Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:15])[C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>O>[CH:16](=[N:15][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccco1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(N)c1Cl
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(N=Cc2ccco2)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 3-methylsulfonyl-4-chloro-5-aminobenzoic acid (3.0 g.; 0.012 mole) and furfural (50 ml.) is heated to 70°-80° C. on a water bath. The water formed during the reaction is azeotropically distilled with the excess furfural at 15 mm Hg. pressure during a one hour period. The reaction mixture is cooled and triturated with carbon tetrachloride (100 ml.) to yield 3.6 g. (90%) of 3-furfurylideneamino-4-chloro-5-methylsulfonylbenzoic acid which melts at 221° C. and is used in Step E without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:2]=1.[C:14](Cl)([Cl:16])=[O:15].C1(C)C=CC=CC=1.CN(C)C1C=CC=CC=1>O1CCCC1>[Cl:16][C:14]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]=1)=[O:15]
Reactant: O=C(Cl)Cl
Reactant: Oc1cccc(-c2cccnc2)c1
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)Oc1cccc(-c2cccnc2)c1
Temperature: 25 °C

Procedure:
A solution of 3-pyridin-3-yl-phenol in tetrahydrofuran was treated with 20% phosgene in toluene (1.0 eq.) at 25° C. The reaction mixture was then treated with N,N-dimethylaniline (1.3 eq) at 0° C. The reaction mixture was stirred at 25° C. over night. The volatiles were removed under reduced pressure. The crude product 3-pyridin-3-yl-phenyl chloroformate was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].CO[CH:11](OC)[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([N:12]([CH:11]=[N:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8])[CH2:15][CH3:16])[CH3:14]
Reactant: Nc1ccncc1O
Reactant: CCN(CC)C(OC)OC
Solvent: Cc1ccccc1
Product: CCN(C=Nc1ccncc1O)CC
Yield: 61.5 %

Procedure:
A mixture of 4-amino-3-pyridinol (3.90 g), N,N-diethylformamide dimethyl acetal (11.68 g) and toluene (20 mL) was heated under nitrogen for 2 hours. The solution was concentrated under reduced pressure. The resulting liquid was filtered through silica gel with 10% ethanol in tetrahydrofuran to give a solid. Recrystallization of the purified product from ethyl acetate/hexanes afforded 4.21 g of crystalline solid, m.p. 104°-106° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C=O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:11]1[C:32]([CH3:33])=[CH:31][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH3:41])[C@H:26]([CH3:30])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C)[C@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
To crude (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-((R)-3-methylpiperazin-1-yl)pyrimidin-4-yl)benzo[d]thiazol-6-yl)acetate (45.8 mg, 0.079 mmol) and sodium triacetoxyborohydride (83.7 mg, 0.395 mmol) in DMF (1 mL) was added acetic acid (23.7 mg, 22.6 μL, 0.395 mmol). The reaction mixture was heated to 60° C., then 37% w/w aq. formaldehyde (9.48 mg, 23.5 μL, 0.316 mmol) was added dropwise over 1 min. The reaction mixture was heated at 60° C. for 2 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent) and concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C31H37ClN5O3S (M+H+): 594.2; Found: 593.7 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1C=CC=CC=1C(C)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CC(C(=O)O)c1ccccc1Cl
Product: CC(C(=O)O)c1cccc(Cl)c1
Yield: 57 %

Procedure:
The titled compound was prepared from m-chlorophenylacetic acid in 57% yield in the same manner as the preparation of 2-(2-Chlorophenyl)propionic acid in Example 184a. MS (ESI) 185 (MH+).
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[NH2:22][C:23]([CH3:30])([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:24]#[N:25]>>[C:24]([C:23]([NH:22][C:12]([C:9]1[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:19])([F:18])[F:20])[C:6]([C:2]2([F:1])[CH2:3][O:4][CH2:5]2)=[CH:11][N:10]=1)=[O:14])([CH3:30])[CH2:26][CH:27]1[CH2:29][CH2:28]1)#[N:25]
Reactant: CC(N)(C#N)CC1CC1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C)(C#N)CC2CC2)ncc1C1(F)COC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (Example 142b) and 2-Amino-3-cyclopropyl-2-methyl-propionitrile (example 66a) as starting materials and isolated (27.5 mg, 26%); MS (ESI, m/z): 416.5 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[N:24]1[CH:28]=[CH:27][CH:26]=[CH:25]1>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:15][C:16]3[C:17](=[CH:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=3)[N:24]3[CH:25]=[CH:26][CH:27]=[C:28]23)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-n2cccc2)c(N)c1
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC1(CCN(C(C)=O)CC1)c1cccn1-2

