Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1cccc(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1cccc(Cl)c1
Reaction time: 16 h
Yield: 33.7 %

Procedure:
A solution of 483 mg (1.4 mmol) of 1-[(3-chlorophenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetamide and 5.6 mL of 1M BBr3 /methylene chloride in 20 mL of methylene chloride was stirred for 5 hours, 2 mL of 1M BBr3 /methylene chloride added and stirred 16 hours. The mixture was poured into water, extracted with ethyl acetate, the ethyl acetate solution washed with brine, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted using a gradient, 50% EtOAc/hexane→EtOAc, to give 155 mg of starting material, 1-[(3-chlorophenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetamide, and 220 mg (48% yield) off 1-[(3-chlorophenyl)methyl]-5-hydroxy-2-methyl-1H-indole-3-acetamide, mp, 173°-177° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([CH3:15])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:16]([N:11]1[C:12]2[C:7](=[C:6]([OH:30])[C:5]([C:3]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][C:13]=2[CH3:15])[CH:8]=[C:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(C)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 58.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (58 mg, 0.15 mmol), glycine (2.61 g, 35 mmol) and NaOMe solution (52 mL, 26 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 39 mg of the title compound as a yellow solid. MS: (+) m/z 444.15 (M+1).
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:12][C:6]=2[N:5]=1.Cl.Cl[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=1>C(O)C>[CH3:29][O:28][C:25]1[C:24]([CH3:30])=[CH:23][N:22]=[C:21]([CH2:20][S:3][C:4]2[NH:8][C:7]3[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:12][C:6]=3[N:5]=2)[C:26]=1[CH3:27]
Reactant: FC(F)(F)Oc1ccc2[nH]c(S)nc2c1
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cnc(CSc2nc3cc(OC(F)(F)F)ccc3[nH]2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
5 ml of 4M sodium hydroxide solution are added dropwise to a mixture of 2.34 g of 2-mercapto-5-trifluromethoxy-1H-benzimidazole and 2.2 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride in 50 ml of ethanol at room temperature and the mixture is stirred overnight at room temperature. The solvent is distilled off in vacuo, water is added, the mixture is extracted with ethyl acetate, the solution is dried and 4.3 g (95%) of the dihydrochloride of the title compound are precipitated with 4M hydrogen chloride in ether. The salt is dissolved in water and the base is precipitated with dilute sodium carbonate solution at pH 8 and recrystallized from diisopropyl ether. 3.0 g (78%) of the title compound of m.p. 152°-154° C. are obtained.
Reaction SMILES: [N:1]1([C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][CH:20]=3)[CH2:11]2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:25][C:26]([CH3:28])=O>CC#N>[CH3:25][CH:26]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([N:10]2[CH2:11][CH:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH3:24])=[O:22])=[N:19][CH:20]=3)[CH2:13]2)=[O:9])[CH2:2][CH2:3]1)[CH3:28]
Reactant: CC(C)=O
Reactant: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCNCC3)C2)cn1
Solvent: CC#N
Product: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCN(C(C)C)CC3)C2)cn1
Yield: 14.2 %

Procedure:
In a similar fashion (Route 1, GP A; except that MeCN was used as solvent), 5-{[1-(1,4-diazepan-1-ylcarbonyl)azetidin-3-yl]oxy}-N-methylpyridine-2-carboxamide (25 mg, 0.075 mmol) and acetone (5.5 μl, 0.075 mmol) gave the title compound as colourless oil (4 mg, 14%) after purification by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]#[N:6]
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
3-Bromo-4-fluorobenzonitrile (0.5 g, 2.4 mmol) was added to a suspension of phenol (0.23 g, 2.4 mmol) and potassium carbonate (0.67 g, 4.8 mmol) in DMSO (2 mL) and the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (3×30 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo to afford the title compound (0.59 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[N+:14]([O-:16])=[O:15])=[O:4].[OH-].[Na+].Cl>O1CCCC1.O>[N+:14]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13]2)([O-:16])=[O:15]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
7-Nitro-1H-indole-2-carboxylic acid methyl ester (13 g, 59 mmol) prepared in Preparation 17 was dissolved in a solvent mixture of tetrahydrofuran and water (1:1, 300 mL), to which was added 1N aqueous sodium hydroxide solution (180 mL, 177 mmol). The mixture was stirred for 3 h at room temperature, and excess 6N hydrochloric acid solution was added thereto. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation under reduced pressure, and the residue was dried to give the title compound (12 g, Yield 99%).
