Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1ONC([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:26](=[O:32])[CH2:27][NH:28][C:29]([NH2:31])=[O:30])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[C:41]([OH:48])(=[O:47])CNC(N)=O>>[OH:48][C:41]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:26](=[O:32])[CH2:27][NH:28][C:29]([NH2:31])=[O:30])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:47]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CNC(N)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: NC(=O)NCC(=O)O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CNC(N)=O)[C@H](C/C=C/c1ccccc1)C(=O)O

Procedure:
The (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(2-ureidoacetyl)valerohydrazide used as the starting material was prepared in a manner analogous to Example 11 using hydantoic acid in place of N-acetyl-glycine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2)=[O:4].C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>O>[N:20]([C:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[OH:15])=[O:21]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2c(N=O)c(O)ccc2c1
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
202.0 g (1.0 mol) of 6-methoxycarbonyl-β-naphthol were suspended in 1120 ml of 90%-strength acetic acid, nitrosated with 182 g (1.05 mol) of 40%-strength sodium nitrite solution at 0°-5° C. in the course of 2.5 hours and then stirring was continued at room temperature for 45 minutes. The suspension obtained was made up to 3 l with water, the solid was filtered off by suction and washed with water until neutral. After drying, 228.1 g (99.7%) of crude 1-nitroso-6-methoxycarbonyl-β-naphthol were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[N:14]=2)[C:9](F)=[N:10][CH:11]=1)=[CH2:5])C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[O:29][CH3:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CN(C=O)C>[NH2:20][C:15]1[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]2[CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[N:10][C:9]=2[NH:28][C:25]2[CH:26]=[N:27][C:22]([Cl:21])=[C:23]([O:29][CH3:30])[CH:24]=2)[N:14]=1
Reactant: COc1cc(N)cnc1Cl
Reactant: C=C(OCC)c1cnc(F)c(-c2nc(C)nc(N)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cnc1Cl
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a mixture of 4-(5-(1-ethoxyvinyl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (100 mg, 0.363 mmol) and 6-chloro-5-methoxypyridin-3-amine (Small Molecules, Inc) (86 mg, 0.545 mmol) in 1 mL of THF and 0.3 mL of DMF at 0° C. was added sodium bis(trimethylsilyl)amide (1.09 mL of 1.0 M solution in THF, 1.09 mmol) dropwise and the dark red solution was stirred at this temperature for 30 min. It was quenched with 4 mL of 0.5 N HCl and stirred at RT for 10 min. The mixture was treated with 1 N NaOH to pH of about 8. It was extracted twice with EtOAc (30 mL). The combined organic phases were washed with brine and dried over Na2SO4. It was concentrated to half of its volume, the precipitated tan solid was filtered through a fritted funnel, rinsed with 2 mL of ether, collected and dried to give 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-chloro-5-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (90 mg, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.63 (s, 1H), 9.29 (s, 1H), 9.03 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.06 (br., 1H), 7.90 (br., 1H), 3.96 (s, 3H), 2.60 (s, 3H), 2.47 (s, 3H). m/z (ESI, positive ion) 386.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24]>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CN(C)c1cccc(C(=O)O)c1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(N(C)C)c4)cc23)CC1

Procedure:
Reacting 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole with 17.0 mg (0.10 mMol) 3-(dimethylamino)benzoic acid at 70° C., 12.4 mg (66%) of the title compound were recovered.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1>>[N+:6]([C:16]1[C:12]([O:11][CH3:10])=[N:13][S:14][CH:15]=1)([O-:9])=[O:7]
Reactant: COc1ccsn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1nscc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
To a solution of 10 ml. of concentrated sulfuric acid and 2 g. (0.022 mole) of 70% nitric acid was added over several minutes 2.3 g. (0.02 mole) of 3-methoxyisothiazole. The temperature rose to 40° C. and was controlled at that point by cooling. After stirring for 5 hours the reaction solution was poured into 30 ml. of ice-water to precipitate 0.5 g. (16%) of 4-nitro-3-methoxyisothiazole as a white solid, m.p. 118°-122° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: OB(O)c1cccs1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: O=C1NC(=O)c2c1c(-c1cccs1)cc1[nH]c3ccc(O)cc3c21
Yield: 69 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione prepared as in example 7 with 2-thiopheneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(2-thienyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (505) (1; Ar=2-thienyl) in a 69% yield; mp (THF/CH2Cl2/hexane) 179–184° C. (dec). 1H NMR [(CD3)2SO] δ 11.75 (br s, 1H), 11.11 (br s, 1H), 9.26 (br s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.75 (s, 1H), 7.73 (dd, J=3.6, 1.0 Hz, 1H), 7.68 (dd, J=5.1, 1.3 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.20 (dd, J=5.1, 3.6 Hz, 1H), 7.07 (dd, J=8.7, 2.5 Hz, 1H). Found: C, 62.38; H, 3.11; N, 7.74. C18H10N2O3S.3/4H2O requires C, 62.15; H, 3.33; N, 8.05.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:11][C:10]2=[N:23][NH:24][CH:25]=[C:9]12>[Pd].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:11][C:10]2=[N:23][NH:24][CH:25]=[C:9]12
Reactant: CCOC(=O)/C=C/C1=C(C#N)C(c2ccccc2Cl)c2c[nH]nc2N1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1=C(C#N)C(c2ccccc2Cl)c2c[nH]nc2N1
Reaction time: 5 h
Yield: 61.2 %

