Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@]12C(=O)CC[C@H]1[C@H]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3CC1)[CH2:4]C2.N[CH2:22][C:23]([OH:25])=[O:24].[OH-].[Na+]>>[CH3:4][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=2[O:25][C:23](=[O:24])[CH:22]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)oc2cc(O)ccc12

Procedure:
4-Methylumbelliferyl sulfate (final concentration 0.3 mmol/L), recombinant human estrone sulfatase (7.8 ng/well) and an estra-1,3,5(10)-triene derivative of each test concentration (the estra-1,3,5(10)-triene derivative was dissolved in 0.001 mL of DMSO) were added to a phosphate buffer (pH 7.5, final volume 0.1 mL) containing 0.28 mol/L of sucrose and 0.04 mol/L of nicotinamide, and the mixture was subjected to enzymatic reaction at 37° C. for 1 hour. The recombinant human estrone sulfatase used herein was prepared from CHO (Chinese hamster ovary) cells, which were transfected with a human estrone sulfatase gene, after partial purification. After the enzymatic reaction, an aqueous solution of 2 mol/L glycine-sodium hydroxide (pH 10.3, 0.13 mL) was added thereto followed by stirring. Using a fluorescent plate reader (Cyto Fluor II), the fluorescent intensity of 4-methylumbelliferone formed in the system was measured. The measurement was carried out at one time by duplication, and the assay fluctuation was 10% or less. The enzymatic reaction in the absence of the test compound was also carried out simultaneously. The inhibitory activity against estrone sulfatase of the test compound of each concentration was calculated according to the equation shown below. Inhibitory Activity against Estrone Sulfatase (%)=100−[100×(A/B)] wherein;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH3:23][O:22][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:25](=[O:26])[O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Product: CCOC(=O)Nc1ccc(C(=O)c2c(C)c(OC)c3ccccn23)cc1OC

Procedure:
This compound was obtained according to the same procedure as that described in Example 199 by acylation of (4-amino-3-methoxyphenyl)(1-methoxy-2-methylindolizin-3-yl)methanone with ethyl chloroformate. The product is purified by flash chromatography on silica, eluting with dichloromethane. A yellow powder is obtained.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([Mg]Br)[CH:2]=1.C([O:12][CH2:13][C:14]([O:16][CH3:17])=O)C>O1CCCC1.C(O)=O>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([C:13]([C:3]2[CH:2]=[C:1]([CH3:9])[CH:6]=[CH:5][CH:4]=2)([OH:12])[CH2:14][O:16][CH3:17])[CH:2]=1
Reactant: Cc1cccc([Mg]Br)c1
Reactant: CCOCC(=O)OC
Solvent: C1CCOC1
Solvent: O=CO
Product: COCC(O)(c1cccc(C)c1)c1cccc(C)c1

Procedure:
A solution of 1,1-bis(3-tolyl)-2-methoxyethanol (24.66 g) (obtained by the reaction of 3-tolylmagnesium bromide with methyl 2-ethoxyacetate in tetrahydrofuran) in formic acid (30 cc) is heated to reflux for 12 hours, cooled and poured into a mixture of saturated sodium carbonate solution (400 cc) and ethyl acetate (400 cc). The organic phase is washed with water (3×300 cc) and with saturated sodium chloride solution (300 cc) then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis(3-tolyl)acetaldehyde (20.45 g) in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH:27]=O)[N:20]=2)[N:10]=[N:9]1.[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH2:27][NH:36][CH2:35][CH2:34][O:33][CH3:32])[N:20]=2)[N:10]=[N:9]1
Reactant: COCCN
Reactant: O=Cc1cccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)c1
Product: COCCNCc1cccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)c1

Procedure:
The title compound was prepared following the procedure described for Example 94, starting from 3-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (100 mg; 0.24 mmol) and 2-methoxyethanamine (36.4 mg; 0.48 mmol) to give Example 147 as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.62, 1.58 Hz), 8.05 (1H, s), 7.95-7.85 (2H, m), 7.76-7.69 (1H, m), 7.64-7.49 (6H, m), 3.90 (2H, s), 3.47 (2H, t, J=5.6 Hz), 3.29 (3H, s), 2.76 (2H, t, J=5.6 Hz). LC/MS (Method C): 472 (M+H)+. HPLC (Method E) Rt 2.18 min (Purity: 94.9%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[N:10]=[C:9]2[C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:35]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[N:10]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(CO)c1cn(-c2ccc(Br)cc2)c(-c2c(Cl)cccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(CO)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2c(Cl)cccc2Cl)n1
Temperature: 60 °C
Yield: 14.8 %

