Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:20]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:30][CH2:29]2)=[CH:20]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 20 °C
Yield: 20.1 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.3 g), 4(3-indolyl)piperidine (4.5 g) and sodium bicarbonate (1.9 g) in a mixture of dimethylformamide (100 cc) and tetrahydrofuran (100 cc). The mixture is heated for 5 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5 - 1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling methyl ethyl ketone (60 cc), 2-{3-[4-(3-indolyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2 g) is obtained, m.p. 162° C.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[OH:8][C@@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:23]2[C:22](=[O:28])[CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:29]([OH:31])=[O:30])[CH2:10]1.ClCC#N>CC(C)=O>[C:6]([CH2:7][O:31][C:29]([C@H:18]1[CH2:17][CH2:16][C@H:15]2[C@H:14]3[C@H:23]([C:22](=[O:28])[CH2:21][C@:19]12[CH3:20])[C@:24]1([CH3:27])[C@H:11]([CH2:10][C@H:9]([OH:8])[CH2:26][CH2:25]1)[CH2:12][CH2:13]3)=[O:30])#[N:3]
Reactant: CCN(CC)CC
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Agent: N#CCCl
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCC#N)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 4 h

Procedure:
Triethylamine (4.5 mmole) was added to a solution of 3α-hydroxy-5α-androstan-11-one 17β-carboxylic acid (1.025g.) in warm acetone (50 ml.) followed by chloroacetonitrile (6 mmole). After refluxing this mixture for 3 hr. further chloroacetonitrile (6 mmole) was added and refluxing continued for 4 hr. Removal of the solvent afforded a residue which was partitioned between ether and water. The ethereal solution was washed with water, dried (MgSO4) and evaporated, to give a foam (1.187g.) which was purified by preparative t.l.c. to afford the pure title compound; m.p. 142°-146°; [α]D + 74°,.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[CH2:17]O)=[CH:3][N:2]=1.P(Br)(Br)[Br:20].O>ClCCl>[Br:20][CH2:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(C(F)(F)F)cc1-c1ccnnc1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1ccc(CBr)c(-c2ccnnc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[2-Pyridazin-4-yl-4-(trifluoromethyl)phenyl]methanol (Preparation 32, 46 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0° C. Phosphorus tribromide (1.0 M in dichloromethane, 199 μL, 0.20 mmol) was added and the reaction stirred for 30 minutes. Water (2 mL) was added dropwise to the reaction at 0° C. before the organics were separated and dried using a phase separation cartridge. The organics were concentrated in vacuo to afford the title compound as a residue which was re-dissolved in THF (1 mL) and used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C:9]1([Li])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: [Li]c1ccccc1
Reactant: Fc1cccc(F)n1
Solvent: C1CCOC1
Product: Fc1cccc(-c2ccccc2)n1
Temperature: -40 °C
Yield: 12 %

Procedure:
Dissolve 2,6-difluoropyridine (5.0 mL, 5.51 mmol) in anhydrous tetrahydrofuran (30 mL) and cool to −40° C. Add a solution of phenyl lithium (1.8 M hexanes, 30.6 mL) dropwise over 5 minutes. Stir the resulting purple reaction at −40° C. for 30 minutes and bring to room temperature. Quench the reaction with water and extract the solution with ethyl acetate several times. Combine the organic extracts, dry over magnesium sulfate, filter and evaporate onto silica gel. Purification by flash column chromatography yields 2-fluoro-6-phenylpyridine 1.0 g (12%) as a yellow oil.
Reaction SMILES: [Se](=O)=O.[CH3:4][O:5][CH2:6][C:7]1([CH3:15])[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8]1.C[O:17]CC1(C)C(=O)CC(C)(C)O1>O1CCOCC1>[CH3:4][O:5][CH2:6][C:7]1([CH3:15])[C:8](=[O:17])[C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[O:11]1
Reactant: COCC1(C)OC(C)(C)CC1=O
Reactant: COCC1(C)CC(=O)C(C)(C)O1
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: COCC1(C)OC(C)(C)C(=O)C1=O
Temperature: 25 °C

Procedure:
A stirred solution of selenium dioxide (2.10 g, 18.91 mmol) in moist dioxane (17 ml, containing 0.5% distilled water by volume) is heated to 100° C., at which point a second (mixed) solution of 5-methoxymethyl-2,2,5-trimethyldihydrofuran-3-one and 2-methoxymethyl-2,5,5-trimethyldihydrofuran-3-one (2.55 g, 14.82 mmol) in moist dioxane (5 ml, containing 0.5% distilled water by volume) is added dropwise over 40 minutes, then further heated at this temperature for 3 hours. After cooling to room temperature the mixture is filtered through diatomaceous earth (washing with diethyl ether) then the solvents are removed at 40° C./50 mbar to give a viscous red-brown oil. This material is purified by bulb to bulb distillation to afford 2-methoxymethyl-2,5,5-trimethylfuran-3,4-dione (2.15 g) as a bright red oil.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:26])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].O1CCCC1.C(C(CCCC)C([O-])=O)C.[Na+:48]>C(OCC)(=O)C>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:26])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([O-:22])=[O:21])=[CH:14][CH:15]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[Na+:48]
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(OCc2ccc(C(O)c3cccc(C(=O)[O-])c3)cc2)ccc(C(C)=O)c1O
Reaction time: 8 h
Yield: 94 %

