Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]2)=[O:14])=[CH:11][C:10]=1[CH2:27][CH:28]([CH3:30])[CH3:29])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:26]=[CH:25][C:12]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]2)=[O:14])=[CH:11][C:10]=1[CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Yield: 89.5 %

Procedure:
1-(4-benzyloxy-3-isobutylbenzoyl)-4-isobutylpiperazine (6.78 g) was dissolved in ethanol (250 ml) and then, with 10% palladium charcoal (0.14 g) added thereto, the mixture was stirred at room temperature for 24 hours in a hydrogen gas atmosphere. After the reaction mixture was filtered under a suction, the filtrate was concentrated under a vacuum, thereby yielding 4.73 g of 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine. In acetone (50 ml), this compound (0.96 g), 2-fluorobenzyl bromide (0.68 g), and potassium carbonate (0.83 g) of were refluxed with stirring for 4 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, and then dried over sodium sulfate anhydride. The residue obtained after concentration was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), thereby yielding 0.90 g of the aimed compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])C)[N:5]=1)(=O)C.C[C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].C(O)=O>CO.O1CCCC1>[NH2:5][C:6]1[C:10](=[O:12])[C:4]2[C:9](=[CH:8][CH:7]=1)[C:19]1[C:18](=[CH:17][C:15]([NH2:16])=[CH:14][CH:20]=1)[CH:1]=2
Reactant: Cc1ccccc1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CO
Solvent: O=CO
Solvent: C1CCOC1
Product: NC1=CC=C2C(=Cc3cc(N)ccc32)C1=O
Yield: 53 %

Procedure:
100 ml of methanol, 6.53 g of 2,6-diacetylpyridine (molecular weight 163.18; 40 mmols) and 21.4 g of 2-methylaniline (molecular weight 107.15; 200 mmols) were put into a 300 ml flask, and thoroughly stirred to prepare a homogeneous mixture. 0.6 ml of formic acid was added to this, and further the mixture was stirred at room temperature for 4 hours to make the compounds reacted completely. The resulting yellow crystal was taken out through filtration, washed with methanol, and dried under reduced pressure to obtain 10.3 g of 2,6-diacetylpyridine-di(2-methylphenyl)imine (molecular weight 341.45; 30.3 mmols, yield 76%) Next, 10 ml of tetrahydrofuran, 20 ml of methanol, 5.1 g (15 mmols) of 2,6-diacetylpyridine-di(2-methylphenyl)imine and 1.96 g of 2,7-diaminofluorenone (molecular weight 196.25; 10 mmols) were put into a 100 ml flask, and thoroughly stirred to prepare a homogeneous mixture. 0.6 ml of formic acid was added to this, and further the mixture was stirred at room temperature for 4 hours to make the compounds reacted completely. The resulting yellow crystal was taken out through filtration, washed with methanol, and dried under reduced pressure. Its NMR spectrum was assigned as the intended ligand (molecular weight 664.84; 2.65 g, 4.0 mmols, yield 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccccc4nc3OC)CC2)c1
Yield: 81.2 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxy-phenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: Cl.COCCOC[N:8]([C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[CH3:29])[S:9]([C:12]1[S:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:11])=[O:10]>C(O)C>[CH3:28][C:25]1[C:24]([CH3:29])=[C:23]([NH:8][S:9]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)(=[O:11])=[O:10])[O:27][N:26]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccc(-c2ccccc2)s1
Agent: Cl
Solvent: CCO
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccc3)s2)c1C
Yield: 41.6 %

