Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH2:20])=[CH:6]2.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:6]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)C=C(CN)C(c1ccccc1)O2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C=C(CNC(C)=O)C(c1ccccc1)O2
Reaction time: 0.5 h

Procedure:
A solution of 0.42 g (1.57 mmol) of the amine obtained in Step C in 5 ml of anhydrous pyridine is cooled to 0° C.; 0.18 ml (1.97 mmol) of acetic anhydride is then added to the medium. After 30 minutes of stirring under argon, the medium is diluted with dichloromethane and then adjusted to an acid pH with a 1N hydrochloric acid solution. The aqueous phase is extracted with dichloromethane; the organic phase is then washed with a saturated solution of sodium hydrogen carbonate. The residue obtained, after evaporation of the solvent in vacuo, is purified on a silica column (eluant: AcOEt/PE: 70/30) to yield the title amide in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].O.[C:28](Cl)(=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:37])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-aminophenoxy)piperidine-1-carboxylic acid tert-butyl ester (6.63 g) and sodium hydrogencarbonate (2.1 g) in a mixture of tetrahydrofuran (100 ml)-water (100 ml) was dropwise added benzyl chlorocarbonate (3.24 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was washed with diisopropyl ether, collected by filtration, and dried under reduced pressure to give the title compound (7.189 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[C:14]([O:27]C(=O)C)=[C:15]([CH:24]=[CH:25][CH:26]=2)[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:32])[C:5]([CH3:31])=[C:6]([CH2:12][C:13]2[C:14]([OH:27])=[C:15]([CH:24]=[CH:25][CH:26]=2)[C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCOCC3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)N3CCOCC3)c2O)=C(C)C1=O
Yield: 48 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]morpholine (0.050 g, 0.113 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.022 g, 0.0542 mmol, 48%).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH2:21])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Reactant: C=Cc1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4ccccc42)CN(C)CC3)cc1
Yield: 2.1 %

Procedure:
The title compound was prepared according to General Method 2. 2,3,4,5-tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (See Example 3) (200 mg, 1.07 mmol), 4-methylstyrene (1.41 mL, 10.7 mmol) and NaH (250 mg, 60% dispersion in oil, 6.25 mmol) in DMF (6 ml) at 200° C. for 16 h to obtain 7 mg of 2,3,4,5-tetrahydro-2-methyl-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](Cl)[CH:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Br)cc1Oc1ccccc1
Yield: 100.7 %

Procedure:
4-Bromo-2-chloro-benzoic acid (10 g, 42 mmol), phenol (4.19 g, 44 mmol), tetrakisacetonitrilecopper hexafluorophosphate (3.95 g, 10.6 mmol), and cesium carbonate (27.6 g, 85 mmol) were added to a 1 L 3-neck round bottom flask equipped with a mechanical stirrer, reflux condenser, and containing toluene (350 mL). The reaction was refluxed overnight under nitrogen with stirring. After cooling, ethyl acetate (200 mL) was added and the reaction was acidified with aqueous 2N HCI. The organic phase was separated, dried (MgSO4), and filtered. The filtrate was concentrated to afford 4-bromo-2-phenoxybenzoic acid (12.4 g) that was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:28])([CH3:27])[CH2:9][C:10]([NH2:26])([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClC(Cl)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:27])([CH3:28])[CH2:9][C:10]([NH:26][C:31](=[O:33])[CH3:32])([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:11]([F:12])([F:14])[F:13])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1ccnc2ccccc12)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CC(Cl)Cl
Product: COc1ccc(F)cc1C(C)(C)CC(Cc1ccnc2ccccc12)(NC(C)=O)C(F)(F)F
Temperature: 85 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A solution of 3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine (42.0 mg, 0.1 mmol) in dichloroethane (4 mL) was treated with acetic anhydride (71 μL, 1.0 mmol). The mixture was stirred for 16 h at 85° C. and quenched with NaHCO3 (sat, 4 mL). Phases were separated and the aqueous layer was extracted with CHCl3 (3×2 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (50%–70%, EtOAc:hexanes) to give 34.0 mg (74%) of the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=O)[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].[OH-].[Na+].Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:23][OH:24])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(=NO)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 0 °C
Yield: 68.1 %