Procedure:
Compound 3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid (357 mg, 0.822 mmol) is stirred in a solution of ethyl acetate (4 mL) and tetrahydrofuran (4 mL) at room temperature. A solution of sodium 2-ethylhexanoate (150 mg, 0.904 mmol) in ethyl acetate (2 mL) is added and the reaction is stirred overnight. The reaction is concentrated and the resulting thick oil is diluted with ether (5 mL) and stirred vigorously. The resulting white precipitate is filtered, and dried under vacuum to give the title compound as a white solid (94%). 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 7.86 (s, 1H), 7.81 (d, 1H), 7.69 (d, 1H), 7.38-7.39 (m, 4H), 7.33 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H), 5.84 (d, 1H), 5.70 (d, 1H), 5.22 (s, 2H), 2.57-2.62 (m, 5H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M−1 433 (parent acid).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C@@H:18]1[CH2:20][O:19]1)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[C:22]([NH:26][C:27](=[O:33])[C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)([CH3:25])([CH3:24])[CH3:23]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17])[C@@H:18]([OH:19])[CH2:20][N:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[C:27](=[O:33])[NH:26][C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)[C@@H]1CO1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C[C@H](O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-(2,5-difluoro-phenyl)-ethyl]carbamic acid tert-butylester (0.213 g, 0.71 mmol) and (S)-proline tert-butyl amide (0.133 g, 0.78 mmol) gives the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][C:42]=1[CH3:43])[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:40]=[CH:41][C:42]([CH3:43])=[C:21]([NH:20][C:8]([C:4]5[O:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:22]=4)=[CH:30][N:29]3[N:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Cc1nc(C)c(C(=O)O)o1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)o1
Yield: 64.3 %

Procedure:
In the same manner as in Example 55 and using 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (56.6 mg, 0.401 mmol), tetrahydrofuran (5 mL), thionyl chloride (69.1 μL, 0.796 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (117 mg, 0.362 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (104 mg, 64%) was obtained as a pale-brown solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[C:14]=2O)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH:19]([C:18]1[O:22][C:14]2[C:15]3[CH:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10]=3[CH:11]=[CH:12][C:13]=2[N:17]=1)([CH3:20])[CH3:21]
Reactant: CC(=O)NCCC1CCc2ccc(NC(=O)C(C)C)c(O)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: CC(=O)NCCC1CCc2ccc3nc(C(C)C)oc3c21
Yield: 56.8 %

Procedure:
N-{3-[2-(Acetylamino)ethyl]-4-hydroxy-2,3-dihydro-1H-inden-5-yl}-2-methylpropanamide (118 mg, 0.369 mmol) and pyridinium p-toluenesulfonate (18.5 mg, 0.074 mmol) were heated under reflux in xylene (3.7 mL) for 5 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (60 mg, yield 57%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]>>[C:18]1([CH3:23])[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(C2CC2C(=O)OC)cc1
Reactant: Cc1ccccc1I
Product: COC(=O)C1CC1c1ccc(C#Cc2ccccc2C)cc1

