Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[CH2:2]([NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrBr>C(O)(=O)C>[CH2:2]([NH:9][CH2:10][C@H:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:1])[CH:17]=2)[O:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CNC[C@H]2CCc3ccccc3O2)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)CC[C@H](CNCc1ccccc1)O2
Temperature: 16 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
In a 500-mL round bottom flask, N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine hydrobromide (33.4 g, 0.1 mole, 1.0 eq.) was suspended in 240 mL of acetic acid. The suspension was cooled to 16° C., then bromine (16 g, 0.1 mole, 1.0 eq.) was added over 20 minutes, maintaining the reaction temperature between 15-16° C. After 60 minutes, an HPLC analysis indicated the reaction was complete. The reaction mixture was then stirred for 30 minutes at room temperature, and the product was collected by filtration. The light gray moist product was suspended in dichloromethane (200 mL) and to this suspension was added 0.5M NaHCO3 (350 mL). Foaming ensued and the suspension became a bi-phasic solution. The aqueous phase was separated (14.5 L; pH=8) and the organic phase was washed with 50 mL water. The phases were separated and the organic phase concentrated in vacuo at 45° C. to yield 31.6 g of N-benzyl-N-{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amine. NMR (DMSO-d6) δ1.56 (m, 1H), 2.02 (m, 1H), 2.25 (bs, 1H), 2.73 (m, 4H), 3.75 (s, 2H), 4.05 (m, 1H), 6.70 (d, J=8.8 Hz, 1H), 7.25-7.40 (m, 7H); MS (El): m/z 232 (MH+), 234 (M+2).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([NH:22][C@@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=[CH2:25])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].ClCCl>C(Cl)(Cl)Cl>[C:12]([NH:22][C@@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]1[O:6][CH2:25]1)([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13]
Reactant: C=C[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C1CO1
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of 600 mg of 3-chloroperoxybenzoic acid in 5 ml of dry chloroform was added a solution of 850 mg of (3S)-3-carbobenzoxyamino-5-methyl-1-hexene in 5 ml of dry chloroform under ice-cooling, and the mixture was stirred for 16 hours. Dichloromethane was added to the reaction mixture, and the mixture was successively washed with an aqueous sodium thiosulfate solution, a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 401 mg of (3S)-3-carbobenzoxyamino-5-methyl-1,2-epoxyhexane as a colorless oil.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:20][C:19]([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[N:18]2)=[CH:13][CH:12]=1.CN(C)[CH:38]=[O:39]>CN(C)C1C=CN=CC=1>[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:20][C:19]([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH:38]=[O:39])=[O:29])=[N:18]2)=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-n2nc(C(=O)N3CCCCN3)cc2-c2ccccn2)cn1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)C(F)(F)F
Product: COc1ccc(-n2nc(C(=O)N3CCCCN3C=O)cc2-c2ccccn2)cn1
Reaction time: 0.33 h
Yield: 30 %

Procedure:
4-Dimethylaminopyridine (0.142 g) and trifluoromethane sulfonic acid anhydrate (0.140 mL) were added to 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]hexahydropyridazine (0.203 g) obtained in Example 162 in N,N-dimethylformamide (4.0 mL) at 0° C., followed by stirring for 20 minutes. The reaction mixture was partitioned between saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with saturated brine, and then dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (65.5 mg, 30%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 2-hydroxy-4-iodobenzoate (22.8 g), benzyl bromide (10.3 ml) and K2 CO3 (22.67 g) in DMF (200 ml) was stirred at rt for 72 h. The mixture was partitioned between diethyl ether and water, the organics separated washed with water, dried and evaporated under reduced pressure to give a white solid, 29.5 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC=CC=2)(=O)=O)=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[C:21](#[N:27])[CH2:22][CH2:23][CH2:24][C:25]#[CH:26]>CCCCCCC.CCOC(C)=O>[C:21]([CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[O:19][CH3:20])#[N:27]
Reactant: COc1cc(C#N)ccc1OS(=O)(=O)c1ccccc1
Reactant: C#CCCCC#N
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C#N)ccc1C#CCCCC#N

Procedure:
