Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(Cl)=O.C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>C1COCC1.CCOCC>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][C:8]([C:3]2[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:10])=[CH:34][CH:33]=1
Reactant: O=C(O)c1ncccc1O
Reactant: NCCc1ccc(Cl)cc1
Agent: O=C(Cl)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(Cl)cc1)c1ncccc1O
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
A stirred mixture of 3-hydroxypyridine-2-carboxylic acid (1.39 g, 0.01 mol) in dry THF (60 mL) under argon was cooled to −20° C. To this was added all at once a 20% solution of phosgene in toluene (5.1 g, 0.01 mol) and the resulting mixture was stirred for 90 minutes while the temperature slowly rose to 0° C. The reaction mixture was then recooled to −20° C. and a solution of diisopropylethylamine (2.58 g, 0.02 mol) in THF (20 mL) was added dropwise over 30 minutes. After the addition was complete, the mixture was stirred an additional 2 hours as the temperature was slowly brought to 0° C. Stirring was continued at 0° C. overnight. To this stirred mixture was added, all at once, 2-(4-chlorophenyl)ethylamine (1.56 g, 0.01 mol), and the resulting mixture was stirred at room temperature for 6 hours. The mixture was diluted with ether (100 mL), washed with 1N HCl (100 mL), dried (MgSO4) and concentrated to give the title compound as an off-white solid (1.95 g). The mass spectrum showed the expected 3:1 parent ion ratio at m/e 276 and 278. Coupling Procedure B: Preparation of 3-Hydroxy-4-Methoxy-N-(4-(4-Trifluoromethylphenoxy)Phenyl)-Pyridine-2-Carboxamide (425).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:18])=[CH:6][N:7]=1
Reactant: BrBr
Reactant: COC(=O)c1nccnc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Commercially available methyl 3-amino-pyrazine-2-carboxylate (available from Aldrich Chemical Company) was brominated using a procedure similar to that of Russ, T., Ried, W., Ullrich, F., and Mutschler, E. Arch. Pharm. (Weinheim) 1992, 325, 761-767. To a solution of methyl 3-amino-2-pyrazine carboxylate (30.0 g, 200 mmol) in acetic acid (200 mL), bromine (11 mL) was added slowly via addition funnel. After complete addition of bromine, sodium carbonate powder was added slowly until precipitation occurred. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was reduced to half-volume in vacuo and then diluted with water (500 mL). The reaction mixture was shaken vigorously and the resulting solid was collected using vacuum filtration. The solid was washed with ether to afford a pure yellow solid (91% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[N+:15]([C:18]1[CH:34]=[CH:33][CH:32]=[CH:31][C:19]=1[O:20][CH:21]([C:23]1[S:27][C:26]([N:28]=[C:29]=[O:30])=[N:25][N:24]=1)[CH3:22])([O-:17])=[O:16]>CCCCCC>[N+:15]([C:18]1[CH:34]=[CH:33][CH:32]=[CH:31][C:19]=1[O:20][CH:21]([C:23]1[S:27][C:26]([NH:28][C:29](=[O:30])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:25][N:24]=1)[CH3:22])([O-:17])=[O:16]
Reactant: CC(Oc1ccccc1[N+](=O)[O-])c1nnc(N=C=O)s1
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccccc2[N+](=O)[O-])s1)OC
Reaction time: 72 h
Yield: 97.2 %

Procedure:
2.1 grams (0.018 mole) of methylaminoacetaldehyde dimethylacetal was added to a 50 ml. benzene solution containing 5.2 grams (0.018 mole) of the 5-(1-(2-nitrophenoxy) ethyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above) and the resulting solution was refluxed for 15 minutes to form a yellow solution. Hexane (100 ml.) was added and the resulting oil was allowed to stand for 72 hours and topped with a roto-vac at 70 degrees Centigrade to yield 7.2 grams of a red-orange oil of 3-[5-(1-(2-nitrophenoxy ethyl)-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].[OH-].[Na+]>>[F:15][CH:2]([F:1])[O:3][C:4]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(F)c1OC(F)F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(F)c1OC(F)F
Temperature: 50 °C
Yield: 74 %