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:27]=[C:26]([C:28](=[O:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:25]=[C:24]([NH2:35])[CH:23]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[C:30]([NH:29][C:28]([C:26]1[CH:27]=[C:22]([C:21]2[C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:3][C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=4)=[C:6]([C:16]([NH:18][CH3:19])=[O:17])[C:5]=3[CH:20]=2)[CH:23]=[C:24]([NH:35][S:43]([CH3:42])(=[O:45])=[O:44])[CH:25]=1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cc(N)cc(C(=O)NC(C)(C)C)c3)cc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3cc(NS(C)(=O)=O)cc(C(=O)NC(C)(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of 6-amino-5-(3-amino-5-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (100 mg) and pyridine (0.170 mL) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (72.4 mg) slowly at 0° C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was concentrated and the residue was purified by preparative HPLC to give 5-(3-(tert-butylcarbamoyl)-5-(methylsulfonamido)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide 4 (92 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=3[CH3:17])[N:7]([CH2:20][CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.O1CCCC1.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=4[CH3:17])[CH2:23][CH2:22][CH2:21][CH2:20][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)nn(C)c3C)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1c(C)nn(C)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.7 %

Procedure:
To a solution of 4-{4-chloro-7-(1-ethylpropyl)-2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]-1H-benzimidazol-1-yl}butan-1-ol (Reference Example 38; 10 mg, 0.024 mmol) in pyridine (0.5 mL) was added a solution of methanesulfonyl chloride in tetrahydrofuran (1.0 M, 0.029 mL, 0.029 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 24 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude mesylate was dissolved in N,N-dimethylformamide (1 mL) and potassium carbonate (17 mg, 0.12 mmol) was added. The mixture was stirred at 80° C. for 60 hr. The mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (4.0 mg, 0.010 mmol, 42%) as a colorless amorphous.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:19][CH2:20][NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.O>[C:13]([C:14]([CH3:16])([CH3:15])[CH2:19][CH2:20][NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:17]
Reactant: CC(C)C#N
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)CCNC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
Treat a −78° C. solution of diisopropylamine (35 g, 0.346 mol) in THF (300 mL), under N2, dropwise with a solution of n-butyllithium (2.5 M, 127 mL, 0.317 mol), warm to −30° C. for 0.5 h, re-cool to −78° C. and treat dropwise with a solution of isobutyronitrile (19.9 g, 0.288 mol) in THF (100 mL). Stir the mixture at −78° C. for 0.5 h, treat with a solution of benzyl (2-bromoethyl)carbamate (74 g, 0.288 mol) in THF (100 mL), stir at −78° C. for 1 h, then warm to RT and stir overnight. Treat the mixture with H2O, separate the layers, extract the aqueous layer with EtOAc, wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Petroleum ether) to afford the title compound (15 g, 21% yield). MS (m/z): 247.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[O:10][CH3:11].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:16]2[C:15](=[O:17])[C:14]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]3[C:12]2=[O:22])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(CBr)ccc1Cl
Agent: [K]
Solvent: CN(C)C=O
Product: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a solution of 4-chloro-3-methoxybenzyl bromide (7.00 g) in anhydrous dimethylformamide (50 mL) was added potassium phthalimide (6.03 g), and the mixture was stirred for 2 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give N-(4-chloro-3-methoxybenzyl)phthalimide as white powders (5.88 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:28])[F:27])=[N:23][N:24]=4)[N:21]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)nc2)CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Product: OC1(c2ccc(Cl)nc2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 80 %

Procedure:
A mixture of 4-(6-chloropyridin-3-yl)piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-(6-chloropyridin-3-yl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 80% yield.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])(=O)=O>CCOC(C)=O>[Si:42]([O:27][CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO)[nH]c2c1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C)(C)C(C)(C)C)[nH]c2c1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A solution (0.039 M) of methyl 3-cyclohexyl-2-[2-(hydroxymethyl)phenyl]-1H-indole-6-carboxylate was treated with 2,6-lutidine (2 eq) and then with tert-butyl(dimethyl)silyl trifluoromethanesulfonate (1.2 eq). The solution was stirred for 15 min. Removal of the volatiles in vacuo gave a residue that was diluted with EtOAc, washed with 1N HCl, saturated aqueous NaHCO3, brine, dried and concentrated in vacuo to afford the title compound (90%) as a solid. MS (ES+) m/z 478 (M+H+).