Procedure:
The title compound was prepared from methyl 2-(4-ethynylphenyl)cyclopropanecarboxylate (80 mg, 0.40 mmol) and 1-iodo-2-methylbenzene (113 mg, 0.56 mmol) according to the general procedure IF to give 45 mg (39%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:10): Rf=0.41 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.52-7.41 (m, 3H), 7.25-7.20 (m, 2H), 7.20-7.12 (m, 1H), 7.07 (d, J=8.2 Hz, 2H), 3.72 (s, 3H), 2.57-2.51 (m, 1H), 2.50 (s, 3H), 1.92 (ddd, J=8.5, 5.3, 4.2 Hz, 1H), 1.63 (dt, J=9.2, 5.0 Hz, 1H), 1.33 (ddd, J=8.4, 6.5, 4.7 Hz, 1H); 13C NMR (CDCl3) δ 173.6, 140.3, 140.2, 131.8, 131.6, 129.5, 128.3, 126.2, 125.6, 123.0, 121.7, 93.1, 88.5, 52.0, 26.2, 24.2, 20.8, 17.2; ESI-MS m/z 313.1 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=[O:6].Cl.[CH2:16](C(=N)OCC)[CH3:17]>C(O)(=O)C>[CH3:16][C:17]1[N:11]([CH2:12][CH2:13][CH3:14])[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=N)CC
Reactant: CCCNc1ccc(C(=O)O)cc1N
Agent: Cl
Solvent: CC(=O)O
Product: CCCn1c(C)nc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4.5 parts of 3-amino-4-(propylamino)benzoic acid, 2.6 parts of ethyl ethanecarboximidate hydrochloride and 50 parts of acetic acid is stirred first for 20 minutes at room temperature and further for 10 minutes at reflux. The reaction mixture is evaporated. The residue is crystallized from 2-propanol. The product is filtered off, washed with water and 2-propanol and dried, yielding 1.8 parts of 2-methyl-1-propyl-1H-benzimidazole-5-carboxylic acid; mp. >260° C.
Reaction SMILES: [CH2:1]([C:4]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])([C:10](OCC)=[O:11])[C:5](OCC)=[O:6])[CH2:2][CH3:3].C(C(CO)(C(O)C)CO)C>>[OH:6][CH2:5][C:4]([CH2:10][OH:11])([CH2:1][CH2:2][CH3:3])[CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17]
Reactant: CCCC(C(=O)OCC)(C(=O)OCC)C(=O)C(F)(F)F
Agent: CCC(CO)(CO)C(C)O
Product: CCCC(CO)(CO)C(O)C(F)(F)F

Procedure:
3,3-Di-(hydroxymethyl)-1,1,1-trifluoro-hexan-2-ol was prepared from diethyl 2-n-propyl-2-trifluoroacetylmalonate using the method described for the preparation of 2-ethyl-2-hydroxymethyl-butan-1,3-diol [example A(ii)].
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1)([O-])=O.[H][H].CCCCCC.C(OCC)(=O)C>C(O)C.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-4-nitrophenethyl-2-amine from Example 2 (24.2 g, 96.7 mmol) in a mixture of ethanol (150 mL) and THF (50 mL) was added 5% Pd/C (4.0 g). This solution was placed on a Parr Hydrogenator under 40 psig of hydrogen gas and shaken for 5 hours. The reaction mixture was filtered and evaporated to leave a colorless oil. This oil was taken up into hot hexane/ethyl acetate and allowed to crystallized overnight. The solid was collected via vacuum filtration and placed under high vacuum for eight hours. 19.31 g of the title compound, as a white solid, was obtained.
Reaction SMILES: C([N:8]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=2)[C:15]2[C:10](=[C:11]([NH:27][CH:28]=[O:29])[C:12]([OH:26])=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[ClH:30]>C(O)C>[ClH:30].[OH:25][C:20]1[CH:19]=[C:18]([CH:16]2[C:15]3[C:10](=[C:11]([NH:27][CH:28]=[O:29])[C:12]([OH:26])=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:17]2)[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: O=CNc1c(O)ccc2c1CN(Cc1ccccc1)CC2c1ccc(O)c(O)c1
Agent: Cl
Solvent: CCO
Product: O=CNc1c(O)ccc2c1CNCC2c1ccc(O)c(O)c1
Yield: 82.4 %