Procedure:
A mixture of methyl 3-fluoro-2-hydroxy-benzoate (1.5 g, 8.8 mmol), 2-chloro-2,2-difluoro-acetic acid (1.62 g, 1.05 mL, 10.6 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were heated in DMF (5 mL) at 120° C. for 5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ether (2×10 mL). The organics were separated and washed sequentially with water (5 mL) and brine solution (5 mL). The organics were dried (MgSO4) and concentrated in vacuo to give residue which was purified by silica gel column chromatography using 0-30% EtOAc/hexanes as eluent to give methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 39%). To methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 3.64 mmol) was added 12% aq. NaOH (3 mL) and the reaction mixture was heated at 50° C. for 1 hour. The aqueous layer was extracted with 1:1 ether/hexane (2×5 mL). The aqueous layer was acidified to pH 1 with 6 N HCl solution to give a suspension. The solid was filtered and washed with water, then dried in vacuo to give 2-(difluoromethoxy)-3-fluoro-benzoic acid (555 mg, 31%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.8 Hz, 1H), 7.43 (dd, J=13.1, 4.8 Hz, 1H), 7.35 (td, J=8.1, 4.9 Hz, 1H), 6.68 (t, J=74.4 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][N:9]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>O1CCOCC1.O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:18]1[N:23]=[C:22]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([F:7])[CH:13]=2)[CH:21]=[CH:20][N:19]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(-c2ccnc(Cl)n2)ccn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
Sodium carbonate (4.91 g, 46.3 mmol) was added to 2-fluoropyridin-4-ylboronic acid (2.61 g, 18.5 mmol) and 2,4-dichloropyrimidine (77.2 mL, 15.4 mmol) in dioxane/water (77 mL, 4:1), and the suspension was purged with argon. PdCl2(dppf)*DCM (0.630 g, 0.772 mmol) was added to the mixture, and the mixture was heated at 80° C. under argon. After 3 hours, the reaction mixture was diluted with water, and the resulting solid was collected by vacuum filtration to yield 2-chloro-4-(2-fluoropyridin-4-yl)pyrimidine (3.12 g, 14.9 mmol, 96.4% yield) with minor impurities.
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>C(Cl)Cl>[F:71][C:69]1[CH:70]=[C:65]([CH:66]=[C:67]([F:72])[CH:68]=1)[CH2:64][C@H:50]([NH:49][C:13]([C:10]1[CH:11]=[CH:12][C:7]2[O:6][N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[C:8]=2[CH:9]=1)=[O:15])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1
Reactant: CCCc1noc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1noc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.2 %

Procedure:
To a stirred solution of 3-propyl-1,2-benzisoxazole-5-carboxylic acid (70 mg, 0.3 mmol) and HATU (130 mg, 0.3 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (110 μL, 0.6 mmol). In a separate flask, N,N-diisopropylethylamine (110 μL, 0.6 mmol) was added to (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (EXA xxx)(140 mg, 0.3 mmol) in methylene chloride (2 mL). This solution was added to the above solution containing the acid and the resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 97:3 to 94:6 methylene chloride/methanol) provided N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-propyl-1,2-benzisoxazole-5-carboxamide (30 mg). ESI-MS m/z 522 [M+H]+
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C@H:5]([CH3:16])[CH2:4][N:3]1[C@H:17]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1.[CH3:38]I>>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C@H:5]([CH3:16])[CH2:4][N:3]1[C@H:17]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:38])[CH:19]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccccc3F)C[C@@H]2C)cc1
Reactant: CI
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccccc3F)C[C@@H]2C)cc1

Procedure:
4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide was alkylated with methyl iodide by a procedure essentially identical to that of Example 29 to give 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide. Calc. for C32H40FN3O2.0.1H2O: C, 73.99; H, 7.80; N, 8.09; F, 3.66. Found: C, 73.98; H, 7.86; N, 8.00; F, 3.77.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[O:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][C:41]=2[NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH2:36][CH2:35]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:43]4[CH:44]=[CH:45][C:40]([N:37]5[CH2:36][CH2:35][O:34][CH2:39][CH2:38]5)=[C:41]([NH:55][S:56]([CH3:59])(=[O:57])=[O:58])[CH:42]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:25])=[O:26])[CH:9]=2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)c(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCOCC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 90.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine Compound of step-I in Example 9) (200 mg, 0.3809 mmol) was coupled with N-(2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (Intermediate 20) (220 mg, 0.5714 mmol), Pd(PPh3)2Cl2 (13.5 mg, 0.01904 mmol), Toluene/ethanol/water (20/10/4 ml) to afford 240 mg (90.2% yield) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2I)=[O:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH3:17])=[O:4]
Reactant: COC(=O)c1ncc2c(I)cccc2c1O
Reactant: COc1ccccc1O
Product: COC(=O)c1ncc2c(Oc3ccccc3OC)cccc2c1O

Procedure:
The title compound was synthesized from 4-hydroxy-8-iodo-isoquinoline-3-carboxylic acid methyl ester and 2-methoxy-phenol in analogy to example 19d; MS-(+)-ion: M+1=326.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:18]([B-](F)(F)F)=[CH2:19].[K+].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:18]=[CH2:19])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: C=C[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of 1.0 g of the compound [1-1], 892 mg of potassium vinyltrifluoroborate, 468 mg of dichlorobis(triphenylphosphine) palladium (II), 10 mL of 2.0M aqueous sodium carbonate solution, and 20 mL of N,N-dimethylformamide, was stirred overnight at 90° C. After standing to cool, water was added to the reaction solution, which was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-75/25), to obtain 485 mg of tert-butyl[(1S)-1-(4-vinylphenyl)ethyl]carbamate [5-1] (hereinafter, referred to as the compound [5-1]) as a white solid.
Reaction SMILES: C1C2C=CC3C4C=CC=CC=4C=CC=3C=2OC=1CO.[CH:20]1[C:21]2[CH:41]=[CH:40][C:39]3[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH:32]=[CH:31][C:30]=3[C:22]=2[S:23][C:24]=1[C:25](OCC)=[O:26]>CCCCCC>[CH:20]1[C:21]2[CH:41]=[CH:40][C:39]3[C:38]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH:32]=[CH:31][C:30]=3[C:22]=2[S:23][C:24]=1[CH2:25][OH:26]
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2s1
Agent: OCc1cc2ccc3c4ccccc4ccc3c2o1
Solvent: CCCCCC
Product: OCc1cc2ccc3c4ccccc4ccc3c2s1
Yield: 98 %

