Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:12][C@H:13]1[CH2:18][N:17]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (21.3 g, 0.09 mol), triethylamine (15 mL, 0.108 mol) and sodium tri(acetoxy)borohydride (42.4 g, 0.2 mol) in 1,2-DCE (500 mL) was stirred at room temperature overnight. Saturated aqueous NaHCO3 solution (200 mL) was added and the mixture stirred for 20-30 minutes. The phases were separated and the aqueous phase was washed with DCM. The combined organics were washed with brine, dried and concentrated. Column chromatography eluting with 0-20% EtOAc/hexane gave the title compound as a yellow oil which crystallized on standing (25.61 g). δH (CDCl3, 400 MHz) 8.19 (2H, d), 7.53 (2H, d), 4.21 (1H, br.s), 3.83 (1H, d), 3.62 (1H, d), 3.50 (1H, d), 3.13 (1H, td), 2.74 (1H, m), 2.54 (1H, m), 2.20 (1H, dd), 2.08 (1H, m), 1.46 (9H, s), 1.25 (3H, d).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:16])=[C:4]([C:9]([CH2:13][CH2:14][CH3:15])=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7]C)=[O:6].B(Br)(Br)Br>C(Cl)Cl.C(OCC)(=O)C>[OH:1][C:2]1[C:3]([CH3:16])=[C:4]([C:9]([CH2:13][CH2:14][CH3:15])=[C:10]([OH:12])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCCc1c(O)cc(O)c(C)c1C(=O)OC
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1c(O)cc(O)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4.61 g of methyl 3,5-dihydroxy-2-methyl-6-propylbenzoate in 20 ml of methylene chloride were added at 0° C. within 30 minutes 50 ml of a 1M solution of boron tribromide in methylene chloride. The mixture was stirred for 5 hours at room temperature and then diluted with 100 ml of ethyl acetate. The mixture was washed with water and with brine, and the organic layer was dried over sodium sulfate and evaporated in vacuo to yield crude 3,5-dihydroxy-2-methyl-6-propylbenzoic acid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[CH3:54][C:55]1[O:59][N:58]=[C:57]([C:60](Cl)=[O:61])[CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:60]([C:57]2[CH:56]=[C:55]([CH3:54])[O:59][N:58]=2)=[O:61])[CH2:48]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CC[C@@H](CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)no1
Yield: 76 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 76% yield. LCMS for C28H28ClN8O3 (M+H)+: m/z=559.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[Br-].[CH:17]1([Zn+])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1COCC1>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>[CH:17]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: [Zn+]C1CCCCC1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccc(C3CCCCC3)nc2)cs1
Temperature: 150 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 50 mg (0.043 mmol, 0.05 eq) tetrakis(triphenylphosphine)palladium(0), and 2 mL of 0.5 M cyclohexylzinc bromide in THF (1 mmol, 1.1 eq) were combined. The reaction mixture was heated at 150° C. in the microwave for 5 min, quenched with pH 7 PBS, extracted with DCM. Silica gel chromatography (gradient 0% to 40% EtOAc/Hexanes) gave 2-cyclohexyl-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (L-001106449). The mono HCl salt was made by dissolving the free base into diethyl ether, adding 1 eq of HCl, and isolated by filtration. LC-MS calculated for C17H18N2S 282, observed m/e 283.3 (M+H)+. 1H-NMR (500 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.30 (d, 1H), 8.03 (s, 1H), 7.71 (d, 1H), 2.94 (m, 1H), 2.69 (s, 3H), 1.35-1.91 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11]C)=[O:10].C(OCC)(=O)C.[Cl-].[Na+]>O1CCOCC1.Cl.O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCC(=O)O)c(Cl)cc2F)c1=O
Temperature: 0 °C
Yield: 64.8 %

Procedure:
First, 0.4 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate was dissolved in 4 ml of 1,4-dioxane, to which a mixed solution of 1 ml of concentrated hydrochloric acid and 1 ml of water was added under stirring, and the mixture was heated and stirred under reflux for 12 hours. The reaction mixture was then left for cooling, into which ice water was poured, and after addition of ethyl acetate and saturated aqueous sodium chloride solution, the mixture was subjected to phase separation. To the organic layer was added aqueous sodium hydrogencarbonate solution, and the mixture was subjected to phase separation. To the aqueous layer was added aqueous hydrochloric acid solution for acidification, to which ethyl acetate was added, and the mixture was subjected to phase separation. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated to give 0.252 g of [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetic acid.