This product was prepared from benzenesulfonic acid 4-cyano-2-methoxy-phenyl ester and 5-hexynenitrile following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (70 mg, 62%); 1H NMR δ (CDCl3): 7.52 (d, J=8.34 Hz, 1H), 7.21 (d, J=8.22 Hz, 1H), 7.11 (s, 1H), 3.81 (s, 3H), 2.69 (t, J=7.25 Hz, 2H), 2.58 (t, J=7.22 Hz, 2H), 1.99 (p, J=7.12 Hz, 2H); LCMS m/z: 224.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH3:24])[N:15]3[CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:10]=2)[C:5]([NH2:31])=[CH:4][CH:3]=1.[CH3:32]OC(OC)OC.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:31]=[CH:32][N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH3:24])[N:15]4[CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:11]([C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[N:10]=3)[C:6]=2[CH:7]=1
Reactant: COC(OC)OC
Reactant: Cc1nc2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3N)nc2n1C1CCOCC1
Agent: CS(=O)(=O)O
Solvent: CO
Product: Cc1nc2c(-c3ccncc3)nc(-n3cnc4ccc(Cl)cc43)nc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To a vial containing crude 5-chloro-N1-(8-methyl-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-9H-purin-2-yl)benzene-1,2-diamine (0.035 mmol) was added anhydrous methanol (2.5 mL), followed by anhydrous trimethylorthoformate (0.5 mL) and methane sulfonic acid (catalytic amount) and the reaction mixture was stirred under Ar at room temperature for 4 h (HPLC monitoring). Preparative HPLC purification, after evaporation of solvent and drying, provided the desired product (3.5 mg, 22% yield on two steps), as a yellow oil. TFA salt. 1H NMR (300 MHz, CD3OD+CDCl3) δ, ppm: 9.32 (s, 1H), 8.91 (br m, 4H), 8.79 (s, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 4.76-4.72 (m, 1H), 4.32-4.29 (m, 2H), 3.72 (app t, J=11.7 Hz, 2H), 3.08-3.05 (m, 2H), 2.87 (s, 3H), 2.02 (br d, J=10.9 Hz, 2H); MS (EI) m/z 446.3 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[Cl:7].[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]2[C:29]3[CH:28]=[N:27][CH:26]=[N:25][C:24]=3[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=2)=[O:20])[CH:16]=[N:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([C:19]([C:21]3[C:29]4[CH:28]=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:30]([CH3:32])[CH3:31])[CH:22]=3)=[O:20])[CH:14]=2)=[O:11])[C:6]=1[Cl:7]
Reactant: O=C(O)Cn1cnc(Cl)c1Cl
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cn3cnc(Cl)c3Cl)c2)c2cncnc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
(4,5-Dichloro-imidazol-1-yl)-acetic acid (25.2 mg, 0.130 mmol) was added to (5-amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (28.1 mg, 0.1 mmol), HATU (49.4 mg, 0.130 mmol) and DIPEA (51.7 uL, 0.300 mmol) in anhydrous DMF (1 mL). The mixture was stirred at 50° C. for 16 hours and then evaporated in vacuo and purified by prep-HPLC (method 5) to afford the title compound in 46% yield, 21.2 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH2:12](O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6])[CH3:12]
Reactant: COC(=O)c1ccccc1N
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)c1ccccc1N
Reaction time: 20 h
Yield: 89 %

Procedure:
453 parts of anthranilic acid methyl ester are refluxed with 900 parts of ethanol and 30 parts of potassium carbonate for half an hour. Methanol which is set free during the reaction is then distilled off over a column. The complete transesterification requires about 20 hours. After an intermediate fraction containing methanol and ethanol as well, the excess of ethanol is distilled off. By distillation of the residue under reduced pressure there are obtained 441 parts of anthranilic acid ethyl ester (boiling point 113°-122° C. under 3-5 mm Hg, nD25 1,564; anthranilic acid methyl ester cannot be traced by gas chromatography). The yield is 89% of the theory.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH:13]1[O:15][CH2:14]1.[NH2:16][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[CH:17]1([NH:16][CH2:14][CH:13]([OH:15])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: c1ccc2cc(OCC3CO3)ccc2c1
Reactant: NC1CCCc2ccccc21
Product: OC(CNC1CCCc2ccccc21)COc1ccc2ccccc2c1

Procedure:
Following the general procedure of Example 98, but starting from 1-(2-naphthyloxy)-2,3-epoxypropane (4.5 g) and 1-aminotetralin (2.95 g), N-(1,2,3,4-tetrahydronaphth-1-yl)-2-hydroxy-3-(2-naphthyloxy)propanamine free base is obtained as an oily product which is dissolved in an isopropyl ether/isopropanol 1/1 mixture (40 ml) and acidified with HC1/isopropanol. The corresponding hydrochloride is thus obtained which is crystallized from isopropanol (20 ml). Yield: 2.2 g; m.p. 135°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(=O)CC
