Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[CH3:4].[NH2:5][C:6]1[C:7]([CH3:12])=[CH:8][CH:9]=[CH:10][CH:11]=1>C1(C)C=CC=CC=1>[C:7]1([CH3:12])[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]1[CH2:4][CH:3]=[CH:2][CH2:1]1
Reactant: C/C=C\C
Reactant: Cc1ccccc1N
Solvent: Cc1ccccc1
Product: Cc1ccccc1N1CC=CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
To a solution of 60.0 g of the cis-2-butene derivative solution prepared in Example 1 and 250 g of toluene in a round flask reactor, 171.7 g (1.6 mol) of toluidine was added dropwise with stirring for 30 min. at 50° C. After 2 hours of stirring, the crystallized solid was removed by filtration; 42.0 g of 35% HCl (aq) was added to the filtrate, and then excess benzylamine hydrochloride was removed by filtration or extraction. After the solvent was evaporated under reduced pressure, 56.8 g of 1-tolyl-3-pyrroline (yield 89.2%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.CCOC(C)=O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1Cl)c1cccc(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene (10 g, 35.5 mmol) was suspended in 50 mL acetic acid and 150 mL EtOAc in a 500 mL flask. Iron (9.9 g, 177.5 mmol) was added to this suspension, and the mixture stirred at rt for overnight. The reaction mixture was filtered through a thin pad of Celite®. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 aqueous solution, followed by EtOAc extraction. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 15% EtOAc/hexanes yielding 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid [8.5 g, 95%, TLC Rf=0.4, 30% EtOAc/Hex.(3:7)]. 1H-NMR (DMSO-d6) δ 4.94 (s, 2H), 5.00 (s, 2H), 6.40 (dd, 1H), 6.60 (s, 1H), 6.87 (d, 1H), 7.10-7.18 (m, 1H), 7.20-7.28 (m, 2H), 7.37-7.44 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([O:17][CH2:22][CH3:23])[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nc(-c2ccc(OC)c(OC)c2)cc(=O)n1C
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (1.0 g) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 0.17 g). The mixture was heated at 60° C. with stirring for 20 minutes and cooled to ambient temperature. To the mixture was added ethyl iodide (5 ml) with stirring, which was continued at ambient temperature for 3.5 hours. To the reaction mixture was added water, and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether and the resulting precipitates were collected by filtration to give 6-(3,4-dimethoxyphenyl)-2-ethoxy-3-methyl-4(3H)-pyrimidinone (0.18 g) as by-product.
Reaction SMILES: [CH3:1][Sn:2](Cl)([CH3:4])[CH3:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Sn:2]([CH3:4])([CH3:3])[CH3:1])=[CH:10][CH:9]=1
Reactant: C[Sn](C)(C)Cl
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc([Sn](C)(C)C)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To trimethyltin chloride (1.71 g, 8.58 mmol, 1.00 equiv) in THF (50 mL) at 23° C. was added 4-methoxyphenylmagnesium bromide (0.50 M in THF, 34.3 mL, 17 mmol, 2.0 equiv). After stirring for 1.0 hr at 60° C., the reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl (50 mL), and Et2O (50 mL) was added. The phases were separated and the aqueous phase was extracted with Et2O (2×50 mL). The combined organic phases were washed with brine (100 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by fractional distillation to afford 1.86 g of the title compound as a colorless oil (80% yield).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:16](/[CH:19]=[CH:14]/[C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:13][CH:12]=1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 6-phenoxy-pyridine-3-carbaldehyde described in Manufacturing Example 232-1-2 (4.75 g, 23.8 mmol), nitromethane (6.45 mL, 119 mmol), ammonium acetate (3.67 g, 47.6 mmol) and acetic acid (20 mL) was stirred for 3 hours at 100° C. This mixture was cooled to room temperature, and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (5.97 g) as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH:44]([NH2:46])[CH3:45]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:46][CH:44]([C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)[CH3:45])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(N)c1cccs1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4cccs4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 92 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-thiophen-2-yl-ethylamine: yield 92%.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]([CH3:11])=[C:6]([C:9]#[N:10])[C:7]#[N:8].C(C(C#N)=C(C)C=C[O:20]C)#N>O>[C:7]([C:6]1[C:9](=[O:20])[NH:10][CH:3]=[CH:4][C:5]=1[CH3:11])#[N:8]
Reactant: COC=CC(C)=C(C#N)C#N
Reactant: COC(CC(C)=C(C#N)C#N)OC
Solvent: O
Product: Cc1cc[nH]c(=O)c1C#N

