Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.Cl[CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37].O>CN(C=O)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Reactant: CN(CCCCl)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCCN(C)Cc3ccccc3)cccc2c1Nc1ccccc1C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.2 g, 10 mmol) and potassium t-butoxide (5.0 g, 40 mmol) were dissolved in dry DMF (100 ml) and N-(3-chloropropyl)-N-methylbenzylamine hydrochloride (4.1 g, 16 mmol) added. The temperature was raised to 90° and the mixture stirred for 2 hours, then poured into water and extracted with ethyl acetate. Drying, evaporation of the solvent, chromatography (silica gel, 0-3% methanolic ammonia in chloroform) and crystallisation from ether gave 3-butyryl-4-(2-methylphenylamino)-8-(3-(N-benzyl-N-methylamino)propoxy)quinoline (0.7 g, 15%), m.p. 100°-102°.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.[C:18](O)(=[O:20])[CH3:19]>>[C:18]([O:1][CH:2]([CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: CCC(O)CCCCC1CCC2CC(=O)CC12
Product: CCC(CCCCC1CCC2CC(=O)CC12)OC(C)=O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The starting material from Example 3, 2-(5-hydroxyhept-1-yl)bicyclo[3.3.0]octan-7-one }hexahydro-4-(5-hydroxyheptyl)-2(1H)-pentalenone} (2.5 g, 10.5 mmoles) is diluted with glacial acetic acid (10 ml) and stirred in a 70° C. water bath for 4 hours. The reaction is cooled to room temperature and partitioned between ether (50 ml) and water (50 ml). The ether layer is separated and the aqueous phase extracted with ether (2×50 ml). The organic layers are combined, neutralized with a solution of saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (2.1 g, 7.4 mmoles).
Reaction SMILES: [C:1]([O:5][C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CCCC1)CC3)(=[O:4])[CH2:2][CH3:3].C(O)(=O)CC.[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]2[C@H:38]3[C@H:49]([CH2:50][CH2:51][C@:33]12[CH3:34])[C@:46]1([CH:47]=[O:48])[C:41](=[CH:42][CH2:43][CH2:44][C@@H:45]1C)[CH2:40][CH2:39]3>>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]2[C@H:38]3[C@H:49]([CH2:50][CH2:51][C@:33]12[CH3:34])[C@:46]1([CH:47]=[O:48])[C:41](=[CH:42][CH2:43][CH2:44][CH2:45]1)[CH2:40][CH2:39]3
Reactant: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C=O
Reactant: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CCCC[C@]4(CO)[C@H]3CC[C@]12C
Solvent: CCC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C=O)[C@@H]1CC[C@@H]2O

Procedure:
Substituting 4-androstene-17β,19-diol 17-propionate for the 17β-hydroxy-1α-methyl-4-androsten-19-one propionate above results in the preparation of 17β-hydroxy-4-androsten- 19-one propionate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1ccc(N)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N(c1ccc(C#N)nc1)[Si](C)(C)C
Yield: 63.5 %

Procedure:
About 6.17 g of 5-amino-2-pyridinecarbonitrile, 11.54 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 25.34 g of trimethylsilyl trifluoromethanesulfonate in 70 ml of toluene. The resulting mixture was heated to reflux for 2.5 hours and then evaporated under vacuum. The residue was extracted with 100 ml of hexane. The hexane layer was washed twice with saturated aqueous sodium bicarbonate solution (80 ml each time), dried with anhydrous sodium sulfate, and evaporated under vacuum, yielding 5-[bis(trimethylsilyl)amino]-2-pyridinecarbonitrile (BTMSAPyCN) as a green oil (8.67 g, 64% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 8.07 (doublet of doublets, 1H, aromatic proton), 6.70 (doublet of doublets, 1H, aromatic proton), 6.45 (doublet of doublets, 1H, aromatic proton), −0.16 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].C([O-])(=O)C([O-])=O>CCO>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:8][CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([I:23])=[CH:25][CH:26]=3)[CH2:13][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(OCCC2CCNCC2)c2ccccc2)cc1
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Ic1ccc(CN2CCC(CCOC(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