Reaction SMILES: N#N.C[O:4][C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:28])[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22]C)[C:19]([O:24]C)=[C:18]([O:26]C)[CH:17]=2)=[CH:8][CH:7]=1.B(Br)(Br)Br.[Cl-].[Na+].O.CCOC(C)=O>C(Cl)Cl.CO>[OH:22][C:20]1[CH:21]=[C:16]([CH2:15][CH2:14][C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:29])=[O:4])=[CH:7][CH:8]=2)=[O:28])[CH:17]=[C:18]([OH:26])[C:19]=1[OH:24]
Reactant: COC(=O)c1ccc(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)cc1
Agent: BrB(Br)Br
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(CCc1cc(O)c(O)c(O)c1)Nc1ccc(C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve 4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-benzoic acid methyl ester (78) (45 mg, 0.12 mmol) in anhydrous DCM (1.2 mL), cool the solution to −78° C. and add dropwise BBr3 (90 μL, 0.96 mmol). Stir the reaction mixture for 30 min at −78° C. and after slowly warming up for additional 3 h at rt. Add dropwise ice-water/THF (1+1) followed by MeOH and remove solvent. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain 4-[3-(3,4,5-Trihydroxy-phenyl)-propionylamino]-benzoic acid (79) (17 mg, 44%) as a white solid. 1H NMR (400 MHz, CD3OD): 2.65 (t, 2H, J=7.5 Hz); 2.83 (t, 2H, J=7.5 Hz); 6.29 (s, 2H); 7.68 (d, 2H, J=8.3 Hz); 7.99 (d, 2H, J=8.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1.[CH3:41][N:42]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)[CH3:43].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl>C(#N)C.CS(C)=O>[Cl:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:42]([CH3:43])[CH3:41])=[O:15])=[CH:12][CH:11]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CS(C)=O
Product: CN(C)C(=O)c1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzoic acid (0.023 g, 0.041 mmol) in acetonitrile (3 ml) was treated with BOP reagent (0.02 g, 0.04 mmol) followed by triethylamine (0.013 mL, 0.09 mmol). To the mixture was added (CH3)2NH2.HCl (4 mg, 0.045 mmol), and the reaction was stirred at ambient temperature overnight. The reaction mixture was then concentrated in-vacuo to afford an oil. The crude product was then dissolved in DMSO and purified via reverse-phase HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to afford the title compound, 186 mg (77%); MS (ESI) m/e 596 [M+H]+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH2:16][CH2:17][CH2:18][N:14]3[C:13](=[O:19])[C:12]=2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:28][O:29][CH2:30][C@@H:31]([NH2:33])[CH3:32]>C1(C)C=CC=CC=1>[CH3:28][O:29][CH2:30][C@@H:31]([NH:33][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH2:16][CH2:17][CH2:18][N:14]3[C:13](=[O:19])[C:12]=2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:8]=[CH:7][N:6]=1)[CH3:32]
Reactant: COC[C@H](C)N
Reactant: Cc1ccccc1Oc1c(-c2ccnc(S(C)(=O)=O)n2)n2n(c1=O)CCC2
Solvent: Cc1ccccc1
Product: COC[C@H](C)Nc1nccc(-c2c(Oc3ccccc3C)c(=O)n3n2CCC3)n1
Temperature: 115 °C

Procedure:
To a solution of 3-(2-methanesulfonyl-pyrimidin-4-yl)-2-o-tolyloxy-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 3, (0.11 g, 0.28 mmol) in toluene (4 mL) is added (S)-1-methoxy-2-propylamine (0.10 g, 1.13 mmol). The reaction mixture is heated to 115° C. for 24 h. The solvent is removed in vacuo and the resulting residue is purified by preparative HPLC to afford 52 mg of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=5.1 Hz, 1H), 7.22 (d, J=7.2 Hz, 1H), 7.16 (d, J=5.4 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.97 (t, J=7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 4.29-4.21 (m, 1H), 4.17 (t, J=7.2 Hz, 2H), 4.01 (t, J=7.2 Hz, 2H), 3.50 (dddd, J=9.3, 9.3, 4.5, 4.5 Hz, 2H), 3.42 (s, 3H), 2.69 (dt, J=7.2 Hz, 2H), 2.46 (s, 3H), 1.31 (d, J=6.6 Hz, 3H); ESI+ MS: m/z (rel intensity) 396.2 (90, M++H); Anal Calcd for C21H25N5O3: C, 63.78; H, 6.37; N, 17.71. Found: C, 63.63; H, 6.20; N, 17.05.