Procedure:
7.06 g (0.05 mole) of 1-acetyl-4-piperidone and 5 ml. of glacial acetic acid are added to a solution of 9.41 g (0.05 mole) of 1-(2-amino-4-methoxy-phenyl)pyrrole [Example 19(b)] in 150 ml. of absolute ethanol. The solution is refluxed for 12 hours. The volume of the solvent is reduced to about one fifth and the solution is cooled. A solid precipitates and is filtered, dried, and recrystallized from ethanol to give 1'-acetyl-4,5-dihydro-7-methoxyspiro[pyrrolo(1,2-a) quinoxaline-4,4'-piperidine], m.p. 211°-213° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:4]=2[CH2:3]1.[Li+].[ClH:15].CN(C)CCCN=C=NCC.O.O[N:29]1[C:33]2C=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=N1>CN(C)C=O>[ClH:15].[NH2:29][C@@H:33]1[CH2:35][CH2:36][CH2:37][C@H:32]1[NH:31][C:11]([C:9]1[S:10][C:4]2[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][C:5]=2[N:8]=1)=[O:13]
Reactant: On1nnc2ccccc21
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3N)sc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.7 %

Procedure:
The compound (175 mg) obtained in Referential Example 61 was dissolved in N,N-dimethylformamide (3 ml), and to the solution lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (purity: 90%, 258 mg), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (252 mg) and 1-hydroxybenzo-triazole monohydrate (60 mg) were added. The mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure using a pump, and methylene chloride and a saturated solution of sodium hydrogencarbonate were added to the residue to separate an organic layer. The resultant organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (methylene chloride:methanol=47:3). The resultant pale yellow oil was dissolved in a ethanol solution (5 ml) of hydrochloric acid, and the solution was stirred at room temperature for 1 hour. Ethyl acetate was then added, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue to collect precipitate formed by filtration, thereby obtaining the title compound (120 mg).
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][CH:17]=[N:18][N:19]=3)=[CH:11][CH:10]=2)[O:3]1.I([O-])(=O)(=O)=O.[Na+].C(O)(=O)C>C1COCC1.O>[O:16]1[CH:17]=[N:18][N:19]=[C:15]1[C:12]1[CH:11]=[CH:10][C:9]([B:4]([OH:5])[OH:3])=[CH:14][CH:13]=1
Reactant: CC1(C)OB(c2ccc(-c3nnco3)cc2)OC1(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2nnco2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.5 %