Procedure:
To a solution of 2.3 g (8.15 mmol) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 32 ml of anhydrous EtOH was added 2.26 g of hydroxylamine hydrochloride, followed by a solution of 1.63 g (8.15 mmol) NaOH in 5 ml water dropwise. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 4.8 ml 6N HCl in 100 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The combined organic phases were washed with brine and dried over MgSO4. After solvent evaporation under vacuum, 4.6 g of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant afforded 1.65 g (67%) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1019.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]([NH:18][C:19](=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[O:29])=[C:23]([O:38][CH3:39])[CH:22]=1)[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]([NH:18][C:19](=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[O:29])=[C:23]([O:38][CH3:39])[CH:22]=1)[CH3:17])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(N)c1
Yield: 82.3 %

Procedure:
A stirred solution of methyl (S)-3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate (310 mg, 0.56 mmol) in MeOH-THF (10 mL, 1:1, v/v) was hydrogenated over 5% Pd—C (50 mg, 16 wt %) overnight. The mixture was filtered to remove the catalyst and the filtrate was evaporated to give methyl (S)-3-amino-4-[2-[3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetylamino]-1-propoxy]benzoate (240 mg) as a gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27](=[O:29])[CH3:28])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[BrH:30].BrBr>C(O)(=O)C>[BrH:30].[BrH:30].[Br:30][CH2:28][C:27](=[O:29])[CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:20][CH2:21]1
Reactant: CC(=O)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A stirred solution of 47.5 parts of 4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone and 500 parts of acetic acid was acidified with a hydrobromic acid solution in glacial acetic acid. Then there was added dropwise 11.8 parts of bromine dissolved in acetic acid. Upon completion, stirring was continued overnight at room temperature. The precipitated product was filtered off and suspended in 2-propanone. The product was filtered off and dried, yielding 23 parts (48.3%) of 1-bromo-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone dihydrobromide (intermediate 92).
Reaction SMILES: [Br:1][CH:2]([CH2:12][CH2:13]Br)[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[H-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][CH:2]1[CH2:12][CH2:13][N:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]1=[O:4]
Reactant: CCOC(=O)CNC(=O)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CN1CCC(Br)C1=O
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
To a stirred solution of crude ethyl 2-(2,4-dibromobutanamido)acetate (2.847 g, 8.60 mmol) in benzene (8.6 mL) at 5° C. was added portionwise a 60% mineral oil dispersion (344 mg) of sodium hydride (206 mg, 8.60 mmol) over 20 minutes. The reaction was stirred an additional 10 minutes before being poured onto ice water and diluted with ethyl acetate. The layers were separated. The organic phase was brine-washed, dried over sodium sulfate, filtered, concentrated down, and dried. The mixture of starting dibromide and product was purified by eluting through a silica gel column with a 0 to 100% ethyl acetate/heptane gradient to afford the title racemic compound (523 mg, 24% yield) as a clear oil. MS (ESI) [m/e, (M+H)+]=251.5. 1H NMR (400 MHz, chloroform-d) δ ppm 4.46 (dd, J=7.07, 3.03 Hz, 1H), 3.96-4.28 (m, 4H), 3.63-3.72 (m, 1H), 3.43-3.53 (m, 1H), 2.63-2.76 (m, 1H), 2.34-2.43 (m, 1H), 1.26-1.34 (m, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12])=[O:4].[CH2:13](O)[CH:14]([OH:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[Cl:1][CH2:2][C:3]1([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=2[CH3:12])[O:16][CH:14]([CH3:15])[CH2:13][O:4]1
Reactant: Cc1ccc(C)c(C(=O)CCl)c1
Reactant: CC(O)CO
Solvent: Cc1ccccc1C
Product: Cc1ccc(C)c(C2(CCl)OCC(C)O2)c1
Reaction time: 1.5 h

Procedure:
A mixture of 36.5 g [0.2 mol] of 2-chloro-1-(2,5-dimethylphenyl)ethanone, 22.8 g [0.3 mol] of propylene glycol, 3.6 g [0.02 mol] of p-TsOH hydrate and 150 ml of xylene is heated to boiling with a water trap for about 1.5 hours. Part of the xylene is then distilled off, and the reaction mixture is extracted at room temperature twice with 100 ml of water each time. The organic phase is dried over sodium sulfate and concentrated in vacuo, and volatiles are distilled off up to about 50° C./0.2 mbar. 39.65 g of an orange-colored oil remain with, according to GC, 93.0% product (76.7% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.FC(F)(F)C(O)=O.[NH:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])[CH:20]=[N:19]1>>[NH:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([N:18]3[CH:22]=[C:21]([C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[CH:20]=[N:19]3)=[C:3]2[CH:10]=[CH:9]1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: N#Cc1cccc(-c2cn[nH]c2)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2cnn(-c3ccnc4[nH]ccc34)c2)c1
Temperature: 180 °C

