Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([N:33](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[C:19]([O:21][CH:22]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=3[Cl:32])[CH3:23])[CH:20]=2)=[CH:11][CH:10]=1.O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([NH2:33])=[C:19]([O:21][CH:22]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=3[Cl:32])[CH3:23])[CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(Oc1cc(-c2ccc(Br)nc2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(Oc1cc(-c2ccc(Br)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 3 h
Yield: 105.9 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 6′-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-yl-bis-(tert-butoxycarbonyl)-amine (1.3 g, 2.0 mmol) in dichloromethane (15 mL). After 3 hours, equal portions of water and saturated aqueous sodium bicarbonate were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation to give 6′-bromo-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ylamine (968 mg, 106%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:7](=[O:8])[CH2:6][C:5](=O)[CH2:4][O:3]1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O.[NH2:21]/[C:22](/[CH3:28])=[CH:23]\[C:24]([O:26]C)=[O:25]>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:6]3[C:7](=[O:8])[C:2]([CH3:10])([CH3:1])[O:3][CH2:4][C:5]=3[NH:21][C:22]3[CH2:28][O:26][C:24](=[O:25])[C:23]2=3)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC1(C)OCC(=O)CC1=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CCO
Product: CC1(C)OCC2=C(C1=O)C(c1ccc(F)c(Br)c1)C1=C(COC1=O)N2
Yield: 21.7 %

Procedure:
The product from Example 66C (0.50 g, 3.5 mmol), 3-bromo-4-fluorobenzaldehyde (0.88 g, 4.2 mmol) and methyl 3-aminocrotonate (0.40 g, 3.5 mmol) in ethanol (5 mL) were processed as described in Example 71 to provide the title compound (0.31 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].ClN([C:25]1[C:34]2[C:29](=[CH:30][C:31](O)=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][N:26]=1)C1C=CC=CC=1F.N1C=CC=CC=1>C(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[N:28]=[CH:27][N:26]=[CH:25]2
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc2cncnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
Trifluoromethanesulphonic anhydride (0.55 ml, 3.3 mmol) was added to a stirred suspension of 4-(chloro-2-fluoroanilino)7-hydroxy-6-methoxyquinazoline (959 mg, 3 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (2.2 ml) and pyridine (2.2 ml) under argon at 0° C. Thee reaction mixture was stirred for 1 hour at 0° C. allowed to warm to ambient temperature and stirred for a further 1.5 hours. The volatiles were removed by evaporation, the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether/petroleum ether to give 444-chloro-2-fluoroanilino)6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (270 mg, 60%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:11]([CH2:26][OH:27])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:11]([CH2:26][O:27][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(CN2CCN(c3cc(Cl)cc(Cl)c3)CC2CO)cc1OC
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN2CCN(c3cc(Cl)cc(Cl)c3)CC2COCc2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
In a manner similar to Preparation 19, react 4-(3,5-dichlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-2-piperazinemethanol with sodium hydride and 1-(chloromethyl)-4-nitrobenzene to give the titlecompound.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:7]=[C:8]([CH:16]=[C:17](Br)[CH:18]=1)[C:9]([O:11][C:12](C)(C)C)=[O:10]>C(N(CC)CC)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>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:7]=[C:8]([CH:16]=[C:17]([C:3]#[C:2][CH2:1][OH:4])[CH:18]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCO)cc(C#CCO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
Pd(Ph3P)4 (1.08 g), CuBrSMe2 (0.41 g) and propargyl alcohol (2.95 g, 50.2 mmol) are added successively to a solution of methyl 3,5-dibromobenzoate (A6, 7.7 g, 22.9 mmol) in triethylamine (130 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 3.5 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr, and the filter cake is washed with ethyl acetate (50 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (5.7 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (7.5:2.5)], Rf=0.15.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][O:21][C:19]([CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16])=[O:20]
Reactant: COC(=O)CBr
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N1CCC(=O)c2cc(OCC(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 119.1 %

