Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](O)[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([CH3:22])=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:33]1C[C@@H](N)C[C@H]1C1OC=CN=1)=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:33])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([CH3:22])=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Reactant: Cc1cnc([C@@H]2C[C@@H](O)CN2C(=O)OCc2ccccc2)o1
Product: Cc1cnc([C@@H]2C[C@H](N)CN2C(=O)OCc2ccccc2)o1

Procedure:
(2S,4S)-4-Amino-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4R)-4-hydroxy-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester. MS calcd. for C16H20N3O3 [(M+H)+] 302, obsd. 302.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O>[CH2:24]([O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCc2ccccc2)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a solution of 1.11 g (4.70 mmol) of tert-butyl 4-hydroxyphenethylcarbamate in 20 mL of DMF at 22° C. was added 1.3 g (9.4 mmol) of potassium carbonate and 0.700 mL (5.87 mmol) of benzyl bromide. The mixture was stirred for about 16 h at 22° C., diluted with 100 mL of water and extracted with ethyl acetate (3×75 mL). The organic layers were combined, washed with 100 mL of 1 N HCl, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography on silica gel eluting with a mixture of hexane and ethyl acetate to give tert-butyl 4-(benzyloxy)phenethylcarbamate as an oil which later solidified under vacuum. Transformation of tert-butyl 4-(benzyloxy)phenethylcarbamate to tert-butyl 4-(benzyloxy)phenethyl(methyl)carbamate was accomplished in a manner analogous to Method B Step 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[N:5]=[C:4]([N:23]([CH3:25])[CH3:24])[N:3]=1.[OH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:22][O:21][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([N:23]([CH3:25])[CH3:24])[N:3]=[C:2]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:34])([F:35])[F:36])[N:7]=2)[CH:14]=[CH:13][C:12]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: COc1cc(Nc2nc(Cl)nc(N(C)C)n2)ccc1-n1cnc(C)c1
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(Nc2nc(Oc3ccccc3C(F)(F)F)nc(N(C)C)n2)ccc1-n1cnc(C)c1
Yield: 15.4 %

Procedure:
6-Chloro-N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′,N′-dimethyl-[1,3,5]triazine-2,4-diamine (200 mg, 0.56 mmol) in 7 ml acetonitrile was treated with 2-hydroxy-benzotrifluoride (95 mg, 0.59 mmol) and potassium carbonate (85 mg, 0.62 mmol). The resulting mixture was stirred under reflux for 5 days. The mixture was then diluted with 25 ml of water and extracted with ethyl acetate. Chromatography on silica gel using ethyl acetate as a solvent and subsequent crystallization from methanol gave the title compound as colorless solid (42 mg, 16%).
Reaction SMILES: [OH:1]O.[C:3]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:3]([NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N+:11]=1[O-:1])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)cn1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1ccc(Cl)c[n+]1[O-]
Temperature: 0 °C
Yield: 65 %