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (25.0 mg, 0.000127 mol) and 3-(1H-pyrazol-4-yl)benzonitrile trifluoroacetate (23.6 mg, 0.0000833 mol) was heated at 180° C., neat overnight. The crude residue was purified by HPLC on a C-18 column eluting with a water; ACN gradient containing 0.2% TFA to give the title compound as an amorphous white solid, LC/MS (M+H)+: 286, 1H NMR (DMSO-d6) δ 11.85 (bs, 1H), 9.18 (s, 1H), 8.42 (s, 1H), 8.28 (s, 1H), 8.25 (d, 1H, J=5.0), 8.07 (d, 1H, J=7.0), 7.64 (d, 1H, J=7.0), 7.56 (t, 1H, J=7.0), 7.51 (m, 1H), 7.47 (d, 1H, J=5.0), 7.03 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])[CH2:8][CH2:7][CH2:6]2.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[S:12]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1S(=O)(=O)N=CN(C)C)CCC2
Agent: BrB(Br)Br
Product: CN(C)C=NS(=O)(=O)c1cc2c(cc1O)CCC2

Procedure:
This compound is prepared analogously to Example 1d from 5-methoxy-6-dimethylaminomethyleneaminosulfonylindane and boron tribromide.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[CH2:14]([NH2:17])[CH2:15][NH2:16]>C(Cl)Cl>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:16][CH2:15][CH2:14][NH2:17]
Reactant: NCCN
Reactant: COc1ccc2nccc(Cl)c2n1
Solvent: ClCCl
Product: COc1ccc2nccc(NCCN)c2n1
Temperature: 100 °C
Yield: 51 %

Procedure:
A mixture of 8-chloro-2-methoxy-[1,5]naphthyridine (commercial; 1.7 g, 8.80 mmol) and ethane-1,2-diamine (1.2 mL, 2 eq.) was heated slowly to 80° C. over 1 h and subsequently up to 100° C. for 2 h. After cooling to rt, the yellow solution was taken up in DCM and successively washed with sat. aq. NaHCO3. The org. layer was concentrated under reduced pressure to afford the title intermediate as a pale yellow oil (981 mg, 51% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[NH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[OH:22])=[O:20])=[CH:16][CH:17]=1)[CH:7]=[CH:6]2)[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Agent: Cl
Product: CCOC(=O)Nc1ccc2c(ccn2-c2ccc(NC(=O)N(O)c3ccc(Cl)c(C(F)(F)F)c3)cc2)c1

