Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:22][P:20]([OH:23])(=[O:21])[O:19][C@H:3]2[C@@H:4]([OH:18])[C@H:5]([N:7]3[C:16](Br)=[N:15][C:9]4[C:10]([NH2:14])=[N:11][CH:12]=[N:13][C:8]3=4)[O:6][C@H:2]12.[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[CH:12]1[N:11]=[C:10]([NH2:14])[C:9]2[N:15]=[CH:16][N:7]([C@@H:5]3[O:6][C@@H:2]4[CH2:1][O:22][P:20]([OH:23])([O:19][C@H:3]4[C@H:4]3[OH:18])=[O:21])[C:8]=2[N:13]=1
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Reaction time: 15 h

Procedure:
A mixture of dry 8-bromo-cAMP (20 g, 49 mmol) and CaCl2 (20 g, 180 mmol, dried at 75° under vacuum overnight) in anhydrous DMF (800 mL, distilled over CaH2 under vacuum) was heated at 80°-85° C. under anhydrous conditions with stirring for 15 h. DMF was evaporated under reduced pressure at 50° C. and the residue was dissolved in cold 2N NaOH (20 mL). The aqueous solution was neutralized (to pH 7) with cold 2N HCl, filtered through a membrane filter and purified by preparative HPLC on a C-18 reverse phase column. Initial washing with 0.5% AcOH/H2O gave 8-hydroxy-cAMP and cAMP. Further elution with 15% MeOH/H2O gave pure title compound. Evaporation of the solvent gave while solid, which was collected, washed with cold water followed by EtOH and dried to furnish 14.0 g (79%) of 4, mp 232°-234° C.: IR (KBr): 655 (C-C1) cm-1 : UV: λmax (pH 1) 260 nm (ε 15,600): λmax (pH 7) 261 nm (ε 15,700): λmax (pH 11) 261 nm (ε 15,900): 1H NMR (Me2SO-d6): δ 4.13 (m, 2, C5'H2), 4.56-4.39 (m, 1, C4'H), 4.99-4.97 and 5.17-5.13 (m, 2, C2'H and C3'H), 5.85 (s, 1, C1H), 7.67 (br, s, 2, NH2) and 8.21 (s, 1, C2H). Anal. Calcd for C10H11C1N5O6P.H2O: C, 31.47: H, 3.43: N, 18.53: C1, 9.29. Found: C, 31.69: H, 3.19: N, 18.26: C 1, 9.52.
Reaction SMILES: [CH:1](OC)=[O:2].[CH3:5][O:6][C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:31])[NH:10][C:11]([C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=1)=[N:12]2>>[CH3:5][O:6][C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]2[C:8]=1[C:9](=[O:31])[NH:10][C:11]([C:19]1[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][N:28]([CH:1]=[O:2])[CH2:29][CH2:30]3)=[CH:21][CH:20]=1)=[N:12]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: COC=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C=O)CC4)cc3)nc2c1
Yield: 99 %

Procedure:
A mixture of methyl formate (75 mL) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.300 g, 0.82 mmol) was heated at reflux for 48 hours. The mixture was concentrated, and purified by silica gel chromatography, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (0.320 g, 99%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.79 (br s, 1H), 8.10-8.19 (m, 3H), 7.06 (d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.46-3.59 (m, 4H), 3.32-3.38 (m, 4H). APCI MS m/z 393 [M−H]−.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:8]
Reactant: BrCc1ccccc1
Reactant: COCCOCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COCCOCC(=O)OCc1ccccc1
Yield: 104 %

Procedure:
2-(2-Methoxyethoxy)acetic acid (10 g; 75 mmole) and tetrabutylammonium bromide (25.3 g; 75 mmole) were dissolved in sodium hydoxide solution (2 M; 75 ml; 75 mmole). Benzyl bromide (15.3 g; 89 mmole) dissolved in dichloromethane (150 ml) was added. The reaction mixture was refluxed 4 hours. After separation the organic phase was dried with magnesium sulfate and evaporated. Chromatography using dichloromethane as eluant gave 17.5 g (94%) of benzyl 2-(2-methoxyethoxy)acetate.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Li+].O1CCCC1>O>[C:13]1([C:12]#[C:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cnc(C#Cc2ccccc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(C#Cc2ccccc2)s1
Yield: 97.1 %