Procedure:
A stirred mixture of 2-[1-(4-bromophenyl)-2-(2,6-dichlorophenyl)-1H-imidazol-4-yl]-2-methyl-propan-1-ol (202 mg, 0.46 mmol), 3-methanesulfonyl-phenylboronic acid (92 mg, 0.46 mmol), potassium carbonate (0.19 g, 1.4 mmol), Cl2 Pd(dppf).DCM (19 mg, 5 mol %) and H2O (0.25 mL) in DME (2.5 mL) was sparged with Argon for 5 min and then heated at 60° C. as a sealed flask. After 30 min the reaction mixture was concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 40:60 to 75:25) to give the title compound (35 mg) as a white solid. 1H-NMR (DCM-d2): δ 8.10 (m, 1H), 7.91 (d, 1H), 7.85 (d, 1H), 7.66 (m, 1-1), 7.60 (d, 2H), 7.29-7.37 (m, 5H), 7.10 (s, 1H), 3.79 (br s, 1H), 3.62 (s, 2H), 3.06 (s, 3H), 1.36 (s, 6H); MS (ES): 515, 517 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccnc(Cl)c2)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(-c2cc(Cl)c3ccccc3n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 250 mL RBF was added 4.6 g (18 mmol) 2-(2-chloro-pyridin-4-yl)-quinolin-4-ol and 100 mL POCl3, and the mixture was treated with 3.1 mL DIEA (18 mmol). The mixture was was stirred at rt for 1 h, and all starting material was converted. All POCl3 was vacuumed down. The residue was dissolved in 250 mL DCM, washed with saturated NaHCO3 carefully to pH 8. The organic phase was dried over Na2SO4, concentrated and purified by column and yielded pale yellow 4-chloro-2-(2-chloro-pyridin-4-yl)-quinoline. MS (ES+): 275 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13]>[Cu](I)I.C(N(CC)CC)C>[OH:14][CH2:10][CH2:11][C:12]1[O:9][C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH:13]=1
Reactant: Oc1cccc(Br)c1O
Reactant: C#CCCO
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: OCCc1cc2cccc(O)c2o1

Procedure:
As shown in Scheme 17, 3-bromo-1,2-benzenediol is treated with bis-triphenylphosphine palladium dichloride, copper iodide, triethylamine, and 3-butyn-1-ol and heated at between 40° C. and 80° C. for several hours or until TLC (thin layer chromatography) indicates the reaction is complete to provide 2-(2-hydroxyethyl)-1-benzofuran-7-ol. 2-(2-Hydroxyethyl)-1-benzofuran-7-ol is then processed according to procedures described for Examples 203-224 as shown as in Scheme 15 to provide 2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-7-yl trifluoromethanesulfonate, which is processed as described in Murata, et al., Journal of Organic Chemistry (2000) 65, 164-168 and followed by treatment with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides, a palladium catalyst, such as palladium (II) acetate, a trivalent phosphine such as biphen-2-yl-dicyclohexylphosphine, and aqueous sodium carbonate or potassium phosphate in an organic solvent such as ethanol or tetrahydrofuran at 25° C. to 120° C. to provide compounds formula (53). Compounds of formula (53) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (53) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Reaction SMILES: Cl.[Cl:2][CH:3]([C:17]1[CH:18]=[CH:19][C:20]([O:27][CH3:28])=[C:21]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=1)[CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]>CO.[C].[Pd]>[ClH:2].[CH3:28][O:27][C:20]1[CH:19]=[CH:18][C:17]([CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[CH:22][C:21]=1[S:23]([NH2:26])(=[O:25])=[O:24]
Reactant: COc1ccccc1OCCNCC(Cl)c1ccc(OC)c(S(N)(=O)=O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccccc1OCCNCCc1ccc(OC)c(S(N)(=O)=O)c1
Yield: 88.3 %

Procedure:
In 150 ml of methanol was dissolved 3.8 g of 5-{1-chloro-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methoxybenzenesulfonamide hydrochloride and after adding thereto 0.5 g of 10% palladium carbon, it was dechlorinated under a hydrogen stream at normal temperatureand pressure. Then, palladium carbon was filtered away and the filtrate wasconcentrated under reduced pressure to provide 3.1 g of 2-methoxy-5-{2-[2-(2-methoxyphenoxy)ethylamino]ethyl}benzene-sulfonamide hydrochloride, which was recrystallized from 120 ml of a mixture of methanol and ethanol (1:4 by volume ratio) to provide 2.3 g of the colorless crystals thereof.
Reaction SMILES: [OH-].[Na+].O.Cl.[CH2:5]([NH2:7])[CH3:6].[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13]>CO>[Br:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:7][CH2:5][CH3:6])=[O:13]
Reactant: CCN
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNC(=O)c1cccc(Br)c1
Reaction time: 0.08 h
Yield: 95.2 %

