Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[NH2:19].C(Cl)(Cl)Cl.C([O:26]CC)C>ClCCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[NH2:19])=[O:26]
Reactant: CCOCC
Reactant: Cc1ccc(N)c(CSc2nc3ccccc3[nH]2)c1
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N)c(CS(=O)c2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared by the method of Example 3 using 2.63 g of the title product of Example 25 instead of the title product of Example 2 and using 1,2-dichloroethane as solvent instead of chloroform. Trituration with diethyl ether gave 3.0 g of the title compound. Analysis. Calc'd. for C15H15N3OS: C, 63.14; H, 5.30; N, 14.73; S, 11.23. Found: C, 61.44; H, 4.98; N, 14.35; S, 11.10.
Reaction SMILES: [Mg].II.[CH2:4](Br)[CH:5]=[CH2:6].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=[O:19]>C(OCC)C>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]([OH:19])[CH2:6][CH:5]=[CH2:4]
Reactant: C=CCBr
Reactant: O=Cc1ccc2ccccc2c1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: C=CCC(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.28 g of magnesium are treated with an iodine crystal and covered with absolute diethyl ether. The reaction is started by the addition of 2 g of allyl bromide. A mixture of 19.78 g of allyl bromide and 15.62 g of 2-naphthaldehyde in absolute diethyl ether is then added dropwise to maintain the mixture at reflux. After the addition is completed, the mixture is left to stir at room temperature overnight. The mixture is poured into an ice - 2 N hydrochloric acid solution and extracted three times with ether. The ether extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to yield 1-(2-naphthyl)-3-buten-1-ol which can be used without further purification for the reaction with cyclopropane carboxylic acid chloride in the process of Example 2. The resulting product is cyclopropane carboxylic acid 1-(2-naphthyl)-3-butenyl ester, m.p. 35°-39° C.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:23]([Si:26]([CH3:28])([CH3:27])[O:14][CH:12]1[CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[N:9][CH:8]=2)[CH2:13]1)([CH3:25])([CH3:24])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CN(c2ccc([N+](=O)[O-])nc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 1-(6-nitro-pyridin-3-yl)-azetidin-3-ol (154 mg, 0.779 mmol) in 2 mL of DMF is added Et3N (0.2 mL, 0.15 mmol), TBDMSCl (117 mg, 0.776 mmol). The resulting mixture is stirred at room temperature for 2 h. Poured into EtOAc/NaHCO3. the aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic layers are ished with brine, dried over Na2SO4. Concentrated to give 5-[3-(tert-butyl-dimethyl-silanyloxy)-azetidin-1-yl]-2-nitro-pyridine (175 mg, 73%).
Reaction SMILES: [CH2:1]([C@H:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2].C([C@H]1N([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)C2C(=CC(F)=CC=2)NC1=O)C>CCOCC>[CH2:1]([C@H:3]1[N:12]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2]
Reactant: CC[C@H]1Nc2cc(F)ccc2NC1=O
Reactant: CC[C@@H]1C(=O)Nc2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Yield: 76 %

Procedure:
(3R)-3-Ethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one in ether was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (76%). MS (ESI) m/z 329 ([M+H]+); MS (ESI) m/z 327 ([M−H]−); HRMS: calcd for C18H17FN2O3, 328.12238; found (ESI_FT), 329.12878.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C@@H:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:20]2)=[O:11])=[N:4][C:5](Br)=[C:6]([F:8])[CH:7]=1.[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=1B(O)O.C(N(CC)CC)C>CCO.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:18]=2[C@@H:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH2:25])[CH2:20]2)=[O:11])=[N:4][C:5]([C:38]2[C:37]([F:36])=[CH:42][CH:41]=[CH:40][C:39]=2[F:43])=[C:6]([F:8])[CH:7]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: Nc1cc(F)c(Br)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1[C@@H]1CCC[C@H](N)C1