Reaction SMILES: [C:1]([N:9]1[CH:13]([CH3:14])[CH2:12][N:11](CC2C=CC(OC)=CC=2)[C:10]1=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([N:9]1[CH:13]([CH3:14])[CH2:12][NH:11][C:10]1=[O:24])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CC(C)N(C(=O)c3ccccc3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC1CNC(=O)N1C(=O)c1ccccc1
Reaction time: 4 h
Yield: 97.5 %

Procedure:
3-Benzoyl-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (220 mg) described in Preparation Example 55 was dissolved in trifluoroacetic acid (2 mL), and the mixture was stirred for 4 hr under heated reflux. The solvent was evaporated from the reaction mixture, 5% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (135 mg).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:46][C:47]([F:56])([F:55])[C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1.CN(C1C=CC=CN=1)C>CN(C)C=O>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:52][C:51]4[CH:53]=[CH:54][C:48]([C:47]([F:46])([F:55])[F:56])=[CH:49][CH:50]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C(F)(F)F)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg), along with 1-hydroxybenzotriazole, was dissolved in N,N-dimethylformamide (1.0 mL). While the solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.4 mg) was added and the mixture was allowed to warm to room temperature and was stirred for 1 hour. Subsequently, 4-trifluoromethylaniline (23.0 μL) was added and the mixture was stirred for additional 12 hours, followed by addition of dimethylaminopyridine (11.3 mg) and stirring for additional 24 hours. The solvent was then evaporated under reduced pressure and the resulting residue was purified by preparative thin-layer chromatography (solvent:dichloromethane:methanol=4:1) to give (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-trifluoromethylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (10.1 mg).
Reaction SMILES: [Br:1]Br.Cl.[CH3:4][N:5]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:13](=[O:22])[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]1[CH3:23].CC#N>CO.O>[Br:1][C:14]1[C:13](=[O:22])[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:23])[N:5]([CH3:4])[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(C)n(C)c(-c2ccccc2)cc1=O
Reactant: BrBr
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)c(=O)c(Br)c(-c2ccccc2)n1C
Temperature: 85 °C
Yield: 84.9 %

Procedure:
2.0 g (0.0125 mol) of bromine dissolved in 50 ml. of methanol is added dropwise over a 15 min. period to a solution of 2.7 g (0.00877 mol) ethyl 1,2-dimethyl-6-phenyl-4-oxonicotinate hydrochloride (Example 2) in 15 ml of methanol and 15 ml of water. The suspension formed is vacuum filtered and the filter cake, a yellow solid, is suspended in 60 g of 5% aqueous sodium hydroxide. The mixture is stirred and heated at 85° C. for 21/2 hrs. and is acidified with hydrochloric acid. The suspension formed is vacuum filtered to afford 2.4 g (85% yield) of 5-bromo-1,2-dimethyl-6-phenyl-4-oxonicotinic acid, mp 257°-258° C. (CH3CN).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH2:32]=[C:33]1[CH2:36][CH:35]([C:37](O)=[O:38])[CH2:34]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:37]([CH:35]2[CH2:36][C:33](=[CH2:32])[CH2:34]2)=[O:38])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: NCc1nccnc1Cl
Reactant: C=C1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C1CC(C(=O)NCc2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol, 1.4 eq.), 4-dimethylaminopyridine (DMAP) (0.141 g, 1.15 mmol, 0.25 eq.), and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) were dissolved in anhydrous CH2Cl2 (25 mL). To this solution, a solution of 3-methylenecyclobutanecarboxylic acid (0.622 g, 5.54 mmol, 1.2 eq.) in anhydrous CH2Cl2 (25 mL) was added under N2 and the reaction was allowed to stir overnight at rt. Reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with water (2×), NaHCO3 (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid. Additionally, the title compound could be prepared by the following route: 1,1′-Carbonyldiimidazole (CDI) (0.824 g, 5.08 mmol, 1.1 eq.) and 3-methylenecyclobutanecarboxylic acid (0.570 g, 5.08 mmol, 1.1 eq.) were dissolved in anhydrous THF (12 mL) and allowed to stir at 60° C. for 2 h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol) and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.) in anhydrous CH2Cl2 (13 mL) was added to the acid mixture and the reaction was allowed to stir at 60° C., under N2, overnight. