Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:14])[C@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[S:23]([NH:26][C:27]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30])(=[O:25])=[O:24]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[S:23]([NH:26][C:27]1[CH:35]=[C:34]([I:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:13][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:14])=[O:30])(=[O:25])=[O:24]
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: Cl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1ccc(I)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
(R)-2-(tert-Butoxycarbonylamino)-3-phenyl-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-phenyl-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 2-(2,6-difluoro-benzenesulfonylamino)-4-iodo-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=9.27 min. MS (ESI−): mass calcd. for C22H17F2IN2O5S, 585.99; m/z found, 584/586 [M−H]. 1H NMR (500 MHz, CDCl3): 11.32 (s, 1H), 8.11 (s, 1H), 7.50-7.46 (m, 1H), 7.38-7.28 (m, 4H), 7.16-7.15 (m, 2H), 7.00-6.96 (m, 3H), 6.51 (d, J=7.6, 1H), 5.07-5.03 (m, 1H), 3.34 (dd, J=14.0, 5.6, 1H), 3.25 (dd, J=14.3, 5.3, 1H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:19](=[O:20])[N:8]2[CH:9]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]12)=[O:4].C(N(CC)CC)C.[SH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][C:29]([S:28][CH2:2][C:3]([NH:5][CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:14]4[NH:18][N:17]=[N:16][N:15]=4)[C:10]([CH3:13])([CH3:12])[S:11][C@H:7]23)=[O:4])=[CH:30][CH:31]=1
Reactant: Sc1ccncc1
Reactant: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(=O)CSc3ccncc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
To a stirred suspension of 1.0 g (0.0028 mole) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.28 g (0.0028 mole) of triethylamine. The mixture is stirred at ambient temperature until a clear solution is obtained, and then 0.39 g of 4-mercaptopyridine is added. Stirring is continued for a further 4 hours at ambient temperature, and then the solid which has precipitated is filtered off. It is washed with methylene chloride, followed by ether, to give 0.68 g (78% yield) of 6(2-[4-pyridylthio]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, m.p. 120° C. (dec.). The infrared spectrum of the product (KBr disc) shows absorption bands at 1790 cm-1 (β-lactam), 1670 cm-1 (amide II). The NMR spectrum (DMSO-d6) shows absorption bands at 9.0-7.0 ppm (multiplet, pyridine hydrogens), 5.9-5.5 ppm (multiplet, C-5 and C-6 hydrogen), 4.0 ppm (singlet, methylene hydrogens), 1.7 ppm (singlet, C-2 methyl hydrogens) and 1.1 (singlet, C-2 methyl hydrogens).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][N:12]=[N+]=[N-])=[CH:6][C:5]=1[O:15][CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH3:1][NH:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][NH2:12])=[CH:6][C:5]=1[O:15][CH2:16][CH3:17]
Reactant: CCOc1cc(CN=[N+]=[N-])c(Br)cc1C(=O)NC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(CN)c(Br)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 96 h
Yield: 104.7 %

Procedure:
After dissolving the N1-methyl-4-(azidomethyl)-5-bromo-2-ethoxybenzamide (5.32 g) in tetrahydrofuran (50 ml) and water (3 ml), triphenylphosphine (5.4 g) was added and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (5.11 g) as a light yellow solid.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].CO.[BH4-].[Na+]>C1COCC1>[C:1]([CH2:3][C@@H:4]([OH:16])[CH2:5][C@@H:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CC#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate (10 g, 0.044 mol) in THF (60 mL) was stirred under nitrogen and methanol (20 mL) was added. The reaction mixture was stirred for 15 min. and cooled to −50° C. to −55° C. CeCl3.7H2O (16.4 g, 0.044 mol) was added and stirred for 30 min., maintaining the temperature between −50 and −55° C. Sodium borohydride (2.5 g, 0.066 mol) was added in 6 portions maintaining the temperature between −70 and −90° C. The resulting mixture was stirred for 1 h at the same temperature. After warming the reaction mixture to RT, it was concentrated to a residue under vacuum at about 45° C. Methanol (60 mL) was added and the resulting mixture was concentrated. The resulting residue was cooled to RT, water (50 mL) was added and the resulting aqueous mixture was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine solution (50 mL), and concentrated to obtain title compound. Yield: 5 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][O:12][C:13]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:14]=1[CH2:15][C:16]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:17]=1[O:18][CH:19]([CH3:23])[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1[CH:35]=CC2N(O)N=[N:40][C:38]=2[CH:39]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.N1CCCC1>C(#N)C>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][O:12][C:13]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:14]=1[CH2:15][C:16]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:17]=1[O:18][CH:19]([CH3:23])[C:20](=[O:22])[N:40]1[CH2:35][CH2:34][CH2:39][CH2:38]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCNC1