Procedure:
A solution of 3-amino-6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide (1.0 equiv), 2,6-difluorophenyl boronic acid (3.0 equiv.), tetrakistriphenylphosphine (0.2 equiv.) and triethylamine (3.0 equiv.) in 1:1 EtOH/toluene (0.1 M) was heated at 120° C. with microwave irradiation for 1200 seconds. Upon cooling, removal of the volatiles in vacuo, the Suzuki product was directly purified by reverse phase HPLC. The product fraction was lyophilized and the resulting phthalimide group was deprotected as described in Method 9 yielding, after RP HPLC purification and lyophilization, 3-amino-N-(4-((1R,3S)-3-aminocyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamideas the TFA salt. LCMS (m/z): 442.2 (MH+); LC Rt=2.24 min.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CC[N:34]([CH:38]([CH3:40])C)[CH:35]([CH3:37])C.N1CCCC1.C(OCC)(=O)C>O1CCCC1.CCO.CCCCCC>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:34]2[CH2:35][CH2:37][CH2:40][CH2:38]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCCC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 39 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and pyrrolidine (0.8 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a deep brown compound CC-38. Mol. Wt.: 467.5158 (C28H25N3O4); Rf: 0.37 (ethyl acetate:n-hexane=1:2); Yield: 39%; Mp.: 193-194° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 467.1845 (C28H25N3O4+); found, 467.1840; 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 1.31 (br, 10H, —CH2—), 2.43 (s, 3H, —CH3), 3.27 (s, 2H, —CH2N—), 7.42 (d, J=8.1 Hz, 2H, Ar—H), 7.87-7.91 (m, 2H, Ar—H), 8.09-8.19 (m, 2H, Ar—H), 8.27 (d, J=8.7 Hz, 1H, Ar—H), 8.73 (d, J=8.4 Hz, 1H, Ar—H), 10.12 (s, 1H, Ar—NH—), 10.54 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.86, 23.20, 53.65, 59.09, 126.30, 126.54, 126.88, 127.80, 127.88, 127.92, 129.05, 129.25, 130.59, 132.33, 134.12, 134.38, 134.42, 136.24, 140.44, 142.43, 166.26 (NCO), 169.56 (NCO), 181.42 (CO), 183.68 (CO).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[Br:12][C:13]1[CH:17]=[CH:16][N:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:14]=1[C:27](OC)=[O:28].O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Br:12][C:13]1[CH:17]=[CH:16][N:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:14]=1[C:27]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:28]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccccc1)c1c(Br)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 114.7 %

Procedure:
In a three-necked round-bottom flask aniline (1.57 mL, 17.20 mmol) was dissolved in 80 mL of toluene under inert atmosphere. To this solution was added trimethyl aluminium (7.82 mL, 15.64 mmol) and the mixture was stirred at room temperature during 10 min. Afterwards, a solution of methyl 3-bromo-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (2.0 g, 5.81 mmol) in 20 mL of toluene was added and the reaction mixture was heated at 80° C. for 3 h. Next, the mixture was allowed to cool to room temperature and 20-30 mL of water and a 0.5M aqueous solution of disodium tartrate dihydrate were added to hydrolize unreacted trimethyl aluminium. After stirring for a while, the two layers were separated and the aqueous phase was extracted with ethyl acetate. The organic mixture was washed with the same 0.5M aqueous solution of disodium tartrate dihydrate (200 mL), water and brine, dried and concentrated in vacuum to afford 2.7 g of a residue that was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([CH:6]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[Cl:19][CH:20]([SiH3:22])[Cl:21]>C1CC=CCCC=C1.Cl[Pt]Cl.C1(C)C=CC=CC=1>[F:14][C:13]([F:15])([F:16])[S:10]([CH:6]([S:3]([C:2]([F:17])([F:1])[F:18])(=[O:4])=[O:5])[CH2:7][CH2:8][CH2:9][SiH2:22][CH:20]([Cl:21])[Cl:19])(=[O:12])=[O:11]
Reactant: [SiH3]C(Cl)Cl
Reactant: C=CCC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F
Agent: Cl[Pt]Cl
Agent: C1=C\CC/C=C\CC/1
Solvent: Cc1ccccc1
Solvent: C1=CCCC=CCC1
Product: O=S(=O)(C(CCC[SiH2]C(Cl)Cl)S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 110 °C
Reaction time: 0.05 h
Yield: 95.3 %