Procedure:
A suspension of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(trans-2-ethoxycarbonylethenyl)-2H-pyrazolo[3,4-b]pyridine (260 mg) and 5% palladium on carbon (110 mg) in ethanol was subjected to catalytic hydrogenation at room temperature for 5 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give a yellow solid. The yellow solid was crystallized from ethyl acetate-diisopropyl ether to give the title compound (160 mg) as pale-yellow crystals.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:22]3[S:21][CH:25]=[CH:24][N:23]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2nccs2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 409.16 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:5][C:6]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:7]#[N:8])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(Cl)c(Cl)c1
Yield: 14.7 %

Procedure:
Using 2.00 g of (3,4-dichlorobenzyl)malononitrile, 20 ml of N,N-di-methylformamide, 0.36 g of sodium hydride (60% in oil), and 2.37 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.42 g of 2-(3,4-dichlorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (21)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:15]=[C:16]([S:20]([CH2:23][CH2:24][S:25][C:26]2[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.CCCCCC>C1(C)C(C)=CC=CC=1.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH:32][C:31]1[C:26]([S:25][CH2:24][CH2:23][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:33])([F:34])[F:12])[CH:15]=2)(=[O:22])=[O:21])=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:10]
Reactant: COC(=O)Cc1ccccn1
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C(Cc1ccccn1)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 32 %

Procedure:
302 mg (2.0 mmol) methyl 2-(pyridin-2-yl)acetate were added to a solution of 362 mg (1.0 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) in xylene (4 ml) and the mixture was then heated for 7 h at 150° C. After cooling to RT the mixture was diluted with EtOAc and the phases were separated. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 6:4) of the residue yielded 154 mg (0.32 mmol, 32%) 2-pyridin-2-yl-N-[2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]acetamide. MS: m/z 482.1 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11]2)=[N:7][CH:6]=1)[NH2:4].[C:26](OC(=O)C)(=O)[CH3:27].Cl>N1C=CC=CC=1.O>[CH3:26][C:27]1[O:1][N:2]=[C:3]([C:5]2[S:9][C:8]([N:10]3[CH2:14][CH2:13][CH:12]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:11]3)=[N:7][CH:6]=2)[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(=NO)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)C3)s2)no1
Temperature: 100 °C

Procedure:
To N′-hydroxy-2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carboximidamide (190 mg, 0.51 mmol) in pyridine (1.5 mL) at rt was added acetic anhydride (48 μL, 0.51 mmol) and heated at 100° C. for 4 h. After cooling, the reaction mixture was diluted with water, acidified with 1 N HCl (20 mL) and extracted with EtOAc. The EtOAc layer was washed with diluted brine, dried (Na2SO4) and concentrated. Combi-Flash chromatography (10 g, 50-100% EtOAc in hexanes in 20 min, 20 mL/min, 15 mL/fraction) gave a white solid which was triturated with Et2O to give the title compound as a white powder. 1H NMR (400 MHz, acetone-d6): δ 7.81 (s, 1 H), 7.71-7.65 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1 H), 5.52 (s, 1 H), 3.98 (m, 1 H), 3.84-3.67 (m, 3 H), 2.61 (s, 3 H), 2.60-2.43 (m, 2 H). MS (+ESI) m/z 397 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][O:17][S:33]([CH3:32])(=[O:35])=[O:34])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(COS(C)(=O)=O)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (1.0 g) in THF (10 mL) were successively added dropwise triethylamine (1.1 mL) and methanesulfonyl chloride (0.41 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (1.2 g).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[C:23]([CH3:30])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:31])(C)(C)C.[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[C:38]([NH:29][S:26]([C:24]1[S:25][C:21]([C:16]([CH2:19][CH3:20])([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH:7]([OH:6])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:11]([CH3:31])[CH:12]=2)[CH2:17][CH3:18])=[CH:22][C:23]=1[CH3:30])(=[O:28])=[O:27])(=[O:41])[CH2:39][CH3:40]
Reactant: CCC(=O)O
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Product: CCC(=O)NS(=O)(=O)c1sc(C(CC)(CC)c2ccc(OCC(O)C(C)(C)C)c(C)c2)cc1C
Yield: 66 %