Procedure:
A mixture of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.314 g), methyl bromoacetate (1.01 g), and potassium carbonate (0.828 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 24 hours, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (15 g) with chloroform as an eluent to give 6-methoxycarbonylmethoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.08 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][NH:37]2)=[CH:33][CH:32]=1)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:39]=[C:38]4[C:34]([CH:35]=[CH:36][NH:37]4)=[CH:33][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc5cc[nH]c5c4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-formylindole to the procedure of step 1, Example 66. MS (ESI) m/z 508.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]#[N:16])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1.Cl.C(N(CC)CC)C.[N-:29]=[N+:30]=[N-:31].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH:6]1[CH2:12][CH:11]2[N:13]([CH2:14][C:15]3[NH:31][N:30]=[N:29][N:16]=3)[CH:8]([CH2:9][CH2:10]2)[CH2:7]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCN1C2CCC1CC(Oc1ccc(Cl)c(Cl)c1)C2
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1ccc(OC2CC3CCC(C2)N3Cc2nnn[nH]2)cc1Cl
Temperature: 61 °C
Reaction time: 120 h

Procedure:
To 1 g of [3-(3,4-dichloro-phenoxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-acetonitrile in 25 ml anhydrous toluene was added 0.7 g of triethylamin hydrochloride and 0.3 g sodium azide. The reaction mixture was stirred at 60-62° C. for 5 days, the product precipitated from the mixture and was isolated by filtration. Yield 0.27 g (24%) Mp. 233-235° C. (sublimation).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:32])=[O:31])[NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].O>CN(C)C=O>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([CH:4]2[N:3]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[C:23]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:24]=1)#[N:27]
Reactant: CCOC(=O)CBr
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C

Procedure:
A mixture of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10, 1.78 g, 3.74 mmol) and cesium carbonate (1.83 g, 5.62 mmol) in N,N-dimethylformamide (25.0 mL) is treated with ethyl bromoacetate (0.50 mL, 4.50 mml), and the mixture is stirred at room temperature over night. Water (30 ml) is added, and the precipitate is filtered and dried. Yield: 1.80 g; ESI mass spectrum: [M+H]+=562; Retention time HPLC: 1.05 min (Z018_S04).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:38][N:39]1[CH:43]=[N:42][C:41]([CH2:44][Cl:45])=[N:40]1.O>CN(C)C=O>[ClH:45].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([CH2:44][C:41]4[N:42]=[CH:43][N:39]([CH3:38])[N:40]=4)[C@@:16]2([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Fc1ccc([C@]23CC[C@H](CC[C@H]2OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N3)cc1
Reactant: Cn1cnc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cl
Product: Cn1cnc(CN2[C@H]3CC[C@@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@]2(c2ccc(F)cc2)CC3)n1
Temperature: 80 °C

