Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])=[O:11])=O)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)=[O:21])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2S, 4R)-2-[(t-butoxycarbonylamino)methylcarbonyl]aminomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5.30 g) in a mixture of anisole (1 ml) and trifluoroacetic acid (50 ml) was stirred at ambient temperature for 1 hour. The mixture was evaporated under reduced pressure to give (2S, 4R)-2-(aminomethylcarbonyl)aminomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine. To a solution of the compound obtained above in a mixture of water (25 ml) and tetrahydrofuran (25 ml) was added a solution of potassium cyanate (4.75 g) in water (15 ml) at 40°~50° C., keeping the pH between 4-5 with concentrated hydrochloric acid. Tetrahydrofuran was removed by evaporation to give an aqueous solution. The aqueous solution was adjusted to pH 6.0 with 1N hydrochloric acid, subjected to a column chromatography on nonionic adsorption resin, "Diaion HP-20" (50 ml), washed with water, and eluted with a mixture of methanol and water (50:50 v/v). The fractions containing the desired compound were collected, concentrated under reduced pressure, and recrystallized from a mixture of methanol and diisopropyl ether to give (2S, 4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[(ureidomethylcarbonyl)aminomethyl]pyrrolidine (3.93 g).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CON(C)[C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[N:14][CH:13]=1>C1COCC1>[CH3:7][N:6]1[C:2]([C:11]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)=[O:22])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Solvent: C1CCOC1
Product: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 5.300000190734863 °C
Reaction time: 1 h

Procedure:
To a 3 L 4-neck flask equipped with an overhead stirrer, nitrogen bubbler, and thermocouple was added 5-bromo-1-methyl-1H-imidazole (47.96 g, 297.9 mmol), followed by THF (537 mL). To this room temperature solution was added isopropylmagnesium chloride/lithium chloride complex [1.3 M] (246.8 mL, 320.8 mmol) (addition temperature maintained between 16.6 and 25° C.) to afford a milky suspension and the reaction was stirred for 60 minutes and then cooled to 5.3° C. in an ice bath. To this mixture was added a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (53.66 g, 229.14 mmol, Intermediate 15, step b) in THF (268.3 mL) (addition temperature between 5.3 and 5.6° C.) to afford an orange mixture. After addition, the reaction was warmed to room temperature over 2 hours. After stirring at room temperature for 18 hours, THF (200 mL) was added and the reaction was stirred for 2 hours. The reaction was then cooled to 4° C. with an ice bath and carefully quenched with 2N HCl to a pH=7, quenching temperature reached 12° C. The mixture was diluted with ethyl acetate (500 mL), phase split and the organic layer was washed with brine (2×200 mL) and dried over sodium sulfate, filtered, and the solvent was removed. Hot ether was added and then filtered to give the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([OH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1)c1ccccc1
Reactant: Oc1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(NC1Cc2cc(Oc3ccccc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 200 °C
Reaction time: 16 h
Yield: 7.1 %