Procedure:
treating the mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetal and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene so produced with a strong acid and water, to yield 3-cyano-4-methyl-2-pyridone
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][F:9])[CH:5]=[C:4]([F:10])[CH:3]=1.C([Li])CCC.CN([CH:19]=[O:20])C>C1COCC1>[F:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH2:8][F:9])[CH:5]=1)[CH:19]=[O:20]
Reactant: FCc1cc(F)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc(CF)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1-bromo-3-fluoro-5-(fluoromethyl)benzene (1.30 g, 6.28 mmol) was dissolved in THF (31.4 mL), then cooling down to −78° C., butyllithium (2.5M in Hexanes) (2.76 mL, 6.91 mmol) was added at −78° C., the reaction mixture was then stirred at −78° C. for 30 min. DMF (0.972 mL, 12.56 mmol) was added, after stirred at −78° C. for 1h, The reaction mixture was quenched by HCl and the reaction mixture was then extracted by EtOAc, the organic was dried and concentrated to yield the crude product. The crude material was used in next step reaction without purification. LCMS (m/z): no mass (MH+), 0.60 min. 1H NMR (400 MHz, CDCl3) δ ppm 10.08-9.93 (m, 1H), 7.68 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 5.53 (s, 1H), 5.42 (s, 1H)
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([C:13](N(OC)C)=[O:14])[N:10]([CH3:19])[C:9]=2[CH:20]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([C:13](=[O:14])[CH3:1])[N:10]([CH3:19])[C:9]=2[CH:20]=1
Reactant: CON(C)C(=O)c1nc2ccc(Br)cc2n1C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1nc2ccc(Br)cc2n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium chloride (1.0 M in THF, 4.70 ml) was added dropwise to a solution of 6-bromo-N-methoxy-N,1-dimethyl-1H-benzimidazole-2-carboxamide (700 mg) in THF (10 ml) at 0° C. The mixture was stirred at 0° C. under Ar atmosphere for 30 min. The mixture was quenched with saturated NH4Cl solution and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated ao in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc), and the resulting solid was washed with IPE to give the title compound (360 mg) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:10]([CH2:12][C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)[CH2:11]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidine-1-carboxylic acid tert-butyl ester (917 mg, 1.72 mmol) in DCM (6 mL) was added TFA (3 mL) and the resulting mixture stirred for 3 h at r.t. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as a colourless oil (647 mg, 87%). LCMS (method H): RT 1.83 min [M+H]+ 433.3
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[S:27][CH:28]=[C:29]([CH:31]=O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:29]2[N:30]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:27][CH:28]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1csc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-phenylthiazole-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 408.99 g/mol.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:15]([N:22]1[C:26]2=[C:27](Cl)[N:28]=[N:29][CH:30]=[C:25]2[CH:24]=[C:23]1[CH3:32])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCC1=O>[CH2:15]([N:22]1[C:26]2=[C:27]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:28]=[N:29][CH:30]=[C:25]2[CH:24]=[C:23]1[CH3:32])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc2cnnc(Cl)c2n1Cc1ccccc1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Yield: 68 %

Procedure:
650 mg (6 mmol) of benzyl alcohol, 10 ml of N-methylpyrrolidone, 1.1 g (10 mmol) of potassium tert-butoxide, 50 mg (0.2 retool) of [18]crown-6 and 500 mg (1.94 retool) of 1-benzyl-7-chloro-2-methylpyrrolo[2,3-d]pyridazine are reacted at room temperature for 2 h. Purification: chromatography on silica gel (eluent: toluene/dioxane=2:1) and crystallization from diisopropyl ether. Yield: 68%, m.p.: 124° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([CH3:39])[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=C)=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=2)=[O:25])=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:42].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:40])[N:7]([C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[O:42])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:28]=2)=[O:25])=[CH:21][CH:22]=1)[CH3:39])([CH3:2])([CH3:3])[CH3:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc(NC(=O)Nc2ccc(-n3cnc4c(N(C)C(=O)OC(C)(C)C)ncnc43)cc2)cc1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(C=O)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.1 %

