 mmol), 2-carboxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (68 mg, 0.34 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarboduimide hydrochloride (58 mg, 0.30 mmol) were dissolved in anhydrous methylene chloride (10 mL). Diisopropylethylamine (52 μL, mmol) added to the mixture. The reaction was allowed to stir overnight at room temperature. The solution was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 3:1 hexanes:ethyl acetate yielded tert-butyl 2-(2-((3-(benzo[d]isothiazol-3-ylamino)propyl)((4′-methoxybiphenyl-4-yl)methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate as a solid (30 mg). 1H NMR (300 MHz, CDCl3): 7.90-7.95 (m, 1H), 7.75-7.85 (m, 1H), 7.35-7.55 (m, 6H), 7.19-7.25 (m, 2H), 6.95-7.00 m, 2H), 4.90-5.00 (m, 1H), 4.55-4.65 (m, 2H), 4.19-4.25 (m, 1H), 3.85 (s, 3H), 3.55-3.65 (m, 2H), 3.30-3.35 (m, 2H), 3.10-3.19 (m, 1H), 2.35-2.45 (m, 1H), 2.05-2.15 (m, 1H), 1.80-1.90 (m, 4H), 1.50 ppm (s, 9H). MW=615 confirmed by LC-MS, tr=5.12 min (Method B) MH+=614-616.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]CCCC(OC)=O)(OC)=O.[OH2:19]>>[CH3:1][C@H:5]([OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)CCCCCCCCCCC(=O)OC
Reactant: O
Product: CCCCCC[C@H](C)O

Procedure:
Interesterification was carried out in the same manner as in Example 13, except for replacing dimethyl tetradecadicarboxylate with 140 g of dimethyl decamethylenedicarboxylate at 80° C. for 25 hours. The water content of the reaction system was 0.04% by weight, and 95% of the lipase particles had a particle size of 20 to 60 μm. Gas chromatography of the reaction mixture revealed that 58 mol % of (R,S)-2-octanol had been converted to its decamethylenedicarboxylic acid esters. The reaction mixture was treated in the same manner as in Example 13 to remove lipase, and the filtrate was subjected to simple distillation at 95° C. and 3 mmHg. It was impossible to isolate (S)-(-)-2-octanol with high purity due to co-distillation of other components.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:6]1[C:7]([F:17])=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][CH:10]=[CH:9]2)[CH3:5].O.[NH2:20][NH2:21]>C(O)C>[F:17][C:7]1[C:6]([CH:4]([CH3:5])[C:3]([NH:20][NH2:21])=[O:2])=[C:15]([F:16])[CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: COC(=O)C(C)c1c(F)cc2ncccc2c1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C(=O)NN)c1c(F)cc2ncccc2c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(5,7-Difluoro-quinolin-6-yl)-propionic acid methyl ester (2.270 g, 9.57 mmol) in ethanol (25 mL) was added hydrazine monohydrate (3 mL, 96 mmol), and the reaction mixture was stirred at 25° C. overnight. Solvent was removed under reduced pressure, and the residue was used without further purification. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.06 (s, 1H), 8.97 (dd, 1H), 8.45 (d, 1H), 7.58-7.67 (m, 2H), 4.23 (br s, 2H), 4.08 (q, 1H), 1.51 (d, 3H). LCMS (method A): [MH]+=252, tR=3.82 min.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:21][CH2:20][NH:19][C:18]5=[O:22])=[CH:13][CH:12]=4)([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[C:38]#[N:39])=[O:32]>CS(C)=O.CCOC(C)=O>[O:22]=[C:18]1[NH:19][CH2:20][CH2:21][N:17]1[C:14]1[CH:13]=[CH:12][C:11]([C:4]23[CH2:10][CH:8]4[CH2:9][C:2]([NH:1][CH2:30][C:31]([N:33]5[CH2:37][CH2:36][CH2:35][C@H:34]5[C:38]#[N:39])=[O:32])([CH2:3]2)[CH:6]([CH2:7]4)[CH2:5]3)=[CH:16][CH:15]=1
Reactant: NC12CC3CC1CC(c1ccc(N4CCNC4=O)cc1)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCNC4=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.9 %

Procedure:
To a stirred mixture of the compound obtained from step II (0.4 g, 1.35 mmol) and K2CO3 (0.56 g, 4.05 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.23 g, 1.35 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.21 g) in 36% yield. m/z (M+1) 434; 1H NMR (CDCl3) 300 MHz δ 7.45 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 4.86-4.76 (m, 1H), 4.67 (s (br), 1H), 3.93 (t, J=7.4 Hz, 2H), 3.75-3.40 (m, 4H), 3.48 (s, 2H), 3.46-2.38 (m, 1H), 2.36-2.23 (m, 2H), 2.23-1.70 (m, 12H), 1.65-1.57 (m, 1H).