Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[C:4]=1[CH3:20]>Br>[OH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)[C:4]=1[CH3:20]
Reactant: COc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Agent: Br
Product: Cc1c(O)ccnc1CSc1nc2ccccc2[nH]1
Yield: 68.4 %

Procedure:
A solution of 2-[(4-methoxy-3-methyl-2-pyridyl) methylthio]benzimidazole (16.6 g) in 47% aqueous solution of HBr (250 ml) was heated for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure. The concentrate was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The oily portion was separated and subjected to a silica gel column chromatography, eluting with chloroform-methanol (25:2, v/v), to give 2-[(4-hydroxy-3-methyl-2-pyridyl)methylthio]benzimidazole (10.8 g) as colorless powder. 1H-NMR(δ ppm in CDCl3): 2.12(3H,s), 4.38(2H,s), 6.43(1H,d,J=7Hz), 7.1-7.3(2H,m), 7.4-7.6(3H,m)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)[CH3:23]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH3:20])[C:10]([O:12][CH3:23])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CCC(O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid in anhydrous THF at 0° C. under a nitrogen atmosphere was added slowly a solution of BH3.Me2S in THF (2 M, 2 eq.). The mixture was stirred for 5 min at 0° C. and 3 hr at 55° C. The reaction was quenched with MeOH and partitioned between EtOAc and sat. aq. NaHCO3. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The obtained product was used in the next step without purification. MS (ES) C16H31NO5 requires: 317, found: 318 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=O.S(Cl)(Cl)=O.[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH2:12]([N:19]1[CH2:20][CH2:21][N:22]([N:25]2[CH2:5][CH2:6][CH:2]([CH3:1])[C:3]2=[O:4])[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NN1CCN(Cc2ccccc2)CC1
Reactant: CC1CCOC1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC1CCN(N2CCN(Cc3ccccc3)CC2)C1=O
Temperature: 80 °C
Reaction time: 15 h
Yield: 36.8 %

Procedure:
A mixture of 3-methyldihydrofuran-2(3H)-one (2.0 g), thionyl chloride (1.5 ml) and zinc chloride (10 mg) was stirred at 80° C. for 15 hours. The mixture was cooled to room temperature, and the reaction mixture was added dropwise to a solution of 4-benzylpiperazin-1-amine (3.8 g) in THF (50 mL) at 0° C., followed by stirring at 0° C. for 2 hours. Sodium hydride (60% in oil; 2.4 g) was added thereto and the mixture was stirred at room temperature for 15 hours. Ice was added thereto, and then the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by basic silica gel column chromatography (ethyl acetate/hexane=1/5) to obtain the title compound (2.0 g, 37%) as a yellow oil.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:11]([O-])=[CH:12][C:13](=O)[C:14]([O:16]CC)=[O:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][NH2:51])[CH:45]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:11]2[N:50]([C:46]3[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=3)[N:51]=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cc(Br)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1

Procedure:
500 mg (1.19 mmol) of the compound of Example 6A is reacted analogously to the synthesis of the compound of Example 20A with 260 mg (1.79 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 240 mg (54% of theory) of the title compound is obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[N:44]=[CH:43][C:42]3[C:37](=[CH:38][C:39]([O:52][CH3:53])=[C:40]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:41]=3)[N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[CH:69]=[C:68]([C:70](O)=[O:71])[O:67][N:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[N:44]=[CH:43][C:42]3[C:37](=[CH:38][C:39]([O:52][CH3:53])=[C:40]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:68]5[O:67][N:66]=[C:65]([CH3:64])[CH:69]=5)=[O:71])[CH2:50][CH2:51]4)[CH:41]=3)[N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2nc(Nc3cccc(Cl)c3F)ncc2cc1OC1CCNCC1
Reactant: Cc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2nc(Nc3cccc(Cl)c3F)ncc2cc1OC1CCN(C(=O)c2cc(C)no2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.9 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolinamine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 3-methyl-5-isoxazolecarboxylic acid (0.126 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(3-methylisoxazol-5-yl)carbonyl]piperidin-4-yl}oxy)quinazolinamine as a white solid (0.145 g). 1H NMR Spectrum: (DMSO d6 373K) 1.89 (m, 2H), 2.10 (m, 2H), 2.35 (s, 3H), 3.64 (m, 2H), 3.88 (m, 2H), 3.99 (s, 3H), 4.82 (m, 1H), 6.73 (s, 1M), 7.29 (m, 1H), 7.29 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.93 (s, 1H), 8.39 (s, 1H), 9.28 (br s, 1H); Mass Spectrum: (M+H)+ 512.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][C:38]([C:44]#[N:45])=[CH:37][C:36]=1[NH:46][C:47](=[O:66])[CH2:48][N:49]([CH2:63][CH2:64]O)[CH2:50][C:51]1[C:56]([O:57][CH3:58])=[CH:55][C:54]([O:59][CH3:60])=[CH:53][C:52]=1[O:61][CH3:62]>C1COCC1.CCOC(C)=O.O>[Cl:34][C:35]1[C:36]([N:46]2[CH2:64][CH2:63][N:49]([CH2:50][C:51]3[C:56]([O:57][CH3:58])=[CH:55][C:54]([O:59][CH3:60])=[CH:53][C:52]=3[O:61][CH3:62])[CH2:48][C:47]2=[O:66])=[CH:37][C:38]([C:44]#[N:45])=[CH:39][C:40]=1[N+:41]([O-:43])=[O:42]
Reactant: COc1cc(OC)c(CN(CCO)CC(=O)Nc2cc(C#N)cc([N+](=O)[O-])c2Cl)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(CN2CCN(c3cc(C#N)cc([N+](=O)[O-])c3Cl)C(=O)C2)c(OC)c1
Reaction time: 0.17 h
Yield: 19.5 %