4-[2-(diphenylmethoxy)ethyl]piperidine (0.23 g, 0.77 mmol) was reacted with 4-iodo benzyl bromide (0.76 g, 2.5 mmol) and K2CO3 (1.00 g, 7 mmol) in EtOH (10 mL) to give a thick oil, 0.17 g (%). 1H NMR (300 MHz, CDCl3): 1.21-1.63 (7H, m), 1.87-1.93 (t, J=11 Hz, 2H, N(CH2)-), 2.79-2.83 (bd, J=12 Hz, 2H, N(CH2)-), 3.41-3.49 (4H, m), 5.31 (s, 1H, Ph2CHO-), 7.05-7.63 (14H, m, ArH). Free base was converted into its oxalate sale, m.p.=160-161° C. Anal. C27H30INO. (COOH)2.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@H:21]2[CH2:29][O:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])(=[O:19])=[O:18])=[C:12]([CH3:39])[CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][C@H:21]2[CH2:29][O:30][CH2:31][C:32]([OH:34])=[O:33])(=[O:19])=[O:18])=[C:12]([CH3:39])[CH:11]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (1.5 ml) was added to a cooled (0° C.) solution of (S)-tert-butyl 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)indolin-2-yl)methoxy)acetate (0.5 mmol) in DCM (6 ml) and the mixture was stirred for 2 h at room temperature. The solvent was removed under vacuum and the residue used in the subsequent stage.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH3:3].[CH2:15]([OH:17])[CH3:16]>C(OCC)C>[CH2:2]([O:4][C:5](=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:17][CH2:15][CH3:16])=[NH:13])[CH3:3]
Reactant: CCO
Reactant: CCOC(=O)CCCCCCC#N
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)CCCCCCC(=O)OCC
Yield: 117.7 %

Procedure:
Bubble hydrogen chloride gas into a solution of 7-cyanoheptanoic acid ethyl ester (3.7 g, 20.0 mmol) in ethanol (24 mL, 40 mmol) and diethyl ether (100 mL) at 0° C. for 15 minutes. Remove the solvent under reduced pressure to provide 7-ethoxycarbonimidoylheptanoic acid ethyl ester (5.4 g, >99%), which is used without further purification.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1>C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:29][CH2:28][C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1cccnc1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3cccnc3)c2)N1C

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted with 3.0 g of 3-picolyl amine and 5 g of triethyl amine according to Example 76, the solvent was distilled off under reduced pressure and the residue was taken up in 70 ml of water. Three extractions followed with 60 ml of ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue crystallized under diisopropyl ether. Melting point: 152° - 153° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][N+:16]([O-:18])=[O:17].C1CCN2C(=NCCC2)CC1>>[N+:16]([CH2:15][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2](=[O:1])[CH2:7]1)([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC=CC1=O
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(C[N+](=O)[O-])CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
A solution of tert-butyl 2-oxo-5,6-dihydropyridine-1(2H)-carboxylate (2.1 g, 11 mmol) in CH3NO2 (22.7 g, 372 mmol) under N2 was added DBU (2.52 g, 16.5 mmol). The mixture was stirred at room temperature overnight and then condensed and purified by flash chromatography to give compound tert-butyl 4-(nitromethyl)-2-oxopiperidine-1-carboxylate (0.6 g, 22%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N1CCCC1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:17]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=C1CCCCC1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Yield: 108.9 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (60 g, 280 mmol) and pyrrolidine (37.8 g, 532 mmol) in methanol (1200 mL) was added cyclohexanone (55 g, 560 mmol), and the mixture was reflux overnight. The solvent was removed in vacuo, and then added H2O and HCl to make the mixture to PH=1, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (90 g, 100%). 1H NMR (CDCl3): 1.49 (d, 4H), 1.64 (d, 4H), 1.83 (s, 1H), 1.98 (d, 2H), 2.11 (t, 1H), 2.31 (s, 1H), 2.68 (s, 1H), 6.87 (d, 1H), 7.50 (d, 1H), 7.92 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:40][CH2:41][C:42]1[NH:43][C:44](=[O:52])[C:45]2[CH:51]=[CH:50][CH:49]=[N:48][C:46]=2[N:47]=1>CN(C=O)C>[O:52]=[C:44]1[NH:43][C:42]([CH2:41][NH:40][C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:47][C:46]2[N:48]=[CH:49][CH:50]=[CH:51][C:45]1=2
Reactant: O=C(O)CCc1ccccc1