Procedure:
To a solution of sodium hydroxide (3.80 g) in methanol (50 ml)—water (15 ml) was added by portions ethylamine hydrochloride (7.80 g) at 0° C. and the mixture was stirred for 5 min. 3-Bromobenzoyl chloride (5.53 g) was added dropwise and the mixture was stirrd at room temperature for 1 h. Methanol was evaporated under reduced pressure, and ethyl acetate was added to the residue for partitioning. The organic layer was washed with water and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (5.47 g) as colorless powder crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][CH2:12][CH2:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH2:13][CH2:12][Cl:11])=[O:16])(=[O:24])=[O:25])=[O:28])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(=O)OCCCl
Reactant: COc1nc(C)nc(N)n1
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OCCCl)n1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To 0.7 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 10 ml anhydrous methylene chloride solvent was added 1.45 g 2-(β-chloroethoxycarbonyl)benzenesulfonyl isocyanate with stirring at ambient temperature. The mixture was thereafter stirred for sixteen hours. The solvent was evaporated under reduced pressure and the residue triturated with hexane and filtered to yield 1.72 g of compound which melted at 167°-170° C. The solid showed infrared absorption peaks at 1700 and 1705 cm-1, consistent for N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-(2-chloroethoxycarbonyl)benzenesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:19])=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To 5.4 g of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid in 50 mL of methanol and 100 mL of chloroform was at 0° C. was added 15 mL of 2 M (trimethylsilyl)diazomethane in hexanes. After allowing the reaction to warm to ambient temperature and stirring for 2 hours, the solvents were removed and the crude product purified by passing through a plug of silica gel with chloroform. The product was then recrystallized from hexanes to give 5.8 g (100%) of 5-tert-butoxycarbonylamino-2-chloro-isonicotinic acid, methyl ester: mp=90-96° C. (decomposed); mass spectrum (m/e): M+H 287.1.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH:12]=[CH:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[O:24]1[CH:12]2[CH:11]1[CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][CH:2]3[O:1][CH2:15]3)[C:14]=1[CH2:13]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=CCc2c(cccc2OCC2CO2)C1
Solvent: ClCCl
Product: c1cc2c(c(OCC3CO3)c1)CC1OC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a well-stirred solution of 7 g. (0.03 m.) of 1-(2,3-epoxy-propoxy)-5,8-dihydro-naphthalene (prepared as described in application Ser. No. 768,176, filed Oct. 16, 1968, issued Oct. 13, 1970, as U.S. Pat. No. 3,534,085) in 60 ml. of CH2Cl2, 7.1 g. (0.03 m.) of 85% m-chloroperbenzoic acid in 100 ml. CH2Cl2 is added dropwise at such a rate that the temperature is maintained between 25° to 30° C. The mixture is stirred overnight at room temperature. The resulting precipitate (m-chlorobenzoic acid) is filtered off and the CH2Cl2 extract is washed successively with sat. NaHCO3 solution, and water. After drying (MgSO4), the solution is evaporated in vacuo to give 7.2 g. (95%) of oil which solidifies. A sample recrystallized from ether gives white needles, m.p. 85°-87°; λNujolmax 1330-1350 cm-1 (epoxy), ƱCDCl3 absence of vinyl protons 4.0-4.2 region.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH2:18].[S-:19][C:20]#[N:21].[K+].BrBr>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:5]=[C:4]([S:19][C:20]#[N:21])[C:3]=1[NH2:18]
Reactant: N#C[S-]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(SC#N)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 2-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine (5.0 g, 18.20 mmol) (prepared according to EP 1,006,102) in acetic acid (30 ml) was added a solution of potassium thiocyanate (7.25 g, 74.62 mmol) in acetic acid (20 ml). The solution was cooled to 5° C. before the addition of bromine (3.2 g, 1.03 ml) in acetic acid (10 ml). The reaction mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 3 hours. The reaction mixture was quenched by pouring into water. The mixture was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed successively with aqueous sodium hydroxide (10 g/l) (100 ml), water (100 ml) and brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3) to give 2-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-6-thiocyanato-phenylamine (3.7 g, 61.2% yield). 1H-NMR (CDCl3, 400 MHz): 7.68 (s, 1H), 7.33 (s, 1H), 5.73 (s, 2H), 2.59 (s, 6H) ppm.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:22])=[CH:19][CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.C(N(CC)CC)C>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](=[O:28])[NH:11][C@@H:10]3[CH2:9][CH2:8][C:7]4[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=4[N:5]4[CH:1]=[CH:2][N:3]=[C:4]34)[CH2:25][CH2:26]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(Cl)cc1
Temperature: -20 °C
Yield: 93.58 %