Procedure:
1.03 g of 2-benzyl-4-(3,4-dihydroxyphenyl)-7-hydroxy-8-nitro-1,2,3,4-tetrahydroisoquinoline hydrobromide was suspended in 20 ml of ethanol, and after adding thereto 1 ml of Raney nickel, hydrogenation reaction was performed at 40° C. The hydrogenation reaction was over, the reaction mixture was filtered, and concentrated, affording 0.88 g of 8-amino-2-benzyl-4-(3,4-dihydroxyphenyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide. (2) To a solution of 0.25 ml of formic acid in 10 ml of chloroform, was added under ice cooling 0.88 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and then after 15 minutes, was added dropwise 5 ml of a solution of 8-amino-2-benzyl-4-(3,4-dihydroxyphenyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (0.88 g) in dimethylformamide. The temperature of the reaction mixture was reverted to room temperature, and the reaction was performed for further 30 minutes. The reaction mixture was concentrated, and the residue obtained was changed to precipitates by addition of standard buffer solution (x5). The precipitates were collected by filtration, and washed perfectly with water, affording 450 mg of 2-benzyl-4-(3,4-dihydroxyphenyl)-8-formylamido-7-hydroxy-1,2,3,4-tetrahydroisoquinoline. (3) 450 mg of 2-benzyl-4-(3,4-dihydroxyphenyl)-8-formamido-7-hydroxy-1,2,3,4-tetrahydroisoquinoline was dissolved in 9 ml of ethanol, and after adding thereto 0.86 ml of 2N hydrochloric acid 0.05 g of 10% paradium-carbon, hydrogenation reaction was performed at room temperature. The hydrogenation reaction was over, the reaction mixture was filtered, and concentrated. The residue was changed to precipitates with treatment of isopropyl alcohol and acetonitrile, and the precipitates was collected by filtration, affording 320 mg of 4-(3,4-dihydroxyphenyl)-8-formamido-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:36][C:37]1[CH:38]=[C:39](O)[CH:40]=[CH:41][CH:42]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:36][C:37]1[CH:42]=[C:41]([CH:40]=[CH:39][CH:38]=1)[O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: COC(=O)c1ccc2ccn(CCO)c2c1
Reactant: Oc1cccc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccn(CCOc3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
To a solution of methyl 1-(2-hydroxyethyl)-1H-indole-6-carboxylate (0.14 g, 0.64 mmol) and Ph3P (0.25 mL, 0.96 mmol) and 3-fluorophenol (0.11 g, 0.96 mmol) in THF (10 mL) was added DIAD (0.19 mL, 0.96 mmol). The solution was stirred 1 hr at room temperature, then concentrated and subjected to flash chromatography (25% ethyl acetate/hexane) to provide 0.22 g (˜100%) of methyl 1-(2-(3-fluorophenoxy)ethyl)-1H-indole-6-carboxylate as a colorless oil.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C@@H:8]1([C:17]2[S:18][CH:19]=[C:20]([C:22]([NH2:24])=[O:23])[N:21]=2)[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10]>N1C=CC=CC=1>[C:9]([O:10][C@@H:9]1[C@H:11]([O:12][C:11](=[O:12])[CH3:13])[C@@H:13]([CH2:15][O:16][C:5](=[O:7])[CH3:6])[O:14][C@H:8]1[C:17]1[S:18][CH:19]=[C:20]([C:22]([NH2:24])=[O:23])[N:21]=1)(=[O:10])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1csc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](c2nc(C(N)=O)cs2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 90 %

Procedure:
Acetic anhydride (2.0 ml) was added to an ice-cold solution of compound 1 (1.04 g, 4 mmol) in anhydrous pyridine (16 ml) and the reaction solution was stirred at room temperature for 17 h. The solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, and the solution was washed with water and dried (MgSO4). The ethyl acetate portion was evaporated in vacuo and the residue thus obtained was crystalized from water to provide 1.4 g (90%) of compound 2 as white needles; mp 103° C.; 1H NMR (CDCl3) 2.1 (3 s, 9, tri-O-acetyl), 6.2 and 7.15 [pair of s(br), 2, CONH2 ], 8.2 (s, 1, H5). Anal. (C15H18N2O8S) C, H, N, S.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:38][CH2:37][N:36]3[C:29](=[CH:30][C:31]4[CH2:32][C:33]([CH3:40])([CH3:39])[CH2:34][C:35]=43)[C:28]2=[O:41])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:38][CH2:37][N:36]3[C:35]4[CH2:34][C:33]([CH3:39])([CH3:40])[CH2:32][C:31]=4[CH:30]=[C:29]3[C:28]2=[O:41])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cnccn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2cnccn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A mixture of 188a (150 mg, 0.27 mmol) and lithium hydroxide (103 mg, 2.7 mmol) in i-propanol/THF (5:3, 8 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 188 (40 mg, 35%) as a white solid. MS-ESI: [M+H]+ 512.3. 1H NMR (500 MHz, CHCl3) δ 8.73 (d, J=2.0 Hz, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.29 (s, 1H), 8.15-8.13 (m, overlap, 2H), 8.02-8.00 (m, 2H), 7.38 (d, J=5.0 Hz, 1H), 6.86 (s, 1H), 5.12 (s, 1H), 4.68-4.51 (m, 2H), 4.33-4.29 (m, 1H), 4.18 (t, J=5.5 Hz, 2H), 3.91-3.86 (m, 1H), 3.75 (s, 3H), 2.60-2.58 (m, 2H), 2.53 (s, 2H), 1.28 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH:1]1([CH2:7][C@@H:8]([C:10]([O:12][CH2:17][CH3:18])=[O:11])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)CC1CCCCC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
b-cyclohexyl alanine (1.5 g) is dissolved in absolute ethanol (75 ml) and the solution cooled to 0° C. Thionyl chloride (1.1 ml) is added dropwise over a period of 10-15 minutes, the solution allowed to warn to room temperature, and then stirred at room temperature for about 18 hours. The reaction mixture is evaporated in vacuo, toluene is azeotroped twice from the residue, and the residue is taken up into ethyl acetate. The ethyl acetate solution is washed with water, 1 N sodium hydroxide, water, brine, dried over sodium sulfate, filtered, and evaporated in vacuo to give b-cyclohexyl alanine, ethyl ester.