Procedure:
Thirty-one percent aqueous hydrogen peroxide (1.0 ml) was added to a solution of N-t-butyl-5-chloro-2-pyridinecarboxamide obtained in Example 40 (0.35 g, 1.65 mmol) in trifluoroacetic acid (5 ml), and heated under reflux for 1.5 hours. The reaction mixture was added portionwise into an ice-cooled 1N aqueous NaOH and extracted three times with ethyl acetate and the extracts were dried over MgSO4. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1 to 2/1) to give the title compound (0.24 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCSC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of Example 17A (19.9 g, 66 mmol) and triethylamine (9.5 mL, 70 mmol) in THF (200 mL) at 0° C. under nitrogen was added methanesulfonyl chloride (15.08 g, 132 mmol) drop wise over 30 minutes. The mixture was allowed to warm up to room temperature, stirred for 12 hours, and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to a yellow oil. The yellow oil was purified using a Biotage 65+ eluting with 100% ethyl acetate to provide the titled compound. MS (ESI) m/e 380 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 1.44 (m, 9 H) 2.22 (m, 1 H) 2.65 (m, 1 H) 3.05 (m, 1 H) 3.14 (d, 3 H) 3.17 (m, 1 H) 3.74 (m, 3.73 Hz, 1 H) 3.81 (m, 2 H) 4.00 (m, 1 H) 4.53 (m, 1 H) 4.70 (m, 2 H) 5.32 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(#N)C>[CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1ncccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ncccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To an acetonitrile solution (5 ml) of 2-methylnicotinic acid (400 mg, 2.92 mmol) and DMF (11.2 μl, 0.156 mmol), oxalyl dichloride (501 μl, 5.83 mmol) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, to obtain a crude product of 2-methylnicotinic acid chloride as a yellow liquid (470 mg).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C=O)C.[CH3:12][O:13][C:14]1[C:15]([N+:23]([O-:25])=[O:24])=C([CH:20]=[CH:21][CH:22]=1)C(O)=O>ClCCl>[CH3:12][O:13][C:14]1[C:15]([N+:23]([O-:25])=[O:24])=[C:1]([CH:20]=[CH:21][CH:22]=1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(=O)Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Oxalyl chloride (2 mL, 24 mmol) and DMF (0.4 mL) are added to a suspension of 3-methoxy-2-nitro benzoic acid (4 g, 20 mmol) in 200 mL of dichloromethane. The reaction mixture is stirred for 3 hours at 25° C. under nitrogen. The reaction solvents are removed under reduced pressure to yield 3-methoxy-2-nitrobenzoyl chloride (4.3 g, quant.) as a yellow solid. 1H NMR (DMSO): δ7.80 (1H, d, J=8 Hz), 7.65 (1H, t, J=9 Hz), 7.42 (1H, d, J=10 Hz).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH3:14][S:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([C:10](=[NH:11])[NH:20][C:19]2[CH:21]=[CH:22][C:16]([S:15][CH3:14])=[CH:17][CH:18]=2)=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CSc1ccc(N)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CSc1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Temperature: 185 °C
Yield: 43.4 %

