Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[C:15]=2[CH3:30])=[O:13])=[CH:7][CH:6]=1)C.O.[OH-].[Li+].O.C1COCC1>CO>[CH3:30][C:15]1[N:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:28])([F:29])[F:27])[C:17]([CH3:19])=[CH:18][C:14]=1[C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:31])=[O:3])=[CH:10][CH:9]=1)=[O:13]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cc(C)n(-c3ccccc3C(F)(F)F)c2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)Nc2ccc(C(=O)O)cc2)c(C)n1-c1ccccc1C(F)(F)F
Reaction time: 17 h
Yield: 14.7 %

Procedure:
A mixture of 4-({2,5-dimethyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbonyl}-amino)-benzoic acid ethyl ester (0.46 g, 1.1 mmol), lithium hydroxide monohydrate (0.15 g, 3.5 mmol, 3.3 eq), 2 mL of water, 2 mL of THF, and 3 mL of MeOH was stirred 17 h and then was concentrated under reduced pressure. The resulting suspension was treated with 200 μL of TFA and was washed into a separatory funnel with DCM and water. The water was separated and extracted with DCM. The combined extracts were dried (Na2SO4) and concentrated in vacuo. The crude acid was purified by reverse-phase HPLC to afford the title compound (65 mg, 15%) as a colorless solid; 1H NMR (DMSO-d6): δ 12.7-12.8 (br s, 1H), 9.84 (s, 1H), 8.12 (d, J=8 Hz, 1H), 8.03 (t, J=8 Hz, 1H), 8.00 (s, 4H), 7.93 (t, J=8 Hz, 1H), 7.61 (d, J=2H), 6.77 (s, 1H), 2.26 (s, 3H), 2.00 (s, 3H); MS (ESI) m/z 403 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:17][O:18][CH3:19])[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10])(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:7][C@H:8]([CH2:17][O:18][CH3:19])[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@@H](N)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 25 mL round-bottomed flask, [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (286 mg, 1.00 mmol) was dissolved in dichloromethane (4 ml). The reaction was cooled to 0° C. and trifluoroacetic acid (1.2 ml, 15.6 mmol) was slowly added. The reaction mixture was stirred at room temperature for 3 h then concentrated to provide 1-((R)-2-amino-3-methoxy-propionyl)-azetidine-3-carbonitrile trifluoroacetate as a colorless viscous oil which was used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:30]1[N:31]=[C:32]([CH3:42])[N:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:34]=1)#[CH:29]>C1COCC1.N1CCCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:41][C:38]1[CH:37]=[CH:36][C:35]([N:33]2[CH:34]=[C:30]([C:28]#[C:29][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=3)[N:31]=[C:32]2[CH3:42])=[CH:40][CH:39]=1
Reactant: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Reactant: Cc1cc(I)ccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Iodo-2-methyl-pyridine (656 mg, 3.0 mmol) was dissolved in 10 mL dry THF and 10 mL piperidine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (20 mg, 0.07 mmol) and bis(triphenylphosphin)palladium(II)chloride (175 mg, 0.10 mmol) were added and the reaction mixture was stirred at RT for 1 h. Copper(I)iodide (14 mg, 0.07 mmol) and 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (IV-1) (500 mg, 2.5 mmol) were added. The reaction mixture was then refluxed for 3 h. The solvent was evaporated. The residue was taken up in 30 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient) and recrystallization from diethylether and the desired product was obtained as a light yellow solid (250 mg, 34%), mp=151° C., MS: m/e=292.1 (M+H+).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([O:24][CH3:25])[CH:23]=3)[O:15][N:14]=2)=[C:9]2[C:5]=1[C:6]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:7][NH:8]2.Cl>C1COCC1.O>[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([O:24][CH3:25])[CH:23]=3)[O:15][N:14]=2)=[C:9]2[C:5]=1[C:6]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:7][NH:8]2
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(OC)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cnc1OC(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Sodium hydroxide (30 mg) was added to a solution of ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D50) (157 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E25) (110 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 2.62 (2H, t), 3.06 (2H, t), 3.95 (3H, s), 5.42 (1H, m), 6.99 (1H, dd), 7.26 (1H, d), 7.92 (2H, m), 8.67 (1H, d), 11.07 (1H, s), 12.14 (1H, br s). δF (DMSO-d6, 376 MHz): −118.8. MS (ES): C22H21FN4O5 requires 440; found 441.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7](=[O:13])[C:8]([CH3:12])=[C:9]([OH:11])[N:10]=[C:5]2[S:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1>CN(C=O)C>[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][O:11][C:9]3[N:10]=[C:5]4[S:4][CH:3]=[C:2]([CH3:1])[N:6]4[C:7](=[O:13])[C:8]=3[CH3:12])=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1
Reactant: Cc1c(O)nc2scc(C)n2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(Cl)nc3)cc2)nc2scc(C)n2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
To a solution of 3,6-dimethyl-7-hydroxy-5H-thiazolo[3,2-a]pyrimidin-5-one (526 mg) and potassium carbonate (574 mg) in DMF (10 ml) was added 4-(6-chloronicotinoyl)benzyl bromide (852 mg) and the mixture was stirred at 80° C. for 2 hours. This reaction mixture was concentrated and the residue was diluted with water-ethyl acetate and extracted with ethyl acetate. The extract was purified by silica gel column chromatography (hexane: ethyl acetate =2:1) and recrystallized from ethyl acetate to provide the title compound as colorless solid (300 mg).
Reaction SMILES: ClC1C=CC(C(O)=O)=CN=1.O(C1C=CC(CCN)=CC=1)C1C=CC=CC=1.Cl[C:28]1[CH:51]=[CH:50][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)=[O:33])=[CH:30][N:29]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[N:52]1([C:28]2[CH:51]=[CH:50][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:39][CH:38]=3)=[O:33])=[CH:30][N:29]=2)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1
Reactant: O=C(NCCc1ccc(Oc2ccccc2)cc1)c1ccc(Cl)nc1
Reactant: C1COCCN1
Agent: NCCc1ccc(Oc2ccccc2)cc1
Agent: O=C(O)c1ccc(Cl)nc1
Product: O=C(NCCc1ccc(Oc2ccccc2)cc1)c1ccc(N2CCOCC2)nc1

