Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([O:26]CC)=[O:25])[CH2:19]1.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=[O:25])[CH2:19]1
Reactant: CCOC(=O)C1CCCN(c2nc3c(c(=O)n(C)c(=O)n3C)n2Cc2c(F)cccc2Cl)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)c2c(nc(N3CCCC(C(=O)O)C3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Yield: 103.7 %

Procedure:
A solution of ethyl 1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylate (5.0 g, 10.5 mmol) in 75 mL THF and 25 mL H2O at room temperature was treated with solid LiOH (1.8 g, 43.9 mmol). After stirring overnight the THF was removed under reduced pressure, and the residue was diluted with H2O. The aqueous layer was acidified to pH 4, and the aqueous layer was extracted with CH2Cl2. The combined extracts were concentrated under reduced pressure to give 4.9 g (>99% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ7.18 (dt, 2H, J=8.1, 5.7), 7.14 (t, 1H, J=7.6), 6.98-6.90 (m, 1H), 5.57 (AB quartet, 2H, J=15.7, 5.7), 3.51 (s, 3H), 3.42 (dd, 1H, J=12.6, 4.0), 3.30 (s, 3H), 3.20-3.05 (m, 2 H), 2.94-2.83 (m, 1H), 2.59-2.47 (m, 1H), 2.03-1.93 (m, 1H), 1.75-1.40 (m, 3H); LRMS (ESI) m/z 450 (M+H+); TLC (hexanes:EtOAc/1:1) Rf=0.10.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:3][CH2:2]1.NN.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][NH:8][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCOCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
2-(tetrahydro-2H-pyran-4-yloxy)-1H-isoindole-1,3(2H)-dione (6.8 mmol, 1.69 g) was combined with hydrazine (6.8 mmol, 0.22 mL) in anhydrous THF (20 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 1 hour. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (6.5 mmol, 1.34 g) and diisopropylethylamine (20.5 mmol, 3.6 mL) was added. After stirring at room temperature for 15 hours, the reaction was refluxed for 4 hours, then stirred at room temperature for 12 days and concentrated to a yellow solid. The resulting solid was partitioned between ethyl acetate and 1N HCl, and the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) and crystallization (hexanes/ethyl acetate) providing 0.554 g (30%) of a white solid. Rf=0.4 (1:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.83(2H,d), 7.00 (2H,d), 6.72 (1H,s), 4.23-4.11 (1H,m), 3.91-3.81 (2H,m), 3.87 (3H,s), 3.46-3.38 (2H,m), 2.03-1.94 (2H,m), 1.63-1.51 (2H,m).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@H:27]2[CH3:32])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@H:27]3[CH3:32])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1COCCN1c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1COCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 1 h
Yield: 88.6 %

Procedure:
Potassium tert-butoxide (0.59 g) was added to a solution of 2-[benzyl({3-chloro-5-[(3R)-3-methylmorpholin-4-yl]pyrazin-2-yl}methyl)amino]ethanol (1.65 g) in DMF (50 mL) at 0° C., and the mixture was stirred for 1 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (1.32 g, 89%) as a pale-yellow solid.
Reaction SMILES: CN1CCCCC1.[O:8]([C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[CH3:33][CH:34]([NH2:47])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1>C(Cl)Cl.O>[CH3:33][CH:34]([NH:47][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:16])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][CH:38]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CC(N)COc1ccc(C(F)(F)F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC(COc1ccc(C(F)(F)F)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
1.6 g of N-methylpiperidine was added to a solution containing 4.0 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20° C. After the mixture was stirred for 15 minutes at the same temperature, 2.2 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 3.5 g of 1-methyl-2-(4-trifluoromethylphenoxy)ethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 2.8 g of the desired product in the form of a white crystal (yield: 40%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:11])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].[OH-].[Li+]>O1CCCC1.O>[Br:11][C:8]1[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
To a solution of 0.81 g 5-bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester in 10 ml tetrahydrofuran was added at room temperature 2.6 ml of a 1M solution of lithium hydroxide in water and the mixture was stirred for 15 minutes. The resulting solution was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic layer washed with water and brine. The organic phase was dried over magnesium sulfate and evaporated to yield 0.78 g of the title compound as white crystals. MS (ISP) (M+H+)=297.2 and 299.0.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1COCC1.CCCCCC>[CH3:19][N:2]([CH3:1])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=2[N:8]=[C:7]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:4])=[O:5]
Reactant: COc1cc2ncn(S(=O)(=O)N(C)C)c2cc1OC
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2cc(OC)c(OC)cc2n1S(=O)(=O)N(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
1-(N,N-dimethylsulfamoyl)-5,6-dimethoxybenzimidazole (5.70 g) was dissolved in dry THF (170 ml) in a dry argon atmosphere, cooled to -60° C. and a solution of n-butyl lithium (1.58M) in hexane (15.2 ml) was added dropwise and stirred for 30 minutes. After ethyl chloroformate (2.60 g) was added dropwise, the mixture was slowly returned to room temperature and allowed to react overnight. THF was distilled off, the residue was dissolved in ethyl acetate, washed with water and dried over anhydrous Na2SO4, and the solvent was distilled off. Purification of the residue by column chromatography on silica gel gave the title compound (5.13 g) as an oily product.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH:39]([CH3:45])[C:40]([O:42]CC)=[O:41])[CH:38]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:22]([F:25])([F:24])[CH2:21][NH:20][C:18]([NH:17][C:13]1[CH:12]=[C:11]([C:8]2[N:5]3[N:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][N:37]([CH:39]([CH3:45])[C:40]([OH:42])=[O:41])[CH:38]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1)=[O:19]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Reactant: CCOC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Temperature: 100 °C

