Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [FH:1].C(Cl)(Cl)(Cl)Cl.[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([O:31][CH:32]([F:34])[F:33])=[C:26]([F:35])[CH:25]=3)[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>>[CH2:7]([C@H:10]1[CH2:11][CH2:12][C@H:13]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([F:35])[C:27]([O:31][C:32]([F:1])([F:34])[F:33])=[C:28]([F:30])[CH:29]=3)[CH2:20][CH2:21]2)[CH2:14][CH2:15]1)[CH2:8][CH3:9]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3cc(F)c(OC(F)F)c(F)c3)CC2)CC1
Reactant: F
Solvent: ClC(Cl)(Cl)Cl
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3cc(F)c(OC(F)(F)F)c(F)c3)CC2)CC1
Temperature: 0 °C

Procedure:
2 mol of anhydrous hydrofluoric acid is poured into an autoclave which has been cooled to 0° C. A mixture of 0.18 mol of carbon tetrachloride and 0.06 mol of 1-[trans-4-(trans-4-n-propylhexyl)cyclohexyl]-2-(4-hydroxy- 3,5-difluorophenyl)ethane (Example 1) is then added. The mixture is stirred at 150° for about 8 hors, cooled, poured into ice water, and the autoclave is subsequently washed out with ether. The two phases are combined, stirred for about 30 minutes, separated, and the ether solution is washed with 5% KOH solution until it remains alkaline. The organic phase is dried, filtered, evaporated, and the residue is purified to give 1-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-2-(4-trifluoromethoxy-3,5-difluorophenyl)ethane.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][N:12]([CH:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[C:31](Cl)[CH:30]=2)=[O:28])[CH2:23][CH2:22]1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH3:11][N:12]([CH:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[C:31]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:30]=2)=[O:28])[CH2:23][CH2:22]1)[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCc1ccccc1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(Cl)nc3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cc(OCc3ccccc3)nc3ccccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
A solution of 0.4 g of benzyl alcohol in 2 ml of dimethylformamide was dropwise added to a suspension of 150 mg of sodium hydride in 5 ml of dimethylformamide with ice-cooling. The mixture was stirred at the same temperature for 30 minutes. Thereto was dropwise added 1.0 g of 4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinyl)carbonyl-2-chloroquinoline in 2 ml of dimethylformamide. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. The reaction mixture was poured into ice water, followed by extraction with methylene chloride. The extract was washed with water and an aqueous sodium chloride solution in this order, then dried with magnesium sulfate and concentrated under reduced pressure to obtain 1.1 g of 4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinyl)carbonyl-2-benzyloxyquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:5]([C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7])[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)N1C(=O)OCC1Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of the compound of example 50 (2.40 g, 6.07 mmol) in anhydrous THF (60 mL) was cooled to −78° C. A solution of NaHDMS in THF (1M, 6.7 mmol, 6.7 mL) was injected over 10 minutes. The reaction mixture was stirred for an additional 20 minutes, after which time, a solution of tert-butyl bromoacetate in anhydrous THF (5 mL) was slowly injected. After stirring for 1 h at −78° C., and 3 h at −48° C., the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted several times using ethyl acetate. The recombined organic layer was extracted successively with brine, saturated sodium hydrogen carbonate, brine and water. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude material was flashed using 20% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 300 MHz: 1.40, 1.41(2s, 9H); 1.74-1.92(m, 5H); 2.45-2.95(m, 4H); 3.31(m, 1H); 3.69, 3.73(2s, 3H); 4.11(m, 2H); 4.50, 4.66(2m, 1H); 7.25(m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([C:18](Cl)=[O:19])=[C:16]([CH:21]([CH3:23])[CH3:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.[BH4-].[Li+].O.C(OCC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([CH2:18][OH:19])=[C:16]([CH:21]([CH3:22])[CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)Cl)n(-c2ccc(F)cc2)c(=O)c2ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)c1c(CO)n(-c2ccc(F)cc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A stirred solution of crude 2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carbonyl chloride (21 g) in dry tetrahydrofuran (300 ml) was treated dropwise with a solution of lithium borohydride in tetrahydrofuran (26 ml; 2.0M) and the mixture stirred at room temperature for 18 hours. The reaction mixture was then treated dropwise with water (50 ml), diethyl ether (500 ml) and more water (200 ml) and the organic layer was separated, washed with water (200 ml) and brine (200 ml), dried over magnesium sulphate and evaporated to leave a yellow oil. This was triturated with a hot mixture of diethyl ether (200 ml) and n-hexane (400 ml) to give 2-(4-fluorophenyl)-3-hydroxymethyl-4-isopropyl-1-oxo-1,2-dihydroisoquinoline (13.7 g) in the form of a white solid, m.p. 157°-158° C. [Elemental analysis: C, 73.1; H, 5.7; N, 4.4%; calculated: C, 73.3; H, 5.8; N, 4.5%; NMR (in CDCl3): 1.55 (7H, d, J=8 Hz,), 3.65 (1H, sept, J=8 Hz), 4.4 (2H, s), 7.1-7.4 (4H, m), 7.5 (1H, t, J=8 Hz,), 7.7 (1H, t, J=8 Hz), 8.04 (1H, d, J=8 Hz), 8.5 (1H, d, J=8 Hz)].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH3:16][CH:17]1[O:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:23][CH:21]1[O:22][CH:17]([CH3:16])[CH2:18][N:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:20]1
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: CC1CNCC(C)O1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCCCCN1CC(C)OC(C)C1