Procedure:
A suspension of 87B (55 mg, 0.12 mmol), phenol (33.9 mg, 0.36 mmol), K2CO3 (50 mg, 0.36 mmol) and copper iodide (17.1 mg, 0.09 mmol) in DMF (1.0 mL) was heated at 200° C. in a sealed tube with stirring for 16 h. After cooling to RT, the reaction mixture was filtered, the filtrate purified using preparative HPLC (YMC S5 ODS 20×100 mm) eluting with MeOH (70-100%) in 1120 for 8 min, and then 100% MeOH in H2O for 7 min to give the title compound (4 mg) as a light brownish solid. HPLC: 91% at 6.99 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 471 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3](C(OC)=O)=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:7]=1.[CH3:21][Mg]Br.[NH4+].[Cl-].O.CCO[C:30]([CH3:32])=[O:31]>C1COCC1>[Cl:1][C:2]1[C:3]([C:30]([OH:31])([CH3:32])[CH3:21])=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12])[CH:7]=1
Reactant: COC(=O)c1ncc(CO[Si](C)(C)C(C)(C)C)cc1Cl
Reactant: C[Mg]Br
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1ncc(CO[Si](C)(C)C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
To a solution of methyl 3-chloro-5-({[(1,1 dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinecarboxylate (488 mg, 1.545 mmol) in THF (5 ml) at −23° C. was added methylmagnesium bromide (4.12 ml, 12.36 mmol) dropwise. After addition, the solution was allowed to warm to rt and stirred for 5 h. Saturated NH4Cl was added after cooling the solution to 0° C. Water and EtOAc were added and the aqueous phase was extracted with EtOAc. The solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by Flashmaster chromatography on a 10 g silica gel cartridge using hexane/EtOAc 95:5 as eluent to obtain 2-[3-chloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-pyridinyl]-2-propanol (328 mg, 60% yield) as colourless oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([S:22][CH2:23][C:24]=2[CH2:25]Cl)[CH:20]([NH:27][C:28](=[O:30])[CH3:29])[C:19]3=[O:31])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:32].[Na+]>CC(C)=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([S:22][CH2:23][C:24]=2[CH2:25][I:32])[CH:20]([NH:27][C:28](=[O:30])[CH3:29])[C:19]3=[O:31])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CSC12
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CSC12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-(acetylamino)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (1, 155 mg, 0.34 mmol) and sodium iodide (253 mg, 1.7 mmol) in 5 mL of acetone was stirred for 1 hr at room temperature. The reaction mixture was concentrated on the rotary evaporator and diluted with 5 mL water. The suspension was extracted with 25 mL of ethyl acetate, and the organic phase was washed with 10% sodium thiosulfate (5 mL×2), brine (5 mL×3) and dried over anhydrous magnesium sulfate. The slightly orange powder 2 (152 mg, 0.45 mmol) was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:29][C:28](=[O:30])[CH:27]=[C:26]([CH3:31])[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C@H:24]1[CH2:25][C@@H:26]([CH3:31])[CH2:27][C:28](=[O:30])[CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)C=C(C)C2)c(OCc2ccccc2)c1
Agent: [Pd]
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@H](C)C2)c(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A mixture of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-methyl-2-cyclohexen-1-one (1.00 g, 2.39 mmole) and 500 mg of 5% palladium on carbon-50% water was stirred under one atmosphere of hydrogen for one hour. A second 500 mg portion of catalyst was added and stirring continued for 30 minutes. A third 500 mg portion of catalyst was added and stirring continued for 13 minutes. The reaction mixture was then filtered through sodium bicarbonate and magnesium sulfate and the filtrate evaporated. The residue was purified via column chromatography on 140 g of silica gel eluted with 10% ether-petroleum ether to yield 323 mg (32%) of the title compound as an oil.
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=3)[N:9]=2)C(C)=CC=1.[C:23]1([CH:29](C)[CH2:30][C:31](O)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:35]CN=C=NCCCN(C)C.C(N(CC)CC)C.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>C(#N)C>[C:23]1([CH2:29][CH2:30][CH2:31][CH2:35][NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:10]3[N:9]=[C:8]([NH2:3])[CH:13]=[CH:12][CH:11]=3)=[CH:19][CH:18]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(CC(=O)O)c1ccccc1
Reactant: Cc1ccc(C)n1-c1cccc(-c2ccc(CCN)cc2)n1
Reactant: CCN=C=NCCCN(C)C
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1cccc(-c2ccc(CCNCCCCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(2-(2, 5-Dimethylpyrrol-1-yl)-6-ethyl]-phenyl}-pyridyl)-(3-phenylbutyramide): To a 100 mL round-bottomed flask equipped with N2 inlet were added 200 mg (0.687 mmol) 2-(2, 5-dimethylpyrrol-1-yl)-6-(4-(2-aminoethyl)phenyl)-pyridine (Example 100D), 113 mg (0.687 mmol) 3-phenylbutyric acid, 132 mg (0.687 mmol) EDAC, 10 mg N-hydroxybenzot-iazole, 5 mL dry acetonitrile, and 211 uL (1.51 mmol) triethylamine. The reaction was stirred at room temperature for 12 h, poured into dilute aqueous citrate solution, and extracted into ethyl acetate. The organic layer was washed with water, aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, and evaporated. The resulting yellow oil, 300 mg (100%) was used directly.
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]CC)=[O:32])[C:29]2([CH3:37])[CH3:36])=[CH:4][CH:3]=1.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[F:47]>>[F:40][C:41]1[CH:42]=[C:43]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:28]3[C@H:30]([C:31]([OH:33])=[O:32])[C:29]3([CH3:36])[CH3:37])=[CH:38][CH:39]=2)[CH:44]=[CH:45][C:46]=1[F:47]
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C
Reactant: OB(O)c1ccc(F)c(F)c1
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3ccc(F)c(F)c3)cc2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 3,4-difluorophenylboronic acid in Step A. MS (ESI): mass calcd. for C36H29F2N3O3, 589.22; m/z found, 590.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=8.5, 1H), 8.11 (d, J=8.6, 1H), 7.85 (d, J=8.2, 1H), 7.79-7.73 (m, 1H), 7.71 (d, J=8.5, 1H), 7.60-7.55 (m, 1H), 7.53-7.49 (m, 2H), 7.39-7.36 (m, 1H), 7.35-7.30 (m, 1H), 7.29-7.28 (m, 1H), 7.27-7.21 (m, 2H), 7.18-7.12 (m, 3H), 5.51-5.38 (m, 4H), 2.35-2.31 (m, 1H), 2.14-2.11 (m, 1H), 1.21 (s, 3H), 1.03 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[C:34]([NH2:42])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:42][C:34]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[O:41])=[O:13])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: NC(=O)c1cccnc1
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)c2cccnc2)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and nicotinamide, the title compound was obtained as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1.S(Cl)([Cl:21])=O>>[ClH:21].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([Cl:21])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)CCc1ccc(-c2ccccc2F)nc1
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)CCc1ccc(-c2ccccc2F)nc1

