Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.N#N.[Cl:15][C:16]1[N:17]=[C:18]([Cl:35])[C:19]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:20]=2[N:21]=1>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([Cl:35])[C:19]2[CH:24]=[C:23]([CH3:1])[N:22]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:26])=[O:27])[C:20]=2[N:21]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Cl)nc(Cl)nc32)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of diisopropylamine(2.2 g, 21.9 mmol, 1.5 eq) in THF (50 mL) was added nBuLi (2.5 mol/L, 6.4 mL, 16.07 mmol, 1.1 eq) dropwise under N2 at −78° C., then the mixture was stirred for 30 min at −78° C. And followed by 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (5 g, 14.6 mmol, 1 eq) in THF (50 mL) was added to the mixture, then the mixture was stirred for another 30 min at −78° C. Mel (2.28 g, 16 mmol, 1.1 eq) was added to the mixture for 30min at −78° C. The mixture was stirred at room temperature overnight and quenched with sat NH4Cl, then extracted with EtOAc. The organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure to give the crude product which was purified by reverse phase preparative HPLC to afford 2.5 g of 2,4-dichloro-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine as a white solid. ESIMS (M+H)+=358.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][CH3:19])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20]CCCl>>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][N:10]=1)[CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cn1
Reactant: ClCCCl
Product: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(tert-Butoxycarbonyl-ethyl-amino)-nicotinic acid (6.40 g, 24.0 mmol) is taken up in 150 mL DCE, 1-chloro-N,N-2-trimethylpropenyl-amine (6.42 mL, 48.1 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is concentrated under reduced pressure and the crude product is used in the next step without purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:21][C:22](=O)[CH2:23][CH3:24])[C:11](=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[O-]CC.[Na+].O>C(O)C>[CH2:23]([C:22]1[CH2:21][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)[C:11](=[O:20])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)[CH3:24]
Reactant: CCC(=O)CN(C(=O)Cc1cccc(Cl)c1)c1cccc(C(C)C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC1=C(c2cccc(Cl)c2)C(=O)N(c2cccc(C(C)C)c2)C1
Yield: 81.5 %

Procedure:
7.61 g (21.3 mmol) of N-(3-isopropylphenyl)-N-(2-oxobutyl)-3-chlorophenylacetamide synthesized in Example 2 or 3 were dissolved in 35 ml of ethanol, and 0.1 ml of an ethanol solution containing 30% of sodium ethoxide was added at room temperature with stirring. The solution was successively stirred at the same temperature for 2 hours, and the resultant reaction mixture was poured into water, followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure, and the solution was then purified through silica gel column chromatography (an eluent: hexane/ethyl acetate=4/1) to obtain 5.9 g of the desired product in an oily state (yield: 77.5%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29](Cl)=[O:30]>ClCCl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[N:10]=1)=[O:30]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine (520 mg, 2.29 mmol, 1.00 equiv) in dichloromethane (5 mL), pyridine (540 mg, 6.84 mmol, 3.00 equiv), and 5-chloro-2-nitrobenzoyl chloride (500 mg, 2.27 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with 2×50 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1). This resulted in 800 mg (85%) of product as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[SH:16].F[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[C:5]2[S:16][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: O=C(O)Cc1cc(S)c2cc(F)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Sc2cc(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 100 °C
Yield: 74.6 %

