Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6]C(=O)C(C)C(O)=O.[CH:18]([CH:21]([C:27]([O:29]CC)=O)[C:22]([O:24]CC)=[O:23])([CH3:20])[CH3:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:27](=[O:29])[CH:21]([CH:18]([CH3:19])[CH3:20])[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CC(C)C(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-2-isopropyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl isopropyl-malonate.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:11]Br)=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8].CCCC[N+](CCCC)(CCCC)CCCC.[F-:30]>>[Br:1][C:2]1[C:3]([CH2:11][F:30])=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(C)c(Br)c(CBr)n1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: COc1cc(C)c(Br)c(CF)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-2-(bromomethyl)-6-methoxy-4-methylpyridine (126 mg) and TBAF (1.71 mL, 1 M solution in THF) was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (37 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34]C1C=CC=CC=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1(N)[CH:46]=[CH:45][C:44](OCC)=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:16])[NH:12][CH2:13][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: CCOc1ccc(N)cc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCc1ccccc1

Procedure:
Synthesis was performed performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and phenetylamine (38 uL) according to Method A to give the title compound (57 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 7.36 (dd, J=1.9 Hz, J=8.3 Hz, 1H), 7.28-7.15 (m, 10H), 7.00 (d, J=8.7 Hz, 1H), 4.79 (s, 2H), 4.50 (t, J=6.8 Hz, 1H), ), 4.25 (dd, J=5.1 Hz, J=9.4 Hz, 1H), 3.40 (m, 1H), 3.02 (m 2H), 2.90 (dd, J=7.7 Hz, J=13.6 Hz, 1H), 1.36 (s, 9H); (KBr) 3297, 2979, 1728, 1688, 1645 cm−1; HRMS m/z 633.2660 (calc. of monoisotopic mass for C34H39N3O9 gives 633.2686).
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([B:27]([OH:29])[OH:28])=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:5]1[NH:6][C:2]([C:20]#[C:19][C:21]2[CH:22]=[CH:23][C:24]([B:27]([OH:29])[OH:28])=[CH:25][CH:26]=2)=[CH:3][N:4]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: C#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(I)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(C#Cc2ccc(B(O)O)cc2)[nH]1
Temperature: 60 °C
Yield: 72.9 %

Procedure:
Nitrogen was bubbled through a solution of (S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (150 mg, 0.41 mmol), 4-ethynylphenylboronic acid (90 mg, 0.62 mmol) and copper(I) iodide (15.7 mg, 0.083 mmol) in DMF (5 mL) and triethylamine (0.30 mL, 2.0 mmol) for 15 min. Then Pd(PPh3)4 (23.86 mg, 0.021 mmol) was added and the reaction mixture was vacuum flushed with nitrogen (4×,), sealed and heated at 60° C. ON. The crude reaction was concentrated to dryness, dissolved into DMF/MeOH and purified by Prep HPLC (MeOH/water with ammonium acetate buffer) to yield (S)-4-((2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)ethynyl)phenylboronic acid (113.8 mg, 0.299 mmol) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[CH3:11][C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([N:9]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(N)nc(Cl)c1Br
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-n2c(C)ccc2C)nc(Cl)c1Br
Temperature: 25 °C
Yield: 15.3 %

Procedure:
A flask containing a mixture of 5-bromo-4-chloro-6-methylpyrimidin-2-amine (34.8 mmol), 2,5-hexanedione (6.15 mL, 52.2 mmol), and p-toluenesulfonic acid (330 mg, 1.74 mmol) in toluene (100 mL) was fitted with a Dean-stark apparatus and condenser and the mixture was heated to reflux. After refluxing overnight the solution was cooled to room temperature and concentrated. The residue was slurried in hexanes, filtered and the filtrate was concentrated. The precipitate was purified by flash chromatography eluting with hexanes/chloroform (0-50%) to afford the 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine (1.60 g, 15%). The concentrated filtrate was purified by flash chromatography eluting with hexanes/chloroform (10-40%) to afford 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine (5.22 g, 50%).