Product: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)OCc1ccccc1)C(=O)N1CCCC1

Procedure:
To a suspension of 2-[2-(2-benzyloxycarbonylmethoxy-5-chloro-benzyl)-4-chloro-phenoxy]-propionic acid (Intermediate A) (100 mg, 0.204 mmol), HOBt (27.6 mg, 0.204 mmol) and PS-CDI (326.4 mg, 1.25 mmol/g, 0.408 mmol) in acetonitrile (15 mL) is added pyrrolidine (17.1 μL, 0.204 mmol). The reaction mixture is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 100° C. for 5 minutes. The PS-CDI resin is removed by filtration, rinsing with DCM and MeOH and the filtrate is concentrated in vacuo. The crude product is dissolved in EtOAc (50 mL) and washed with water (50 mL), aqueous sodium carbonate solution (30 mL), brine (50 mL) and then dried (MgSO4). The solvent is removed in vacuo and purification of the crude product by chromatography on silica eluting with EtOAc/iso-hexane (1:4) affords the titled product as a racemic mixture; MH+=542.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[O:20][CH:21]=[CH:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[O:20][CH:21]=[CH:22][C:23]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: Cc1occc1C(=O)O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1occc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 4 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.3 mg (0.09 mMol) 2-methyl-3-furoic acid, 0.4 mg (4%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])=[CH:4][CH:3]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[N:16]1[CH:15]=[CH:14][C:13]([C:10](=[N:11][OH:12])[CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:3][CH:4]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[CH:18][CH:17]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(Br)cc1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(-c2cncnc2)cc1

Procedure:
In analogy to example 22, from 3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 31) and pyrimidine-5-boronic acid was prepared the title compound as a mixture of E and Z isomers (2.3:1) as a white foam, MS (ESI+): m/z=395.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=[O:9])=[CH:4][CH:3]=1.[C:12]([OH:17])(=[O:16])[CH:13]([CH3:15])O.B(F)(F)F.CCOCC>CCOCC.O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]2[O:17][C:12](=[O:16])[CH:13]([CH3:15])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=CCOc1ccc(Cl)cc1
Reactant: CC(O)C(=O)O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1OC(COc2ccc(Cl)cc2)OC1=O
Reaction time: 24 h

Procedure:
To a solution of 17.05 g (0.07 mole) of 4-chlorophenoxyacetaldehyde in 100 ml of ether was added 9.0 g (0.1 mole) of lactic acid dissolved in 50 ml of tetrahydrofuran. To the clear solution was added 15 g (0.105 mole) of boron trifluoride etherate. After 24 hours at ambient temperature, the reaction mixture was washed with aqueous sodium bicarbonate, dried, concentrated, and purified by silica chromatography. The first fraction that emerged from the column was 2-(4-chlorophenoxymethyl-10-5-methyl-1,3-dioxolan-4-one, the transisomer, having a melting point of 37°-40°. The second fraction was the cis isomer which melted at 53°-55°.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH:23](N1CCOCC1)=[O:24].Cl>C1COCC1.C1CCCCC1>[F:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH:10]=[CH:11][C:12]=1[CH:23]=[O:24]
Reactant: O=CN1CCOCC1
Reactant: Fc1cccc(-c2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=Cc1ccc(-c2ccc3ccccc3c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A 86.86 ml cyclohexane solution of sec-butyl lithium in a concentration of 1.01M was dropped into a 300 ml THF solution of 15.00 g (=67.49 mmol) of 2-(3-fluorophenyl)naphthalene at −70° C. After the dropping was finished, the reaction solution was stirred at the same temperature for 1 hour, added with a 150 ml THF solution of 10.88 g (=94.49 mmol) of 4-formylmorpholine through dropping and then slowly heated to room temperature. After being stirred for 18 hours, 25 ml of 6N HCl(aq) was dropped into the reaction solution, and then the reaction mixture was extracted thrice with toluene. The extract was washed with water and an aqueous solution of NaHCO3, and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellow solid of 16.83 g was purified with silica gel chromatography using toluene as the eluent to obtain a yellowish solid of 13.26 g, which was further recrystallized with toluene to obtain 10.09 g of 2-fluoro-4-naphthalene-2-yl-benzaldehyde as yellowish crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 58.6 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-ethanone (5.3 g, 22 mmol), and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]#[N:22])=[N:4][CH:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])[CH:7]=1>C(O)C.Cl.