Procedure:
A solution of 2-phenylethynyl-thiazole-5-carboxylic acid ethyl ester (9.00 g, 35.0 mmol), lithium hydroxide (13.5 g, 563 mmol), tetrahydrofuran (190 mL) and water (143 mL) was stirred at 25° C. for 64 h. The material was concentrated to remove most of the THF, taken up in 350 mL of water and washed with EtOAc (3×50 mL); acidified with 3.7% HCl to pH<1 and the precipitate extracted with 3×100 mL of EtOAc. The combined EtOAc extracts were washed with 50 mL of water, 50 mL of brine, dried (Na2SO4) and concentrated to give the titled compound, 2-phenylethynyl-thiazole-5-carboxylic acid (7.79 g; 97%), as a yellow powder, which was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.69-7.60 (m, 2H), 7.51-7.38 (m, 3H). LC/MS (Method 1), RT=0.57 min. Calculated [M+H]+=230; Observed [M+H]+=230.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)(=O)C(Cl)=O.[CH:27]1[CH:32]=[CH:31][CH:30]=CC=1>>[CH:32]1([CH2:27][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([OH:20])=[O:19])[CH2:30][CH2:31]1.[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: c1ccccc1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CCCCCCCCC=CCCCCCCC(CC1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oleic acid (1.8 g.) is dissolved in about 100 ml. of dry benzene and 2.4 g. of oxalyl chloride is added with stirring, under nitrogen, at room temperature. After 2 hours, solvent is removed under reduced pressure in 30° water bath. Fresh dry benzene (100 ml.) is added and 9.4 g. of cyclopropylmethyl alcohol. The reaction mixture is stirred overnight at room temperature. The reaction is worked up by washing with water and brine, drying over calcium sulfate and evaporation of solvent to yield the cyclopropylmethyl ester of oleic acid (cyclopropylmethyloctadec-9-enoate) b.p. 120° (bath) at 0.01 mm., which can be further purified by distillation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.3 h
Yield: 76 %

Procedure:
A solution of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.25 g, 12.0 mmol), in anhydrous THF (10 ml) was added portionwise to a slurry of sodium hydride (60% dispersion in oil, 0.63 g, 13.8 mmol) in THF (35 ml) and the mixture stirred for 0.3 h at 0° C. A solution of benzyl bromide (2.37 g, 13.8 mmol) in dry THF (2 ml) was added and the mixture warmed to room temperature and stirred for 18 h. Water (70 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried (MgSO4) and evaporated. The crude product was chromatographed on silica gel eluting with CH2Cl2 /MeOH (100:0→97:3) to give the desired product (2.53 g, 76%), δ (250 MHz, CDCl3) 1.46 (9H, s, OC(Me)3), 1.87-2.11 (2H, m, CH2), 3.42-3.50 (4H, m, 2 of CH2), 4.10-4.16 (1H, m, CH--OBn), 4.53 (2H, s, OCH2Ar), 7.26-7.39 (5H, m, Ar).
Reaction SMILES: C1(OC(=O)[CH2:9][CH2:10][C@@H:11]([CH2:27][O:28]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])CCCCC1.C[Mg]Br.[CH2:43]1[CH2:47]OC[CH2:44]1>>[CH3:44][C:43]1([CH3:47])[O:28][CH2:27][C@@H:11]([CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:10][CH2:9]1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC2CCCCC2)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Agent: C[Mg+]
Agent: C[Mg]Br
Agent: [Br-]
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@H]2CCC(C)(C)OC2)COC1(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
The (S)-tert-butyl 4-((R)-5-(cyclohexyloxy)-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (309 mg, 0.545 mmol, 1.0 equiv) was dissolved in 17 mL of THF and the solution cooled to 0° C. Methylmagnesiumbromide (3.0 M in THF, 1.64 mL, 3.0 equiv) was added via syringe. LC/MS analysis showed ca 15% conversion to the mono-tosylate. An additional 0.55 mL of MeMgBr solution was added and the mixture warmed to ambient and stirred overnight. LC/MS analysis showed complete conversion to the mono-tosylate. The mixture was heated to reflux for 24 hr. After this time, complete conversion to the cyclised product was observed. The mixture was cooled to ambient and quenched with water. The layers were separated and the organic layer washed with brine, dried over Na2SO4, filtered and evaporated. The pyran derivative was purified by flash chromatography on silica, (12 g), eluting with 0-41% EtOAc in hexanes. This afforded 138 g (78% yield) of (S)-tert-butyl 4-(((R)-6,6-dimethyl-tetrahydro-2H-pyran-3-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate as a clear syrup. MS ESI +ve m/z 350 (M+Na).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:11]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 96 %