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc, washed with NaHCO3 (2×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo, giving crude title compound, as a brown oil. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 2.86-2.96 (m, 2H), 3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78 (s, —NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, 1H); MS (ES+): m/z 238.19 (90) [MH+]; HPLC: tR=2.67 min (OpenLynx, polar—7 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1.[CH2:30]([N:32](CC)CC)[CH3:31].C(N)C.O>CN(C)C=O.CO>[CH2:30]([NH:32][S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)(=[O:17])=[O:16])[CH3:31]
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(=O)(=O)Cl)c3)nc(OC)n2)cc1
Reactant: CCN(CC)CC
Agent: CCN
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCNS(=O)(=O)c1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonylchloride [0.065 g, Intermediate (10)] and triethylamine (0.25 mL) in dimethylformamide (3 mL) is cooled to 0° C. and the treated with a solution of ethylamine in MeOH (3 mL, 2 M). The mixture is allowed to reach room temperature overnight and poured into water (100 mL). This mixture is extracted twice with EtOAc (100 mL). The combined extracts are washed with water, dried over sodium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give N-ethyl-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [20 mg, Example 4(b)]. MS: 443 (M+H), 1H NMR [(CD3)2SO]: δ 8.4 (1H, s); 8.2 (1H, m); 7.85 (1H, d, J=3 Hz); 7.75-7.8 (1H, m); 7.5-7.6 (2H, m); 7.2 (2H, d, J=7 Hz); 6.95 (2H, d, J=7 Hz); 6.6 (1H, s); 3.9 (3H, s); 3.7 (3H, s); 3.5-3.6 (2H, m); 2.8 (4H, m); 1 (3H, t). IC50=6.6 nM
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.N12CCCNC1CCCC=[CH:13]2.IC>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: C1=CN2CCCNC2CCC1
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: CC#N
Solvent: CI
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
20 ml acetonitrile was added to 4-bromophenylacetic acid (2 g, 9.3 mmol) and 1,8-diazabicyclo[5.4.0]undec-2-ene (1.7 g, 11.2 mmol) was added at 0° C. Iodomethane (1.98 g, 14.0 mmol) was slowly dropped to the mixture and stirred for 2 hours at room temperature. After the reaction is complete, the mixture was extracted using water (100 ml×2) and dichloromethane (100 ml). The title compound (1.7 g, 75%) was obtained by column chromatography (ethylacetate/n-hexane, 1/15).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][CH2:25][CH2:24][S:23]4(=[O:28])=[O:27])=[CH:18][C:17]=3[S:29]([CH3:32])(=[O:31])=[O:30])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:35]B(O)O>>[O:27]=[S:23]1(=[O:28])[CH2:24][CH2:25][CH2:26][N:22]1[C:19]1[CH:20]=[CH:21][C:16]([C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:33]=[CH:34][C:2]([CH3:35])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[O:15])=[C:17]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:18]=1
Reactant: CB(O)O
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)cc1