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane (Example 18; 101 mg, 0.23 mmol), potassium carbonate (159 mg, 1.15 mmol), and 1-methyl-3-chloromethyl-1,2,4 triazole (386 mg, 2.30 mmol) were combined in dimethylformamide and heated at 80° C. for 5 days. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [7.5% methanol in dichloromethane] to give desired product. The hydrochloride salt was made by adding 1 equivalent of 1N hydrogen chloride in diethyl ether to a solution in diethyl ether. The salt was further purified by SCX cartridge eluting with methanol then ammonia in methanol. The ammonia washings were collected and concentrated in vacuo and the hydrochloride salt made by adding 1 equivalent of 1N hydrogen chloride in diethyl ether to a solution in-diethyl ether. The solid formed was filtered and dried at 60° C. in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([OH:26])[CH:28]=3)[CH2:15]2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCCNC3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCN(C(=O)c4cccc(O)c4)C3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-2-methyl-5-(piperidin-3-ylmethoxy)quinoline-3-carboxylate (Example 110b) and 3-hydroxybenzoic acid as a white solid (34%). MS 464 (MH+).
Reaction SMILES: C([O:4][C@H:5]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:7](=O)[C@H:6]1[C@H:19]([O:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH3:20])(=O)C.[C:28]1([S:34][C:35]([O:37][Si](C)(C)C)=[CH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:25]([O:24][C:22]([O:21][C@@H:19]([C@@H:6]1[C@@H:7]([CH2:36][C:35]([S:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:37])[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]1=[O:4])[CH3:20])=[O:23])[CH:26]=[CH2:27]
Reactant: C=C(O[Si](C)(C)C)Sc1ccccc1
Reactant: C=CCOC(=O)O[C@H](C)[C@@H]1C(=O)N(Cc2ccc(OC)cc2)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(Cc2ccc(OC)cc2)[C@@H]1CC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 377 mg of (3S, 4R)-4-acetoxy-3-[(R)-1-(allyloxycarbonyloxy)ethyl]-1-(p-methoxybenzyl)-2-azetidinone in 2 ml of dry methylene chloride were added 448 mg (2 mmole) of 1-phenylthio-1-(trimethylsilyloxy)ethylene and then the mixture was stirred at room temperature, A catalytic amount of trimethylsilyltrifluoromethanesulphonate was added to the mixture, which was then left to stand at room temperature overnight. The precipitate produced was dissolved in 200 ml of ethyl acetate, and the resulting solution was washed successively with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulphate and subjected to Lobar column chromatography eluted with a 1:1 by volume mixture of cyclohexane and ethyl acetate, to afford 430 mg (yield 91%) of the title azetidinone.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:21][C:2]([CH3:20])([CH3:1])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:12])=[O:4]
Reactant: CCNCCC(C)C
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCN(CCC(C)C)C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 10.1 mg N-ethyl-iso-amylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.29 min. (m/Z=304.2, 388.2, 410.2).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[CH3:12][C:13]([CH3:31])([CH3:30])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[CH3:12][C:13]([CH3:31])([CH3:30])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18][N:19]([CH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:24]([CH:25]=[CH2:1])[CH:23]=1)[CH3:20]
Reactant: [Li]CCCC
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=Cc1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
Methyl triphenylphosphonium bromide (0.99 g; 2.78 mmol) was added to benzene (20 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.8 ml; 2.78 mmol) was added dropwise. The mixture was stirred for 10 minutes, and Compound 8 (0.50 g; 1.86 mmol) in benzene (20 ml) was added dropwise thereto, followed by stirring for 3 hours at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with benzene (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 0.21 g of the target compound as pale yellow oily matter (yield: 42.2%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]2[S:21][C:20]3[C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1.[F:35][C:36]1[CH:41]=[C:40](I)[C:39]([CH2:43][F:44])=[CH:38][N:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)(Cl)Cl.C(O)(C)C>[F:1][C:2]1[C:3]([C:17]2[S:21][C:20]3[C:22]([C:40]4[C:39]([CH2:43][F:44])=[CH:38][N:37]=[C:36]([F:35])[CH:41]=4)=[CH:23][CH:24]=[CH:25][C:19]=3[CH:18]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc3cc(-c4nc(NCCN5CCNC5=O)ncc4F)sc23)OC1(C)C
Reactant: FCc1cnc(F)cc1I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=C1NCCN1CCNc1ncc(F)c(-c2cc3cccc(-c4cc(F)ncc4CF)c3s2)n1
Temperature: 100 °C
Yield: 58.2 %