Procedure:
To a solution of triphenylphosphine (263 mg, 1.002 mmol) in THF (2 mL) was added DIAD (0.195 mL, 1.002 mmol). The reaction mixture was stirred for 10 min. Then a solution of N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(2,4,6-trimethoxybenzyl)amino)acetamide (160 mg, 0.334 mmol) in TIIF (1.000 mL) was added drop wise. The reaction mixture was then stirred at room temperature for 3 h. LC-MS indicated the desired peak. It was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography (0-100% EtOAc in Hexanes, 12 g) gave 4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzonitrile (30 mg) as a yellow solid. TFA (1 mL) was added to the above obtained solution of 4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzonitrile (30 mg, 0.065 mmol) and ANISOLE (0.028 mL, 0.260 mmol) in DCM (1 mL) and the reaction mixture was stirred at room temperature for 2 h. LC-MS showed completion. Solvent was evaporated and purification via flash chromatography (0-10% MeOH in DCM, 24 g) gave 4-chloro-3-nitro-5-(2-oxopiperazin-1-yl)benzonitrile (20 mg) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17]>>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH:17][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: CN(C)CCCN
Product: Cc1cc(NCCCN(C)C)c2[nH]ncc2n1

Procedure:
The title compound was prepared from 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (D4) and 3-dimethylaminopropylamine by the method given in Example 2. On neutralization of the thus formed hydrochloride salt a clear solution was produced. After freeze drying, purification was carried out on Dowex 50W as described in Example 4, followed by crystallization from ethyl acetate to give the title compound as a white crystalline solid, m.p. 112°-117°.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:33]([CH2:32][N:7]1[C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:2]1=[O:1])#[N:34]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)c3sc(-c4ccccc4)cc3n(CC#N)c2=O)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (5 g; compound B50) and chloroacetonitrile (883 mg) in DMF (45 ml) is added potassium carbonate (1.62 g). The mixture is stirred for 1 h at 100° C. and then poured into ice-cold water. The resulting precipitate is filtered off, washed with water and dried under reduced pressure to give tert-butyl 4-[1-(cyanomethyl)-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (compound B14a) as a solid, which is used without further purification for the next step.
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[C@H:5]([CH2:8][CH3:9])[CH2:6][OH:7].[H-].[Na+].CO>C1COCC1>[CH2:8]([C@H:5]1[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:3]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:2]=2[O:7][CH2:6]1)[CH3:9]
Reactant: CC[C@H](CO)N(CC(F)(F)F)c1ccc([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@H]1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 190 g (0.612 mole) of the crude (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-1-butanol in 1 Liter of dry THF was added dropwise to a stirred suspension of 36.77 g (0.919 mole, 1.5 eq) of sodium hydride in 1.5 L of dry THF under nitrogen atmosphere. After complete addition, the reaction mixture was refluxed for 3 h when TLC of the reaction mixture indicated complete conversion. After cooling to room temperature, 400 mL of methanol was added to destroy excess sodium hydride. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic portions were combined, washed with brine and dried over MgSO4. After filtration, the solvents were evaporated under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography (ethyl acetate:hexanes 1:9) to obtain (+)-(3R)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine as a yellow crystalline solid. Yield 71 g (40%). [α]D=+56.6 (CHCl3, c 7.8); 1H NMR (CDCl3) δ 7.80 (1H, dd, J=2.56, 8.98), 7.71 (1H, d, J=2.57), 6.72 (1H, d, J=9.07), 4.34 (1H, dd, J=1.44, 11.02), 4.12 (1H, m), 4.06 (1H, dd, J=2.12, 11.04), 3.79 (1H, m), 3.37 (1H, m), 1.68 (2H, m), 1.00 (3H, t, J=7.54). 13C NMR: ppm 142.6, 139.1, 138.6, 126.1, 118.6, 112.6, 110.8, 64.9, 58.9, 50.6, 22.5 and 10.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([NH2:15])(=O)C.C([O-])([O-])=O.[K+].[K+]>>[NH2:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: CC(N)=O
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1ccnc2ccccc12
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A mixture of 4-chloroquinoline (486 mg, 3 mmol), acetamide (2.13 g, 36 mmol) and K2CO3 (2.9 g, 21 mmol) was thoroughly vortexed on a mixer and subjected to microwave irradiation at 175° C. for 1 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo to yield 4-aminoquinoline as a brown solid (260 mg, 60%). EIMS m/z: 145 ([M+1]+).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:18][C:19]1[CH:26]=[C:25](F)[C:24]([F:28])=[CH:23][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[C:14]([O:13][C:3](=[O:12])[CH:4]([C:25]1[CH:26]=[C:19]([F:18])[C:20]([C:21]#[N:22])=[CH:23][C:24]=1[F:28])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c(C#N)cc1F
Reaction time: 0.25 h
Yield: 188.7 %