Procedure:
In analogy to example 21 6-chloro-nicotinic acid was coupled with 4-phenoxyphenethylamine. The intermediate 6-chloro-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide was reacted with morpholine. White solid. MS (ISP): 404.6 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-])=O)=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][N+]([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:4]=1[NH:14][CH:7]=[CH:6]2
Reactant: COc1cccc(C=C[N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cccc2cc[nH]c12
Reaction time: 8 h

Procedure:
Compound 3 was synthesized according to the procedure of A. Kalir et al. [supra]. To a 250-mL Parr hydrogenation bottle, 4.893 g of 2 (21.84 mmol) was added. Compound 2 was dissolved in 90 mL of hot ethyl acetate and 9.0 mL of acetic acid. To this solution 0.260 g of 10% palladium on activated carbon (Aldrich) was added. This mixture was hydrogenated overnight at 4 atm. When the pressure stabilized, the reaction mixture was filtered and the solvent removed by rotary evaporation. The residue was dissolved in 60 mL of diethyl ether. The ether solution was washed with 35 mL of 5% aqueous ammonium hydroxide, 5% aqueous hydrochloric acid, and water, dried with MgSO4, and filtered. The ether was removed by rotary evaporation to yield 2.00 g of a green oil. This oil was chromatographed over 85 g of silica gel with 6:1 hexanes:ethyl acetate to yield 1.863 g (58%) of 3 as a very pale yellow oil: 1NMR (CDCl3) δ 3.99 (s, 3H, OCH3), 6.61 (m, 2H), 7.18 (m, 3H), 8.43 (br s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), (2-aminoethyl)(5-nitro(2-pyridyl))amine (11.3 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[H][H].[N+:15]([O-])(O)=O>C(O)C.S(=O)(=O)(O)O.[Pd]>[NH2:15][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[C:3]2=[O:12])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: [H][H]
Reactant: Cn1ccc2ccccc2c1=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN1CCc2ccc(N)cc2C1=O

Procedure:
2-Methyl-2H-isoquinolin-1-one was subjected to catalytic hydrogenation in a hydrogen atmosphere in ethanol in the presence of palladium/carbon. The resulting compound and concentrated nitric acid were allowed to undergo the reaction in concentrated sulfuric acid. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 7-amino-2-methyl-3,4-dihydro-2H-isoquinolin-1-one. NMR2: 2.88 (2H, t, J=6.8 Hz), 3.13 (3H, s), 6.95 (1H, d, J=8.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=[C:9]([C:20]#[N:21])[N:8]=2)[N:5]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.C([O-])([O-])=[O:30].[K+].[K+]>CS(C)=O.OO>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:10]=[C:9]([C:20]([NH2:21])=[O:30])[N:8]=2)[N:5]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: N#Cc1nc(Nc2ccccc2)cc(-n2nc(Nc3ccccc3)nc2N)n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1nc(Nc2ccccc2)cc(-n2nc(Nc3ccccc3)nc2N)n1
Reaction time: 0.17 h
Yield: 61 %

