Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][N:16]2[C:12](=[N:13][C:14]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][C:15]=32)[CH2:11][C@@H:10]1[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][N:16]2[C:12](=[N:13][C:14]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:15]=32)[CH2:11][C@@H:10]1[C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)nc1n2C[C@H](NC(=O)OC(C)(C)C)[C@@H](c2cc(F)c(F)cc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3cc(C(=O)O)ccc32)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 380 mg (0.80 mmol) of the product from Step B in 7.5 mL of 2:1 THF/methanol was added 2.5 mL (2.5 mmol) of 1N aqueous lithium hydroxide solution. The reaction mixture was stirred at ambient temperature for 3 h, then the organic solvent removed in vacuo. The mixture was quenched with 50 mL of 1N aqueous hydrochloric acid, and extracted with 50 mL of ethyl acetate. The organic solution was next washed with 1N aqueous hydrochloric acid, once with saturated aqueous brine (50 mL each), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 0% to 80% acetonitrile/water with 0.1% TFA) to afford the title compound as a white foam. LC/MS 462.4 (M+1).
Reaction SMILES: [CH2:1]=C1CCC2(OCCO2)CC1.[CH2:12]1[C:16]2([CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1.O1C2(CCC(=O)CC2)OCC1>>[CH2:1]=[C:19]1[CH2:20][CH2:21][C:16]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:17][CH2:18]1
Reactant: O=C1CCC2(CCCC2)CC1
Reactant: C=C1CCC2(CC1)OCCO2
Agent: O=C1CCC2(CC1)OCCO2
Product: C=C1CCC2(CCCC2)CC1

Procedure:
The title compound was prepared following the method reported here for Compound 31a. As starting material spiro[4.5]decan-8-one replaced 1,4-dioxaspiro[4.5]decan-8-one. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®M-Biotage; CH2Cl2) to give the title compound as a colorless oil. Yield: 98.5%.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[C:3]([NH2:5])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:3][NH2:5]
Reactant: NC(=O)C(N)Cc1ccccc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(N)Cc1ccccc1F
Temperature: 5 °C
Reaction time: 18 h

Procedure:
2-Amino-3-(2-fluorophenyl)propionamide was added carefully to a chilled (50°) mixture of LAH (1.0 g, 26.3 mmol) and 20 ml THF under argon. The reaction was then heated at reflux for 10 hrs. The reaction was cooled to 5° C. and carefully treated with Na2SO4.10H2O. The resulting mixture was stirred for 18 hrs, then filtered to remove the solids. The filtrate was concentrated in vacuo to give an amber oil. MS (m/z): 169 (M+H)+; C9H13FN2 requir. 168.19.
Reaction SMILES: C(O)C.[NH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([NH:14][OH:15])=[NH:8]
Reactant: N#Cc1cccnc1N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cccnc1N
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of ethanol (10 mL) and 2-amino-nicotinonitrile (590 mg) were added hydroxylamine hydrochloride (510 mg) and potassium carbonate (1.4 g) at room temperature, which was stirred for 7 hours and 30 minutes under reflux. After this, the reaction mixture was stirred for 13 hours and 30 minutes at room temperature, then water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, after which the filtrate was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the titled compound (520 mg) as a cis-trans mixture. The titled compound was used in the subsequent reaction without further purification.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:24])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([C:21](O)=[O:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:26][O:27][C:28](=[O:35])[C@@H:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32].[K+].[Br-]>>[CH3:26][O:27][C:28](=[O:35])[C@@H:29]([NH:34][C:21]([C:19]1[O:18][N:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:24])=[CH:15][CH:14]=2)[CH:20]=1)=[O:22])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Nc1ccc(-c2cc(C(=O)O)on2)cc1)NC1CCCCC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cc(-c2ccc(NC(=O)NC3CCCCC3)cc2)no1
Yield: 67.9 %