Procedure:
Combine 1-(2-{5-fluoro-4-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-2-yl]-pyrimidin-2-ylamino}-ethyl)-imidazolidin-2-one (120 mg, 248.26 μmol), 2-fluoro-5-fluoromethyl-4-iodo-pyridine (100 mg, 392.15 μmol) tris(dibenzylideneacetone)dipalladium (0) (11.37 mg, 12.41 μmol) tricyclohexylphosphine (2.09 mg, 7.45 μmol), potassium phosphate (105.39 mg, 496.51 μmol) in 5 mL of dioxane in a sealed pressure tube. Heat the mixture at 100° C. for 3 hours in the oil bath. LC-MS shows a peak at 485. Cool the reaction mixture down to room temperature and dilute it with chloroform-isopropyl alcohol (3/1). Wash the organic solution with saturated aqueous sodium chloride, dry it over sodium sulfate and concentrate it to crude. Purify the crude by flash chromatography (10% methanol in dichloromethane) to give the target product (70 mg, 58.2%). MS (ES) m/z 485 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17]C)=[O:16])=[CH:5][C:4]=2[NH:3]1.CO.C1COCC1.[Li+].[OH-]>O>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([OH:17])=[O:16])=[CH:5][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 618 mg, 2.38 mmol) was suspended in 10 ml of a mixture of MeOH, THF, and water (1:1:1, v:v:v). LiOH (2.0 eq, 114 mg, 4.76 mmol) was added and the mixture was stirred at room temperature for 2 hours. An additional amount of LiOH (114 mg) was added and the mixture was stirred for an hour. LiOH (50 mg) was added and the mixture stirred for an additional 2 hours. Water was added and the solution filtered through a pad of celite. The pad of celite was thoroughly washed with aqueous 1 N NaOH. The solution was acidified with 6 N aqueous HCl to induce precipitation of the expected material. Filtration and drying afforded 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylic acid as a yellow solid (562 mg, 96% yield). LCMS (ES): 95% pure, m/z 246 [M+1]+; 1H NMR (DMSO-d6, 400 MHz) δ 7.61 (d, J=5.2, 1H), 7.73 (dd, J=1.6, J=8.0, 1H), 7.88 (d, J=5.6, 1H), 7.92 (d, J=8.4, 1H), 8.02 (d, J=1.6, 1H), 11.92 (s, 1H), 13.21 (br. s, 1H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[Br:16]CC(C1C=CC(CCN[C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=CC=1)=O.NC(N)=S>C(O)(C)C>[BrH:16].[NH2:15][C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=2)[N:11]=1
Reactant: O=C(CBr)c1ccc(CCNC(=O)C(F)(F)F)cc1
Reactant: NCCc1ccc(-c2csc(N)n2)cc1
Agent: NC(N)=S
Solvent: CC(C)O
Product: Br
Product: Nc1nc(-c2ccc(CCNC(=O)C(F)(F)F)cc2)cs1
Yield: 100 %

Procedure:
4-{4-(2-Aminoethyl)phenyl}-2-thiazolamine: A solution of N-{2-{4-(2-bromoacetyl)phenyl}ethyl}-2,2,2-trifluoroacetamide (5.55 g, 16.4 mmol), prepared in Example 1(b), and thiourea (1.25 g, 16.4 mmol) in isopropanol (60 mL) was heated at reflux for 1 h. The reaction mixture was concentrated under reduced pressure to give crude N-{2-{4-(2-amino-4-thiazolyl)phenyl}ethyl}-2,2,2-trifluoroacetamide hydrobromide (6.51 g, ~100% yield). A solution of the crude hydrobromide and aqueous 4N NaOH (14.3 mL, 57.4 mmol) in MeOH (70 mL) and H2O (10 mL) was heated at reflux for 20 min. The solution was cooled, H2O (30 mL) was added and the MeOH was carefully evaporated under reduced pressure while keeping the solution cool. The resulting suspension was cooled to 0°. The crystals obtained by filtration were washed with cold H2O then air-dried to give 4-{4-(2-aminoethyl)phenyl}-2-thiazolamine (3.3 g, 92% yield): 1H NMR (DMSO-d6) δ 7.69 (d, J=8.2 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H), 7.03 (broad s, 2H), 6.92 (s, 1H), 2.76 (t, J=7.1 Hz, 2H), 2.62 (t, J=7.1 Hz, 2H).
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:9]([NH:12][C:13]1[CH:14]=[C:15]([OH:26])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:11])[CH3:10]>O>[C:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:26][CH2:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1cc(O)ccc1Oc1ccccc1
Reactant: O=C(O)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(OCCC(=O)O)ccc1Oc1ccccc1
Yield: 31.7 %

Procedure:
8.0 g of sodium hydroxide was dissolved in 240 ml of water. In this solution was dissolved 24.3 g of 3-acetylamino-4-phenoxyphenol. Thereto was added 10.9 g of 3-chloropropionic acid. The mixture was refluxed for 30 minutes. The reaction mixture was water-cooled. The resulting crystal was removed by filtration. The filtrate was adjusted to pH 9 with 4N hydrochloric acid and washed with two 50-ml portions of ethyl acetate. The aqueous layer was separated, adjusted to pH 4 with 4N hydrochloric acid, and extracted with 200 ml of ethyl acetate. The extract (the organic layer) was washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was mixed with diethyl ether. The resulting crystal was collected by filtration to obtain 10.0 g (yield: 31.7%) of 3-(3-acetylamino-4-phenoxyphenoxy)propionic acid having a melting point of 138°-140° C.