Procedure:
To a solution of (6-fluoro-4-mercapto-naphthalen-2-yl)-acetic acid (30 mg, 0.127 mmol) in N,N-dimethylformamide (2 mL), was added 1-fluoro-4-methanesulfonyl-benzene (43.4 mg, 0.25 mmol) and potassium carbonate (35 mg, 0.25 mmol) under a nitrogen atmosphere. After being heated under microwave conditions (100° C., 30 minutes), the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (0-20% methanol in dichloromethane) to afford [6-fluoro-4-(4-methanesulfonyl-phenylsulfanyl)-naphthalen-2-yl]-acetic acid (37.0 mg, 74.6%) as an off-white powder. 1H NMR (400 MHz, CDCl3) δ ppm 7.86-7.93 (m, 4H), 7.69-7.74 (m, 2H), 7.34 (td, J=8.53, 2.65 Hz, 1H), 7.08-7.15 (m, 2H), 3.85 (s, 2H), 3.01 (s, 3H); MS cald. for C19H15FO4S2 390, obsd. (ESI+) [(M+H)+] 391.
Reaction SMILES: CCCCCC.Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][CH2:11]2.C([O:19][B:20](OCC)[O:21]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:13]1[C:14]2[C:10](=[CH:9][C:8]([B:20]([OH:21])[OH:19])=[CH:16][CH:15]=2)[CH2:11][CH2:12]1
Reactant: Brc1ccc2c(c1)CCC2
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2c(c1)CCC2
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butylithium in hexane (13.2 mL of 1.6 M, 21 mmol) is added to a stirred solution of 5-bromo-indane (1.06 g 4 mmol) in dry tetrahydrofuran (30 mL) at −75° C. under an argon atmosphere. The mixture is stirred for 30 min at −65° C., then treated with triethylborate (3.07 g, 21 mmol) and stirred for 60 min at −50° C. The resulting mixture is allowed to warm to 0° C. and then treated with a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 50% ethyl acetate in hexaen) and recrystallised from ethyl acetate-hexane to give indan-5-boronic acid as a colourless crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15](Br)[CH:16]=[C:11]2[N:10]=[N:9]1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)CCC>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([O:18][CH2:19][C:20]3[N:21]([CH3:25])[N:22]=[CH:23][N:24]=3)=[C:15]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: Cn1ncnc1COc1nc2c(cc1Br)nnn2-c1ccccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cc1-c1ccccc1)nnn2-c1ccccc1F
Temperature: 100 °C
Yield: 51.8 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-bromo-1,2,3-triazolo[4,5-b]pyridine (0.15 g, 0.37 mmol), tributylphenyltin (0.14 ml, 0.44 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.02 g, 5 mol %) in dry DMF (2 ml) was purged with nitrogen and heated in a sealed tube at 100° C. for 24 h. The mixture was cooled, diluted with water (50 ml) and extracted with 10% methanol-dichloromethane (2×25 ml). The extracts were washed with brine (20 ml), dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 2% methanol-dichloromethane, gave a yellow oil that solidified on trituration and washing with diethyl ether (2 ml). The material was recrystallised from ethyl acetate-hexane to give 3-(2-fluorophenyl)-5-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-6-phenyl-1,2,3-triazolo[4,5-b]pyridine (0.077 g, 52%) as a cream-coloured solid, m.p. 144-146° C. (EtOAc-hexane). Found: C, 62.00; H, 4.00; N, 24.01. C21H16N7OF.0.33(H2O) requires C, 61.91; H, 4.12; N, 24.07%. δH (360 MHz; CDCl3) 3.64 (3H, s), 5.56 (2H, s), 7.38-7.47 (5H, m), 7.53 (2H, dd, J=8 and 1), 7.56-7.62 (1H, m), 7.71 (1H, dd, J=8 and 8), 7.82 (1H, s) and 8.32 (1H, s); m/z (ES+) 402 (M+H+).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])(O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:24])(=O)=O>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([Cl:24])([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: CC1(Cl)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.8 %

Procedure:
To a mixture of TEA (30 g, 296 mmol) and 1-benzhydryl-3-methyl-azetidin-3-ol (30 g, 118 mmol) in DCM (300 mL) at 0° C. was added a solution of methanesulfonyl chloride (20.49 g, 179 mmol) in DCM (15 mL) keeping the internal temperature below 5° C. The mixture was stirred at ambient temperature for 20 h and quenched by addition of water (50 mL). The organic phase was separated, dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0% EtOAc to 50% EtOAc in petroleum ether) to give 1-benzhydryl-3-chloro-3-methyl-azetidine (7 g, 22%): 1H NMR (CDCl3, 400 MHz): δ7.42-7.45 (m, 4H), 7.27-7.31 (m, 4H), 7.18-7.23 (m, 2H), 4.48 (s, 1H), 3.38-3.44 (m, 4H), 1.87 (s, 3H) and methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (16 g, 41%). 1H NMR (CDCl3, 400 MHz): δ7.40-7.37 (m, 4H), 7.20-7.28 (m, 4H), 7.16-7.20 (m, 2H), 4.42 (s, 1H), 3.33 (s, 4H), 3.02 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:35]=[CH:34][C:28]([CH2:29][C:30]2([NH2:33])[CH2:32][CH2:31]2)=[CH:27][CH:26]=1>C(O)CCC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:21])[CH2:22][NH:33][C:30]2([CH2:29][C:28]3[CH:34]=[CH:35][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)[CH2:32][CH2:31]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC2(N)CC2)cc1
Reactant: O=c1ccc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]1
Solvent: CCCCO
Product: COc1ccc(CC2(NCC(O)c3ccc(OCc4ccccc4)c4[nH]c(=O)ccc34)CC2)cc1

