Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:20]=[C:21]=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1.[CH3:25][NH:26][O:27][CH3:28]>C1C=CC=CC=1>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([NH:20][C:21](=[O:22])[N:26]([O:27][CH3:28])[CH3:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CNOC
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Solvent: c1ccccc1
Product: CON(C)C(=O)Nc1ccc(Oc2ccc3ccccc3c2)c(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
Five grams of 3-trifluoromethyl-4-(2-naphthyloxy)phenyl isocyanate were dissolved in 100 ml of benzene, and a solution of 2 g of N,O-dimethylhydroxylamine in 50 ml of benzene was added dropwise thereto at a temperature below 30° C. The reaction mixture was allowed to stand at room temperature for 30 minutes, and the solvent was then removed under reduced pressure. The residue was recrystallized from ethanol to obtain 4.2 g of N'-[3-trifluoromethyl-4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea as white needles. M.P. 129°-130° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>CCO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)/C=C/c1cccc(N)c1
Yield: 56.6 %

Procedure:
A solution of (E)-methyl 3-(3-nitrophenyl)acrylate (20.14 g, 0.097 mol), Fe (32.5 g, 0.58 mol), concentrated HCl (3.5 ml) in 50% EtOH (100 ml) was refluxed for 2 h. Upon completion, the solution was filtered through Celite and washed with EtOH. The filtrate was concentrated and extracted with dichloromethane. The combined organic phase was dried over MgSO4 and concentrated to afford (E)-methyl 3-(3-aminophenyl)acrylate as a yellow solid (9.73 g, 57%).
Reaction SMILES: [CH2:1]([C:4]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5]1)[CH2:2][CH3:3].[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]([OH:21])[CH2:18][C:19]#[N:20])[CH:14]=[CH:15][CH:16]=1>>[OH:21][CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][CH2:6][C:4]([OH:5])([CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH3:3])[CH:12]=1)[CH2:18][C:19]#[N:20]
Reactant: CCCC1(CCC)CO1
Reactant: N#CCC(O)c1cccc(N)c1
Product: CCCC(O)(CCC)CNc1cccc(C(O)CC#N)c1

Procedure:
Reaction between 2,2-dipropyloxirane and aniline 12 gave 3-hydroxy-3-(3-(2-hydroxy-2-propylpentylamino)phenyl)propanenitrile as a pale yellow semi-solid. Yield (1.0 g, 40%); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=8.0 Hz, 1H), 6.69-6.67 (m, 2H), 6.63 (d, J=8.0 Hz, 1H), 4.96-4.94 (m, 1H), 4.05 (bs, 1H), 3.08 (s, 2H), 2.76 (d, J=6.4 Hz, 2H), 2.36 (bs, 1H), 1.52 (t, J=8.4 Hz, 4H), 1.41-1.32 (m, 4H), 0.94 (t, J=7.2 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35]CC3C=CC=CC=3)=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)C.[Pd]>[CH3:1][C:2]1[NH:3][C:4]([CH3:43])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][OH:35])=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCCOCc3ccccc3)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCCO)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 6.2 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-benzyloxyethoxy)-phenyl]ethoxycarbonyl)-1,4-dihydropyridine in 100 ml of ethanol with 0.5 g of 10% palladium on carbon is hydrogenated at 50 psi for 18 h. The mixture is filtered and the filtrate evaporated to afford 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2-hydroxyethoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine.
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[N:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:7][C:8]1[N:9]=[C:10]([S:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cccc(Br)n1
Reactant: Sc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(Sc2nc[nH]n2)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 14.4 %

Procedure:
A mixture of 3-mercapto-1H-1,2,4-triazole (200 mg), 2,6-dibromopyridine (560 mg), anhydrous potassium carbonate (420 mg) and N,N-dimethylformamide (1 ml) was heated and stirred for 3 hours on an oil bath at 100° C. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica-gel column chromatography with 5 to 30% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (73 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-])=O)[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[NH2:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[O:15][C@@H:13]([CH3:14])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: Cc1ccc([N+](=O)[O-])c(O[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)c(O[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O)c1
Yield: 33.8 %