Reaction SMILES: [ClH:1].Cl.Cl.[C:4]1([CH:10]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([C:20]3[CH:31]=[CH:30][C:23]4[N:24]([CH2:28][CH3:29])[C:25]([CH3:27])=[N:26][C:22]=4[CH:21]=3)O)[CH2:13][CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:40])=O>ClC(Cl)Cl>[ClH:40].[ClH:1].[ClH:40].[Cl:40][CH:18]([C:20]1[CH:31]=[CH:30][C:23]2[N:24]([CH2:28][CH3:29])[C:25]([CH3:27])=[N:26][C:22]=2[CH:21]=1)[CH2:17][N:14]1[CH2:15][CH2:16][N:11]([CH:10]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:13]1
Reactant: O=S(Cl)Cl
Reactant: CCn1c(C)nc2cc(C(O)CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCn1c(C)nc2cc(C(Cl)CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a stirred mixture of 10.3 parts of α-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-ethyl-2-methyl-1H-benzimidazole-5-methanol trihydrochloride in 75 parts of trichloromethane are added dropwise 4.3 parts of thionyl chloride at room temperature. Upon completion, stirring is continued for 30 minutes at reflux temperature After cooling, the precipitated product is filtered off, washed with trichloromethane and with 2,2'-oxybispropane, and dried, yielding 9 parts (85.8%) of 5-{1-chloro-2-[4-(diphenylmethyl)-1-piperazinyl]-ethyl}1-ethyl-2-methyl-1H-benzimidazole trihydrochloride.
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH:6]([CH3:8])[CH3:7].ClO[N:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1>CCO>[CH2:14]([O:13][C:11]([C:10]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[N:18][O:9][C:5]=1[CH:6]([CH3:8])[CH3:7])=[O:12])[CH3:15]
Reactant: Fc1cccc(C=NOCl)c1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(-c2cccc(F)c2)noc1C(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 3.39 g (53 mmol) of NaOEt in 30 mL of EtOH, at 0° C., was added dropwise 8.56 mL (53 mmol) of ethyl isobutyrylacetate (commercially available) in 10 mL of EtOH. The reaction mixture was stirred at room temperature for 40 minutes, and then 8.68 g (0.05 mol) solution of 3-fluoro-benzaldehyde-chloro-oxime (Prepared according to: J. Agric. Food Chem. 1995, 43, 219-228.) in 30 mL of EtOH was added dropwise in an ice-bath and the resulting suspension was stirred at room temperature for 2 h. The mixture was then evaporated and the residue partitioned between 200 mL of ethyl acetate and 100 mL of H2O. The aqueous phase was then separated and extracted with ethyl acetate (2×60 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and evaporated to give 15 g of crude product (purity ˜30%) as a yellow syrup. The crude product was used in the subsequent hydrolysis without purification.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br-].[C:22]([CH2:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:24])=[O:23]>C1COCC1.O>[CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:26]/[CH2:25][C:22]([OH:24])=[O:23]
Reactant: Cc1cccc(C=O)c1C
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(/C=C/CC(=O)O)c1C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a solution of 2,3-dimethylbenzaldehyde (17.0 g, 41.0 mmol) in THF (40 mL) was added NaHMDS (41.1 mL, 82.1 mmol) at −20° C., and the reaction was stirred for 20 min. (2-Carboxyethyl)triphenylphosphonium bromide (5.0 g, 37.3 mmol) was added to the reaction at −78° C., and reaction was stirred while warming to rt overnight. The solution was diluted with water (50 mL) and extracted with EtOAc (50×3 mL). Organics were washed with brine (50 mL), dried (Na2SO4), and concentrated to give 7.00 g (99%) of the crude title compound as a yellow solid. [M+H] calc'd for C12H14O2, 191; found 191.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[Br:25][C:26]1[CH:37]=[CH:36][C:29]([C:30](N(OC)C)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[Br:25][C:26]1[CH:37]=[CH:36][C:29]([C:30]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Reactant: Brc1ccc(N2CCOCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)c1ccc(N2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 31.4 %