Yield: 50.7 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (138 mg) described in Preparation Example 22 and 4-(4-chlorobenzoyl)piperidine (97 mg) and by the reaction and treatment in the same manner as in Example 87, [4-(4-chlorobenzoyl)piperidin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylphenyl]methanone (76 mg) was obtained. Using the obtained [4-(4-chlorobenzoyl)piperidin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylphenyl]methanone (76 mg) and methylboronic acid (37 mg) and by the reaction and treatment in the same manner as in Example 115, the title compound (37 mg) was obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=[O:17])[CH2:15][CH3:16])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:34]2[CH2:40][CH:39]3[N:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:36]([CH2:37][CH2:38]3)[CH:35]=2)O1.FC(F)(F)S([O-])(=O)=O>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.O.C1(C)C=CC=CC=1.C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:34]2[CH2:35][CH:36]3[N:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:39]([CH2:38][CH2:37]3)[CH:40]=2)=[C:8]([C:14](=[O:17])[CH2:15][CH3:16])[CH:9]=1
Reactant: CCOC(=O)N1C2C=C(B3OC(C)(C)C(C)(C)O3)CC1CC2
Reactant: CCC(=O)c1cc(Cl)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1C2C=C(c3ccc(Cl)cc3C(=O)CC)CC1CC2
Temperature: 75 °C

Procedure:
To a mixture of 4-chloro-2-propionylphenyl trifluoromethanesulfonate (2-5) (21.0 g, 66.3 mmol), absolute ethanol (120 mL), toluene (120 mL), and 2M aqueous solution of sodium carbonate (100 mL) was added ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (2-3) (20.3 g, 66.3 mmol). The mixture was evacuated and flushed with nitrogen three times. After addition of tetrakis(triphenylphosphine)palladium(0) (7.69 g, 6.63 mmol), the mixture was heated at 75° C. for 1 h and TLC showed no remaining trifluoromethanesulfonate. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (2-6) as a colorless oil.
Reaction SMILES: C(OC([N:7]1[C@H:11]([CH2:12][C:13]2[S:17][C:16]3=[CH:18][N:19]=[CH:20][N:15]3[CH:14]=2)[CH2:10][C@H:9]([S:21][C:22]2[C@H:23]([CH3:39])[C@@H:24]3[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:25]3[C:26]=2[C:27]([O:29]CC=C)=[O:28])[CH2:8]1)=O)C=C.CNC1C=CC=CC=1.O.C(OCC)(=O)C>ClCCl.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:37][C@@H:35]([C@H:34]1[C:33](=[O:38])[N:25]2[C:26]([C:27]([OH:29])=[O:28])=[C:22]([S:21][C@H:9]3[CH2:10][C@@H:11]([CH2:12][C:13]4[S:17][C:16]5=[CH:18][N:19]=[CH:20][N:15]5[CH:14]=4)[NH:7][CH2:8]3)[C@H:23]([CH3:39])[C@H:24]12)[CH3:36]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4cncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CNc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](Cc4cn5cncc5s4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 16.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (16.4 mg) is added to a solution of 81.1 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate and 0.092 ml of N-methylaniline in 1.0 ml of dry dichloromethane, and the mixture is stirred in an argon atmosphere at room temperature for 45 min. Distilled water (3 ml) and 10 ml of ethyl acetate are added thereto remove insolubles. The aqueous layer is washed twice with 3 ml of ethyl acetate and concentrated under reduced pressure, and the concentrate is freeze dried to give a yellow flocculent material which is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 10.3 mg of the title compound as a colorless flocculent material.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:22])(=[O:21])[N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1.[OH-].[Na+]>CO>[CH3:20][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[S:12]([C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:23])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:21])=[O:22]
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)N(C)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(c1ccccc1)S(=O)(=O)c1cccc(C=CC(=O)O)c1
Yield: 94.5 %

Procedure:
3-[3-(Methylphenylsulfamoyl)phenyl]acrylic acid methyl ester (4b) (0.150 g, 0.45 mmol) was suspended in methanol (2 ml), 1 N NaOH solution (1.35 ml, 1.35 mmol) was added and the resultant solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 10% HCl and extracted with ethyl acetate. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed to give the title compound (0.135 g, 94%).