Procedure:
As described for example 2b, 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.5 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (167 mg, 96%) which was obtained as a white solid. MS: m/e=350.3 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].Cl.[CH2:16](O)[CH3:17]>>[CH2:16]([O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH3:17]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCCCBr
Agent: Cl
Product: CCOC(=O)CCCCCCCCCCBr
Temperature: 25 °C

Procedure:
Compound 1, 11-Bromoundecanoic acid (41.38 g, 156 mmol), was placed in a 250 ml round-bottomed flask equipped with a reflux condenser. After absolute ethanol (60 ml) and concentrated HCl (1/2 ml) were added, the reaction mixture was refluxed overnight. The reaction mixture was allowed to cool to room temperature before the solvent was removed under reduced pressure. The resulting yellow oil was dissolved in ether. The ether solution was extracted with saturated sodium carbonate (NaHCO3) and H2O, and dried over magnesium sulfate (MgSO4). The solvent was removed under reduced pressure. Purification of the crude product was obtained by vacuum distillation which yielded a colorless oil, ethyl-11-bromoundecanoate, compound 2 (37.32 g, 82.5% yield).
Reaction SMILES: O.C(O)(=O)C.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]12[CH2:20][O:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH:17]1[CH2:16][O:15][NH:14]2.[NH4+].[OH-]>C1COCC1.[Zn].C(Cl)Cl>[NH2:14][C@@:13]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])[CH2:20][O:19][C@H:18]([C:21]([F:24])([F:22])[F:23])[C@H:17]1[CH2:16][OH:15]
Reactant: Fc1ccccc1C12COC(C(F)(F)F)C1CON2
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
Zinc (389.2 g, 5.95 mol) was placed in a reaction vessel, and water was added (893 mL). Acetic acid (135 mL, 2.38 mol) was added while maintaining the temperature below 10° C. After 15 min, 6a-(2-fluorophenyl)-4-(trifluoromethyl)hexahydrofuro[3,4-c]isoxazole (550.0 g, 1.98 mol) was added as a solution in THF (665 mL). The reaction mixture was stirred over 16 h at rt. Methylene chloride (1.89 L) was added, followed by 28% aq. NH4OH (552 mL) while the temperature was kept below 30° C. The mixture was stirred for 30 min, and then filtered over Celite (80 g) rinsing with methylene chloride (378 mL). The aq. layer was extracted with methylene chloride (1.89 L). The organics were combined, washed with sat. aq. NaCl (1.0 L) and concentrated under vacuum to afford an oil (502 g, 90.6%). The crude residue was used in the following step without additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=CC3NC4CCN(CCN(CC)CC)C(=O)C=4C=3C)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:31].[C:32](Cl)(=[O:34])[CH3:33]>O1CCCC1>[F:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:32](=[O:34])[CH3:33])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CC(=O)Cl
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 0 °C
Yield: 100.1 %