Procedure:
Finely powdered anhydrous aluminium chloride (0.83 g, 6 mmol) was added to a stirred mixture of 4-chlorobenzonitrile (0.6875 g, 5 mmol) and 4-methylthioaniline (0.695 g, 5 mmol) over a period of 30 min. The reaction mixture was heated at 180-190° C. for 3 hours with stirring and allowed to cool to 50° C. The resultant mixture was triturated with ethyl acetate and basified with sodium hydroxide (20%) solution. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate and concentrated to give the crude product, which was purified by column chromatography to yield the title compound (0.6 g, 43.4%, purity 98.8% by HPLC), mp 148-150° C. 1H-NMR (CDCl3):δ 2.48 (s, 3H), 6.90-6.97(m, 2H), 7.11-7.41(m, 4H), 7.74 (bs, 2H). MS m/z:277.0 (M+)
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23](Cl)=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN1CCCC1=O>[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Sodium hydride (400 mg of an 80% suspension in paraffin oil, 13.3 mmol) was added to a solution of phenol (1.26 g, 13.3 mmol) in dry N-methylpyrrolidone (20 ml) and the mixture stirred for 10 minutes. 7-Benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.6 g, 4.7 mmol), (prepared as described for the starting material in Example 1), was then added and the reaction mixture heated at 110° C. for 2 hours. The mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were then washed with 2M sodium hydroxide solution, water and brine. Removal of the solvent under reduced pressure gave 7-benzyloxy-6-methoxy-4-phenoxyquinazoline (1.6 g, 95%) as a yellowish solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CCOC(=O)C(C)Br
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Br)cc1C=O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 5-bromo-2-hydroxybenzaldehyde (4.97 mmol) in acetonitrile (30 mL) was treated with potassium carbonate (14.92 mmol) and ethyl 2-bromopropanoate (5.97 mmol). The resulting mixture was stirred at room temperature overnight. Analysis by LCMS indicated the formation of the desired intermediate ester, and the reaction mixture was concentrated to dryness in vacuo. The crude material was dissolved in a 3:1 methanol:water mixture (20 mL) and was heated to 50° C. with stirring. The reaction was then cooled to room temperature and was acidified to pH˜3 using 1N aq HCl. The methanol was removed in vacuo and the resulting aqueous suspension was diluted with water (100 mL). The solution was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting beige solid was used without further purification (1.38 grams, 80% yield). MS(ES)+ m/e 273/275 [M+H]+ (bromide isotope pattern).
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[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH3:28].O>CN(C=O)C>[CH2:27]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C: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)=[N:12]1)[CH3:28]
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.42 mmol) was dissolved in DMF (3 mL) and K2CO3 (220 mg, 1.6 mmol) and ethyl iodide (37 μL, 0.46 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 290.1, found 290.2.
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[Na+].[Br:16]Br>C(O)(=O)C>[Br:16][C:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]([NH2:10])=[CH:8][CH:7]=1
Reactant: Nc1cccnc1[N+](=O)[O-]
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(Br)nc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a stirred suspension of 2-nitro-pyridin-3-ylamine (5.06 g, 36.40 mmol) and sodium acetate (2.99 g, 36.46 mmol) in acetic acid (40 mL), a solution of bromine (2.5 mL, 48.79 mmol) in acetic acid (8 ml) was added drop-wise and the reaction mixture was stirred overnight. The acetic acid was removed under reduced pressure. The residue was cooled to 0° C., neutralized with saturated sodium bicarbonate solution to adjust the pH to ˜7, and extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was triturated with ethyl acetate to afford compound (5) (5.1 g) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13](Cl)(=[O:17])[CH2:14][CH2:15][CH3:16]>>[C:13]([NH:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CCCC(=O)Cl
Agent: Cl
Product: CCCC(=O)Nc1cc(C(=O)OC)ccn1
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield (1.94 g, a white solid) from methyl 2-aminoisonicotinate hydrochloride (2.00 g, 10.6 mmol) and butyryl chloride by the similar manner in Step-1 of Carboxylic acid-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]([C:7]1[CH:28]=[CH:27][C:10]2[S:11][CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:25])[CH3:24])[C:15]=3[OH:26])[C:9]=2[CH:8]=1)[CH3:6].I[CH3:31].[F-].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]([C:7]1[CH:28]=[CH:27][C:10]2[S:11][CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:24])[CH3:25])[C:15]=3[O:26][CH3:31])[C:9]=2[CH:8]=1)[CH3:6]
Reactant: CI
Reactant: COC(=O)C=C(C)c1ccc2scc(-c3cc(C(C)C)cc(C(C)C)c3O)c2c1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=C(C)c1ccc2scc(-c3cc(C(C)C)cc(C(C)C)c3OC)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
3-[3-(2-Hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoic acid methyl ester (100 mg, 0.24 mmol) was dissolved in DMF (5 ml), and iodomethane (0.0183 ml, 0.29 mmol) and cesium fluoride (149 mg, 0.98 mmol) were added to this solution. The reaction was stirred at ambient temperature under nitrogen overnight, then water (2 ml) was added and the mixture extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine, then dried over MgSO4 and concentrated in vacuo to yield 3-[3-(3,5-di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]but-2-enoic acid methyl ester as a pale yellow solid (101 mg, 98%). 1H NMR (250 MHz, CDCl3): δ 7.85 (d, 1H, J=6.2), 7.80 (s, 1H), 7.46 (s, 1H), 7.40 (dd, 1H, J=0.6, J=8.8), 7.09 (d, 1H, J=1.2), 7.03 (d, 1H, J=1.2), 6.12 (d, 1H, J=0.6), 3.65 (s, 3H), 3.32 (m, 1H), 3.18 (s, 3H), 2.85 (m, 1H), 2.53 (d, 3H, J=0.6), 1.24 (s, 3H), 1.22 (s, 6H), 1.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)(=[O:22])=[O:21])[C@@H:14]([C:16]([O:18]C)=[O:17])[CH3:15].O.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)(=[O:22])=[O:21])[C@@H:14]([C:16]([OH:18])=[O:17])[CH3:15]
Reactant: COC(=O)[C@@H](C)N(c1c(Cc2c(F)cccc2F)cccc1OC)S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N(c2c(Cc3c(F)cccc3F)cccc2OC)[C@H](C)C(=O)O)cc1OC
Reaction time: 48 h
Yield: 50.1 %

Procedure:
To 0.164 g of methyl N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]-(R)-alaninate dissolved in 8 ml of a 1,4-dioxane/water mixture (4/1) is added, at room temperature, 0.015 g of lithium hydroxide monohydrate. The mixture is left at room temperature for 48 hours. The reaction medium is washed with 1M hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a dichloromethane/ethanol mixture to give 0.08 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:20].I[CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:15][CH2:14]2)=[CH:4][C:3]=1[Cl:20]
Reactant: COc1nc(N)c(Cl)cc1C(=O)CCC1CCNCC1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN1CCC(CCC(=O)c2cc(Cl)c(N)nc2OC)CC1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of 1-[6-amino-5-chloro-2-(methyloxy)-3-pyridinyl]-3-(4-piperidinyl)-1-propanone (step 5 in example 9, 110 mg, 0.369 mmol), 1-iodobutane (0.046 ml, 0.406 mmol) and potassium carbonate (102 mg, 0.738 mmol) in tetrahydrofuran (3 ml) was refluxed for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 ml), washed with water (5 ml) and brine (10 ml), and dried over potassium carbonate. Removal of solvent gave a pale yellow oil, which was crystallized from methanol to afford 92 mg (64%) of the title compound as a white crystal.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH3:13])[N:9]=[CH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:13][C:8]1[N:9]=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=2
Reactant: COc1ccc2cc(C)ncc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1cc2ccc(O)cc2cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.5 %