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 0.49 mL, 0.79 mmol) was added dropwise to a solution of 4-(4-bromophenyl)morpholine (191 mg, 0.79 mmol; described in: Jones, D. H. J. Chem. Soc. (C), 1971, 132-137 ) in tetrahydrofuran (5 mL) under nitrogen at −78° C. After 10 minutes, a pre-cooled solution (−78° C.) of 4-bromo-N-methoxy-N-methylbenzamide (212 mg, 0.87 mmol; described in: Turnbull, K. Tet. Lett. 1998 39(12), 1509-12) in tetrahydrofuran (3 mL) was added via a double-tipped needle. The mixture was stirred at −78° C. for 5 min. The cooling bath was removed and the mixture was allowed to reach ambient temperature under 30 min. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using heptane/ethyl acetate, 70:30, as the eluent affording 86 mg (32% yield) of the title compound as colorless crystals: mp 177.8-179.2° C.; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=9.0 Hz, 2 H), 7.61 (s, 4 H), 6.89 (d, J=9.0 Hz, 2 H), 3.89-3.85 (m, 4 H), 3.35-3.32 13C NMR(400 MHz, CDCl3) δ 194.5, 154.6, 137.8, 132.8, 131.8, 131.6, 127.7, 126.8, 113.6, 67.0, 47.9; MS (TSP) m/z 346 (M+1).
Reaction SMILES: [C:1]1([CH:7]([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.O>CN(C)C=O>[O:10]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[CH:9])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C#CC(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a solution of 5.0 g (37.9 mmol) of 1-phenyl-2-propyne-1-ol in 20 ml of dimethyl formamide were added 6.9 g (45.8 mmol) of t-butyl dimethylsilyl chloride and 6.2 g (91.1 mmol) of imidazole, and the resulting mixture was stirred at room temperature for 3 hours, 50 ml of water was added and the mixture was extracted with a pentane-ether (1:1) mixture (4×30 ml). The organic layer was washed with water (30 ml) and saturated brine, dried over anhydrous magnesium sulfate (30 mg) and thereafter concentrated. The residue was purified by column chromatography (silica gel 100 g, cyclohexane-ethyl acetate) and further distilled (dp 98° C./1 mm Hg) to give 5.7 g (24.7 mmol, 65%) of the subject compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C@H:15]3[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[CH:13]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[Br:37][C:38]1[CH:39]=[N:40][C:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[N:42][CH:43]=1>O1CCOCC1>[Br:37][C:38]1[CH:39]=[N:40][C:41]([N:44]2[CH2:45][CH2:46][N:47]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[N:11][N:12]([CH2:14][C@H:15]5[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]5)[CH:13]=4)[N:3]=3)[CH2:48][CH2:49]2)=[N:42][CH:43]=1
Reactant: Brc1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(Br)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (1.8 g, 4.5 mmol) in dioxane (50 mL) was added diisopropylethylamine (4 mL) and 5-bromo-2-(piperazin-1-yl)pyrimidine (1.3 g, 5.5 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvents were removed, and the residue was washed with methanol (10 mL) to afford (S)-tert-butyl 2-((4-(4-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)-morpholine-4-carboxylate as a white solid (2.4 g, 89%), which was directly used in the next step without further purification. MS (ES+) C24H32BrN11O3 requires: 601, 603, found: 602, 604 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[C:11]([N+:15]([O-:17])=[O:16])=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: O=c1[nH]c2cc(F)cc(Br)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])c(Br)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
The method of Cheeseman, supra. was adapted. 5-Bromo-7-fluoro-1,4-dihydroquinoxaline-2,3-dione (77 mg, 0.30 mMol) was dissolved in concentrated H2SO4 (1 mL) at 0° C. for 30 min, and KNO3 (35 mg, 0.346 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then at room temperature for 30 h. The mixture was poured into ice water (10 g) and the precipitate was collected by filtration. The precipitate was dissolved in 1N NaOH (10 mL), then was acidified to pH=2 with 4N HCl to give cream precipitate, which was collected by filtration, and was dried in the air at 50° C. for 4 h affording pure (by NMR) 5-bromo-6-nitro-7-fluoro-1,4-dihydro-2,3-quinoxalinedione (81 mg, 90%), as a white amorphous solid; mp: 320°-25° C. (dec. from 290° C.). IR (KBr, cm-1): 3416, 3071, 2952, 1721, 1609, 1546. NMR (1H, DMSO-d6): δ 7.146 (d, J=10.2 Hz, 1H), 11.432 (s, 1H), 12.340 (s, 1H). HRMS: calcd. for C8H3N3O4BrF (M+) m/z: 302.9290, found: 302.9290.