Procedure:
HCl (3 mL of a 3 N aqueous solution) was added to a solution of N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide (100 mg, 0.24 mmol) in 3 mL of 95% ethanol and the resulting mixture was refluxed for 6 h. The mixture was then concentrated, diluted with 5 mL of water, neutralized with saturated aqueous sodium bicarbonate solution and acidified to pH 4 using glacial acetic acid. The mixture was extracted with ethyl acetate (2×25 mL) and the combined organic extract was washed with brine (1×5 mL), dried and evaporated. Flash chromatography of the residue on silica gel using 2% MeOH/CHCl3 and further purification by reverse phase HPLC yielded 33.4 mg (42%) of the pure sulfonamide as a white powder, m.p. 176-178° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[N:7]([CH2:8][CH2:9][CH2:10]O)[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[NH:3]1.S(Cl)([Cl:19])=O.CN(C)C=O>ClCCl>[Cl:19][CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[NH:3][S:2]1(=[O:16])=[O:1]
Reactant: O=S(Cl)Cl
Reactant: O=S1(=O)Nc2ccccc2CN1CCCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S1(=O)Nc2ccccc2CN1CCCCl
Temperature: 23 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
A solution of 3-(2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl)propan-1-ol (1.0 g, 4.1 mmol) in dichloromethane (20 mL) was treated with thionyl chloride (0.91 mL, 12.3 mmol) and dimethylformamide (0.20 mL) and stirred at 23° C. for 16 hours. Additional thionyl chloride (0.30 mL, 4.1 mmol) was added and stirring was continued for an additional 4 hours. The reaction mixture was quenched by the addition of methanol (5 mL) and evaporated. Flash chromatography (SiO2, 3-40% ethyl acetate/hexanes) provided 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.85 g, 79%) as a yellow oil:
Reaction SMILES: [H-].[Na+].[C:3](=O)([O:6]C)[O:4][CH3:5].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+]>C1(C)C=CC=CC=1.CO.O.C(O)(=O)C>[CH3:5][O:4][C:3]([CH:20]1[C:19](=[O:22])[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15])[CH2:21]1)=[O:6]
Reactant: COC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a suspension of 60% sodium hydride (3.5 g, 88 mMol) in dry toluene (50 mL), dimethyl carbonate (4.32 g, 48.0 mMol) was added dropwise in 0.5 h at room temperature under an atmosphere of nitrogen. After addition of a few drops of methanol, a solution of 1-tert-butoxycarbonyl-4-piperidone (4.8 g, 24 mMol) dissolved in dry toluene (20 mL) was added dropwise to the reaction mixture while stirring at 80° C. over 1 h. The reaction mixture was stirred for 3 h at the same temperature and then cooled to 0° C. (ice bath) and adjusted to pH 6-6.5 with acetic acid. The resulting cold mixture was diluted with water (10 mL) and adjusted to pH 8 with 5% sodium hydroxide solution. The toluene layer was separated and the aqueous layer was extracted with toluene (20 mL). The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure The compound was dried in vacuum to give methyl-1-tert-butoxycarbonyl-4-oxo-3-piperidine carboxylate (5.0 g, 80%). The compound obtained was carried to next reaction without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43]([OH:45])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][NH2:47]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](=[O:45])[NH:47][CH3:46])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: CNC(=O)C[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1C(=O)OCc1ccccc1

Procedure:
Similar to example 6a, 50.0 mg of (2S,4R,5R)-2-carboxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 9b) reacted with methylamine to afford the title compound as a yellow oil. Rf=0.35 (dichlormethane-methanol 9:1); Rt=4.57.
Reaction SMILES: [OH2:1].[ClH:2].Cl.[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:8]=2[CH2:7]1.CN(C)C1CC[C:26]2[O:27][C:28]3C=CC(N)=C[C:29]=3[C:25]=2[CH2:24]1.Cl.Cl.[Cl-]>>[ClH:2].[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:24]([C:25]4[CH:29]=[CH:28][O:27][CH:26]=4)=[O:1])=[CH:13][C:12]=3[C:8]=2[CH2:7]1
Reactant: O
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Agent: Cl
Agent: [Cl-]
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccoc4)cc3c2C1
Yield: 69.7 %