Procedure:
To (20 mg; 0.054 mMol) of 4-(5-amino-3-phenylamino-[1,2,4]triazol-1-yl)-6-phenylamino-pyrimidine-2-carbonitrile in 500 μL of DMSO was added, at ambient temperature, (5 mg; 0.036 mMol) of anhydrous K2CO3, followed by 10 drops of 30% aqueous H2O2. The reaction was stirred for 10 min and quenched with water. The aqueous layer was extracted with EtOAc (2×). The organic fractions were combined and washed with water, brine, and then dried (Na2SO4), filtered and concentrated. The solid was triturated with hot 2-propanol, allowed to cool and the solid was collected via suction filtration, washed with 2-propanol, and MTBE, and air-dried to provide an off white powder (61% yield).
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:26])[C:14]2[C:19]([NH:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:26][N:13]([CH:10]1[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]1)[C:14]1[C:19]([NH:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH3:23])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCC(C)(C)Nc1cccnc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)Nc1cccnc1N(C)C1CCNCC1
Reaction time: 1.5 h

Procedure:
To a mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[N-methyl-N-(3-(1,1-dimethylpropylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 63, 2.39 g) in dry methylene chloride (30 ml) under nitrogen at 0° is added trifluoroacetic acid (6.37 ml) over 1 min. The resulting mixture is warmed to 20°-25°, stirred for 1.5 hrs, and then added to a mixture of sodium hydroxide (3.31 g) in water (40 ml) at 0°. The layers are separated, the aqueous phase is extracted with methylene chloride (4×40 ml), and the combined organic phases are washed with saline (40 ml), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound, NMR (CDCl3) 7.66, 7.02, 6.84, 4.86, 3.39, 3.13, 2.63, 1.81-1.52, 1.31 and 0.87δ.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26].C1CCCCC1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([NH:8][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1ccc(-c2cccc(N)c2C)cc1
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCCC(=O)Nc1cccc(-c2ccc(C)cc2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of 2,4′-dimethyl-1,1′-biphenyl-3-ylamine (20 g, 0.1015 mol) in anhydrous CH2Cl2 (250 ml) at 0° C. under nitrogen was added triethylamine (28.29 ml, 0.203 mol). Butyrylchloride (11.07 ml, 0.1066 mol) was added dropwise over 0.5 h, the rate of addition ensured temperature of reaction mixture was below 10° C. Reaction mixture was then stirred at room temperature for 2 h under nitrogen, diluted with CH2Cl2 (200 ml), washed with water (400 ml), saturated sodium bicarbonate (400 ml) and saturated sodium chloride (400 ml). The organic solution was dried (Na2SO4) and the solvent removed in vacuo to give a cream solid. To the solid was added cyclohexane (400 ml), the mixture stirred for 2 h and filtered. The solid residues were dissolved in CH2Cl2 and the solvents removed in vacuo to afford the title compound as a cream solid (25 g).
Reaction SMILES: COC1C=CC(C2C[CH2:27][C:26]3C(=CC=[C:24]([O:29]C)[CH:25]=3)C2)=C(NCCC2C=CC(O)=CC=2)C=1.[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH:47][C:48]2[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=2[CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)CC)C.C1(C(Cl)=O)CC1>O1CCCC1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH2:46][N:47]([C:48]2[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=2[CH:56]2[CH2:65][CH2:64][C:63]3[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=3)[CH2:57]2)[C:24]([CH:25]2[CH2:26][CH2:27]2)=[O:29])=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C2
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(O)cc1)C2
Agent: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)C1CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesized from 4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamino]ethyl}phenol according to an analogous synthetic method to Example 201, to a solution of the resulting {2-[4-(tert-butyldimethylsilyloxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (2.3 g) in tetrahydrofuran (50 ml) was added triethylamine (895 mg), cyclopropanecarbonyl chloride (693 mg) was added dropwise thereto on an ice bath followed by stirring for 30 minutes at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.3 g).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11].O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(=S)=S.Br>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[C:5]([OH:11])=[C:6]([F:10])[CH:7]=1
Reactant: Oc1c(F)cccc1F
Reactant: BrBr
Agent: Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: S=C=S
Solvent: O
Product: Oc1c(F)cc(Br)cc1F