Procedure:
The title compound was prepared from 3-[4-(3-cyclohexyl-ureido)-phenyl]-isoxazole-5-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid methyl ester hydrochloride as set forth in Example 5 and was obtained in 67.9% yield. Mass (ES+): 457 (M++1); IR (KBr): 3328, 2931, 1752 (br), 1655 (br), 1542 (br); 1H NMR (DMSO-d6) δ: 0.87, 0.91 (2×d, 6H), 1.14-1.81 (5×m, 13H), 3.47 (br, 1H), 3.65 (s, 3H), 4.49 (m, 1H), 6.17 (d, 1H), 7.52 (d, 2H), 7.59 (s, 1H), 7.77 (d, 2H), 8.59 (s, 1H), 8.96 (br, 1H), 9.32 (d, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:17]([NH:25][C:26]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:4][CH2:3]1)=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCC1CCC(N)CC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCC(NC(=S)NC(=O)c2ccccc2)CC1
Yield: 91.2 %

Procedure:
A solution of tert-butyl N-[(4-aminocyclohexyl)methyl]carbamate (4.683 g, 20.5 mmol) and benzoyl isothiocyanate (3.77 g, 23.1 mmol) in 180 ml THF was stirred at room temperature for 20 hours. The solvent was removed in vacuo to yield a golden viscous oil. The oil was triturated with 250 ml hexane and the resulting solid was collected by filtration and washed with hexane. The off-white solid was washed several times with hexane and was dried under vacuum to yield 91% (7.32 g) of the desired product as an off-white solid: 1H-NMR (CDCl3) δ 1.20 (6H, m), 1.44 (9H, s), 1.83 (2H, m), 2.25 (2H, m), 3.01 (2H, t, J=6.4 Hz), 4.20 (1H, m), 4.62 (1H, m), 7.51 (2H, t, J=7.9 Hz), 7.60 (1H, t, J=7.4 Hz), 7.81 (2H, d, J=7.2 Hz), 8.93 (1H, s); 392 (ESMS, MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([F:11])[C:4]([F:10])([F:9])[S:5]([O-:8])(=[O:7])=[O:6].C(OC(C[O:22][C:23]1[CH:28]=[CH:27][C:26]([S+:29]([C:45]2[CH:50]=[CH:49][C:48]([O:51]CC(OC(C)(C)C)=O)=[CH:47][CH:46]=2)[C:30]2[CH:35]=[CH:34][C:33]([O:36]CC(OC(C)(C)C)=O)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)=O)(C)(C)C.FC(F)(F)C(F)C(F)(F)S(O)(=O)=O>C(O)C>[F:13][C:2]([F:1])([F:12])[CH:3]([F:11])[C:4]([F:9])([F:10])[S:5]([O-:8])(=[O:6])=[O:7].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([S+:29]([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=2)[C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)COc1ccc([S+](c2ccc(OCC(=O)OC(C)(C)C)cc2)c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Agent: O=S(=O)(O)C(F)(F)C(F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)C(F)C(F)(F)F
Solvent: CCO
Product: Oc1ccc([S+](c2ccc(O)cc2)c2ccc(O)cc2)cc1
Yield: 100 %

Procedure:
56.8 g (0.08 mol) of tris-(4-butoxyphenyl) sulfonium 3,3,3,2,1,1-hexafluoropropane sulfonate (Synthesis Example 110) and 1.86 g (0.008 mol) of 3,3,3,2,1,1-hexafluoropropane sulfonic acid were dissolved in 200 ml of ethanol. The solution was heated under ref lux for 8 hours with stirring. After removal of the solvent by distillation, the obtained crude product of tris-(4-hydroxyphenyl) sulfonium 3,3,3,2,1,1-hexafluoropropane sulfonate (yield about 100%) was dissolved in 160 g of N,N-dimethylformamide and reacted with 55.4 g (0.40 mol) of anhydrous potassium carbonate and 60.3 g (0.40 mol) of di-t-butyl dicarbonate at 20° C. for 3 hours. The reaction solution was poured into 700 ml of water and extracted with dichloromethane. The organic phase was washed with water and dried. The solvent was removed by distillation. The oily residue was purified by column chromatography on silica gel using a dichloromethane and methanol as the developing solvent. The white product was collected to yield 31.8 g (yield 45%) of analytically pure tris-(4-t-butoxycarbonylmethoxyphenyl) sulfonium 3,3,3,2,1,1-hexafluoropropane sulfonate. The melting point of the product was 78° C. The 1H-NMR spectrum gave the following signals (CDCl3): δ=1.45 (s, 27H), 5.30-5.56 (d[m], 1H), 7.10-7.13 (d, 6H), 7.55-7.60 (d, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H].[ClH:20]>[Pd]>[ClH:20].[ClH:20].[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: N=C(Nc1cccc(N)c1)N1CCCC1