Procedure:
Under nitrogen atmosphere, a three-neck flask equipped with a reflux condenser and having a volume of 100 ml was charged with each of 126.7 g (0.393 mol) of 1,1-bis(trifluoromethanesulfonyl)-3-butene, 68.7 g of toluene, 15.2 mg (0.0002 parts by mass relative to BTSB) of dichloro(1,5-cyclooctadiene)platinum(II) (made by Tokyo Chemical Industry Co., Ltd.), and 50.0 g (0.4 parts by mass relative to BTSB) of dichloromethylsilane (made by Tokyo Chemical Industry Co., Ltd.). Continuously, under nitrogen atmosphere, stirring was conducted for three minutes for mixing. After that, while this flask was heated by immersion in an oil bath adjusted to 50° C., an addition reaction was conducted for 30 minutes. After termination of the addition reaction, toluene was distilled out under reduced pressure and recovered. Then, a distillation under reduced pressure was conducted. Under a reduced pressure of 533 Pa (4 mmHg), it was distilled out by heating at 105-115° C., thereby obtaining 163.0 g of 4,4-bis(trifluoromethanesulfonyl)butyldichloromethylsilane (in the following, it may be abbreviated as BTSB-DCMS) as a perfluoromethidization agent.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH:13]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH2:19][N:20]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCC1CCCCC1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(CC2CCCCC2)C1=O
Yield: 86.4 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and cyclohexylmethanamine (0.574 mL; 4.41 mmol) in ethanol (3 mL). 1-(cyclohexylmethyl)-2-oxopyrrolidine-3-carboxylic acid 0.286 g (86%) was obtained as a yellow solid.
Reaction SMILES: I.[C:2]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][C@@H:10]([C:19]([OH:21])=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[OH-].[Na+].[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1.O.C(OCC)C>[CH2:26]([O:33][C:34]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C@@H:10]([C:19]([OH:21])=[O:20])[NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:22][CH:23]=1)=[NH:3])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: I
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)C(=O)O

Procedure:
To a mixture of 4-amidino-N-t-butoxycarbonyl-L-phenylalanine hydroiodide (1.00 g), 4N sodium hydroxide aqueous solution (1.15 ml), tetrahydrofuran (2 ml), and water (10 ml), a solution of benzyloxycarbonyl chloride in tetrahydrofuran (2 ml) was added, being adjusted to pH=12~12.5 with 4N sodium hydroxide aqueous solution. The reaction mixture was diluted with water and diethyl ether, and the separated aqueous layer was neutralized with 10% hydrochloric acid and extracted with ethyl acetate, and washed with water and brine, and dried over magnesium sulfate. After evaporation in vacuo, the resulting precipitate was collected by filtration and washed with diethyl ether to give 4-(N-benzyloxycarbonylamidino)-N-t-butoxycarbonyl-L-phenylalanine (0.53 g).
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Cl[CH2:19][S:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1(C)C=CC=CC=1>[CH2:21]([S:20][CH2:19][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Reactant: ClCSCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(CSCc1ccccc1)(CC(C)C)C(=O)OCC
Reaction time: 1 h
Yield: 98 %

Procedure:
Diethyl isobutylmalonate (22.0 g.) was added to a stirred suspension of sodium hydride (4.8 g. 50% dispersion in oil) in dry toluene (200 ml.), under nitrogen. The mixture was stirred at 80° for one hour. The mixture was cooled and benzyl chloromethyl thioether 5 (16.0 g.) in dry toluene (50 ml.) was added and the mixture was stirred at 80° for two hours. The mixture was cooled and poured into water. The aqueous mixture was extracted into diethyl ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. Diethyl 2-benzylthiomethyl-2-isobutylmalonate (32.0 g.) was obtained as a yellow oil and was used without further purification.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([NH2:21])[C:15](=[CH:19][CH:20]=1)[C:16](O)=[O:17]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15]([C:16](=[O:17])[N:6]3[C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[NH:3][C:2]3=[N:21]2)=[CH:19][CH:20]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: O=c1c2ccc(Cl)cc2nc2[nH]c3ccccc3n12

Procedure:
3-Chlorobenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chlorobenzimidazole and 4-chloroanthranilic acid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:29]([O:28][C:27]([NH:26][CH:23]1[CH2:24][CH2:25][N:21]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:22]1)=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 95.4 %