Reactant: NCc1nc2ncccc2c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1)NCc1nc2ncccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To 3-phenylpropionic acid [501-52-0] (66.6 mg, 0.444 mmol) in DMF (4 ml) was added EDCI [25952-53-8] (102 mg, 0.532 mmol), HOBt [2592-95-2] (8 mg, 0.059 mmol) and NMM [109-02-4] (0.15 ml, 1.18 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h, and then was added to a solution of the salt of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (CH3CO2H, HBr) (100 mg) in DMF (2 ml). Stirring was continued for 18 h, the solvents were evaporated and the residue as redissolved in EtOAc/THF and a saturated solution of ammonium chloride. The inorganic layer was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtrated and evaporated. Column chromatography with CH2Cl2/MeOH 9:1, followed by trituration with TBME gave N-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide (43.1 mg, 47%) as a off-white solid, MS (m/e): 309 [M+H+].
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:6][S:7]([C:10]#[N:11])(=[O:9])=[O:8]>ClCCl>[CH3:6][S:7]([C:10]1[CH:5]2[CH2:1][CH:2]([CH:3]=[CH:4]2)[N:11]=1)(=[O:9])=[O:8]
Reactant: CS(=O)(=O)C#N
Reactant: C1=CCC=C1
Solvent: ClCCl
Product: CS(=O)(=O)C1=NC2C=CC1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.93 g of cyclopentadiene (120 mmol) was added to a solution of 10.51 g of methanesulfonyl cyanide (100 mmol) in 30 ml of dichloromethane within 5 minutes at -20° C. The colorless solution was stirred for another 2 hours at room temperature and then the solvent was distilled off, and the Diels-Alder adduct remains as yellowish solid. Properties of the compound were:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(Cl)c(N)c1
Product: Cc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-chloro-5-methylaniline (41 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (15 mg, 21%). 1H NMR (CDCl3): 9.62-9.61 (m, 1H), 8.73-8.69 (m, 2H), 7.89 (s, 1H), 7.44-7.40 (m, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.00 (dd, J=0.9, 8.4 Hz, 1H), 6.88 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH3:21][OH:22].C[O-].[Na+]>CO>[CH3:21][O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCCCBr)CC1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COCCCCCOC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 4-(5-bromopentyloxy)-1-N-t-butoxycarbonylpiperidine (2.44 g) in methanol (13 ml) was added 28% sodium methoxide methanol solution (14.2 ml), and the mixture was stirred under reflux for 4 hours. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (250 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give 4-(5-methoxypentyloxy)-1-N-t-butoxycarbonylpiperidine (1.97 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:30])[CH2:23][C:22]([CH3:25])([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:26][C:27]([OH:29])=[O:28])[CH:20]=2)[O:15]1.[CH2:31](I)[CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[CH3:13][C:14]1([CH3:30])[CH2:23][C:22]([CH3:24])([CH3:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:27]([OH:29])=[O:28])[CH:20]=2)[O:15]1
Reactant: CCCCCI
Reactant: CC1(C)CC(C)(C)c2cc(CC(=O)O)ccc2O1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCC(C(=O)O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.55 ml of diisopropylamine were dissolved in 60 ml THF and treated dropwise, at 0° C., with 7.2 ml of butyl lithium (2.5M). After 30 min. at 0° C., a solution of 1.8 g of (2,2,4,4-tetramethyl-chroman-6-yl)-acetic acid in 8 ml of THF was dropped in. The reaction mixture was stirred at 0° C. for one hour then at room temperature for 30 min. After cooling back to 0° C., a solution of 1.42 ml of pentyl iodide in 4 ml THF was added dropwise. The mixture was kept at 0° C. for one hour then at room temperature for two hours. The mixture was quenched with the addition of 50 ml of water and the pH was adjusted to 2 with HCl 1N. The mixture was extracted with three portions of 50 ml of ether. The combined organic extracts were washed with two portions of 50 ml of water and one portion of 50 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes), yielding 1.2 g of a pale yellow oil. 1H NMR (CDCl3): 7.17 (d, J=2.2 Hz, 1H), 7.03 (dd, J=8.4, 2.2 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 3.45 (t, J=7.7 Hz, 1H), 2.10-1.90 (m, 1H), 1.81 (s, 2H), 1.80-1.65 (m, 1H), 1.33 (s, 6H), 1.32 (s, 6H), 1.40-1.20 (m, 6H), 0.85 (t, J=6.9 Hz, 3H).