Procedure:
(2S,3S)-2-tert-butoxycarbonylamino-3-(5-methyl-2-nitro-phenoxy)-butyri c acid (0.95 g, 2.68 mmol, Eq: 1.00) and 5% Pd/C (200 mg, 94.0 μmol, Eq: 0.0351) in EtOH (100 mL) were hydrogenated overnight at RT and ambient pressure and an additional portion of 10% Pd/C (100 mg, 47.0 μmol, Eq: 0.0176) was added. After 2 h the mixture was filtered through Celite, the filtrate was concentrated and the residue was purified by silica gel chromatography to afford (2S,3S)-3-(2-amino-5-methyl-phenoxy)-2-tert-butoxycarbonylamino-butyric acid (294 mg, 34%) as a solid.
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[N:43]=[C:42]([O:44][CH3:45])[C:41]([CH2:46][CH2:47][C:48]([O:50]C(C)(C)C)=[O:49])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[N:43]=[C:42]([O:44][CH3:45])[C:41]([CH2:46][CH2:47][C:48]([OH:50])=[O:49])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)OC(C)(C)C)c(OC)n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)O)c(OC)n2)c(OC)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Anisole (1 mL) was added to a solution of tert-butyl 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)propanoate (293 mg) in trifluoroacetic acid (2 mL), and the mixture was stirred at 65° C. for two hours. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)propanoic acid as a colorless amorphous (172 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH3:31]>>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH3:31])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:7]1)[CH3:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: CCOC(Cn1nc(-c2cncnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cncnc2)cc1Nc1cc([N+](=O)[O-])ccc1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 2.22 g (8.01 mmol) of the compound of Example 78A and 1.90 g (8.81 mmol) of 2-bromo-4-nitrotoluene gave, after 3 h of heating under reflux, a crude product which was purified by chromatography on a Biotage system (100 g Snap column; mobile phase gradient ethyl acetate/0-8% methanol). This gave 1.93 g (49% of theory) of the title compound.
Reaction SMILES: [C:1]([C:6]1(C)[CH2:10][CH:9]([CH3:11])[C:8](=[O:12])[CH:7]1C#N)(OCC)=O.[OH:16]OS([O-])=O.[K+]>O>[CH3:1][C:6]1[CH2:10][C:9]([CH3:11])([OH:16])[C:8](=[O:12])[CH:7]=1
Reactant: CCOC(=O)C1(C)CC(C)C(=O)C1C#N
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CC1=CC(=O)C(C)(O)C1
Yield: 70 %

Procedure:
The same product as that of paragraph (d) of Example 5 can also be obtained by treating 3-carboethoxy-2-cyano-3,5-dimethylcyclopentanone [see paragraph (a) of Example 5] with Caroat, acidifying the resulting mixture to pH 1 and then refluxing the mixture for 24 hours. Working-up as described in paragraph (d) of Example 5 yields 70% of pure crystalline 3,5-dimethylcyclopent-2-en-5-olone of melting point 92°-93° C. (from water).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:5]=[C:6]([CH:18]=1)[O:7][CH2:8][CH2:9][O:10]C1C=CC=CC=1C.C(O)C>[Pd].O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([CH3:32])(=[O:30])=[O:31])(=[O:22])=[O:21])[CH:5]=[C:6]([CH:18]=1)[O:7][CH2:8][CH2:9][OH:10]
Reactant: Cc1cc(OCCOc2ccccc2C)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OCCO)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103.5 %