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of bromine (1.6 g) in dry carbon disulphide (10 cm3) was added over 5 minutes to a solution of 2,6-difluorophenol (1.3 g) in dry carbon disulphide (10 cm3). To the stirred reaction mixture was added 5 drops of 48% hydrogen bromide solution. The mixture was heated for 2 hours at the reflux temperature, then allowed to stand at the ambient temperature (ca 22° C.) for 16 hours. After a further period of heating (4 hours) the mixture was allowed to stand for 24 hours before being poured into water (20 cm3). To the mixture was added saturated sodium metabisulphite solution (30 cm3). The layers were separated, and the organic phase was washed with saturated sodium hydrogen carbonate solution (20 cm3) and water (20 cm3). The organic layer was dried over anhydrous sodium sulphate then evaporated under reduced pressure to give an oil which solidified. The crude product was distilled in a Kugelrohr apparatus at an oven temperature of 100° C. under reduced pressure (ca 20 mm Hg). The distillate crystallised to give 4-bromo-2,6-difluorophenol as a white solid (0.48 g).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][C:11]3=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>C(O)CC>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:9]1[N:10]=[C:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:8]=1[C:5]1[N:6]=[N:7][C:2]([NH:25][NH2:26])=[CH:3][CH:4]=1
Reactant: Fc1ccc(-c2nc3n(c2-c2ccc(Cl)nn2)CCC3)c(F)c1
Reactant: NN
Solvent: CCCO
Solvent: O
Product: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3n2CCC3)nn1
Temperature: 105 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A 500 mL round bottom flask was charged with 3-(6-chloropyridazin-3-yl)-2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (7.50 g, 22.5 mmol), 1-propanol (225 mL) and hydrazine hydrate (11.3 g, 225 mmol). The mixture was then heated at about 105° C. for about 10 h. The reaction mixture was cooled to ambient temperature and stirred overnight. The mixture was concentrated under reduced pressure to remove about ¾ of the volume. The remaining mixture was stirred with DCM (250 mL) and saturated aqueous NaHCO3 (200 mL). The layers were partitioned, the aqueous layer was diluted with water (100 mL) and extracted with DCM (2×200 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was triturated with Et2O (50 mL) and the solid was collected by vacuum filtration. The filter cake was washed with additional Et2O (10 mL) and then dried in a vacuum oven for about 1 h at about 60° C. to give the title compound (4.59 g, 62%): LC/MS (Table 1, Method g) Rt=1.41 min; MS m/z: 329.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29](OC)=O)=[CH:27][CH:26]=1)#[N:24].[H-].[Na+]>CN(C=O)C>[OH:15][CH2:14][C@H:9]1[C@H:8]([C:7]2[C:6]([O:16][CH3:17])=[CH:5][C:4]([O:18][CH3:19])=[C:3]3[C:2]=2[O:1][C:29]([C:28]2[CH:33]=[CH:34][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:21][C:20]3=[O:22])[CH2:12][CH2:11][N:10]1[CH3:13]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(C#N)cc3)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
Compound of example 6 (1.5 g, 4.85 mmol) in dry DMF (15 mL) reacted with methyl 4-cyanobenzoate (2.57 g, 17.2 mmol) in the presence of NaH (50%, 1.2 g, 25 mmol), as described example 16, afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([N:16]([CH3:22])[CH2:17][C:18](OC)=[O:19])=[O:15])=[CH:4][CH:3]=1.[Na].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]2[C:18](=[O:19])[CH2:17][N:16]([CH3:22])[C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)CN(C)C(=O)Cc1ccccc1Oc1ccc(Cl)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CC(=O)C(c2ccccc2Oc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
27.8 g (79.9 mmol) of methyl N-{2-[2-(4-chlorophenoxy)phenyl]-1-oxoethyl}-N-methylglycinate (compound IIIb) was dissolved in 150 mL of toluene. 11.5 g of sodium tert-butoxyde were added, and the resulting mixture was stirred overnight at room temperature. 350 mL of water were added, and the resulting mixture was extracted three times with 150 mL of ethyl acetate. The combined organic phases were washed with 200 mL of water. The aqueous phases were combined and pH was adjusted to 1 with HCl 2 M. The solvent was removed by filtration, and the solid was recrystallized twice with methanol, to obtain 5.4 g of 3-[2-(4-chlorophenoxy)phenyl]-1-methylpyrrolidine-2,4-dione (compound IVb) as a solid. Yield: 21.4%.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:16](N(CC)C(C)C)(C)[CH3:17].C(I)C>CN(C=O)C>[CH2:16]([N:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][C:7]1[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(Cc2ncc[nH]2)cc1
Solvent: CCI
Solvent: CN(C)C=O
Product: CCn1ccnc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Yield: 20.5 %

Procedure:
To a solution of 2-(4-nitro-benzyl)-1H-imidazole (1.58 g, 7.37 mmol) in DMF (10 mL) was added N,N-diisopropylethyl amine (1.93 mL, 11.05 mmol) and heated to 5° C. for 30 min. Ethyl iodide (1.18 mL, 7.37 mmol) was added dropwise and the reaction mixture heated to reflux for 6 h. The solvent was evaporated under reduced pressure, the residue dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, evaporated and the residue purified by column chromatography over silica gel (60-120 mesh) using 3% methanol/chloroform as eluent to afford 1-ethyl-2-(4-nitrobenzyl)-1H-imidazole (0.35 g, 21%).