Procedure:
To a suspension of NaH (2.6 g, 64 mmol, and 60.0% dispersion in oil) in DMF (80 mL) was added a solution of di-tert-butyl malonate (3.57 g, 16.50 mmol) in DMF (20 mL) at 0° C. and this was stirred for 15 min. Subsequently, 2,4,5-trifluorobenzonitrile (3.0 g, 15.0 mmol) was added in one portion and the reaction mixture was stirred for 8 h at 80° C. and three hours at room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4 and filtered. After evaporation in vacuo, the residue was purified by flash chromatography (20% EtOAc in hexane) to give 10.0 g of di-tert-butyl(4-cyano-2,5-difluorophenyl)propanedioate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.51 (dd, J=5.5, J=5.4 Hz, 1H), 7.37 (dd, J=5, J=6 Hz, 1H), 4.84 (s, 1H), 1.50 (s, 18H). LC-MS (IE, m/z): 298.2 [(M+1)]+-t-Bu].
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([OH:19])[CH2:13][CH2:14][C:15]([O:17]C)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl>[O:17]=[C:15]1[O:19][C@H:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)CC[C@H](O)c1ccc(NS(C)(=O)=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc([C@@H]2CCC(=O)O2)cc1
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Methyl (γS)-4-[(methylsulfonyl) amino]-γ-hydroxybenzenebutanoate (17.9 g, 62.3 mmol) from Preparation 2 was placed in a flask with 350 ml of CH2Cl2 and the resulting slurry was cooled to 0° C. To this mixture was added 0.12 g of p-TsOH•H2O (1.5 mol %). The reaction was monitored for completion by HPLC until NMT 2% hydroxy ester remained (expect 4-6 h). The reaction mixture was washed with H2O (2×250 ml) and brine (250 ml) while maintaining the temperature at 0° C. The pH of the final wash must be maintained at GT 5). The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The resulting solids were recrystallized from EtOAc (25 ml) to provide 12.1 g (76% yield) of the title compound as white solids (95 area %, 97% ee). Melting point 101-102° C. 1H NMR (400 MHz, CDCl3) δ 7.24 (dt, J=8.0, 8.6 Hz, 4H), 5.43 (m, 1H), 2.97 (s, 3H), 2.63 (m, 3H), 2.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ C 177.0, 137.2, 136.0; CH 126.8, 120.7, 80.9; CH2 30.7, 29.0; CH3 39.4; MS m/z calcd for C11H13NO4S, 255.056 (M+); found 254.95 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]>>[C:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(Br)c1
Reactant: O=C1CCCN1
Product: CC(=O)c1cccc(N2CCCC2=O)c1
Yield: 98 %

Procedure:
The title compound was prepared in 98% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 1-(3-bromophenyl)ethanone and 2-pyrrolidinone.
Reaction SMILES: O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:16]([C:20]1[CH:25]=[CH:24][C:23](/[C:26](/[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53]CC3C=CC(OC)=CC=3)[N:46]=2)=[CH:27]\[C@@H:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=3[O:42][CH3:43])[C:31](=[O:44])[CH2:30][CH2:29]2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([C:20]1[CH:21]=[CH:22][C:23](/[C:26](/[C:45]2[NH:46][C:47](=[O:53])[C:48]([O:51][CH3:52])=[CH:49][CH:50]=2)=[CH:27]\[C@H:28]2[CH2:29][CH2:30][C:31](=[O:44])[N:32]2[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc(COc2nc(/C(=C/[C@H]3CCC(=O)N3Cc3ccc(OC)cc3OC)c3ccc(C(C)(C)C)cc3)ccc2OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(OC)c(=O)[nH]2)c(OC)c1
Temperature: 65 °C
Reaction time: 21 h
Yield: 39.7 %