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.53 g), 2-(4-chlorobenzyl)-3-oxopentanoic acid ethyl ester (0.66 g), methanesulfonic acid (0.032 mL) and toluene (20 mL) was heated at reflux for 20 hours. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was diluted with water, extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (9:1 by volume) to afford title compound, 0.034 g
Reaction SMILES: N1([C:7]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[O:8])CCCCC1.Cl.[OH-:22].[K+]>>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]([OH:8])=[O:22])=[N:14][CH:13]=2)[CH2:16][CH2:17]1
Reactant: O=C(c1ccc(N2CCOCC2)cn1)N1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)c1ccc(N2CCOCC2)cn1
Yield: 71 %

Procedure:
25% KOH (100 mL) was added to 4-[6-(piperidin-1-ylcarbonyl)pyridin-3-yl]morpholine (18.3 g), and the mixture was refluxed and then neutralized with HCl. The solution was evaporated in vacuum, and the product was extracted with hot isopropanol to give the title compound (yield 71%, 11.5 g). +ESI MS (M+H) 209.7; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (br. s., 1H), 8.03 (d, 1H), 7.65 (dd, 1H), 3.75 (br. s., 4H), 3.40 (br. s., 4H).
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])(C)(C)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:16][C:14]([CH:9]1[CH2:10][CH2:11][C:12](=[O:13])[N:8]1[C:6]([OH:5])=[O:7])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCC(=O)N1C(=O)O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A suspension containing (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (10.00 g, 0.044 mol, 1.0 equivalent), benzyl bromide (7.88 g, 0.046 mol, 1.05 equivalents), and potassium carbonate (15.20 g, 0.11 mol, 2.5 equivalents) in DMF (200 ml) was allowed to stir at 65° C. overnight. The reaction was allowed to cool to room temperature and the mixture was filtered through Celite. The solid was rinsed with ethyl acetate (100 ml) and the resulting filtrate was partitioned between ethyl acetate and saturated brine solution. The organic layer was washed with saturated brine (3×100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude, colorless oil was chromatographed on silica to afford 5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester, 1-tert-butyl ester as a colorless oil (8.20 g, 0.026 mol, 59% yield). Analysis H1 NMR (400 Hz CDCl3): 7.36 (5H, broad s), 5.20 (2H, d), 4.64 (1H, dd), 2.44-1.96 (4H, m), 1.41 (9H, s). MS (LC-MS): Calculated for C17H21NO5 319.14, found 320.19 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:14]2)=[CH:10][CH:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:14]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccco3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccco3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-furylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (624 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml), and ethanol (6 ml) was stirred at room temperature for 3 hours, and 1N hydrochloric acid (3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and 3-[1-[4-(2-furylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (386 mg, yield: 66%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[O:12]=[C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:15]=[C:14]1[C:29]([O:31]C)=O>C(Cl)Cl>[O:12]=[C:13]1[CH:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[N:15]=[C:14]1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
A solution of aniline (0.360 mL, 3.95 mmol) in methylene chloride (10 mL) was cooled on an ice water bath then treated with a solution of trimethyl aluminum (2 M in toluene, 2.0 mL, 4.0 mmol). After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. At that point, methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (0.595 g, 2.00 mmol) was added and the reaction was heated at reflux for 18 h. After that time, the reaction was cooled to room temperature and carefully quenched with HCl aqueous solution (1 N, 5 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (3×10 mL). The combined organic extracts were washed with saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL), dried (MgSO4), and concentrated. The residue was recrystallized from ethyl acetate/hexanes to give 0.214 g (30%) of 4-oxo-N-phenyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide as yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([NH2:14])=[O:13])[NH:8]2)=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1.[CH3:26][O:27][CH2:28][CH2:29]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[C:10]([O:11][CH2:29][CH2:28][O:27][CH3:26])=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([NH2:14])=[O:13])[NH:8]2)=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3cc(C(N)=O)[nH]c3c(O)c2F)cn1