Procedure:
A stirred solution of 6-amino-5-fluoro-1,3-dihydro-indol-2-one (1.0 g, 6 mmol) obtained from Example 7 in 30 ml of tetrahydrofuran was added with tirethylamine (1.3 ml, 9 mmol). The solution was cooled down to 0° C. in an ice-water bath and added with acetyl chloride (1.3 ml, 9 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated to reflux for 1.5 hours and cooled until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide (1.25 g, 99%) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.[I:24]I.[Cl-].[Na+]>O1CCCC1.CCCCCC.C(OCC)(=O)C.O1CCCC1.O>[F:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[I:24])=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: Fc1cnc2ccccc2c1
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Fc1cnc2ccccc2c1I
Temperature: -70 °C
Yield: 68.4 %

Procedure:
17.3 cm3 of diisopropylamine in 650 cm3 of tetrahydrofuran were cooled to a temperature in the region of −75° C. and 76 cm3 of a 1.6M solution of butyl lithium in hexane were added, with stirring and under an inert atmosphere, while maintaining the temperature at about −70° C. After stirring for 20 minutes at a temperature in the region of −75° C., a solution of 11.9 g of 3-fluoroquinoline in 200 cm3 of tetrahydrofuran was added. The solution obtained was stirred for a further 4 hours at −75° C., followed by addition of a solution of 32.2 g of double-sublimed iodine in 150 cm3 of tetrahydrofuran. After stirring for 2 hours at a temperature in the region of −40° C., the reaction mixture was hydrolyzed with 200 cm3 of a tetrahydrofuran/water mixture (90/10 by volume) and then with 200 cm3 of saturated sodium chloride solution. In the region of 20° C., the mixture was diluted with 300 cm3 of ethyl acetate and washed with twice 250 cm3 of saturated sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 10 cm; height 30 cm), eluting with dichloromethane and collecting 100-cm3 fractions. Fractions 45 to 80 were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 15.1 g of 3-fluoro-4-iodoquinoline were obtained in the form of a cream-colored solid melting at 110° C.
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:16][S:17][CH2:18][C@H:19]([NH:28]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:20]([NH:22][C:23]1([CH2:26][OH:27])[CH2:25][CH2:24]1)=[O:21])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C.C(Cl)Cl>[NH2:28][C@H:19]([C:20]([NH:22][C:23]1([CH2:26][OH:27])[CH2:25][CH2:24]1)=[O:21])[CH2:18][S:17][CH2:16][C@H:15]([NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:46][O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC
Solvent: CC#N
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (R)-3-((R)-2-dodecanamido-3-(hexadecyloxy) propylthio)-1-(1-(hydroxymethyl)cyclopropylamino)-1-oxopropan-2-ylcarbamate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting gel was diluted with DCM and sonicated for 3 minutes. The mixture was added to toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give N-((R)-1-((R)-2-amino-3-(1-(hydroxymethyl)cyclopropylamino)-3-oxopropylthio)-3-(hexadecyloxy)propan-2-yl)dodecanamide. 1H NMR (DMSO d-6): δ 8.13 (s, 2H), 7.73 (d, 2H), 4.68 (t, 2H), 3.89-3.97 (m, 2H), 3.35-3.44 (m, 5H), 3.20-3.24 (m, 1H), 2.59-2.74 (m, 4H), 2.32-2.34 (m, 1H), 2.05 (t, 2H), 1.42-1.50 (m, 4H), 1.21-1.28 (m, 40H), 0.85 (t, 6H), 0.67 (dd, 2H), 0.56 (dd, 2H). LRMS [M+H]=670.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([N+:12]([O-])=O)[CH:3]=1.O.[Cl-].[NH4+]>C(O)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[C:4]([CH:3]=1)[NH2:12]
Reactant: O=[N+]([O-])c1cc(Br)ccc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(Br)ccc1C(F)(F)F
Temperature: 80 °C
Yield: 89.5 %