Procedure:
A sample of the product of step (a), 17 g, was dissolved in 200 ml of 1M hydrochloric acid. The mixture was then hydrogenated with 1 g of 5% Pd/C. When hydrogen uptake had stopped the catalyst was filtered off. The solvent was evaporated in vacuum, and the residue dissolved in isopropanol, evaporated in vacuum again and the residue dissolved in 100 ml of methanol. To this mix was added 200 ml of toluene. This was then concentrated on a steam bath until the volume had decreased to approximately 175 ml. The crystals that precipitated were filtered to give N-(3-aminophenyl)-1-pyrrolidinecarboximidamide dihydrochloride, m.p. 250°-251° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[F:11][C:12]([F:16])([F:15])[CH2:13]O.C(P(CCCC)CCCC)CCC>C1C=CC=CC=1>[F:11][C:12]([F:16])([F:15])[CH2:13][O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: OCC(F)(F)F
Reactant: OCCOC1CCCCO1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: FC(F)(F)COCCOC1CCCCO1
Reaction time: 6 h

Procedure:
According to the procedure of Tet. Let., 35, 5997-6000 (1994), combine 1-hydroxy-2-tetrahydropyran-2-yloxyethane (J. Chem. Soc. Chem. Commun., 1766 (1990)) (5.0 mmol), 1,1-diethylazodicarboxylate (10 mmol), 2,2,2-trifluoroethanol (100 mmol), and tributylphosphine (10 mmol) in benzene (100 mL). After 6 hours, concentrate in vacuo to give a residue. Chromatograph on silica gel to give 2-tetrahydropyran-2-yloxyethyl 2,2,2-trifluorethyl ether.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:29])[C:20]1[CH:28]=[CH:27][C:26]2[O:25][CH2:24][O:23][C:22]=2[CH:21]=1>>[O:25]1[C:26]2[CH:27]=[CH:28][C:20]([C:19]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:16]=[CH:15][CH:14]=[C:13]5[C:8]=4[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]5)[CH2:2][CH2:3]3)=[O:29])=[CH:21][C:22]=2[O:23][CH2:24]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccc5c(c4)OCO5)CC3)cccc2n1
Yield: 54 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and piperonyloyl chloride (75.7 mg; 0.41 mmol) to obtain 42.5 mg. (54% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.39 (t, J=8.0 Hz, 1H), 7.15 (br s, 1H), 7.03 (s, 1H), 6.99 (m, 3H), 6.89 (dd, J=7.6, 0.8 Hz, 1H), 6.08 (s, 2H), 5.93 (br s, 2H), 3.27 (m, 4H), 3.06 (m, 2H), 2.76 (m, 2H). ESIMS+394.2 m/z
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:30]([CH3:33])([CH3:32])[CH3:31].O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C)C(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:19])=[CH:21][CH:22]=1)[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 55 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
To a solution of 4-((1S)-1-{[(benzyloxy)carbonyl]amino}ethyl)benzoic acid (step 1, 3.7 g, 12.4 mmol) and benzyltriethylammonium chloride (3.0 g, 13 mmol) in N,N-dimethylacetamide (100 mL) was added anhydrous potassium carbonate (47 g, 340 mmol) followed by 2-bromo-2-methylpropane (89 g, 650 mmol). The resulting mixture stirred for 24 h at 55° C. After cooling to room temperature, the reaction mixture was poured into cold water (500 mL) under stirring. The resulting solution was extracted with ethyl acetate (500 mL). The organic phase was washed with water (300 mL) and brine (200 mL), dried (sodium sulfate), and evaporated. The residue was purified by flush column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (3/1) to afford 3.48 g (79%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 7.95 (2H, d, J=8.3 Hz), 7.44–7.24 (7H, m), 5.15–4.99 (3H, m), 4.88 (1H, br.s), 1.58 (9H, s), 1.47 (3H, d, J=7.0 Hz).
Reaction SMILES: N1CC(=O)C1.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[N:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1.CS(C)=O.C(Cl)(=O)C(Cl)=O>ClCCl.C(N(CC)CC)C>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[N:12]1[CH2:13][C:14](=[O:16])[CH2:15]1
Reactant: OC1CN(C(c2cccs2)c2cccs2)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C1CNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CN(C(c2cccs2)c2cccs2)C1
Yield: 80.6 %