Procedure:
Beginning with 0.105 gm (0.35 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine dihydrochloride hemihydrate and 0.069 gm (0.53 mMol) furo-3-yl chloride, 0.088 gm (70%) of the title compound were recovered as an off-white solid by the procedure of Example 17.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]4[CH2:21][CH2:22][C:23](=O)[C:16]4=[CH:15][C:14]=3[CH:13]=2)=[C:10]([CH2:25][CH3:26])[CH:9]=[C:8]([C:27]([O:29]C)=[O:28])[C:7]1=[O:31].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(C(F)(F)F)=O>ClCCCl.CC(O)=O>[CH2:25]([C:10]1[CH:9]=[C:8]([C:27]([OH:29])=[O:28])[C:7](=[O:31])[NH:6][C:11]=1[C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH:23]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[C:16]3=[CH:15][C:14]=2[CH:13]=1)[CH3:26]
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc1n2CCC1=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCc1cc(C(=O)O)c(=O)[nH]c1-c1ccc2c(c1)cc1n2CCC1N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a solution of methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-2-oxo-6-(1-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)-1,2-dihydropyridine-3-carboxylate (0.11 g, 0.22 mmol) in DCE (2 mL) was added pyrrolidine (80 μL, 0.88 mmol) and AcOH (30 μL). After stirring at room temperature for 1 h, NaBH(OAc)3 (0.1 g, 0.44 mmol) was added and the reaction mixture was stirred for an additional 2 h before TFA (1.5 mL) was added. After stirring for 30 min, the reaction mixture was concentrated and the crude residue was dissolved in THF (1 mL) and aqueous NaOH (2 mL, 4M) was added and the resulting mixture was heated to 60° C. for 15 h. The reaction mixture was then poured into H2O, acidified with 4M HCl, and extracted with CH2Cl2 (2×30 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to afford a crude oil which was triturated with Et2O to afford the title compound as an orange solid (35 mg, 41% over 3 steps).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([S:22]C#N)=[CH:14][C:13]=1[CH3:25].Cl>C1COCC1.CCOC(C)=O.O.[H][H]>[C:18]([C:16]1[C:15]([SH:22])=[CH:14][C:13]([CH3:25])=[C:12]([CH:17]=1)[O:11][CH2:10][CH2:9][OH:8])([CH3:21])([CH3:20])[CH3:19]
Reactant: [H][H]
Reactant: COC(=O)COc1cc(C(C)(C)C)c(SC#N)cc1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(S)c(C(C)(C)C)cc1OCCO
Temperature: 0 °C

Procedure:
To a round bottom flask equipped with a magnetic stirrer and addition funnel were added 1.50 g (39.5 mmol) of lithium aluminum hydride and freshly distilled THF (40 mL). This slurry was cooled to 0° C. and treated dropwise with a solution of (5-tert-butyl-2-methyl-4-thiocyanato-phenoxy) acetic acid methyl ester (prepared in Example KKK; 4.48 g, 15.3 mmol) dissolved in freshly distilled THF (40 mL). The reaction was worked up by diluting the slurry with EtOAc and slowly adding H2O until hydrogen gas evolution had ceased. The solution was neutralized with 1N HCl and extracted with EtOAc. The organic layers were combined, dried (MgSO4) and concentrated. The residue was dried under high vacuum and carried on crude to the next step (see Example MMM).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.[CH:11](=O)[CH3:12]>C(N(CC)CC)C>[CH:9]1[CH:8]=[C:7]2[N:6]([O-:10])[CH:11]=[CH:12][N+:4](=[O:5])[C:3]2=[CH:2][CH:1]=1
Reactant: CC=O
Reactant: [O-][n+]1onc2ccccc21
Solvent: CCN(CC)CC
Product: O=[n+]1ccn([O-])c2ccccc21
Reaction time: 24 h

Procedure:
A mixture of benzofuroxan (2.5 g.), acetaldehyde (2.5 ml.) and triethylamine (20 ml.) is allowed to stand at room temperature for 24 hours. The solid material which precipitates is filtered and dried to give product, M.P. 223°-224° C. dec. (MIC against P. vulgaris is 12.5 mcg./ml.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].[Li+].[OH-].O.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(F)cc3F)c(-c3ccc(F)cc3F)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCN1CCCc2nc(-c3ccc(F)cc3F)c(-c3ccc(F)cc3F)nc21
Reaction time: 72 h

Procedure:
Ethyl 7-(2,3-bis(2,4-difluorophenyl)-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 1) (480 mg, 0.931 mmol) in THF (2.5 ml) was treated with LiOH (178 mg, 7.45 mmol) followed by water (2.5 ml) and stirred vigorously for 3 days. The mixture was acidified to pH4/5 using 5M HCl and extracted with DCM. The combined organic extracts were dried (sodium sulphate), filtered and concentrated under reduced pressure. Purification was carried out on silica eluting with 20-25% TBME in DCM. The resulting product was further purified under the following conditions to afford the titled compound;
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.Cl.[C:29]([S:48][CH2:49][CH2:50][NH2:51])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:17])([F:18])[F:19])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH:51][CH2:50][CH2:49][S:48][C:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:14])=[CH:8]2
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.30 g), 2-(tritylthio)ethylamine hydrochloride (0.32 g), triethylamine (0.13 mL) and N,N-dimethylformamide (10 mL) were added 1H-1,2,3-benzotriazol-1-ol (0.15 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.19 g) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-20:80), and the obtained crystals were washed with diethyl ether-hexane to give the title compound (160 mg, yield 31%) as colorless crystals. melting point 222-223° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:12][O:13][CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:16][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCCO
Reactant: COc1ccc(C=O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCOc1cc(C=O)ccc1OC
Reaction time: 20 h