Procedure:
A mixture of 2-[5-methyl-3-(2-(methylsulfonyl)phenylsulfonyloxy)phenoxy]ethoxytoluene (480 mg, 1.01 mmol), as prepared in the preceding step, 10% palladium on activated carbon (48.2 mg, ethanol (2 mL) and tetrahydrofuran (9 mL) was stirred at ambient temperature under hydrogen (balloon) for 45 minutes. The mixture was filtered through Celite and the filtrate was concentrated to give the title compound (404 mg, quantitative) as a colorless gum. 1H-NMR (300 MHz, CDCl3) δ8.45 (dd, 1H, J=7.8, 1.4 Hz), 8.13 (dd, 1H, J=7.8, 1.4 Hz), 7.88 (td, 1H, J=7.7, 1.4 Hz), 7.75 (td, 1H, J=7.7, 1.4 Hz), 6.60-6.66 (m, 3H), 3.77-3.98 (m, 4H), 2.25 (s, 3H), 1.95 (t, 1H, J=6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H18O7S2: 409.0 (M+Na). Found: 408.7.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28]([OH:30])=O)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.Cl.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:31])[CH:15]([CH2:27][C:28]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:30])[NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:18])=[CH:11][CH:12]=1
Reactant: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)O)NC(=O)Nc2ccc(Cl)cc2)cc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CN1CCN=C1c1ccc(NC(=O)C(CC(=O)Nc2ccccc2)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1:1 mixture of the R and S isomers of N-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-carboxymethyl-2-(4-chlorophenylaminocarbonylamino)-acetamide (from EXAMPLEs 60 and 62, 45 mg, 0.10 mmol) and aniline hydrochloride (28 mg, 0.22 mmol) in pyridine (2 mL) cooled in an ice-bath, POCl3 (0.040 mL, 0.44 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by HPLC to the titled compound as a powder (12 mg). MS 519.1 and 521.1 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N:43]1[CH:48]=[CH:47][C:46]([CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:45][CH:44]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][C:46]3[CH:45]=[CH:44][N:43]=[CH:48][CH:47]=3)[CH2:51][CH2:52]2)=[O:17])[CH:18]=[CH:19][CH:20]=1
Reactant: c1cc(CN2CCNCC2)ccn1
Reactant: O=C(O)c1cccc(OCCc2ccc(Cl)cc2Cl)c1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cccc(OCCc2ccc(Cl)cc2Cl)c1)N1CCN(Cc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.100 g (0.321 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acid was dissolved in 2 ml of DMF and treated with 0.148 g (1.28 mmol) of N-NEM and 0.105 g (0.321 mmol) of TOTU and 0.0569 g (0.32 mmol) of 1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and the solution was washed twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with a gradient of 0-17% MeOH in DCM.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2(CC3C=CC=CC=3[O:11]2)[CH2:3][NH:2]1.[H][H].FC1C=CC=CC=1CCl.FC1C=CC=CC=1CBr>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([OH:11])[CH2:3][NH:2]1
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Reactant: [H][H]
Agent: Fc1ccccc1CBr
Agent: Fc1ccccc1CCl
Product: OC1CNCc2ccccc21

Procedure:
To prepare the parent ring system 7, i.e., the spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] 1 wherein R is hydrogen, a 2,3-dihydro-4(1H)isoquinoline 3 wherein R is loweralkyl or benzyl is treated with a Grignard reagent 4, prepared from a 2-fluorobenzyl chloride or 2-fluorobenzyl bromide by conventional methods, to afford the 1,2,3,4-tetrahydro-4-isoquinolinol 2, which is cyclized to the spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] 5, wherein R is loweralkyl or benzyl and dealkylated or debenzylated to spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] 7, via the alkoxycarbonyl or phenoxycarbonyl derivative 6 wherein R1 is loweralkyl or phenyl, respectively. (See Reaction Scheme I).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([CH2:45][CH2:46][N:47]4[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 76.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and neutralized with 1 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (97 mg, 0.138 mmol, 68%). 1H NMR (400 MHz, CDCl3) δ ppm 9.52 (d, J=6.97 Hz, 1H), 9.29 (s, 1H), 8.63 (d, J=2.20 Hz, 1H), 8.30 (d, J=8.80 Hz, 1H), 8.23 (d, J=5.13 Hz, 1H), 7.87 (dd, J=8.43, 2.57 Hz, 1H), 7.66-7.75 (m, 2H), 7.30-7.38 (m, 1H), 7.15-7.23 (m, 1H), 7.13 (d, J=8.80 Hz, 1H), 6.94-7.01 (m, 2H), 6.84-6.90 (m, 1H), 6.78-6.82 (m, 2H), 6.64 (d, J=5.13 Hz, 1H), 4.11 (s, 3H), 3.92 (s, 3H), 2.75-2.86 (m, 2H), 2.43-2.74 (m, 10H), 2.32 (s, 3H). MS (ESI): 705 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11](N)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.BrC1C=C([NH2:22])C=CC=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([NH2:22])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Nc1cccc(Br)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: CN1CCN(c2cccc(N)c2)CC1