Procedure:
1-[Bis-thien-2-yl)methyl]azetidin-3-one may be prepared by carrying out the operation as described in Example 73, starting with 4 g of 1-[bis(thien-2-yl)methyl]azetidin-3-ol, 2.6 cm3 of dimethyl sulfoxide, 7.7 cm3 of triethylamine, 7.7 cm3 of oxalyl chloride, and 100 cm3 of dichloromethane. The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) with, as eluent, a mixture of cyclohexane/ethyl acetate (1/1 by volume). The fractions obtained are evaporated to dryness under reduced pressure (2.7 Kpa). 3.2 g of 1-[bis(thien-2-yl)methyl]azetidin-3-one are obtained in the form of cream-colored crystals melting at 70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[N:30]([CH3:32])[CH3:31].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:31][N:30]([CH3:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[NH:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: CN(C)c1ccccc1Br
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)c1ccccc1Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To toluene 3.0 mL suspension of tert-butyl 2-amino-4-phenylbenzoate 0.12 g and cesium carbonate 0.36 g were added 2-bromo-N,N-dimethylaniline 0.18 g, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 11 mg, tris(dibenzylideneacetone)dipalladium(0) 4.1 mg and palladium acetate 2.0 mg at room temperature, and it was stirred at 110° C. for 24 hours. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 11 mg, tris(dibenzylideneacetone)dipalladium(0) 4.1 mg and palladium acetate 2.0 mg were added to it, and it was stirred at 110° C. for 21 hours. Cesium carbonate 73 mg, 2-bromo-N,N-dimethylaniline 45 mg, 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl biphenyl 11 mg, tris(dibenzylideneacetone)dipalladium(0) 4.1 mg and palladium acetate 2.0 mg were added to it, and it was stirred at 110° C. for 24 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((2-(dimethylamino)phenyl)amino)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH3:3].C(O[C@@H:16]1[CH2:48][C@:20]23[C:24]4[C@H:33]([CH2:34][CH2:35][C@H:19]2[C@@:18]([CH3:49])([CH2:23][O:22][CH2:21]3)[C@H:17]1[O:50][CH2:51][C@:52]([CH3:58])([NH:56][CH3:57])[CH:53]([CH3:55])[CH3:54])[C@:32]1([CH3:36])[C@:27]([CH3:46])([C@H:28]([C:43]([OH:45])=[O:44])[C@:29]([C@H:38]([CH3:42])[CH:39]([CH3:41])[CH3:40])([CH3:37])[CH2:30][CH2:31]1)[C:26](=[O:47])[CH:25]=4)(=O)C>ClCCCl>[CH3:58][C@@:52]([NH:56][CH3:57])([CH:53]([CH3:55])[CH3:54])[CH2:51][O:50][C@@H:17]1[C@@:18]2([CH3:49])[C@@H:19]3[CH2:35][CH2:34][C@H:33]4[C:24]([C@@:20]3([CH2:21][O:22][CH2:23]2)[CH2:48][C@H:16]1[N:8]1[C:7]([C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6])=[N:11][CH:10]=[N:9]1)=[CH:25][C:26](=[O:47])[C@:27]1([CH3:46])[C@:32]4([CH3:36])[CH2:31][CH2:30][C@@:29]([C@H:38]([CH3:42])[CH:39]([CH3:40])[CH3:41])([CH3:37])[C@H:28]1[C:43]([OH:45])=[O:44]
Reactant: CC(C)NC(=O)c1nc[nH]n1
Reactant: CN[C@@](C)(CO[C@H]1[C@H](OC(C)=O)C[C@@]23COC[C@]1(C)[C@@H]2CC[C@H]1C3=CC(=O)[C@@]2(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]12C)C(C)C
Solvent: ClCCCl
Product: CN[C@@](C)(CO[C@H]1[C@H](n2ncnc2C(=O)NC(C)C)C[C@@]23COC[C@]1(C)[C@@H]2CC[C@H]1C3=CC(=O)[C@@]2(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]12C)C(C)C
Temperature: 50 °C
Reaction time: 50 h