Procedure:
587 mg (2.0 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 480 mg (2.7 mmol) 1-(4-methoxy-benzyl)-cyclopropylamine are refluxed in 10 mL n-butanol for 10 hours. Then the solvent is distilled off and the residue is purified by chromatography (reverse phase, water/acetonitrile gradient). Yield: 259 mg (27%); mass spectroscopy: [M+H]+=471.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2([C:30]#N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1)C1C=CC=CC=1>O1CCCC1.BrCCBr>[CH2:11]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2([C:30]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:22][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(N2CCN(Cc3ccccc3)CC2)CCCCC1
Reactant: Brc1ccccc1
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(C3(c4ccccc4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To bromobenzene (0.6 g) and magnesium turnings (0.2 g) in 30 ml dry tetrahydrofuran under nitrogen was added a small crystal of iodine and 10 drops of 1,2-dibromoethane. After small bubbles began to form, the reaction was stirred and heated to reflux for 4 hours. After cooling to room temperature, 1-benzyl-4-(1-cyanocyclohexyl)piperazine (1 g) was added. After 23 hours, the reaction was filtered, 20 ml saturated aqueous ammonium chloride was added and the mixture was extracted with diethyl ether. The ether was dried and removed in vacuo. The residue was chromatographed on silica gel eluted with chloroform to yield pure 1-benzyl-4-(1-phenylcyclohexyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH2:28])=[N:9]2)=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH:28][C:35]([C@H:32]3[CH2:31][C:30](=[O:29])[NH:34][CH2:33]3)=[O:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(Cl)cc2)c1)C(F)(F)F
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of 1-(4-chlorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (about 0.110 mol) prepared in the previous step in N,N-dimethylacetamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (17 mg) prepared in Preparation 14 and WSC.HCl (32 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. The resulting solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1) to give the titled compound (18 mg).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[F:15][C:16]1[CH:42]=[CH:41][C:19]([O:20][C:21]2[C:35]([CH:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)=[CH:34][C:24]3[NH:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:27][C:23]=3[CH:22]=2)=[CH:18][CH:17]=1>C(O)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][C:21]2[C:35]([CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:34][C:24]3[NH:25][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:27][C:23]=3[CH:22]=2)=[CH:41][CH:42]=1
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: Clc1ncccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2c2ncccn2)cc1

Procedure:
0.013 ml of triethylamine and 6.3 mg of 2-chloro-pyrimidine were added in order to an ethanol (2 ml) solution of 17.1 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was heated under reflux for 3 hours. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid], and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:21][CH2:22][C:23](O)=[O:24])=[CH:14][C:15]=2[C:17]([F:20])([F:19])[F:18])[N:10]([CH3:26])[N:9]=1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][C@H:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:21][CH2:22][C:23]([NH:54][C@H:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH3:46])=[O:24])=[CH:14][C:15]=2[C:17]([F:20])([F:18])[F:19])[N:10]([CH3:26])[N:9]=1
Reactant: Cn1nc(-c2ccccc2F)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Reactant: C[C@H](N)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)COc1cc(C(F)(F)F)c2c(-c3ccccc3F)nn(C)c2n1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
A solution of 2-(3-(2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetic acid (70 mg, 0.189 mmol), DIC (31.1 mg, 0.246 mmol) and HOBt (38.4 mg, 0.285 mmol) in DMF (3 ml) was stirred at rt for 15 min. (S)-(−)-α-methyl benzyl amine (25.3 mg, 0.208 mmol) was added dropwise to the reaction mixture at rt and then the mixture was heated at 100° C. for 1 h. After completion of the reaction, ice-cold water was added and the reaction mixture was stirred for 10 min. The resulting precipitate was collected by filtration. The crude product was re-crystallized from diethyl ether to yield 46 mg (51%) of the title compound. [1H-NMR (CDCl3, 300 MHz) δ 7.55-7.05 (m, 9H), 7.01 (s, 1H), 6.55 (d, 1H), 5.23 (m, 1H), 5.01 (s, 2H), 4.03 (s, 3H), 1.60 (d, 3H); HPLC RtA=5.384 min (98%); LCMS RtD=3.055; [M+H]+=473.1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[NH:19][C:24]2=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c(N)c1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=O)N3c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of N4-(3-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (80 mg, 0.24 mmol) (from Example 11, Step B, supra) in 1,2-dichloroethane (30 mL) was added 1,1′-carbonyldiimidazole (0.2 g, 1.21 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The solvents were evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 3-(3-chloro-phenyl)-8,9-dimethoxy-1H,3H-1,3,4,6-tetraaza-phenalen-2-one as a brown solid. (Yield 50 mg, 58%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C1COCC1>[C:22]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])[CH:23]=[CH2:24]
Reactant: OCCOCCOCc1ccccc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCCOCCOCc1ccccc1
Temperature: 0 °C
Yield: 84 %