Procedure:
3-(4-Methyl-piperazin-1-yl)-phenylamine is prepared as described for 4-(4-methyl-piperazin-1-yl)-phenylamine (see Example 1) using 3-bromo-phenylamine.
Reaction SMILES: [C:1]([N:4]1[C@H:16]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]1[CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)(=[O:3])[CH3:2].[H-].[Na+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:4]1[C@H:16]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:6]=2[C@H:5]1[CH2:27][C:28]12[CH2:29][CH:30]3[CH2:31][CH:32]([CH2:33][CH:34]([CH2:36]3)[CH2:35]1)[CH2:37]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)c2[nH]c3ccccc3c2C[C@H]1C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)c2c(c3ccccc3n2Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (1R,3S)-benzyl 2-acetyl-1-(1-adamantyl)methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate (6.3 g, 12.7 mmol) in dry DMF (50 ml) was added dropwise to a slurry of sodium hydride (60% dispersion in oil/0.56 g, 14 mmol) in dry DMF (20 ml) under nitrogen at room temperature. The reaction mixture was stirred for 15 minutes at room temperature to which was added dropwise a solution of benzyl bromide (1.6 ml, 13.5 mmol) in DMF (10 ml). The reaction was stirred for a further one hour, diluted with ethyl acetate (150 ml), washed successively with 2N HCl (150 ml), brine (3×150 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the product as a yellow foam which was used without further purification. (7.45 g, 100%).
Reaction SMILES: [NH2:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:14].[CH2:15]([O:22][CH2:23][C:24](Cl)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C.Cl>ClCCl.C1COCC1>[CH2:15]([O:22][CH2:23][C:24]([NH:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:14])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NN1Cc2cccc([N+](=O)[O-])c2C1=O
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(COCc1ccccc1)NN1Cc2cccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
870 mg (4.5 mmol) 2-amino-7-nitro-2,3-dihydro-isoindol-1-one (prepared analogously to method 2) are dissolved in 82 ml dichloromethane and 64 ml THF. The solution is combined with 2.8 ml (3.3 eq, 20 mmol) benzyloxyacetyl chloride, 4.8 ml (28.0 mmol) N-ethyldiisopropyl-amine and 10 mg N,N-dimethylaminopyridine and stirred for 3 h at 25° C. Then the reaction mixture is combined with 100 ml aqueous 0.1 N hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The organic phase is dried with magnesium sulphate, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane:methanol (95:5).
Reaction SMILES: [C:1]1([C:7]2([CH2:46][CH2:47][CH2:48][CH2:49][C:50]([O:52]CC)=[O:51])[CH2:12][CH2:11][N:10]([C:13]([C@:15]3([O:36][C:37]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[S:39][CH:38]=4)[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:32])[C:22]4[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=4)[C@@H:16]3[CH2:33][CH2:34][CH3:35])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2([CH2:46][CH2:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51])[CH2:8][CH2:9][N:10]([C:13]([C@:15]3([O:36][C:37]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[S:39][CH:38]=4)[CH2:20][CH2:19][CH2:18][N:17]([C:21](=[O:32])[C:22]4[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:25]=[CH:24][N:23]=4)[C@@H:16]3[CH2:33][CH2:34][CH3:35])=[O:14])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(CCCCC(=O)OCC)(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC[C@H]1N(C(=O)c2ncccc2C(F)(F)F)CCC[C@@]1(Oc1csc(C(F)(F)F)c1)C(=O)N1CCC(CCCCC(=O)O)(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To ethyl 5-(4-phenyl-1-((2R,3S)-2-propyl-1-(3-(trifluoromethyl)picolinoyl)-3-(5-(trifluoromethyl)thiophen-3-yloxy)piperidine-3-carbonyl)piperidin-4-yl)pentanoate in ethanol was added 2.0 M NaOH aqueous solution and the mixture was stirred at 70° C. for 1 h. Then the solvent was removed in vacuo. The residue was redissolved in water, acidified with 6N HCl to PH ˜4, then extracted with EtOAc (2×30 ml), dried (MgSO4), concentrated, purified on Gilson, treated with 4.0 M HCl in dioxane (2-3 drops), lyophilized, to give 5-(4-phenyl-1-((2R,3S)-2-propyl-1-(3-(trifluoromethyl)picolinoyl)-3-(5-(trifluoromethyl)thiophen-3-yloxy)piperidine-3-carbonyl)piperidin-4-yl)pentanoic acid A81 as white solid.
Reaction SMILES: [O:1]([C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH2:5][OH:6])[CH3:2].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:28]1[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:2][O:1][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH2:5][O:6][C:32]1[CH:31]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:29]=[CH:28][CH:33]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: COc1cccc(OC)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1cccc(OCc2c(OC)cccc2OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,6-Dimethoxylbenzyl alcohol (3.33 g, 19.8 mmol) and diisopropyl azodicarboxylate (DIAD, 4.36 g, 21.6 mmol) in THF (30 ml) was added drop wise to a solution of Ethyl 2-(3-hydroxyphenyl)acetate (4 g, 22.2 mmol) and triphenylphosphine (5.66 g, 21.6 mmol) in THF (80 ml). The reaction mixture was stirred at room temperature for 8 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.