Procedure:
In a mixed solution of 10 mL of tetrahydrofuran and 5 mL of water, 324 mg (0.59 mmol) of methyl-(9-{4-[3-(3-trifluoromethyl-4-vinylphenyl)ureido]phenyl}-9H-purin-6-yl)-carbamic acid tert-butyl ester was dissolved, and 200 μL of a 0.1 M osmium tetraoxide aqueous solution and 510 mg (2.38 mmol) of sodium periodate were added thereto, and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The product was purified by a silica gel column (hexane:ethyl acetate=1:2) to obtain 243 mg (75%) of a target product as a white crystal.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3](OS(C)(=O)=O)([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][O:13][CH3:14])=[CH:7][N:6]=1)[CH3:4].[CH3:22][Al](C)C.O>ClCCl>[CH3:14][O:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([CH3:22])([CH3:4])[C:2]([F:21])([F:20])[F:1])=[N:6][CH:7]=1
Reactant: COCOc1ccc(C(C)(OS(C)(=O)=O)C(F)(F)F)nc1
Reactant: C[Al](C)C
Solvent: ClCCl
Solvent: O
Product: COCOc1ccc(C(C)(C)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.4 %

Procedure:
1.7 g (4.13 mmol) methanesulfonic acid 2,2,2-trifluoro-1-(5-methoxymethoxy-pyridin-2-yl)-1-methyl-ethyl ester was dissolved in 20 ml dichloromethane. The reaction mixture was cooled to 0° C. where 2.065 ml (4.13 mmol) trimethylaluminum was added slowly. The reaction mixture was stirred at room temperature for 20 h. After that water was added slowly and the mixture was extracted 2 times with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel (EtOAc, heptane) to yield to afford 0.55 g of the pure title compound. LCMS (method L): tR=1.09 min, M+H=250.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[CH:10][C:9]([Cl:31])=[CH:8][CH:7]=2.[F:45][C:46]([F:60])([F:59])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH:53]([S:55](Cl)(=[O:57])=[O:56])[CH3:54]>>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:31])[CH:10]=3)[N:5]([CH:32]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:4]=2[CH2:3][CH2:2][NH:1][S:55]([CH:53]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[C:46]([F:45])([F:59])[F:60])[CH3:54])(=[O:57])=[O:56])(=[O:16])=[O:17])=[CH:19][CH:20]=1)[CH3:30]
Reactant: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: CC(c1ccccc1C(F)(F)F)S(=O)(=O)Cl
Product: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)C(C)c3ccccc3C(F)(F)F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 40 %

Procedure:
Using the procedure in Example 1, Step 9, ethyl 3-[4-({2-[2-(2-aminoethyl)-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (Example 38, Step 14) was reacted with 1-(2-trifluoromethyl-phenyl)-ethanesulfonyl chloride (0.13 g, 0.46 mmol) to afford 3-{4-[2-(1-benzhydryl-5-chloro-2-{2-[1-(2-trifluoromethyl-phenyl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethanesulfonyl]-phenyl}-propionic acid ethyl ester (0.110 g, 40%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>>[O:39]=[C:35]1[CH2:36][CH2:37][CH2:38][N:34]1[CH2:33][CH2:32][CH2:31][NH:30][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([OH:29])[CH2:27][CH2:28]3)[C:10]=2[C:17]=1[CH3:18])=[O:21]
Reactant: NCCCN1CCCC1=O
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12
Product: Cc1c(C(=O)NCCCN2CCCC2=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.042 g 4-[4-fluoro-2-(trans-4-hydroxycyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and 0.015 g 1-(3-aminopropyl)-2-pyrrolidinone. The residue was purified by chromatography.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:40][C:17]3=[N:18][CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:37]=[CH:38][CH:39]=4)[C:25]([NH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([CH3:30])[CH3:29])=[O:26])[CH:21]=[C:16]3[C:15]=2[CH:41]=[O:42])=[CH:10][CH:9]=1>CN(C=O)C.CCOC(C)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:40][C:17]3=[N:18][CH:19]=[C:20]([C:22]4[CH:39]=[CH:38][CH:37]=[C:24]([C:25](=[O:26])[NH:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([CH3:30])[CH3:29])[CH:23]=4)[CH:21]=[C:16]3[C:15]=2[C:41]([OH:1])=[O:42])=[CH:10][CH:9]=1
Reactant: O=S([O-])OO
Reactant: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C(=O)O)c3c2)c1)c1ccccc1
Reaction time: 72 h
Yield: 33.3 %