Procedure:
7-Methoxy-3-methylisoquinoline (15 g, 89 mmol, 1 equiv.) was dissolved in methylene chloride (150 mL). A 1.0 M solution of BBr3 in methylene chloride (240 mL, 240 mmol, 2.7 equiv.) was added slowly to this solution at room temperature observing a slight exotherm. This solution was stirred at room temperature for 2.5 hours. After cooling to 0° C., methanol (150 mL) was added slowly to quench the reaction. The solution was stirred for an additional 15 minutes. The solution was concentrated under reduced pressure and treated with methanol (150 mL) and concentrated under reduced pressure. The resulting oil was treated with saturated aqueous sodium bicarbonate slowly with stirring until a pH˜7-8 was achieved. The solid resulting was collected under vacuum filtration and was washed with water (300 mL) and methylene chloride (200 mL) giving a tan solid which was dried in a vacuum oven at 50° C. overnight to give 3-methylisoquinolin-7-ol (13.1 g, 92% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([C:15]2[C:16]3[C:21]([C:22]([C:29]4[C:34]5=[CH:35][CH:36]=[C:37]6[C:46]([CH:45]=[C:44]7[C:39]([CH:40]=[CH:41][CH:42]=[CH:43]7)=[CH:38]6)=[C:33]5[CH:32]=[CH:31][CH:30]=4)=[C:23]4[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>CN(C=O)C>[Br:1][C:38]1[C:37]2[C:46]([CH:45]=[C:44]3[C:39]=1[CH:40]=[CH:41][CH:42]=[CH:43]3)=[C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[CH:27]4)[C:34]1=[CH:35][CH:36]=2
Reactant: c1ccc(-c2c3ccccc3c(-c3cccc4c3ccc3cc5ccccc5cc34)c3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1c2ccccc2cc2c1ccc1c(-c3c4ccccc4c(-c4ccccc4)c4ccccc34)cccc12
Reaction time: 3 h

Procedure:
20 g (116 mmol) of N-bromosuccinimide are added at 100° C. to a suspension of 55 g (116 mmol) of 4-(9-phenylanthracen-10-yl)benz[a]anthracene in 500 ml of DMF. After 3 h, 500 ml of ethanol are added at room temperature, and the solid is filtered off with suction, washed with ethanol and dried. Yield: 63 g (113 mmol), 65%.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].O[NH:21][C:22]([C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)=[NH:23]>>[F:31][C:30]([F:32])([F:33])[C:28]1[CH:29]=[C:24]([C:22]2[N:23]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[O:15][N:21]=2)[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Reactant: N=C(NO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: N#Cc1ccc2c(ccn2Cc2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)no2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 37 from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and N-hydroxy-3,5-bis(trifluoromethyl)benzenecarboximidamide: MS (ES) m/z 503 (M−1).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[CH:32]([N:35]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[N:36]1)([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[F:30][CH:28]([F:29])[O:27][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:2])=[O:31])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:37]2[CH:38]=[CH:39][N:35]([CH:32]([CH3:34])[CH3:33])[N:36]=2)=[CH:22][CH:21]=1
Reactant: CC(C)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-c2ccn(C(C)C)n2)cc1
Temperature: 140 °C
Yield: 27.2 %

Procedure:
A mixture of [3-(4-bromobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.05 g), 1-isopropyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.047 g), tetrakis(triphenylphospine)palladium (0) (0.012 g), N,N-dimethylformamide (0.3 mL) and 2.0 M aqueous cesium carbonate solution (0.2 mL) was heated by microwave irradiation at 140° C. for 6 minutes. The mixture was cooled to room temperature, acidified by the addition of 1.0 M aqueous hydrochloric acid solution and then extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound (0.014 g).