Reaction SMILES: [CH3:1][NH:2]/[C:3](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:4]1\[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2S\1.OO.[S:22]([O-:25])([O-])=[O:23].[Na+].[Na+]>C(O)(=O)C>[CH3:1][NH:2]/[C:3](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:4]1\[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[S:22]\1(=[O:25])=[O:23]
Reactant: O=S([O-])[O-]
Reactant: CN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CN/C(=C1\C(=O)c2ccccc2S1(=O)=O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 6.0 gm (0.0224 mol) of (E)-2-[(methylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one, 100 ml of glacial acetic acid and 3.5 ml (0.034 mol) of an aqueous 30% hydrogen peroxide solution was heated at 50° C. for four hours while stirring and then allowed to stand overnight at room temperature. After the addition of 40 ml of a 10% sodium sulfite solution, the mixture was concentrated by evaporation in vacuo, and the residue was suspended in 200 ml of water. The solid material precipitated thereby was suction-filtered off and then broken down into its constituents by column chromatography on 300 gm of silica gel, using 1,2-dichloroethane/ethyl acetate (97:3 v/v) as the eluant. By evaporating the appropriate fractions, 2.0 gm (33% of theory) of pale yellow (E)-2-[(methylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one-1-oxide, m.p. 205-206° C (decomposition) from ethanol), and 0.10 gm (1.5% of theory) of light yellow (E)- 2-[(methylamino)phenylmethylene]-benzo[b]-thiophen-3(2H)-one-1,1-dioxide, m.p. 302°-303° C., were obtained.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33](OC)=[O:34])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CN(C)C1C=CN=CC=1.N1CCCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH2:31][CH2:32][C:33]([N:16]4[CH2:17][CH2:13][CH2:14][CH2:15]4)=[O:34])=[CH:15][N:16]3[CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(C(=O)NCC3CCCC3)ccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCNC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cn1cc(CCC(=O)N2CCCC2)c2ccc(C(=O)NCC3CCCC3)cc21
Yield: 169.9 %

Procedure:
A solution of 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.84 g) (prepared as described in Example 1, parts (a) through (i)) and 4-(dimethylamino)pyridine (0.21 g) in pyrrolidine (5 ml) was heated at 80° for 48 hours under a nitrogen atmosphere. The reaction was diluted with water and acidified with 10% (v/v) hydrochloric acid. The resultant precipitate was collected by filtration and washed with water to give 4-[6-(N-cyclopentylmethylcarbamoyl)-3-[2-(pyrrolidinocarbonyl)ethyl]indol1-ylmethyl]-3-methoxybenzoic acid as a white powder (0.77 g, 85%): partial NMR (80 MHz, DMSO-d6 : 1.1-2.0 (m, 12H), 2.1(m, 1H, NHCH2CH), 3.9(s, 3H, OCH3), 6.7(d, 1H, Ar), 7.3(s, 1H, H2 -indole), 8.3(t,1H, NH).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].S(Cl)([Cl:23])=O.Cl>Cl.C(N(CC)CC)C.C(Cl)(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([Cl:23])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1Oc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