Procedure:
The title compound was prepared in quantitative yield by boiling 3-[6-(2-fluoro-phenyl)-pyridin-3-yl]-propionic acid in thionyl chloride, followed by removal of the volatiles by coevaporating three times with toluene.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=2)[C:9]([OH:11])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:39][C:40]1[C:41]2[C:51]([O:52][CH2:53][C:54]([NH2:57])([CH3:56])[CH3:55])=[CH:50][CH:49]=[CH:48][C:42]=2[NH:43][S:44](=[O:47])(=[O:46])[N:45]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:39][C:40]1[C:41]2[C:51]([O:52][CH2:53][C:54]([NH:57][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][N:14]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:7]=3)([CH3:55])[CH3:56])=[CH:50][CH:49]=[CH:48][C:42]=2[NH:43][S:44](=[O:47])(=[O:46])[N:45]=1
Reactant: O=C(O)c1ccnc(-n2ccnc2)c1
Reactant: CC(C)(N)COc1cccc2c1C(N)=NS(=O)(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(COc1cccc2c1C(N)=NS(=O)(=O)N2)NC(=O)c1ccnc(-n2ccnc2)c1
Temperature: 50 °C
Yield: 7.1 %

Procedure:
To a solution of 2-(1H-imidazol-1-yl)isonicotinic acid (1.00 g, 5.29 mmol), in DMF (41 mL) at room temperature, was added HOBt.H2O (891 mg, 5.82 mmol), EDCI.HCl (1.11 g, 5.82 mmol), 4-amino-5-(2-amino-2-methylpropoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (1.70 g, 5.29 mmol) and triethylamine (1.54 mL, 11.1 mmol). The reaction was heated to 50° C. for one hour, and upon completion was cooled to room temperature, filtered and the filtrate was purified by HPLC (10-90% acetonitrile in water), then the purified product was washed in boiling ethanol for thirty minutes, then cooled to room temperature. The solid was collected by vacuum filtration, sodium carbonate (178 mg) in water (50 mL) was added and the mixture was heated to 60° C. until in solution, then was cooled to 0° C. and neutralized with hydrochloric acid (1N). The white solid was collected by vacuum filtration and dried under vacuum at 50° C. (295 mg). Sodium carbonate (87.3 mg) in water (7 mL) was added to the white solid and the mixture was heated to 60° C. until in solution. The warm solution was filtered, cooled to room temperature, and neutralized with hydrochloric acid (1N). The white solid was collected by vacuum filtration and dried under vacuum at 50° C. to yield N-(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)-2-(1H-imidazol-1-yl)isonicotinamide as a white solid (171 mg, 7% yield). 1H NMR (DMSO-d6, 400 MHz): δ 1.50 (s, 6H), 4.41 (s, 2H), 6.62 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 7.14 (s, 1H), 7.47 (t, J=8.4 Hz, 1H), 7.63 (dd, J=6.0 Hz, 1H), 7.81 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 8.47 (s, 1H), 8.58 (m, 3H), 11.00 (s, 1H). MS 456 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH:7]1[C:11]([C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)=[C:23]([C:33]([NH:35][CH3:36])=[O:34])[C:22]=4[CH:37]=3)[CH:15]=[CH:16][CH:17]=2)=NN=[N:8]1>N1C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[O:25][C:21]3[CH:20]=[CH:19][C:18]([C:14]4[CH:15]=[CH:16][CH:17]=[C:12]([C:11]5[O:5][C:1]([CH:2]([CH3:4])[CH3:3])=[N:8][N:7]=5)[CH:13]=4)=[CH:37][C:22]=3[C:23]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:31][CH:30]=1
Reactant: CC(C)C(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnc(C(C)C)o4)c3)cc12
Reaction time: 8 h
Yield: 20.7 %