Procedure:
A solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-oxadiazole (0.504 g, 1.85 mmol) in THF (10 mL) and water (5 mL) was treated with sodium periodate (1.19 g, 5.56 mmol). The resultant slurry was stirred at RT for 5 h. Glacial acetic acid (0.21 mL, 3.7 mmol) was added and the mixture was stirred for 1 h and filtered. The filtered solid was washed with ethyl acetate (75 mL) and THF-methanol (1:1, 100 mL) and the filtrates were concentrated in vacuo to a white solid. The solid was suspended in THF (75 mL) and 10 mL of 0.1 M aq HCl and was sonicated to promote dissolution. The trace of insolubles were filtered and the organic layer was diluted with ethyl acetate (25 mL), washed with 0.1 M Na2S2O3 (2×20 mL), water (2×20 mL) and brine (20 mL), dried (Na2SO4) and concentrated in vacuo to provide 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid (304 mg, 86% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1 H), 8.32 (s, 2 H), 7.99 (s, 4 H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](Cl)=[O:31].Cl>C(Cl)Cl.O>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:27]([C:26]([F:25])([F:40])[F:41])[CH:28]=2)[CH2:12][CH2:13]1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC1CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 1-Boc-4-(aminomethyl)piperidine (18.0 g, 84.1 mmol) and DIPEA (12.9 g, 100 mmol) in anhydrous CH2Cl2 (200 mL) at 15° C. was added 3,5-bis-(trifluoromethyl)benzoyl chloride (23.4 g, 85.0 mmol) slowly. After the reaction mixture was stirred at room temperature for 30 min, water (50 mL) was added followed by adding aqueous HCl (0.5 N, 100 mL). The organic fraction was collected. The aqueous fraction was extracted with CH2Cl2 (100 mL). The combined organic solution was dried over anhydrous Na2SO4 and passed through a silica gel plug. The desired compound was eluted off with EtOAc/petroleum ether (1:3 in v/v). Solvents were removed and the product was dissolved in EtOAc (200 mL). To the solution HCl (g) bubbled for 5 min to form a white suspension. The suspension was stirred at room temperature for 30 min, and then concentrated to around 100 mL. Diethyl ether (150 mL) was added and the suspension was cooled at 7° C. for 1 h. A white HCl salt was collected by filtration. The salt was dissolved in a mixture of methanol/water (30/300 mL), and aqueous NaOH (2 N) was added until pH=˜11. The mixture was extracted with CH2Cl2 (5×200 ML) and the combined organic solution was dried over anhydrous Na2SO4. After filtration the filtrate was concentrated in vacuo to give pale yellow sticky foam (28.8 g, 97%).).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH:29]1[CH2:37]O.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:37][CH:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:28]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCC1Cc2ccccc2O1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(CC2Cc3ccccc3O2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), 2,3-dihydro-1-benzofuran-2-ylmethanol (1.02 g), tributylphosphine (2.1 mL), 1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine (1.72 g) and tetrahydrofuran (60 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.86 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].CO>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:20]([C:19]2[CH:27]=[CH:28][C:16]([Cl:15])=[CH:17][CH:18]=2)([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: Clc1ccc(Cc2ccncc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccncc2)(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 0.7 %

Procedure:
Under nitrogen, a solution of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester* (1.54 g, 6.36 mmol) in toluene (10 mL) was cooled in ice. 4-(4-Chloro-benzyl)-pyridine (1.30 g, 6.36 mmol) was added, followed over two minutes by sodium hexamethyldisilazide solution (10 mL, 20 mmol, 2M in THF). The mixture was stirred at 0° C. for 3.5 hours then allowed to warm to room temperature and stirred for a further 20 hours. Methanol was added then the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 1N hydrochloric acid (×3) and brine, dried (MgSO4), filtered and concentrated to afford a residue which was purified by column chromatography (SiO2), eluting with gradient of 2M methanolic ammonia in dichloromethane (1% to 5%). A second purification by column chromatography (SiO2), eluting with 50% ethyl acetate/petrol gave the title compound (16 mg, 0.7%). LCMS (PS-A2) Rt 2.65 min [M+H]+ 373.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N+:33]=1[O-:42].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:34][N+:33]=3[O-:42])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)c[n+]3[O-])cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 35 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 2-amino-5-(trifluoromethyl)pyridine 1-oxide (Intermediate-41, 0.096 g, 0.600 mmol), THF (5.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.12 (s, 2H), 7.32 (m, 2H), 7.41 (m, 1H), 7.52 (s, 1H), 7.80 (d, J=9.3 Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 8.94 (s, 1H), 9.50 (s, 1H), 11.21 (s, 1H), 12.30 (s, 1H); MS [M+H]+: 536.12.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CC#N.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([I:10])[CH:5]=1
Reactant: C1COCCN1
Reactant: Fc1cc(I)c(CBr)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: Fc1cc(I)c(CN2CCOCC2)cn1
Temperature: 81 °C
Yield: 99.7 %

Procedure:
In a flask, combine 5-bromomethyl-2-fluoro-4-iodo-pyridine (6.13 g, 19.4 mmol), morpholine (3.38 g, 38.8 mmol) and dry CH3CN (100 mL) under nitrogen. Add N,N-diisopropylethylamine (6.76 mL, 38.80 mmol, 2 M THF solution). Heat at 81° C. for 2 h and cool to RT. Dilute with DCM and wash with water and aqueous saturated sodium chloride. Separate the organic layer from the aqueous layer and dry over magnesium sulfate. After filtration, concentrate in vacuo to give the title compound 6.23 g (100%). MS (ES) m/z 323 [M+1]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[S:27][C:26]([NH2:28])=[N:25][CH:24]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:28][C:26]2[S:27][C:23]([S:22][CH3:21])=[CH:24][N:25]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CSc1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cnc(NC(=O)c2ccc(OC(C)=O)cc2)s1
Yield: 84.1 %