Reaction SMILES: Cl.[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH2:18])[C@@H:12]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:20]([O:19][C@H:12]1[C@H:13]([NH:18][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH2:14][C@H:15]([CH2:16][OH:17])[C@H:11]1[O:10][C:2](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccncc1
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diyl dibenzoate hydrochloride (150. mg, 0.380 mmol) in DCM (10.0 mL) at 0° C. was treated with Et3N (0.170 mL, 1.22 mmol) and stirred for 20 min. Isonicotinoyl chloride (88.0 mg, 0.490 mmol) was then added and the mixture was stirred for 2 h. The reaction was treated with saturated aqueous solution of ammonium chloride (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (100. mg, 60%). LC/MS: Rt=1.49 min, ES+ 461 (FA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C(Cl)=O)=CC=1.[CH3:42][CH2:43][O:44][C:45]([C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[CH:51][CH:52]=1)=[O:46]>C1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:45]([O:44][CH2:43][CH3:42])=[O:46])=[CH:52][CH:51]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=C(Cl)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of 23.55 g. of bis(p-chlorophenyl)acetic acid in 250 ml. of benzene is added dropwise 33.1 g. of sulfonyl chloride. The mixture is refluxed 5 hours, the solvent is evaporated, and the residue is evaporated from three 250 ml. portions of benzene, giving 26.06 g. of bis(p-chlorophenyl)acetyl chloride as an oil. To this oil is added a solution of 27.7 g. of benzocaine. The mixture is stirred overnight, filtered, washed with 200 ml. each of 10% hydrochloric acid, saturated sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and evaporated. The residue is crystallized twice from 200 ml. of ethanol, giving 25.76 g. of the desired product as colorless needles, m.p. 171°-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13]OS(C)(=O)=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:19]([CH2:13][CH:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:12]1)=[N+:20]=[N-:21]
Reactant: CS(=O)(=O)OCC1CC(c2ccc(Br)cc2)=NO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 75 °C
Yield: 112.7 %

Procedure:
Methanesulfonic acid 3-(4-bromo-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl ester (55 g, 164.2 mmol) was added to dimethyl formamide (200 ml) followed by addition of sodium azide (21.4 g, 328.4 mmol). The mixture was heated to 75° C. for six hours and then added to aqueous sodium chloride (300 ml) followed by extraction with gethyl acetate (3×300 ml). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to yield the desired product (52 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:12][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[F:11]
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)c(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.81-mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (522 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:14])=[C:11]([F:13])[F:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]([F:13])([F:12])[CH:10]([F:14])[F:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: FC(F)=C(F)F
Product: FC(F)C(F)(F)Oc1ccc(Cl)cc1

Procedure:
4-Chlorophenol reacts under basic catalysis with tetrafluoroethylene to give 1-chloro-4-(1,1,2,2-tetrafluoroethoxy)benzene as a colorless oil of b.p. 68° at 12 Torr. [For example, see J. Am Chem. Soc. 73, 5831 (1951) and Chem. Abstr. 73, 36584q.]