Procedure:
Isobutyryl chloride (90 mg, 0.847 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.085 mmol) in pyridine (1 mL) at 100° C. It was allowed to stir overnight. The reaction was concentrated and diluted with EtOH (3 mL) and treated with excess 1N NaOH (500 μL) and stirred at 60° C. for 2 hours to hydrolyze the acylated amide. The mixture was filtered and the filtrate was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (8 mg, 20%). 1H NMR (500 MHz, CD3OD) δ ppm 8.31-8.35 (1H, m), 8.03 (1H, d, J=7.94 Hz), 7.95-8.00 (3H, m), 7.93 (1H, d, J=7.93 Hz), 7.67-7.74 (3H, m), 7.25-7.30 (2H, m), 3.37-3.40 (1H, m), 2.99 (3H, s), 1.49 (6H, d, J=7.02 Hz). LC-MS retention time: 2.28 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=14.30 min, purity=94%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=12.50 min, purity=93%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:42][C:43]1[CH:55]=[CH:54][CH:53]=[CH:52][C:44]=1[O:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([N:49]1[CH2:48][CH2:47][CH:46]([O:45][C:44]2[CH:52]=[CH:53][CH:54]=[CH:55][C:43]=2[Cl:42])[CH2:51][CH2:50]1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC(=O)O
Reactant: Clc1ccccc1OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a stirred solution of malonic acid monoethyl ester (1.2 g, 0.0089 mole) in DMF (10 mL) was added DIPEA (2.5 g, 0.02 mole), HOBt (1.3 g, 0.0097 mole) and EDCI.HCl (1.9 g, 0.0097 mole). After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (2 g, 0.0081 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 1.1 g (42%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 326.11 (M+1)+, 90.2%. To a stirred solution of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (1.1 g, 0.0034 mole) in a mixture of THF (20 mL), methanol (4 mL) and H2O (4 mL) was added LiOH.H2O (0.286 g, 0.0068 mole) at ambient temperature. The resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.75 g (75%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22](O)=[O:23])[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[O:14][C:15]=3[C:4]=2[N:3]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N>ClCCl>[CH3:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([C:22]([NH2:30])=[O:23])[C:10]3[CH2:11][CH2:12][CH:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:14][C:15]=3[C:4]=2[N:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1nc2c3c(c(C(=O)O)cc2n1C)CCC(c1ccccc1)O3
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Product: Cc1nc2c3c(c(C(N)=O)cc2n1C)CCC(c1ccccc1)O3
Temperature: 25 °C
Reaction time: 64 h
Yield: 50.2 %

Procedure:
To a suspension of 0.3 g (0.93 mmol) 2,3-dimethyl-8-phenyl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole-5-carboxylic acid in dichloromethane (9 ml) were added 0.45 g (1.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate (TBTU) and the suspension was stirred for 64 h at room temperature. 11.1 ml (5.6 mmol) Ammonia (0.5 M in dioxane) were added and the mixture was stirred for 24 h at room temperature. The precipitate was filtered off and dried in vacuo at 40° C. to afford 0.15 g (48%) of the title compound as a yellow solid. m.p. 264°-267° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([CH2:8][C:9](=O)[CH3:10])(=O)[CH3:6].[ClH:12]>C(O)C>[ClH:12].[SH:3][C:2]1[N:4]=[C:9]([CH3:10])[CH:8]=[C:5]([CH3:6])[N:1]=1
Reactant: NC(N)=S
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)nc(S)n1

Procedure:
Thiourea (76 g, 1.0 mole) was suspended in a solution of 120 g (1.2 moles) of acetylacetone in 2,500 ml of ethanol. The resulting suspension was mixed with 250 ml of concentrated hydrochloric acid, and then reacted under reflux for 2 hours. After completion of the reaction, the reaction liquid was cooled, whereby beautiful yellow needle-like crystals of 2-mercapto-4,6-dimethyl-pyrimidine hydrochloride were formed. The reaction liquid was allowed to stand for a day to deposit sufficiently the crystals, which were then recovered by filtration and dried to obtain 140 g of 2-mercapto-4,6-dimethyl-pyrimidine hydrochloride in yield of 80 %.