Procedure:
A mixture of N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (0.206 g, 0.556 mmol, Example 30, Step 3), ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate (0.18 g, 0.61 mmol), tetrakis(triphenylphosphine)palladium(0) (32.1 mg, 0.00278 mmol) and K3PO4 (0.30 g, 1.4 mmol) in 1,4-dioxane (3.0 mL) and water (2.0 mL) was heated at 100° C. under an atmosphere of nitrogen for 3 h. After cooling, the reaction mixture was adjusted to pH=4, extracted with ethyl acetate (3×30 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product without further purification. LCMS (M+H)+: m/z=474.1.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Product: CN(C)CCN(C(=O)c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and benzoyl chloride
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[I:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[O:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[I:30])=[O:39])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C=Nc1ccccc1I
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1I

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-iodophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 635.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH3:10])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19].O>CC(C)=O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([N:9]([CH3:10])[C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)Oc1ccc(C(F)(F)F)cc1
Reactant: CNc1cccc(OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(N(C)C(=O)Oc2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 62 %

Procedure:
To the mixture of 1.38 g of 2-methoxy-6-methylaminopyridine and 1.38 g of anhydrous potassium carbonate in 20 ml of acetone was added dropwise the solution of 2.25 g of 4-trifluoromethylphenyl chloroformate in 20 ml of acetone under stirring at room temperature. The mixture was stirred for 30 minutes and then was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and the product was extracted with benzene. The benzene solution, successively washed with water and brine, was dried over anhydrous magnesium sulfate. The residue obtained by the removal of benzene under reduced pressure was chromatographed through silica gel column using benzene as an eluent to give 2.02 g of pure 4-trifluoromethylphenyl N-(6-methoxy-2-pyridyl)-N-methylcarbamate as solid in the yield of 62%. A part of the solid was recrystallized from hexane and crystalls having melting point of 85° to 86° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=[C:14]3[NH2:39])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:50][N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:65]=[CH:64][C:60]([C:61](Cl)=[O:62])=[C:59]([N+:66]([O-:68])=[O:67])[CH:58]=2)[CH2:53][CH2:52]1>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:15]=[C:14]3[NH:39][C:61](=[O:62])[C:60]2[CH:64]=[CH:65][C:57]([N:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)=[CH:58][C:59]=2[N+:66]([O-:68])=[O:67])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12
Reactant: CN1CCN(c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(S(=O)(=O)c5cccc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a mixture of 5-(3-fluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-ylamine (100 mg, 0.187 mmol), N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) and dry-tetrahydrofuran (30 mL), at room temperature, was added 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoyl chloride hydrochloride (66 mg, 0.206 mmol, prepared as described in Example 20). The mixture was stirred at room temperature for 1 hour then evaporated to dryness. The residue was dissolved in dichloromethane (50 mL), washed with saturated solution of sodium hydrogenocarbonate (50 mL), dried over sodium sulfate, evaporated to dryness and triturated with diethylether affording the title compound as a yellow powder (102 mg, 70% yield).
Reaction SMILES: O1CCCC1.[CH2:6]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C([Li])CCC.[C:28]1([C:34]2[CH:43]=[CH:42][CH:41]=[C:36]([C:37](OC)=[O:38])[C:35]=2[OH:44])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH2:6]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:37]([C:36]2[C:35]([OH:44])=[C:34]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:43]=[CH:42][CH:41]=2)=[O:38])=[CH:21][CH:22]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCc1ccc(N)cc1
Reactant: COC(=O)c1cccc(-c2ccccc2)c1O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc(NC(=O)c2cccc(-c3ccccc3)c2O)cc1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a tetrahydrofuran (20 ml) solution of 4-decylaniline (3.07 g, 13.14 mmol), cooled to 0°-5° C. (inert atmosphere), is added n-butyllithium (2.3 M, 13.14 mmol). The deeply colored solution is stirred for ten minutes, after which a tetrahydrofuran (20 ml) solution of methyl 3-phenylsalicylate (1.00 g, 4.38 mmol) is added. The temperature is allowed to rise to 25° C. over a 30 minute period. The reaction is quenched by pouring the contents into 10% hydrochloric acid (100 ml). The organics are extracted into ethyl acetate, washed with 10% hydrochloric acid, dried (sodium sulfate), and concentrated to give 2.77 g of crude solid. Chromatography (Kieselgel 60, dichloromethane) affords N-(4-decylphenyl)-2-hydroxy-[1,1'-biphenyl]-3-carboxamide (1.69 g, 90%), mp 74°-75° C.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.C(N(CC)CC)C.Cl.[NH2:22][C@H:23]1[C:31]2[C:26](=[CH:27][C:28]([C:33]([O:35][CH3:36])=[O:34])=[C:29]([F:32])[CH:30]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:22]([C@H:23]1[C:31]3[C:26](=[CH:27][C:28]([C:33]([O:35][CH3:36])=[O:34])=[C:29]([F:32])[CH:30]=3)[CH2:25][CH2:24]1)[CH2:11]2
Reactant: COC(=O)c1cc2c(cc1F)[C@H](N)CC2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(cc1F)[C@H](N1Cc3cccc(Cl)c3C1=O)CC2
Yield: 65 %