Procedure:
Concentrate the ethanolic solution of (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine to dryness prior to use in the coupling reaction. Dissolve 15.0 g (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine and 18.03 g 1-[(4-Chlorobenzoyl)amino]cyclopropanecarboxylic acid in 120 ml of dichloromethane and 32 ml triethylamine. After cooling to −20° C., add 53.0 ml (1.2 eq.) of T3P within 40 minutes maintaining a temperature of −19° C. Allow the reaction to warm to room temperature over night. Test by HPLC for complete consumption of starting materials. After aqueous quench (75 ml of water) at 0 to 6° C. and further dilution with dichloromethane (precipitating solids dissolved after adding additional 180 ml of dichloromethane), separate the phases. Wash the organic layer two times with 75 ml of water and then back-extract the combined aqueous layers once with 75 ml of dichloromethane. Concentrate the organic extract phases (420 ml) removing 290 ml of solvents (beginning precipitation of solids). Add 240 ml of isopropyl acetate and then remove a further 250 ml of solvents. Warm the resulting thick suspension to 70° C., add 30 ml of n-heptane and slowly cool the suspension to room temperature over night. Filter the suspension via glass filter nutsch and wash the filter cake with n-heptane. After drying with a rotavap, results in a pale brown solid, 29.65 g (93.58% yield, HPLC (achiral). LC-MS (mass spectrometry) (m/z): 421.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1>C(OCC)C>[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:29])[C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=4[CH:12]=3)=[O:27])[CH2:23][CH2:24]2)=[CH:16][CH:15]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: CCOCC
Product: O=C1COc2ccc(NC(=O)C(=O)N3CCC(Cc4ccc(F)cc4)CC3)cc2N1

Procedure:
The title compound is prepared from 6-amino-4H-benzo[1,4]oxazin-3-one [Indian J. Chem. Sect. B, 24, 1263. (1985)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) according to the method described in Example 2. Melting Point: 197-200° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:20][C:21]1[CH:29]=[C:28]([I:30])[CH:27]=[C:26]([F:31])[C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:29]=[C:28]([I:30])[CH:27]=[C:26]([F:31])[C:22]=1[C:23]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:24]
Reactant: O=C(Cl)c1c(F)cc(I)cc1Cl
Reactant: Nc1ccnc(Cl)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccnc(Cl)c1F)c1c(F)cc(I)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 2-chloro-3-fluoro-pyridin-4-amine (3.31 g, 22.6 mmol) in THF (50 mL) at 0° C. was slowly added LiHMDS in THF (1.0 M, 45 mL). The mixture was warmed to room temperature and allowed to stir for 1 hour. It was then cooled to −78° C. A THF solution of 2-chloro-6-fluoro-4-iodo-benzoyl chloride (15.1 mmol, 15 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hour. The reaction was then quenched with sat. NH4Cl, extracted with EtOAc (3×). The combined organics were dried over Na2SO4, concentrated. The crude product was purified by silica gel column chromatography (0-25% EtOAc/hexane) to give the title compound (4.97 g, 76.8% yield) as an off-white solid. 1H NMR (400 MHz, methanol-d4) δ 8.37 (t, J=5.4 Hz, 1H), 8.18 (d, J=5.5 Hz, 1H), 7.80 (s, 1H), 7.69 (dd, J=8.2, 1.2 Hz, 1H). LCMS (ESI) m/z 429.0 [M+H+].
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]>>[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([NH2:7])=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 221-223° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.47-7.37 (m, 4H), 7.20-7.15 (m, 1H), 4.43 (s, 2H), 4.03-3.98 (m, 2H), 3.50-3.45 (m, 2H), 2.46 (s, 3H); MS (ES+) m/z 352.7 (M+1).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH2:6]([CH:8]1[CH:12]([CH3:13])[CH2:11][N:10]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[C:9]1=[C:25]=[O:26])[CH3:7]>>[CH2:6]([CH:8]1[CH:12]([CH3:13])[CH2:11][N:10]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:23][CH:24]=2)=[O:15])[C:9]1=[C:25]=[O:26])[CH3:7]
Reactant: CCC1C(=C=O)N(C(=O)NCCc2ccccc2)CC1C
Reactant: O=S(=O)(O)Cl
Product: CCC1C(=C=O)N(C(=O)NCCc2ccc(S(=O)(=O)Cl)cc2)CC1C
Temperature: 32.5 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0–5° C.) solution of chlorosulfonic acid (22.4 ml), 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene (15 gm) was added in small portions over a period of 1 to 2 hrs. Further it was stirred for 30 minutes at this temperature and then temperature was gradually raised to 30 to 35° C. and stirred for 5 hrs. The reaction mixture was quenched into ice-water, and stirred for 1 hr and filtered to obtain the product 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonyl chloride (18.8 g). To a cooled (0–5° C.) solution of concentrated ammonia (100 ml), 4[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonyl chloride (10 gm) was added in small portions over 30 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then the reaction mixture was allowed to come to room temperature and then stirred for 5 hrs and filtered and dried to obtain 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonamide (7.9 gm) having HPLC purity of about 83 to 85%.