[Pd].C>[NH2:22][CH2:21][C:3]1[N:4]=[CH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[C:17]([F:20])([F:18])[F:19])=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc(Nc2cnc(C#N)c(Cl)c2)c(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(Nc2cnc(CN)c(Cl)c2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridine-2-carbonitrile (0.64 mmol) in 10 mL ethanol and 0.1 mL hydrochloric acid (37%) was combined with 30 mg of Pd/charcoal (10%) and hydrogenated with stirring at ambient temperature. Then the catalyst was filtered off and the solution was evaporated down. The product thus obtained was reacted further without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[ClH:12]>C(OCC)C>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([Cl:12])([CH3:11])[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: CC1=CCC2(CC1)OC2(C)C
Reactant: Cl
Solvent: CCOCC
Product: CC1=CCC(O)(C(C)(C)Cl)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 15.2 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 200 ml of diethyl ether held at -10° C. was added dropwise 32 ml of 3.8N ethereal hydrogen chloride. After one hour at 0°-5° C., the mixture was washed with three 50 ml portions of water, dried and distilled to give 14.5 g of the desired product, b.p. 70°-75° C. (0.4 mm).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:27])([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14](=[O:28])[C:13]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>ClCCl>[F:7][CH2:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:27])([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14](=[O:28])[C:13]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)N1COC(CO)=C(c2ccccc2)C1=O
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)N1COC(CF)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethylaminosulphur trifluoride (1.27 ml) was added to a stirred solution of tert butyl 2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (3.5 g) in dichloromethane at -78° C. After 0.5 hour the solution was allowed to warm to room temperature and stirred for 16 hours. The mixture was poured into saturated ammonium chloride solution and the organic phase washed (brine), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica get, eluting with dichloromethane/hexane (1:1) to give tert butyl 2-(6-fluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (1.31 g) as a white solid, m.p. 80.5-82.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:20])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:20]=[C:9]2[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])([CH3:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=N)Nc1ccc(Br)cc1)c1ccccc1F
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(Br)cc2)c(C(C)(C)c2ccccc2F)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a 250 mL round bottom flask attached with condenser was added N-(4-bromophenyl)-2-(2-fluorophenyl)-2-methylpropanimidamide (5.0 g, 15 mmol), anhydrous THF (80 mL), NaHCO3 (2.52 g, 30 mmol), and 90% ethyl bromopyruvate (1.90 mL, 15.1 mmol). The reaction mixture was stirred at 70° C. for 2 hr prior to analysis by LCMS. The cooled reaction mixture was decanted and concentrated in vacuo. The residue was taken into toluene (65 mL) and acetic acid (1.8 mL). The solution was stirred at reflux for 1 hr. The cooled solution was washed with H2O (150 mL×3), dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a SiO2 column using a 100% Hx to 70% EtOAc gradient to afford purified title compound (4.3 g, 67% yield). LCMS (ES): m/z=431.3, 433.3 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][N:9]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:30](=[O:37])[NH:31][C:32]2[S:33][CH:34]=[N:35][N:36]=2)[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:10][CH2:11][O:12][CH3:13])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:25]1([CH2:24][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([S:14]([N:9]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:7][C:6]([OH:38])=[O:5])(=[O:16])=[O:15])=[CH:18][CH:19]=2)[C:30](=[O:37])[NH:31][C:32]2[S:33][CH:34]=[N:35][N:36]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COCCN(CCC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nncs2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(CCC(=O)O)S(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 