Procedure:
N-(1-methylethyl)-1H-1,2,4-triazole-3-carboxamide (82.3 mg, 0.534 mmol) and BF3OEt2 (200 μl, 1.578 mmol) were added to a stirred solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-14-(acetyloxy)-15-[[(2R)-2,3-dimethyl-2-(methylamino)butyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-6-oxo-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (free base form of Example 152 in WO2007127012, herein incorporated by reference in its entirety, 70.2 mg, 0.107 mmol) in 1,2-dichloroethane (1.5 ml). The reaction mixture was a light amber solution that was heated to 50° C. After 50 hours, the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the resulting residue was placed under high vacuum. The residue was dissolved in methanol and purified using two HPLC runs (˜35 mg/run) on a 19×150 mm Sunfire Prep C18 OBD 10 μm column by eluting with acetonitrile/water+0.1% TFA. The total flow rate was 15 ml/min and the HPLC method employed a 12 minute 20%-100% acetonitrile/water gradient followed by a 7 minute acetonitrile flush. The product HPLC fractions were combined, the solvent was evaporated under reduced pressure, and the residue was lyophilized from ethanol and benzene to give the title compound (24.2 mg, 0.028 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[C:16]([O:25][CH3:26])[C:15]=2[O:27][CH3:28])=[CH:9][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pd].[C]>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[C:16]([O:25][CH3:26])[C:15]=2[O:27][CH3:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Yield: 85 %

Procedure:
The compound (1.07 g, 2.67 mmol) obtained in step 4 was dissolved in ethanol (100 ml) and 5% Pd-carbon (200 mg) was added thereto, which was then stirred under a stream of hydrogen at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to yield the title compound (914 mg, 2.27 mmol, yield 85%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(N(CC)CC)C.[F:12][C:13]1[C:18]([C:19](Cl)=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[F:25].CC[O:28]CC>>[F:12][C:13]1[C:18]([C:19]([OH:28])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[F:25].[F:12][C:13]1[C:18]([C:19]([OH:28])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[F:25].[CH2:1]([NH2:4])[CH2:2][NH2:3]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CCOCC
Solvent: NCCN
Solvent: CCN(CC)CC
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Ethylene diamine (130 mg, 2.1 mmol) and triethylamine (510 mg, 5.0 mmol), together dissolved in 10 mL anhydrous ether is added to pentafluorobenzoyl chloride (1.2 g, 5.0 mmol) in 10 mL anhydrous ether. White precipitate is obtained and filtered off. The residue is washed with chloroform, then water and then filtered to recover ethylene diamine bis(pentafluorobenzoate) (III) as white needle crystals (yield, 100%). Sodium azide (270 mg, 4.2 mmol) in 1.7 mL water and 4.0 mL DMF is then reacted with III (870 mg, 2.0 mmol) in 20 mL DMF, and stirred overnight on a 60° C. hotplate. A white precipitate is obtained. The solution is reduced to half-volume by evaporation and the precipitate is filtered off (yield, 35%), dried and recrystallised from DMF to give ethylene diamine bis(4-azido-2,3,5,6-tetrafluorobenzoate) (IV) as white crystals. FTIR: 2129 (N3 asymmetric stretch), 1666 (C═O stretch), 1554, 1483, 1242 (N3 symmetric stretch), no acid OH band at 3000-3500.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[O:25]([C:32]1[CH:42]=[CH:41][C:35]([CH:36]=[CH:37][C:38](O)=[O:39])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:25]([C:32]1[CH:33]=[CH:34][C:35]([CH:36]=[CH:37][C:38]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:39])=[CH:41][CH:42]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(Oc2ccccc2)cc1
Yield: 94.4 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 4-phenoxycinnamic acid (3.4 g), WSC.HCl (2.7 g, 14.1 mmol), and methylene chloride (80 mL), to give the captioned compound (4.9 g, 94%) as an oily product.