Procedure:
To a solution of 3-hydroxy-4-methoxy-benzaldehyde (3.04 g, 20 mmol) and 3-methoxy-propanol (1.80 g, 20 mmol) in THF (150 mL) is added triphenylphosphine (5.24 g, 20 mmol) at room temperature under nitrogen atmosphere. To the stirring mixture is added diethyl azodicarboxylate (3.11 mL, 20 mmol) over 10 min at room temperature, and the resulting solution is further stirred over 20 h. THF is removed under reduced pressure and the remaining residue is purified by flash chromatography on silica gel (hexane/EtOAc 2/1) to afford the title compound: TLC, Rf (hexane/EtOAc 2/1)=0.2.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24]>ClCCl>[CH3:21][C:22]([CH3:27])([CH3:26])[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][N:11]=1)=[O:24]
Reactant: Nc1ccc(-c2ccccc2)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
5-phenylpyridin-2-amine (2.4 g, 14.10 mmol) was dissolved in 75 ml of dichloromethane. The solution was treated with triethylamine (1.57 g, 15.51 mmol) and trimethylacetylchloride (1.87 g, 15.51 mmol) and the mixture was stirred at room temperature for 1 hour. Silica gel (9 g) was added and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (5:1) to afford 2,2-dimethyl-N-(5-phenylpyridin-2-yl)propanamide (2.58 g) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH3:34])[C:17]2[C:22]([C:23]=1[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[CH:21][CH:20]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:18]=2)C1C=CC=CC=1>CO.CC(O)=O.[OH-].[Pd+2].[OH-]>[CH:24]1([C:23]2[C:22]3[C:17](=[CH:18][C:19]([C:30]([O:32][CH3:33])=[O:31])=[CH:20][CH:21]=3)[N:16]([CH3:34])[C:15]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCc3ccccc3)n(C)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)n(C)c2c1
Reaction time: 12 h

Procedure:
A solution of intermediate 3 (4.00 g) in MeOH (36 mL) and AcOH (4 mL) was hydrogenated in presence of palladium hydroxide as catalyst. After 12 h, the reaction mixture was filtered and the filtrate was evaporated to give methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1-methyl-1H-indole-6-carboxylate 4: m/z=364 (M+H)+.
Reaction SMILES: C1(C[O:8][P:9]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]2C(=O)C3=CC=CC=C3C2=O)([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)C=CC=CC=1.[OH2:55].NN>O1CCOCC1.C1(C)C=CC=CC=1>[C:14]1([CH2:13][O:55][N:11]([PH:9]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[O:8])[C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(=O)(CCCCCCN1C(=O)c2ccccc2C1=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O
Agent: NN
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)N(OCc1ccccc1)[PH](=O)CCCCCCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-[N-[(phenylmethoxy)(6-phthalimidohexyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After 24 hours, the mixture is diluted with toluene and the solvents decanted and evaporated to dryness. The residue is purified by extraction and flash chromatography to give N-[(phenylmethoxy)[(6-aminohexyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[F:1][C:2]([F:15])([F:16])[C:3]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: O=[N+]([O-])O
Reactant: OC(c1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-phenylpropan-2-ol (6.1 g, 25 mmol) was dissolved in concentrated H2SO4 (15 mL) and cooled to −10° C. HNO3 (90%, 5 mL, 100 mmol) was added dropwise and the temperature was maintained below −5° C. The mixture was stirred at −5° C. for 10 min and was poured into ice. The precipitate was collected via filtration, washed with ice water until pH˜6, and was dried to yield 1,1,1,3,3,3-hexafluoro-2-(3-nitrophenyl)propan-2-ol (6.3 g) that was used in next step without further purification.