Procedure:
Oxone (28 mg, 0.046 mmol) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (20 mg, 0.042 mmol) in DMF (0.5 mL) at room temperature. It was allowed to stir for 3 days. An additional amount of Oxone (28 mg, 0.046 mmol) was added and the reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxylic acid (7 mg, 0.014 mmol, 34% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, MeOD) δ ppm 7.42 (1H, d, J=2.14 Hz), 7.31-7.39 (2H, m), 6.93-7.02 (2H, m), 6.87 (1H, s), 6.59 (2H, t, J=8.70 Hz), 6.34 (1H, t, J=7.63 Hz), 6.20 (2H, d, J=7.63 Hz), 5.97-6.07 (4H, m), 5.92 (1H, t, J=7.32 Hz), 0.52 (6H, s). LC-MS retention time: 1.15 min; m/z (MH+): 495. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: OS(O)(=O)=O.C[C:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][NH:9][C:8]=1[C:15]([OH:17])=[O:16].O.[CH3:19]O>>[CH3:19][O:17][C:15]([C:8]1[NH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:16]
Reactant: CO
Reactant: Cc1c([N+](=O)[O-])c[nH]c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c[nH]1

Procedure:
A solution of H2SO4 (0.8 mL) in MeOH (8 mL) was added to Py-1 (0.77 g, 4.53 mmol) and the mixture heated at reflux for 24 hr. Water was added and the mixture extracted with DCM. The organic solvent was dried using MgSO4, and solvent evaporated under vacuum to yield the product as a crystalline solid. Yield 0.55 g, 66%). 1H NMR (DMSO): δ 7.57 (d, 1H, J=2.1 Hz); 7.40 (d, 1H, J=2.0 Hz); 3.99 (s, 3H); 3.86 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.ClCC1N=C(NC2C=CC(OC)=C(F)C=2)C2C(=CC=CC=2)[N:28]=1.CI.[H-].[Na+]>C1COCC1>[NH2:28][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc(Nc2nc(CCl)nc3ccccc23)cc1F
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(3-fluoro-4-methoxy-phenyl)-methyl-amine: A suspension of (2-chloromethyl-quinazolin-4-yl)-(3-fluoro-4-methoxy-phenyl)-amine hydrochloride (497 mg, 1.4 mmol) and MeI (0.18 mL, 2.9 mmol) in THF (7 mL) was treated with NaH (60% disp., 158 mg, 3.95 mmol) and stirred for 2 h at rt. The reaction was quenched by the addition of MeOH, concentrated onto SiO2 and purified by gradient MPLC (SiO2, EtOAc/hexanes, 0-100%) to provide 281 mg (61%) of the title compound. 1H NMR (CDCl3) δ 7.85 (d, 1H), 7.61 (ddd, 1H), 6.97-7.13 (m, 3H), 6.86-6.97 (m, 2H), 4.75 (s, 2H), 3.93 (s, 3H), 3.62 (s, 3H); LC-MS (ESI+; 332 ([M+H]+)).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH2:43]C)[C:35]([N:37](C)[CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>CC(CC)=O.C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:40][CH2:41][CH2:42][CH3:43])[C:35]([NH:37][CH:38]3[CH2:4][CH2:3][CH2:2][CH2:1][CH2:5]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCN(C(=O)N(C)C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: Cc1ccccc1C
Solvent: CCC(C)=O
Product: CCCCc1nc2ccc(N(CCCC)C(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-(N-(dimethylaminocarbonyl)-n-pentylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylethylketone/xylene=1:1)