There were combined 14.1 grams (0.05 mole) 2-(3-trifluoromethylphenoxy)nicotinic acid, 0.1 grams triethylamine hydrochloride and 150 milliliters of chloroform. The mixture was stirred and heated to reflux. Then, 6.5 grams (0.055 mole) thionyl chloride was slowly added. After addition was complete the reaction mass was heated under reflux until hydrogen chloride evolution had ceased (about 30 minutes); it was then cooled to room temperature, filtered, and the solvent removed under vacuum producing 10.0 grams (66.7% of theoretical yield) of 2-(3-trifluoromethylphenoxy)nicotinoyl chloride. The structure was confirmed by infrared spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:10]1([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:9][CH:22]2[CH2:23][CH2:24][N:19]([C:16]3[N:15]=[CH:14][C:13]([CH:10]4[CH2:12][CH2:11]4)=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: OC1CCN(c2ncc(C3CC3)cn2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(OC2CCN(c3ncc(C4CC4)cn3)CC2)c(Cl)c[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.2 %

Procedure:
To a stirring mixture of 5-chloro-4-hydroxypyridin-2(1H)-one (212 mg, 1.46 mmol), 1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-ol (320 mg, 1.459 mmol, prepared according to procedures described in Example 173 Step A substituting 2-chloro-5-cyclopropylpyrimidine for 2-chloro-5-propylpyrimidine) and triphenylphosphine (574 mg, 2.19 mmol) in DMF (10 mL) at 0° C. was added diisopropyl azodicarboxylate (0.43 mL, 2.2 mmol). The reaction was stirred under Ar at room temperature for 2 days and then H2O was added. The resulting mixture was concentrated in vacuo to a yellow oil. The oil was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2 and then SiO2, 0 to 10% MeOH in CH2Cl2) to yield 153 mg of desired product as a white solid. MS (ESI) 347 (M+H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH:20]([CH2:25][CH3:26])[C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:14]2>C(Cl)Cl>[C:5]([C:19]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][CH:16]2[CH:20]([CH2:25][CH3:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:12][C:11]=1[O:10][CH3:9])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCC(C(=O)OC)C1CCc2cc(OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(C(=O)OC)C1CCc2cc(OC)c(C(C)=O)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
To a solution of AlCl3 (103 mg, 0.78 mmol) in methylene chloride (2.5 mL) at 0° C., was added acetyl chloride (0.044 mL, 0.63 mmol), followed by the addition of a solution of methyl 5-methoxy-2,3-dihydro-1H-indene-1-yl-butanoate (130 mg, 0.52 mmol) in methylene chloride (2.7 mL) dropwise. The mixture was stirred at 0° C. for 15 minutes. The ice bath was removed and the mixture stirred at rt for 16 hours. The mixture was poured over ice and 4 drops of conc. HCl were added. This mixture was extracted with methylene chloride twice. The combined organic layers were washed with water, 0.05 N NaOH and water. The organic layer was dried, concentrated, and purified by chromatography with 10% EtOAc:hexane to give desired product (103 mg, 68%). Rf=0.28 (4:1 hexane:EtOAc); GC-MS (+Cl): m/z=291 (M+); 1H NMR (DMSO-d6): δ 0.840 (m, 3H), 1.536 (m, 2H), 1.876 (m, 1H), 2.108 (m, 1H), 2.505 (s, 3H), 2.521 (m, 1H), 2.760-2.889 (m, 2H), 3.236 (m, 1H), 3.511 and 3.589 (s, 3H), 3.836 (s, 3H), 7.012 and 7.253 (s, 1H), 7.440 (s, 1H).