Procedure:
This intermediate (12.0 g.) was prepared using the procedure described in Example 4a except using 12 g. (0.045 mole) of methyl 11-bromoundecylate, 5.5 ml. (0.045 mole) of 2,6-dimethylmorpholine, 6.12 ml. of triethylamine, and 15 ml. of toluene and was isolated as a yellow, viscous liquid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=[N:16][N:17]1[C:22]([S:23][CH2:24][CH3:25])=[N:21][C:20](=[O:26])[N:19]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:18]1=[O:32])(C)C>C(O)(C)C>[NH2:16][N:17]1[C:22]([S:23][CH2:24][CH3:25])=[N:21][C:20](=[O:26])[N:19]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:18]1=[O:32]
Reactant: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCSc1nc(=O)n(CC(C)(C)C)c(=O)n1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1.1 g of p-toluenesulphonic acid and 5.4 ml of water were added to a solution of 34.1 g (0.114 mol) of 1-isopropylideneamino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H, 3H)-dione (the compound of formula (V-1)) in 150 ml of isopropanol at 60° C., and the mixture was stirred for one hour at 60° C., the bulk of the reaction product crystallizing out. Approximately 80 ml of the mixture were distilled off at 200 to 300 mbars, the mixture was cooled to 0° C. and was filtered under suction, and the residue was washed with a little methanol. 26.8 g (91% of theory) of 1-amino-6-ethylthio-3-neopentyl-1,3,5-triazine-2,4(1H, 3H)-dione of melting point 202° to 204° C. were obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[N:5][N:6]2[CH2:11][CH2:12][CH3:13].[S:22]1[CH:26]=CC(B(O)O)=C1.C(N(C(C)C)CC)(C)C.C(Cl)[Cl:40]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:40][C:8]1[CH:9]=[CH:10][CH:2]=[C:3]2[C:7]=1[N:6]([C:11]1[CH:12]=[CH:13][S:22][CH:26]=1)[N:5]=[C:4]2[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: ClCCl
Reactant: OB(O)c1ccsc1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2c(Cl)cccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nn(-c3ccsc3)c3c(Cl)cccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of -chloro-3-(4-methoxyphenyl)-1-propyl-1H-indazole (1.0 g, 3.93 mmol), 3-thienylboronic acid (1.0 g, 7.8 mmol), anhydrous copper(II)acetate (0.71 g, 3.9 mmol) and diisopropylethylamine (1.36 mL, 7.8 mmol) in 50 mL CH2Cl2 was stirred at ambient temperature overnight. The reaction mixture was preabsorbed on silica gel and the absorbed solid purified by flash chromatography (hexane, EtOAc: 3:1) to give the product (0.15 g) as a white solid,
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([NH:19][C:18](=[O:20])[C:17]4[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:23]=[CH:24][C:16]=4[O:15]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)C[Cl:32].C1C=CC2[N:42]([OH:43])N=NC=2C=1.NOC1CCCCO1>C(Cl)Cl>[ClH:32].[C:1]1([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12]3([NH:19][C:27](=[O:28])[C:26]4[CH:25]=[C:22](/[CH:21]=[CH:17]/[C:18]([NH:42][OH:43])=[O:20])[CH:23]=[CH:24][C:16]=4[O:15]3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(CCc3ccccc3)CC1)O2
Reactant: ClCCCl
Reactant: On1nnc2ccccc21
Agent: NOC1CCCCO1
Solvent: ClCCl
Product: Cl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCN(CCc3ccccc3)CC1)O2)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
(E)-3-{1′-(2-Phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid (240 mg, 0.612 mmol) was dissolved in DCM (20 ml) and TEA (0.17 ml, 1.23 mmol). EDC (169 mg, 0.88 mmol), HOBT (119 mg, 0.88 mmol) and NH2OTHP (86 mg, 0.74 mmol) were added and the mixture was stirred at RT overnight. The mixture was partitioned between DCM and 5% aqueous NaHCO3 and the organic phase was dried over Na2SO4 and evaporated. The crude mixture was purified by column chromatography (eluent: DCM/MeOH 95:5). The resulting (E)-3-{1′-(2-phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide was dissolved in DCM and treated with 4 M HCl in dioxane for 3 h. The precipitate was filtered off and washed with DCM to give (E)-3-{1′-(2-phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide hydrochloride (175 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.CS(O[CH2:22][CH2:23][C:24]1[CH:39]=[CH:38][C:27]2[O:28][CH2:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32](=[O:33])[C:26]=2[CH:25]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(O)C.CO.C(OCC)(=O)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:22][CH2:23][C:24]3[CH:39]=[CH:38][C:27]4[O:28][CH2:29][C:30]5[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=5[C:32](=[O:33])[C:26]=4[CH:25]=3)[CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1c2ccccc2COc2ccc(CCN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc21