75 mg (0.133 mmol) of title F compound, 3-[{4-[2-cyclopentyl-1-([1,3,4]thiadiazol-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-(2-methoxy-ethyl)-amino]-propionic acid tert-butyl ester is added 2 mL of DCM and 0.5 mL of trifluoroacetic acid. The reaction mixture is stirred at ambient temperature for one hour. The reaction is evaporated to a brownish resin and subsequently dissolved in ether and decanted from some insoluble material. The organic layer is evaporated to a light orange resin which is dissolved in 2 mL methanol in a 50 mL round bottom flask. Aqueous potassium hydroxide (0.265 mL of 0.5094 M potassium hydroxide solution) is added and stirred for 30 min. The methanol is evaporated, 8 mL of water added, and the mixture lyophilized to afford 3-[{4-[2-cyclopentyl-1-([1,3,4]thiadiazol-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-(2-methoxy-ethyl)-amino]-propionic acid as a light orange-brown solid: 1H NMR (400 MHz, DMSO-d6) δ 1.1 (m, 1H), 1.4 (m, 1H), 1.6 (m, 2H), 1.7 (ddd, J=13.1, 6.9, 6.7 Hz, 2H), 2.1 (ddd, J=11.2, 8.2, 7.8, 2H), 3.2 (s, 2H), 3.2 (m, 3H), 3.7 (t, J=7.5 Hz, 1H), 7.56 (d, J=8.3, 2H), 7.63 (d, J=8.3 Hz, 2H), 8.58 (s, 1H); L/MS 511 (M+1), 509 (M−1). EC50 in primary enzyme assay 50 μM.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[CH3:38])[NH2:31]>>[CH3:38][C:37]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:30]1[N:31]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:26][N:29]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: Cc1ccncc1C(N)=NO
Product: Cc1ccncc1-c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
250 mg (about 0.520 mmol) of the compound from Example 49A and 87 mg (0.580 mmol) of N′-hydroxy-4-methylpyridine-3-carboximidamide (Example 70A) were reacted according to the General Method 1. Yield: 22 mg (8% of theory).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:21][C:22](=[O:52])[N:23]([CH2:36][C:37]2[CH:51]=[CH:50][C:40]([C:41]([NH:43][CH2:44][C@@H:45]([OH:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:39][CH:38]=2)C2C=CC(C3CCCCC3)=CC=2)[CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])(C(C)(C)C)(C)C.[F-].[Cs+].[C:55](#N)[CH3:56].O>>[CH:10]1([C:56]2[CH:55]=[CH:39][C:38]([CH:36]([NH:23][C:22]([NH:21][C:12]3[CH:13]=[CH:14][C:15]([O:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH2:9][OH:8])[CH:11]=3)=[O:52])[C:37]3[CH:51]=[CH:50][C:40]([C:41]([NH:43][CH2:44][C@@H:45]([OH:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:39][CH:38]=3)=[CH:37][CH:36]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC#N
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(NC(=O)N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)c2ccc(C3CCCCC3)cc2)ccc1OC(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)c(CO)c1)NC(c1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
(R)-3-{4-[3-[3-(tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid (17 mg, 0.023 mmol) was dissolved in acetonitrile:water (9:1) (2 mL) and caesium fluoride (35 mg, 0.35 mmol) added. The reaction mixture was stirred at 80° C. for 6 hours and additional amounts of caesium fluoride (35 mg) added. The mixture was stirred at 60° C. overnight, concentrated in vacuo and diluted with ethyl acetate (10 mL) and water (5 mL). The organic phase was washed with water (3×5 mL) and dried with magnesium sulphate and concentrated in vacuo. The residue was purified by preparative HPLC affording the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]([C:24]1[CH:43]=[CH:42][C:27]([CH2:28][CH:29]([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[CH:26][CH:25]=1)=[O:23]>CN(C=O)C>[CH3:20][O:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][C:29]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)([C:36]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[CH:42][CH:43]=1)=[O:23]
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 62.66 g (192 mmol) of cesium carbonate and 46.75 g (154 mmol) of methyl 4-(2-bromoethyl)benzoate [CAS Reg. No. 136333-97-6] are added to a solution of 42.61 g (128 mmol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate in 450 ml of DMF. The mixture is then stirred at room temperature overnight. After the reaction has gone to completion, the reaction solution is evaporated to dryness, and the residue is taken up in water and extracted three times with ethyl acetate. The combined organic phases are then washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is removed to dryness under reduced pressure. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 13:1). This gives 41.35 g (83.6 mmol, 65% of theory) of a colorless solid.