Procedure:
Using procedures analogous to Example 158B and Example 158C, 5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonic acid amide and propionic acid give the title compound (66%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]([OH:34])[CH2:20][C@H:21]([CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OC1C=CC(C2C=CC([C@@H](O)C[C@H](CCCC3C=CC=CC=3)C(O)=O)=CC=2)=CC=1)CCCC>>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:34])[CH2:20][CH:21]([CH2:25][CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2ccc([C@H](O)C[C@H](CCCc3ccccc3)C(=O)O)cc2)cc1
Agent: CCCCCOc1ccc(-c2ccc([C@@H](O)C[C@H](CCCc3ccccc3)C(=O)O)cc2)cc1
Product: CCCCCOc1ccc(-c2ccc(C(O)CC(CCCc3ccccc3)C(=O)O)cc2)cc1

Procedure:
the more active of the compounds [2S, 4R]-4-[4-(4-pentyloxyphenyl)phenyl]-4-hydroxy-2-(3-phenylpropyl)-butanoic acid and [2S, 4S]-4-[4-(4-pentyloxyphenyl)phenyl]-4-hydroxy-2-(3-phenylpropyl)-butanoic acid;
Reaction SMILES: [H][H].[CH3:3][C:4]1[NH:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=2)[C:6](=[O:19])[CH:5]=1>[Pd].O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([N:7]2[C:6](=[O:19])[CH:5]=[C:4]([CH3:3])[NH:8]2)=[CH:10][C:11]=1[CH3:18]
Reactant: Cc1cc(=O)n(-c2ccc([N+](=O)[O-])c(C)c2)[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(=O)n(-c2ccc(N)c(C)c2)[nH]1

Procedure:
Hydrogen was introduced under atmospheric pressure into the mixture of 350 mg of 5-methyl-2-(3-methyl-4-nitrophenyl)-1,2-dihydropyrazol-3-one, 70 mg of Pd/C and 50 ml of tetrahydrofuran until the theoretical uptake. Afterwards, the catalyst was filtered off with suction and the mixture was concentrated to dryness under reduced pressure and the residue was stirred in t-butyl methyl ether. The solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[C:26]([CH2:37][O:38][CH3:39])[CH:25]=3)[O:21][N:20]=2)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].[ClH:40]>O1CCOCC1>[CH3:39][O:38][CH2:37][C:26]1[CH:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[CH:15][C:3]([CH2:4][N:5]([CH3:14])[CH2:6][C:7]([OH:9])=[O:8])=[CH:2][C:18]=3[Cl:40])[N:23]=2)[CH:29]=[CH:28][C:27]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36]
Reactant: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)c(Cl)c3)no2)ccc1-c1ccccc1C
Reactant: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)O)cc3Cl)no2)ccc1-c1ccccc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To tert-butyl 2-((2-chloro-4-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl)amino)acetate (0.192 g, 0.35 mmol) was added a 4N solution of HCl in dioxane (2 mL) and the reaction mixture stirred at 80° C. for 2 hours. The reaction mixture was allowed to cool and the solvent evaporated in vacuo. The residue was purified by SCX-2 chromatography eluting with methanol followed by DCM and ammoniacal MeOH (7M) to afford the title compound as a colorless gum. 1H NMR (CDCl3, 400 MHz) δ 8.38 (1H, s), 8.12 (1H, d, J=7.9 Hz), 8.07 (1H, d, J=8.0 Hz), 7.72 (1H, s), 7.55 (1H, d, J=8.1 Hz), 7.32-7.19 (4H, m), 7.10 (1H, d, J=7.4 Hz), 4.19 (4H, m), 3.57 (2H, s), 3.28 (3H, s), 2.72 (3H, s), 2.05 (3H, s). LC/MS (Method A): 492 (M+H)+. HPLC (Method F) Rt 3.19 min (Purity: 98.8%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[I:17].C(N(CC)CC)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O1CCCC1>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([C:7]2[C:2]([I:1])=[C:3]([CH2:8][CH2:9][NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[I:17])[CH:4]=[CH:5][CH:6]=2)=[O:33])=[CH:35][CH:36]=1)([O-:27])=[O:26]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Ic1ccccc1CCNc1ccccc1I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1cccc(CCNc2ccccc2I)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of 0.90 g of 2-iodo-N-(2-iodophenyl)benzeneethanamine in 4 ml of tetrahydrofuran is added 0.41 g of triethylamine, and 0.57 g of 4-nitrobenzoyl chloride. The mixture is stirred at room temperature for 2 hours and the solvent removed under vacuum. The residue is dissolved in ethyl acetate-dichloromethane (5:1) and the solution washed with 1N HCl, saturated NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated and the residual solid triturated with diethyl ether and hexane to give 1.10 g of product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:21](=O)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[C:14]2=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-]>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)c3ccc(Cl)cc3C2=O)C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2Cc3ccc(Cl)cc3C2)C1
Temperature: 0 °C
Yield: 41.3 %