Procedure:
To a suspension of 4-bromo-2-nitro-1-(trifluoromethyl)benzene (4.0 g, 14.9 mmol) in ethanol (230 mL), THF (85 mL), and water (40 mL) was added ammonium chloride (1.0 g, 18.8 mmol) and ferrous powder (5.06 g, 90 mmol). The resulting mixture was heated at 80° C. for 1 hr and the progress of the reaction was monitored by TLC. Upon complete consumption of staring material, the reaction mixture was filtered off while it was hot. The filtrate was evaporated under vacuum and the crude residue was diluted with ethyl acetate (100 mL) and washed with water (3×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum to afford 5-bromo-2-(trifluoromethyl)aniline as a solid (3.2 g, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:5]2[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.ClCCl>O1CCOCC1.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]>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]3[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:33][CH:32]=1
Reactant: CCCCCc1c(-c2ccccc2)n(C)c2ccc(Br)cc12
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OC)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 5-bromo-1-methyl-3-pentyl-2-phenyl-1H-indole (1.105 g, 3.101 mmol) was reacted with aqueous 2M K2CO3 (3.1 ml), 4-methoxyphenylboronic acid (0.660 g, 4.341 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.076 g, 0.093 mmol) in dioxane (31 ml) to give the product (0.512 g, 1.335 mmol, 43%) as an oily solid. 1H NMR (DMSO-d6) δ 0.76 (t, J=6.9 Hz, 3H), 1.15-1.23 (m, 4H), 1.52-1.56 (m, 2H), 2.66 (t, J=7.5 Hz, 2H), 3.56 (s, 3H), 3.79 (s, 3H), 7.02 (d, J=8.7 Hz, 2H), 7.41-7.46 (m, 3H), 7.47-7.49 (m, 2H), 7.53-7.56 (m, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.72 (d, J=1.5 Hz, 1H); [ESI(+)], m/z 384 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(NCC)C.[ClH:29]>CO>[ClH:29].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@@H:9]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[C@@H](NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCNCC
Product: C[C@@H](N[C@H]1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1

Procedure:
(1S)-6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of diastereomeric 6-bromo-N-[(1R)-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazol-1-amine by SFC (Berger Amino, Chiral Technologies, 10% methanol, (2% diethyl amine/10% chloroform) 1500 psi, 50° C., 2 mL/min, retention time: 19.8 min.) The oil obtained was converted to the HCl salt to give a white solid. [α]25=−4.3 (c 0.23, MeOH); 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 10.08 (s, 1H), 9.64 (s, 1H), 7.86 (d, J=6.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.55-7.45 (m, 3H), 7.42 (d, J=8.6 Hz, 1H), 7.29 (dd, J=6.8 Hz, J=1.8 Hz, 1H), 4.75 (m, J=6.4 Hz, 1H), 4.57 (m, 1H), 3.47-3.37 (m, 2H), 2.70-2.64 (m, 2H), 2.13-2.07 (m, 2H), 1.65 (d, J=6.8 Hz, 3H); MS m/z 367, 369 (M−1); Anal. Calcd. For C20H22BrN2Cl: C, 59.20; H, 5.46; N, 6.90. Found: C, 59.29; H, 5.55; N, 6.92.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:21]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:23])[F:24])[CH:15]=2)=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
3-(Trifluoromethyl)aniline 10 g (62.1 mmol) was added to 500 ml of anhydrous dichloromethane in a 500 ml round bottomed flask. This stirred solution was cooled to 0° C. using an ice water bath. 3-(Trifluoromethyl)phenyl isocyanate 15 g (80.1 mmol) was added drop-wise over a period of 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred at ambient temperatures for 18 hours. During this time a heavy precipitate was formed. This solid was collected by filtration on a Buchner funnel, and was re-suspended in 250 ml of dichloromethane. After approximately 30 minutes of stirring, the solid was again filtered on a Buchner funnel and then placed under vacuum at 40° C. to dry for a period of 24 hours to give 20 g of a white solid (92.5% yield). 1H NMR (400 MHz DMSO) δ 9.20 (s 2H) 8.04 (s 2H) 7.61 (m 2H) 7.54 (t 2H) 7.34 (m 2H). MS: M+1 found 349.