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:13]([CH3:14])[NH:12][C:11](=[O:15])[C:10]1([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:26]([CH3:27])=[C:25](I)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@H:9]1[C@H:13]([CH3:14])[N:12]([C:25]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([Cl:18])[C:26]=2[CH3:27])[C:11](=[O:15])[C:10]1([CH3:16])[CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1NC(=O)C(C)(C)C1O[Si](C)(C)C(C)(C)C
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1c(N2C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
Using (4RS,5SR)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethylpyrrolidin-2-one (200 mg), 2-chloro-4-iodo-3-methylbenzonitrile (250 mg), cesium carbonate (380 mg), tris(dibenzylideneacetone)dipalladium(0) (36 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (45 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a pale-yellow oil (yield: 103 mg, yield: 33.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33].C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33])=[O:6]
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1ccc(C(=O)O)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CCC(=O)NC2=O)c(N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
A mixture of 2-amino-4-methylbenzoic acid (2.0 g, 13 mmol) and CDI (2.0 g, 12 mmol) in acetonitrile (20 mL) was stirred at room temperature for 1.5 hours. To the suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.0 g, 12 mmol) and sodium hydrogen carbonate (1.3 g, 16 mmol), and the mixture was heated at 50° C. for 21 hours. The suspension was cooled to room temperature for 1 hour. The suspension was filtered and washed with water (50 mL) and ethyl acetate (20 mL). The solid was dried in a vacuum oven overnight to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-4-methyl-benzamide as a white solid (2.2 g, 69% yield): 1H NMR (DMSO-d6) δ 1.90-1.96 (m, 1H, CHH), 2.05-2.14 (m, 1H, CHH), 2.18 (s, 3H, CH3), 2.49-2.55 (m, 1H, Cull), 2.72-2.84 (m, 1H, CHH), 4.67-4.75 (m, 1H, NCH), 6.36 (dd, J=2, 8 Hz, 1H, Ar), 6.43 (br, 2H, NHH, Ar), 6.51 (s, 1H, NHH), 7.43 (d, J=8 Hz, 1H, Ar), 8.38 (d, J=8 Hz, 1H, NH), 10.83 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.05, 24.21, 30.99, 48.97, 111.26, 115.74, 116.48, 128.09, 141.71, 149.96, 168.54, 172.50, 173.04; LCMS: MH=262.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([CH:17]=2)[NH:15][CH3:16])[CH:6]=[CH:5][N:4]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:17]=[C:14]([NH:15][CH3:16])[C:13]([NH2:18])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CNc1cc(Oc2ccnc(OC)c2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CNc1cc(Oc2ccnc(OC)c2)ccc1N
Yield: 99.3 %

Procedure:
The reaction and post-treatment were carried out according to Example (1b) using 5-[(2-methoxypyridin-4-yl)oxy]-N-methyl-2-nitroaniline produced in Example (16c) (3.90 g, 14.2 mmol), iron powder (3.96 g, 70.8 mmol), ammonium chloride (0.38 g, 7.08 mmol), ethanol (80 mL) and water (40 mL) to obtain the title compound (3.46 g, 99%) as a brown oil.