Procedure:
A suspension of 49.5 g (0.175 mole) of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3-carboxylic acid, 37.3 g (0.2 mole) of 1,1dimethylethyl (3-pyrrolidinyl)carbamate, 40.4 g (0.4 mole) of triethylamine in 1.5 1 of acetonitrile was refluxed for three hours. The precipitate was removed by filtration, washed with acetonitrile, then ethyl ether, and dried in vacuo to give 75.0 g of the title compound, mp 239°-240° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Br
Solvent: CC(=O)O
Product: O=C1CCCc2cc(O)ccc21
Temperature: 25 °C
Yield: 70.5 %

Procedure:
6-Methoxytetralone (50 g, 280 mmol) was suspended in glacial acetic acid (250 mL). Hydrobromic acid (47%; 500 mL) was added and the mixture was heated at reflux for 6 h, cooled to room temperature, and poured onto 500 g of crushed ice. After 1 h the precipitate was collected and recrystalized from ethanol to provide 32 g of 6-hydroxytetralone. Concentration of the mother liquor provided an additional 9 g of product, mp 149°-152° C.; 1H NMR (CDCl3) δ 7.80 (d, 1H), 6.78 (d, 1H), 6.68 (s, 1H), 2.90 (t, 2H), 2.55 (t, 2H), 2.05 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:23])=[C:4]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:5]([CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[C:3]([Cl:23])=[C:4]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(Br)c1Cl
Yield: 48.3 %

Procedure:
To an emulsion of diethyl 2-(3-bromo-2-chloro-4,5-difluorobenzoyl)malonate (11.44 g) in water (16 ml) was added p-toluenesulfonic acid (15 mg) and refluxed for 3 hours with stirring vigorously. After cooling, the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:1) to give the title compound (4.56 g), mp 47°-51° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][C:14]=1[Cl:15].[CH3:16][OH:17]>>[Cl:15][C:14]1[C:4]([Cl:3])=[CH:5][C:6]([C:11]([OH:10])=[O:12])=[C:7]([C:8]([O:17][CH3:16])=[O:9])[CH:13]=1
Reactant: CO
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc(Cl)c(Cl)cc1C(=O)O
Reaction time: 1 h

Procedure:
To methanol (200 mL) was added sodium hydride (2.72 g, 60% dispersion, 68.0 mmol) portionwise under nitrogen at ambient temperature. To the solution was then added a solution of 4,5-dichlorophthalic anhydride (5.90 g, 27.2 mmol) in methanol (50 mL) dropwise under nitrogen at room temperature. The reaction was stirred for one hour and then concentrated to remove the methanol. The residue was taken up in aqueous 10% potassium carbonate solution and extracted with ethyl acetate (2×). The aqueous portion was acidified to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate (3×), dried (Na2SO4) and concentrated to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.81 (s, 3H) 7.94-8.01 (m, 2H) 13.60-13.70 (br, 1H); MS (+DCI/NH3) m/z 266.0 [M+NH4]+.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][C:20]([O:22]CC)=[O:21])[CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C>Cl>[NH:1]([C:8]([NH:10][C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)Nc3ccccc3)ccc21
Agent: Cl
Solvent: CC#N
Product: O=C(O)CC(c1ccccc1)n1cnc2cc(NC(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 3-{5-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (491 mg, 1.14 mmol) in a mixture of hydrochloric acid (40 mL of a 5N solution) and acetonitrile (20 mL) was stirred at room temperature for 24 hours. Additional aliquotes of hydrochloric acid (20 mL of a 5N solution) and acetonitrile (10 mL) were then added, and stirring was continued for a further 72 hours. The solution was then evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.11 min, MH+ 401].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:27]([O:29][CH2:30][CH3:31])=[CH2:28])CCC.N#N>CN(C=O)C.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>[CH2:30]([O:29][C:27]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1)=[CH2:28])[CH3:31]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Temperature: 100 °C

Procedure:
A solution of 6-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline (intermediate O) (50 mg, 0.169 mmol) and tributyl(1-ethoxyvinyl)stannane (0.06 mL, 0.178 mmol) in DMF (6 mL) was purged with N2 for 30 min and then Pd(PPh3)4 (9.77 mg, 0.0085 mmol) was added. The resulting solution was heated at 100° C. for 3 h. The reaction mixture was quenched with water, extracted with EtOAc three times. The organic layers were combined, washed with KF solution and brine, dried over Na2SO4. After concentration, the crude was used in the next step without further purification. LCMS (method A): [MH]+=332.1, tR=4.969 min.