Procedure:
A mixture of 5 g (0.023 m) of 4-(2-keto-1-benzimidazolinyl)piperidine, 7.65 g (0.023 m) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate of Example 1 and 3.17 g (0.023 m) of K2CO3 in 30 ml of absolute ethanol and 60 ml of methanol was refluxed overnight (about 16 hours). The reaction mixture was diluted with 800 ml of ethyl acetate, filtered and evaporated in vacuo. The residue was recrystallized from methanol to give after drying at 100° C. in vacuo, 5.78 g (56%) of 4-(2-keto-1-benzimidazolinyl)-1-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]piperidine, m.p. 116°-120° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:11]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:12]=2[CH2:13][N:14]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)([O:9][CH3:10])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:45](F)(F)C1C=CC(C#N)=CC=1.C1([Mg]Br)CCCCC1.C([Mg]Br)C.CI>>[CH:6]1([C:7]([C:11]2[CH:39]=[CH:38][C:37]([C:40]([F:41])([F:42])[F:43])=[CH:36][C:12]=2[CH2:13][N:14]([CH2:21][C:22]2[CH:23]=[C:24]([C:32]([F:33])([F:35])[F:34])[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=2)[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)([O:9][CH3:10])[CH2:8][CH3:45])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(C)(CC1CCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: Br[Mg]C1CCCCC1
Agent: CC[Mg]Br
Solvent: CI
Product: CCC(OC)(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1

Procedure:
This compound was prepared by an analogous series of reactions to that used for the preparation of N-(2-(1-cyclopentyl-2-methoxypropan-2-yl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine from 2-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazole-5-yl)amino)methyl)-4-(trifluoromethyl)benzonitrile by the addition of cyclohexylmagnesium bromide followed by ethylmagnesium bromide then alkylation with methyl iodide. LC-MS calc 637.5, found 638.5 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C@H:13]2[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14]2)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].[C:34](Cl)(=[O:50])[O:35][CH2:36][CH:37]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2>O1CCOCC1.O>[CH:48]1[C:49]2[CH:37]([CH2:36][O:35][C:34]([N:16]3[CH2:17][C@H:13]([O:12][C:3]4[C:2]([Br:1])=[CH:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH2:14][C@H:15]3[C:18]([OH:20])=[O:19])=[O:50])[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H]1C[C@@H](Oc2nc3ccccc3cc2Br)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](Oc2nc3ccccc3cc2Br)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
To a solution of (2S,4R)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid, TFA (310 mg, 0.687 mmol) in 1,4-dioxane (3 mL) and water (12 mL) was added potassium carbonate (380 mg, 2.75 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (178 mg, 0.687 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and treated with water (10 ml). The resulting mixture was extracted with diethyl ether (2×15 ml). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The crude product was purified via prep HPLC (10-100% CH3CN:Water, 0.1% TFA buffer) to afford the product (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid (250 mg, 65% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.90-7.75 (m, 2H), 7.73-7.63 (m, 2H), 7.58-7.49 (m, 2H), 7.49-7.39 (m, 2H), 7.37-7.31 (m, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.20-7.14 (m, 1H), 7.12 (t, J=7.4 Hz, 1H), 7.04 (td, J=7.4, 1.0 Hz, 1H), 4.68-4.56 (m, 2H), 4.51 (t, J=8.3 Hz, 1H), 4.44-4.33 (m, 2H), 4.27-4.16 (m, 2H), 3.99-3.92 (m, 1H), 3.81-3.73 (m, 1H), 3.73-3.64 (m, 1H). ESI-MS(+) m/z=337 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([SH:14])=[S:13])[CH2:8][CH2:7]1.[OH-].[Na+].[CH3:25]I>CO>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([S:14][CH3:25])=[S:13])[CH2:10][CH2:11]1
Reactant: CI
Reactant: COc1ccc(CN2CCN(C(=S)S)CC2)c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CN2CCN(C(=S)SC)CC2)c(OC)c1OC
Yield: 97.9 %