Procedure:
Following the procedure for the synthesis of example 82, intermediate 510 (0.815 g, 4.10 mmol) dissolved in dry THF (25.0 mL), triethylamine (0.572 mL, 4.10 mmol), and 512 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL) gave 76 (0.887 g, 84%) as a tan solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([OH:54])=O)=[CH:40][CH:41]=2)[N:36]=1.[NH2:55][CH:56]([CH2:62][C:63]1[CH:64]=[N:65][C:66]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=2[F:76])=[CH:67][CH:68]=1)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58]>CN(C)C=O>[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([NH:55][CH:56]([CH2:62][C:63]3[CH:64]=[N:65][C:66]([C:69]4[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=4[F:76])=[CH:67][CH:68]=3)[C:57]([N:59]([CH3:61])[CH3:60])=[O:58])=[O:54])=[CH:40][CH:41]=2)[N:36]=1
Reactant: CN(C)C(=O)C(N)Cc1ccc(-c2cccc(F)c2F)nc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(N)nc3cc(C(=O)NC(Cc4ccc(-c5cccc(F)c5F)nc4)C(=O)N(C)C)ccc23)CC1
Reaction time: 2 h
Yield: 17.4 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 uL, 0.07 mmol) were added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) and 2-amino-3-[6-(2,3-difluorophenyl)pyridin-3yl]-N,N-dimethylpropanamide (20 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) at r.t. The reaction was stirred for 2 h. and the product was purified with out workup by RP-HPLC (pH=2) to afford the desired compound (0.003 g, 10%) as an amorphous white solid TFA salt. Analytical LCMS (M+H)+: m/z=575.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C[CH:25]=[CH:26][CH2:27][NH2:28].[CH3:29]C(N(C)C)=O>>[C:1]([O:5][C:6](=[O:23])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:28]([CH2:27][CH:26]=[CH2:25])[CH3:29])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=CCN
Reactant: CC(=O)N(C)C
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(OCCCCCCBr)cc1
Product: C=CCN(C)CCCCCCOc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87 %

Procedure:
A solution of 40 g (103.7 mmol) of [4-(6-Bromo-hexyloxy)-phenyl]-methyl-carbamic acid tert-butyl ester in 400 ml DMA was treated at RT with 19.9 ml (207.4 mmol) of N-methylallylamine and stirred at RT for 22 h. The solution was concentrated and dissolved in aqueous saturated NaHCO3 /Et2O (3×). The organic phase was dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (95:5) yielded 33.9 g (87%) of {4-[6-(Allyl-methyl-amino)-hexyloxy]-phenyl}-methyl-carbamic acid tert-butyl ester, MS: 377 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]=[C:20]=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[NH2:22][OH:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:21])[NH:22][OH:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=C=Nc1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Reactant: NO
Solvent: ClCCl
Product: O=C(NO)Nc1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Yield: 86.7 %

Procedure:
Fourteen grams of 3-chloro-4-(2-naphthyloxy)phenyl isocyanate were dissolved in 60 ml of methylene chloride, and the resulting solution was added dropwise to 10 ml of an aqueous solution containing 4 g of hydroxylamine at a temperature below 20° C. Precipitated crystals were collected on a filter, washed with water and dried to obtain 13.5 g of N'-[3-chloro-4-(2-naphthyloxy)phenyl]-N-hydroxyurea. Thereafter, 13.5 g of the product was dissolved in 150 ml of a benzene-methanol (1:1) mixture, and 13 ml of dimethyl sulfate and 30 ml of 10 N sodium hydroxide were alternately added dropwise thereto at a temperature below 30° C. After stirring at room temperature, the reaction mixture was diluted with water, followed by extraction with benzene. The benzene layer was washed with water, and the solvent was removed under reduced pressure. The oily substance obtained was purified by column chromatography (silica gel, 100-120 mesh; eluting solvent, tetrahydrofuran-benzene (1:1) mixture) to obtain 7.3 g of N'-[3-chloro-4-(2-naphthyloxy)phenyl]-N-methoxy-N-methylurea. nD25.0 :1.5860.