Procedure:
(R)-3-(5-Chloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.200 g, 0.57 mmol) was dissolved in ether and cooled to 0° C. and LiAlH4 (2.85 mL, 2.8 mmol) was added dropwise, followed by AlCl3 (0.380 g, 2.8 mmol). The solution was allowed to stir at 0° C. for 1½ h and then slowly quenched with water and extracted with ethyl acetate (3×). The organic were collected together and dried over Mg2SO4, filtered and evaporated in vacuo, to yield the title compound (0.076 g, 41%) without further purification. ESI-MS m/z: 323 (M+1), retention time 1.27.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:11][C@@H:10]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[CH3:27])[CH2:16][CH2:15]3)=[O:13])[NH:9][C:8]2=[O:28])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:9]1[C@H:10]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:16][CH2:15]2)=[O:13])[CH2:11][N:7]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:5])=[O:6])[C:8]1=[O:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)C4CC4)C(=O)N3)CC2)c1
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)C4CC4)C(=O)N3Cc3ccccc3)CC2)c1

Procedure:
In analogy to example 66, step 4, from (S)-1-cyclopropanesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one and benzyl bromide was prepared
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C=O)C>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Following a literature procedure (Asso, V.; Ghilardi, E.; Bertini, S.; Digiacomo, M.; Granchi, C.; Minutolo, F.; Rapposelli, S.; Bortolato, A.; Moro, S. Macchia, M. ChemMedChem, 2008, 3, 1530-1534) powdered KOH (0.103 g, 1.85 mmol) was added to a solution of 3,6-dibromocarbazole (0.500 g, 1.54 mmol) in DMF (1.5 mL) at ambient temperature and stirred for 30 min until dissolved. Epibromohydrin (0.32 mL, 3.8 mmol) was added via syringe and the reaction was stirred at room temperature overnight. Upon completion, the solution was partitioned between EtOAc and H2O. The aqueous layer was washed 3× with EtOAc, and the combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was recrystallized from EtOAc/Hexane to afford the desired product (389 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[N:24]([CH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:36])[C:3]=1[C:37](=[O:39])[NH2:38].[ClH:40].CCOCC>O1CCOCC1>[ClH:40].[NH2:1][C:2]1[N:24]([CH2:25][CH2:26][CH2:27][NH2:28])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:16][CH:17]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:36])[C:3]=1[C:37]([NH2:38])=[O:39]
Reactant: CC(C)(C)OC(=O)NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCCCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.16 g (0.30 mmol) of the product prepared in step 11.4 is suspended in 4 mL of anhydrous dioxane, and 0.74 mL (2.95 mmol) of a 4N solution of hydrogen chloride in dioxane is added. The mixture is stirred at room temperature for 5 hours, and ether is added. The solid is drained by suction, rinsed with pentane and dried in an oven. 0.14 g of the expected product is obtained in the form of a white powder. Yield (dihydrochloride)=quantitative. m.p.=250°C. M+H+=439.