Procedure:
Water (0.2 mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (72 mg) were added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-methoxy-6-[(4-methoxybenzyl)oxy]-pyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (202 mg) in chloroform (4 mL), and the mixture was stirred at 65° C. for 21 hours. Chloroform was added. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=1:0→95:5 9:1) to give 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-methoxypyridin-2(1H)-one (65 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([S:20]([N:23]1[CH2:28][C@H:27]([CH3:29])[NH:26][C@H:25]([CH3:30])[CH2:24]1)(=[O:22])=[O:21])=[CH:5]2.C(N(C(C)C)CC)(C)C.[Br:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([N:26]2[CH:27]([CH3:29])[CH2:28][N:23]([S:20]([C:6]3[N:7]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:13])=[O:12])[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)(=[O:21])=[O:22])[CH2:24][CH:25]2[CH3:30])=[O:46])=[CH:43][CH:42]=1
Reactant: C[C@@H]1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)C[C@H](C)N1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3n2S(=O)(=O)c2ccccc2)CC(C)N1C(=O)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
In dichloromethane (40 ml), cis-1-[(5-chloro-1-phenylsulfonylindol-2-yl)sulfonyl]-3,5-dimethylpiperazine (1.30 g) was dissolved. To the resulting suspension, diisopropylethylamine (645 μl) was added under ice cooling, followed by the dropwise addition of a solution of 4-bromobenzoyl chloride (0.74 g) in dichloromethane (5 ml). Stirring was then effected at room temperature for 3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The organic layer thus separated was washed with 0.5N hydrochloric acid and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1 to 1:1), whereby the title compound (1.8 g, 97%) was obtained as a pale yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([O-:30])=O)[CH2:27][CH2:26]1)=[O:24].[Li+].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[F:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:68][C:67]2[CH:69]=[CH:70][C:64]([F:63])=[CH:65][CH:66]=2)=[O:30])[CH2:27][CH2:26]1)=[O:24]
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)[O-])CC4)cc3F)ccn2)cn1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a solution of Example B5 (9.91 g, 23.58 mmol) in DMF (80 mL), under an atmosphere of argon, were added TBTU (11.36 g, 35.4 mmol), DIPEA (20.59 ml, 118 mmol) and 4-fluoroaniline (3.93 g, 35.4 mmol). The reaction mixture was stirred at RT overnight. An additional portion of TBTU (7.5 g, 17.8 mmol) was added and stirring was continued. After 2 h, an additional portion of TBTU (3.5 g, 8.33 mmol) was added and stirring was continued for 2 h. The solvent was removed under high vacuum and the residue was dissolved in EtOAc (700 mL) and washed with sat. aq. NaHCO3 (2×200 mL) and brine (50 mL), dried (MgSO4), concentrated to dryness and purified by silica gel chromatography (MeOH-DCM) to provide N-(2,5-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (7.2 g, 59% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 9.76 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 8.13 (dd, J=12.1, 7.1 Hz, 1H), 7.99 (s, 1H), 7.62-7.53 (m, 3H), 7.27 (d, J=2.6 Hz, 1H), 7.22-7.15 (m, 2H), 6.71 (dd, J=5.6, 2.4 Hz, 1H), 3.86 (s, 3H), 1.69-1.56 (m, 4H); MS (ESI): m/z 508.1 [M+1]+.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.CN([CH:24]=[O:25])C>C1COCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH:24]=[O:25]
Reactant: c1cc2sccc2cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc2cnccc2s1
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
A solution of thieno[3,2-c]pyridine (500 mg, 3.70 mmol) in anhydrous THF (10 mL) was stirred under argon and maintained at −78° C. while a solution of 1.6 M n-butyllithium in hexane (2.5 mL, 4.07 mmol) was added dropwise. The resulting wine red solution was stirred for 5 min. then DMF (573 μL, 7.4 mmol) was added. The cooling bath was removed and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was treated with 10% aqueous HCl, made alkaline with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×50 mL) The combined organic fractions were concentrated in vacuo to give an oily residue which was subjected to flash chromatography on silica gel (70% ethyl acetate:hexanes) to give the title compound as a white solid (41.5%): 1H-NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.19 (d, J=5.6 Hz, 1H); MS (ES) m/e 164 (M+H)+.