Procedure:
To a 1 L three-neck round bottom flask equipped with mechanical stirrer were charged diethylene glycol monobenzyl ether (98.0 g, 0.5 mol), anhydrous triethylamine (120 mL, 0.85 mol), and anhydrous THF (300 mL). The solution was cooled in an ice/salt bath under dry air blanket for 15 minutes. Acryloyl chloride (55 mL, 0.68 mol) was added into the vigorously stirred cold solution through an addition funnel over 90 minutes and the addition rate was adjusted to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was stirred in the ice/salt bath for additional two hours followed by quenching with the addition of 2M HCl (400 mL). The mixture was extracted with ethyl acetate (300 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (4/1, v/v) as eluent to give the final product as a colorless oil (105.0 g, 0.42 mol, yield: 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.[N:14]([O-:16])=[O:15].[Na+]>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:14]([O-:16])=[O:15])[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: O=N[O-]
Reactant: COc1ccc2c(c1)CCC(=O)N2
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (400 mg, 2.25 mmol, Precursor Chemicals) in trifluoroacetic acid (4 mL, Aldrich) was treated with sodium nitrite (156 mg, 2.26 mmol, added slowly in about 4 portions, Aldrich). The dark brown reaction was stirred for 1 h after which an aliquot was taken out, diluted with water and extracted with ethyl acetate. TLC analysis of the ethyl acetate layer revealed that starting material remained. More sodium nitrite (50 mg, 0.72 mmol) was added and the reaction stirred for another 2 h at which point some precipitation was observed in the reaction. The reaction was poured over ice and then extracted with ethyl acetate. The organic layer, which still had undissolved solids in it, was concentrated to give 6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (372 mg, 70%) as a white powder. 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.45-2.49 (m, 2 H), 2.98 (t, J=7.5 Hz, 2 H), 3.88 (s, 3 H), 7.29 (s, 1 H), 7.38 (s, 1 H), 10.18 (bs, 1 H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[CH2:32][C:15]2=[C:16]3[C:20](=[CH:21][CH:22]=[C:14]2[O:13][CH2:12][CH2:11]1)[N:19]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]3>C1COCC1>[Cl:1][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]3[O:13][CH2:12][CH2:11][N:10]([CH3:9])[CH2:32][C:15]3=2)[N:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:18]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Solvent: C1CCOC1
Product: CN1CCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c2C1
Temperature: 50 °C

Procedure:
N-chlorosuccinimide (NCS) (29 mg, 0.21 mmol) was added to a solution of 2-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole Example 5, 0.050 g, 0.15 mmol) in THF (2 mL) and the reaction mixture was heated at 50° C. overnight. Additional NCS (0.030 g, 0.22 mmol) was added and the mixture was heated for 4 days at 50° C. The mixture was evaporated and the crude material was purified by flash chromatography on silica gel using MeOH:DCM:NEt3 (2:97:1) to give 7.3 mg of a white solid. MS m/z 377 [M+H]+.