Procedure:
2-Bromomethyl-6-chlorobenzoic acid methyl ester (1.75 mmol, 1.0 eq) was dissolved in toluene (5.3 ml) and triethylamine (3.675 mmol, 2.1 eq), and (R)-methyl 1-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-05) (1.75 mmol, 1 eq) was added. The reaction mixture was refluxed for 16 h and then diluted with ethyl acetate and sat. NaHCO3 solution. The phases were separated, and the organic phase was washed with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:EA 2:1). Yield: 65%
Reaction SMILES: [NH4+].[Cl-].[CH2:3]([O:10][C:11]1[C:12]([F:25])=[CH:13][C:14]([N+:22]([O-])=O)=[C:15]([CH:21]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C(O)(C)C.C1COCC1>[NH2:22][C:14]1[CH:13]=[C:12]([F:25])[C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1N
Temperature: 90 °C
Yield: 82 %

Procedure:
1.76 g of NH4Cl dissolved in 21 ml of water are added to a mixture heated to 90° C. of 7.0 g of the compound obtained in Step 4.1, and 4.44 g of Fe(0) in 400 ml of isopropanol and 100 ml of THF. The reaction mixture is heated for 4 hours at 90° C. A further 0.88 g of NH4Cl is added and the mixture is heated for 2 hours at 90° C. The resulting mixture is filtered while hot and the filtrate is evaporated under reduced pressure. The residue is taken up in EtOAc and washed twice with saturated NaHCO3 solution. The organic phase is dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (100/0, v/v) to (40/60, v/v) to give 5.2 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[CH2:40]([N:47]1[CH2:50][C:49]([C:54]([OH:56])=[O:55])([C:51]([OH:53])=[O:52])[CH2:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:40]([N:47]1[CH2:48][C:49]([C:51]([OH:53])=[O:52])([C:54]([OH:56])=[O:55])[CH2:50]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:54]([C:49]2([C:51]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=3)=[O:52])[CH2:50][N:47]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:48]2)=[O:55])=[CH:20][CH:21]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(O)C1(C(=O)O)CN(Cc2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CN(Cc5ccccc5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.5 %

Procedure:
1-Benzyl-azetidine-3,3-dicarboxylic acid was prepared by following the literature procedure (Miller, R. A.; et al. Syn. Comm. 2003, 33, 3347). To a solution of 4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine (4.2 mmol, 1 equiv.) and 4-fluoroaniline (4.2 mmol, 1 equiv.) in DMF (20 mL) was charged with DIEA (12.6 mmol, 3 equiv) and a solution of 1-benzyl-azetidine-3,3-dicarboxylic acid (4.2 mmol, 1 equiv.) in DMF (10 mL). The reaction mixture was allowed to stir at RT and monitored by LCMS. The reaction was complete in 6 h. The reaction mixture was diluted with ethyl acetate and washed with 10% LiCl (3×), brine (3×), dried with sodium sulfate, filtered and the solvent was reduced in vacuo. The crude product was purified by silica gel chromatography eluting with 2% of MeOH in EtOAc. The fractions containing the desired product were further purified using preparative HPLC to give ′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide (300 mg, 12% yield) as a white solid. 1HNMR (DMSO-d6): 10.0 (s, 1H), 9.90 (s, 1H), 8.45 (d, 1H), 7.80 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.48-7.15 (m, 9H), 3.95 (s, 6H), 3.70 (s, 4H), 3.60 (s, 2H). LCMS (POS): 607.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C.C(OCC)(=O)C>[CH:18]([N:10]1[C:11]2[C:7](=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH:8]=[CH:9]1)([CH3:20])[CH3:19]
Reactant: CC(C)I
Reactant: COc1ccc([N+](=O)[O-])c2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c2ccn(C(C)C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-methoxy-4-nitro-1H-indole (S) (1 eq) in DMF cooled in an ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for 1 hr at room temperature then recooled in an ice bath. 2-Iodopropane (1.1 eq) was added then the reaction was stirred for 2 hrs at room temperature. Water and ethyl acetate were added. The ethyl acetate layer was separated and washed repeatedly (3×) with water. The ethyl acetate layer was concentrated then evaporated to dryness. Further purification by column chromatography produced the pure desired product.