Procedure:
In a nitrogen atmosphere, 2.0 g of 4-(2,3,4-trimethoxybenzyl)-1-piperazinecarbodithioic acid, 0.26 g of granular sodium hydroxide, and 3 ml of methanol were mixed, and stirred atroom temperature to yield a homogeneous reaction solution. To the solution was dropwise added under chilling with ice a solution of 0.39 ml of methyliodide in 2.4 ml of methanol. After the addition was complete, the reactionsolution was stirred for 2.5 hours at room temperature. The solvent was then distilled off under reduced pressure, and chloroform and water were added to the residue. The chloroform portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to leave 2.0 g of the desired compound as a white powder, yield 97.9%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2.[H-].[Na+].[CH3:19]OCCOC.CI>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:19])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)Cc1ccc2cc(C)ccc2c1
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Solvent: O
Product: COC(=O)C(C)c1ccc2cc(C)ccc2c1

Procedure:
To a mixture of 22 g. of methyl 6-methyl-2-naphthylacetate, 2.5 g. of sodium hydride and 150 ml. of 1,2-dimethoxyethane, 25 g. of methyliodide are added. The reaction mixture is allowed to stand for several hours; then it is diluted with ethanol followed by water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to yield methyl 6-methyl-2-naphthyl-α-methylacetate. This derivative is hydrolyzed by means of the process described in Part H of Example 2 to obtain 6-methyl-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([CH3:13])=[C:6](Cl)[C:5]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH3:20]>>[CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH2:20])[C:7]([CH3:13])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: N
Reactant: CCN(CC)c1c([N+](=O)[O-])cc(C)c(Cl)c1[N+](=O)[O-]
Product: CCN(CC)c1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]

Procedure:
This compound was prepared in a similar manner by reaction of N,N-diethyl-3-chloro-2,6-dinitro-4-methylaniline with ammonia. The crystalline product melts at 108°-109°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37]([OH:39])=O)[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[NH2:89][C@@H:90]([CH2:103][C:104]1[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=1)[CH2:91][CH2:92][C:93]1[CH:98]=[CH:97][C:96]([S:99]([OH:102])(=[O:101])=[O:100])=[CH:95][CH:94]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37](=[O:39])[NH:89][C@H:90]([CH2:91][CH2:92][C:93]1[CH:94]=[CH:95][C:96]([S:99]([OH:102])(=[O:100])=[O:101])=[CH:97][CH:98]=1)[CH2:103][C:104]1[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@H](CCc1ccc(S(=O)(=O)O)cc1)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](CCc1ccc(S(=O)(=O)O)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 43 mg (0.06 mmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide in 1.9 ml of DMF were added 29 mg (0.07 mmol) of HATU and 33 μl (0.19 mmol) of Hünig's base. The reaction mixture was stirred at RT for 30 min and then admixed with 29 mg (0.07 mmol) of 4-[(3R)-3-amino-4-phenylbutyl]benzenesulphonic acid trifluoroacetate. After stirring overnight, the reaction mixture was purified by prep. HPLC. This gave 58 mg of a 45:55 mixture of the title compound and of the already deprotected amine.
Reaction SMILES: [CH2:1]([O:5][CH3:6])[C@H:2]1[O:4][CH2:3]1.[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([N:14]([CH2:3][C@H:2]([OH:4])[CH2:1][O:5][CH3:6])[CH2:3][C@H:2]([OH:4])[CH2:1][O:5][CH3:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: COC[C@@H]1CO1
Solvent: CO
Product: COC[C@@H](O)CN(Cc1ccccc1)C[C@H](O)COC
Temperature: 55 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A solution of (S)-methyl glycidyl ether (10 g) and benzylamine (3.62 g) in methanol (50 ml) was stirred at 55° C. for 2 hours. To the mixture was added (S)-methyl glycidyl ether (1 g), and the mixture was stirred at 55° C. for 2 hours, and then evaporated under reduced pressure. Toluene was added to the residue and evaporated under reduced pressure to give (2S)-1-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-3-methoxypropan-2-ol (8.84 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1>[CH2:17]([O:16][C:14]([NH:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([OH:5])=[O:4])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(CC(F)(F)F)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC(CC(F)(F)F)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.1 %

Procedure:
To a solution of 2-amino-4,4,4-trifluorobutyric acid (543 mg, 3.45 mmol) in aq. 1N NaOH (13 mL, 13.0 mmol), a solution of benzyl chloroformate (0.600 mL, 4.26 mmol) in dioxane (5 mL) was added. The mixture was stirred at room temperature for 18 h. It was then washed with EtOAc. The aqueous solution was acidified to pH 1-2 with 6N HCl. The product was extracted with EtOAc. The EtOAc phase was dried over Na2SO4, concentrated in vacuo to give 2-(benzyloxycarbonylamino)-4,4,4-trifluorobutanoic acid (202 mg).