Reactant: COCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 50 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
A mixture of 6-fluoro-7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.98 g), 2-methoxyethanol (0.43 mL), tributylphosphine (1.24 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.35 g) in tetrahydrofuran (130 ml) was stirred at 50° C. for 6 h under argon atmosphere. To the mixture were added 2-methoxyethanol (0.43 mL), tributylphosphine (1.24 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.35 g) and the mixture was stirred at 50° C. for 15 h under argon atmosphere. Furthermore, 2-methoxyethanol (0.43 mL), tributylphosphine (1.24 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.35 g) were added to the mixture. After stirred at 50° C. for 18 h under argon atmosphere, the mixture was concentrated in vacuo. The resulting insoluble materials were filtered off and the filtrate was concentrated in vacuo. The residue was purified by basic silica gel chromatography (ethyl acetate:hexane=30:70 to 100:0, volume ratio) to give the title compound (0.61 g, 54%) as a pale pink amorphous solid. MS 424 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=O)=[C:24]([O:32][CH3:33])[CH:23]=2)[N:17]=1.[F:34][CH:35]([F:43])[C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([NH:39][C:38]3[CH:40]=[CH:41][CH:42]=[C:36]([CH:35]([F:43])[F:34])[CH:37]=3)=[O:28])=[C:24]([O:32][CH3:33])[CH:23]=2)[N:17]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cccc(C(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in step-6 of Intermediate-26 by using methyl 4-(3-(2-chloro-5-((2,2,2-trifluoroacetamido)methyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-5 of Intermediate-26, 0.100 g, 0.20 mmol), 3-(difluoromethyl)aniline (Intermediate-29, 0.045 g, 0.30 mmol), trimethyl aluminium (2M solution in toluene) (1.0 mL) and dry toluene (5.0 mL) to afford 0.080 g of crude product which was triturated with methanol:DCM:ether to afford 0.080 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 3.95 (s, 3H), 4.47 (d, J=5.7 Hz, 2H), 7.05 (m, 1H), 7.30 (m, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.70 (m, 3H), 7.80 (d, J=6.3 Hz, 3H), 8.08 (s, 1H), 10.11 (br s, 1H), 10.28 (s, 1H), 12.72 (br s, 1H); MS (m/z): 596.12 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH:7]=[C:8]([O:9][CH3:10])[C:4]=2[CH:3]=1.[H-].[Na+].[C:15]([O:18][CH2:19][CH2:20]Br)(=[O:17])[CH3:16]>CN(C=O)C>[CH3:10][O:9][C:8]1[C:4]2[CH:3]=[C:2]([O:1][CH2:20][CH2:19][O:18][C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][C:5]=2[O:6][CH:7]=1
Reactant: COc1coc2ccc(O)cc12
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1coc2ccc(OCCOC(C)=O)cc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
164 mg (1.0 mmol) XXI and 48 mg (1.2 mmol, 60%) NaH were stirred for 30 mins. in 20 ml DMF at 0° C. 227 μl (2.0 mmol, 97%) 2-bromoethyl acetate were added to the resulting suspension which was then stirred for 72 h at room temperature. The reaction was quenched by addition of 3 ml saturated NH4Cl solution and the solvents were removed in vacuo. The residue was taken up in ethyl acetate and water, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over Na2SO4. After column filtration (40 g SiO2, n-hexane:ethyl acetate=2:1, applied with ethyl acetate), XXII was obtained in a yield of 220 mg (0.88 mmol, 88%).
Reaction SMILES: [CH3:1][CH:2]([CH:6]([CH3:10])[C:7](O)=[O:8])[C:3](O)=[O:4].[NH4+:11].Cl>C(OCC)(=O)C>[CH3:1][CH:2]1[CH:6]([CH3:10])[C:7](=[O:8])[NH:11][C:3]1=[O:4]
Reactant: CC(C(=O)O)C(C)C(=O)O
Reactant: [NH4+]
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1C(=O)NC(=O)C1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1 g of 2,3-dimethylsuccinic acid (a mixture of D-, L-, and meso-isomers) was added to 10 ml of 28% aqueous ammonium solution. The mixture was heated and stirred at about 60° C. for 1 hour. After cooling, to the reaction mixture was added aqueous hydrochloric acid solution so as to neutralize, and then the mixture was extrated twice with 10 ml of ethyl acetate. The extract was concentrated to obtain 0.73 g of 2,3-dimethylsuccinimide (a mixture of D-, L, and meso-isomers).
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[ClH:43].[ClH:1].[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[C:39]([Cl:43])=[CH:40][CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][CH2:58]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118, see example 76) and amine 21 analogously to the method described in example 1.