Procedure:
The title compound can be synthesized from 1-[4-(5-aminoindol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-hydroxyurea hydrochloride and ethyl chloroformate by using the same techniques as in Example 41.
Reaction SMILES: C(N(CC)CC)C.[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:14][C:15]1[NH:16][C:17](=[O:33])[C:18]2[C:23](I)=[CH:22][N:21]([C@@H:25]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[CH2:26]3)[C:19]=2[N:20]=1>[Cu](I)I>[NH2:14][C:15]1[NH:16][C:17](=[O:33])[C:18]2[C:23]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:22][N:21]([C@@H:25]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[CH2:26]3)[C:19]=2[N:20]=1
Reactant: C#CCCCC
Reactant: Nc1nc2c(c(I)cn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c2nc(N)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Copper iodide (38.1 mg, 0.2 mmol), triethylamine (2.8 ml, 2 mmol), tetrakis(triphenylphsophine)palladium(0) (40.5 mg, 0.1 mmol) and 1-hexyne (492 mg, 6 mmol) are added to an argon-flushed solution of compound (58) (390 mg, 1 mmol in 5 ml of dried DMF), and the solution is stirred at room temperature for 24 h. It is then evaporated and the residue is loaded onto a silica gel column (5×25 cm). Title compound (65) is obtained following stepwise elution with 5%, 10% and 20% MeOH in CH2Cl2. Recrystallization from MeCN affords a colorless solid (120 mg, 35%). 1H-NMR ([D6 ] DMSO): δ=0.94 (m, CH3), 1.49, 2.38 (m, CH2), 2.0 (M, Hα --C(2')), 2.35 (m, Hβ --C(2')), 3.50 (m, H2 --C(5')), 3.76 (m, H--C(4')), 4. (m, H--C(3')), 4.88 (t, 5'-OH), 5.18 (d, J=3.5, 3'-OH), 6.27 (m, H--C(1')+NH2), 7.13 (s, H--C(6)), 10.34 (br., NH). MS: m/e 346 (M+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:34]([O:41][C:42]1[C:47]([CH2:48][N:49]([CH2:63][CH2:64][OH:65])[C:50](=[O:62])[C:51]2[C:56](O)=[CH:55][CH:54]=[C:53]([O:58][CH2:59][CH3:60])[C:52]=2[CH3:61])=[C:46]([CH3:66])[CH:45]=[C:44]([CH3:67])[N:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([O:41][C:42]1[C:47]([CH2:48][N:49]2[C:50](=[O:62])[C:51]3[C:52]([CH3:61])=[C:53]([O:58][CH2:59][CH3:60])[CH:54]=[CH:55][C:56]=3[O:65][CH2:64][CH2:63]2)=[C:46]([CH3:66])[CH:45]=[C:44]([CH3:67])[N:43]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOc1ccc(O)c(C(=O)N(CCO)Cc2c(C)cc(C)nc2OCc2ccccc2)c1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1C)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
A solution of triphenylphosphine (0.176 g, 0.671 mmol) in THF (5 mL) in an ice bath was treated with diisopropyl azodicarboxylate (0.140 mL, 0.67 mmol) dropwise. After 10 minutes, N-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-3-ethoxy-6-hydroxy-N-(2-hydroxyethyl)-2-methylbenzamide (114e, 0.155 g, 0.334 mmol) was added in one portion. The reaction mixture was stirred in the ice bath overnight and the reaction mixture gradually warmed to room temperature. The reaction mixture was concentrated under vacuum and purified by column chromatography (0-40% ethyl acetate/heptane) to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-ethoxy-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (114f, 0.087 g, 58%) as a clear, thick oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>COCCOC>[OH:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:13]=[C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[N:1]=2)[CH:6]=1)([CH3:9])[CH3:10]
Reactant: O=C(CBr)C(=O)Nc1ccccc1
Reactant: CC(C)(O)c1ccc(N)nc1
Solvent: COCCOC
Product: CC(C)(O)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.5 %

Procedure:
A solution of 100 mg of 2-(6-aminopyridin-3-yl)propan-2-ol in 10 ml of 1,2-dimethoxyethane is treated with 190 mg of 3-bromo-2-oxo-N-phenylpropionamide, then stirred at 25° C. for 15 hours and brought to reflux for 3 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is taken up in 40 ml of ethyl acetate and 40 ml of a saturated sodium carbonate solution. The aqueous phase is washed twice with 40 ml of ethyl acetate. The combined organic phases are dried and concentrated to dryness under reduced pressure. The residue is chromatographed on a cartridge of 40 g of silica, elution being carried out with dichloromethane and then with mixtures of dichloromethane and methanol, 97/3 and then 95/5. The fractions comprising the expected product are combined and concentrated to dryness to give 63 mg of 6-(1-hydroxy-1-methylethyl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([Br:27])[CH:21]=2)=[C:14]([Cl:28])[C:13]=1[CH2:29][CH3:30])(=[O:10])[CH:2]=CC1C=CC=CC=1.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>>[C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[C:22]([Br:27])[CH:21]=2)=[C:14]([Cl:28])[C:13]=1[CH2:29][CH3:30])(=[O:10])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc(N)c(Br)c2)c1Cl
Product: CCc1c(OC(C)=O)cc(Cl)c(Oc2ccc(NC(=O)C(C)C)c(Br)c2)c1Cl
Yield: 103.7 %

Procedure:
Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) cinnamate (70 mg) was coupled with isobutyryl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 70 mg of ethyl(3,5-dichloro-4-[3-bromo-4-isobutyramidophenoxy]phenyl) acetate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 50 mg of 3,5-dichloro-4-(3-bromo-4-isobutyramidophenoxy)phenylacetic acid.