Procedure:
Using the procedure outlined in 14A, ethyl phenanthro[1,2-b]thiophene-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 98.0% yield of phenanthro[1,2-b]thiophene-2-methanol, mp 169°-170.5° (C,H,S), (Ch2Cl2 /hexane).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:13]2[CH:14]=[CH:15][C:16]([CH2:18]C(=O)C)=[CH:17][C:12]=2[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]1=[O:22].[O:23]1CC[CH2:25][CH2:24]1.CSC.B>O1CCCC1>[OH:23][CH2:24][CH2:25][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[N:4]([CH2:3][O:2][CH3:1])[C:5](=[O:22])[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[C:12]=2[CH:17]=1
Reactant: C1CCOC1
Reactant: COCn1c(=O)c2cccnc2c2cc(CC(C)=O)ccc21
Agent: B
Solvent: CSC
Product: COCn1c(=O)c2cccnc2c2cc(CCCO)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
The compound (780 mg, 2.50 mmol) prepared in step 5 was dissolved in tetrahydrofuran, added dropwise with 2 M borane dimethyl sulfide tetrahydrofuran solution (6.24 ml, 12.49 mmol). The resulting mixture was stirred for 3 hours at room temperature and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness. The residue was then purified by flash column chromatography (chloroform:methanol=15:1) to obtain title compound (45 mg, yield: 75%, white solid).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1.[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])O.[Na+]>C(#N)C.O.C(OCC)(=O)C>[F:15][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(Cl)cnc1[N+](=O)[O-]
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1nc(F)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
In 2.0 mL of acetonitrile was dissolved 0.1 g of methyl 6-chloro-3-nitro-2-pyrazinecarboxylate. After adding 40 mg of potassium fluoride and 61 mg of 18-crown-6-ether successively, the mixture thus obtained was stirred at room temperature for 1.5 hours. Then, a mixture of 10 mL of ethyl acetate and 10 mL of water was added, pH was adjusted to 7.0 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel chromatography [eluent: n-hexane:ethyl acetate=7:1] to obtain 0.03 g of methyl 6-fluoro-3-nitro-2-pyrazinecarboxylate as a light yellow-colored oily product.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:43]=[CH:42][C:13]([C:14]([C:16]3[C:17]4[CH:38]=[CH:37][C:36]([C:39]([NH2:41])=O)=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([C:16]3[C:17]4[CH:38]=[CH:37][C:36]([C:39]#[N:41])=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:25][CH:26]=3)=[O:15])=[CH:42][CH:43]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reaction time: 72 h
Yield: 90.4 %

Procedure:
To a solution of 3.1 g (5.2 mmol) of 3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene-6-carboxamide (Example 30, Part E) in 75 mL of anhydrous THF was added 3.1 g (13.0 mmol) of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (inner salt) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 3 days and then filtered through a medium frit, concentrated at reduced pressure, and chromatographed on silica gel (1:1 TEA/MeOH in THF, 0 to 10%) to give 2.70 g (4.7 mmol, 90%) of a brown foam.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH2:24][O:25][CH3:26])[CH2:10][C@H:9]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=1)=[O:7]>CO.[C].[Pd]>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[CH:38]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH2:24][O:25][CH3:26])[CH2:10][C@H:9]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([CH3:35])[CH:29]=1)=[O:7]
Reactant: COC[C@H]1COCCN1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Agent: [Pd]
Solvent: CO
Product: COC[C@H]1COCCN1CCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Reaction time: 1 h

Procedure:
A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-methoxymethylmorpholino)-2-butynyl]piperazine (0.09 g) in methanol (10 ml) was hydrogenated in the presence of 10% palladium-carbon (40 mg) at room temperature. After 1 hour, palladium-carbon was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with a mixture of methanol and ethyl acetate as an eluent to give (2R)-1-[3,5-bis-(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-methoxymethylmorpholino)butyl]piperazine. It was dissolved in ethyl acetate (10 ml) and 4N hydrogen chloride in ethyl acetate (0.5 ml) was added thereto. The mixture was evaporated in vacuo and the residue was triturated with a mixture of ethyl acetate and isopropyl ether to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-((3S)-3-methoxymethylmorpholino)butyl]piperazine dihydrochloride (0.03 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:11]=[C:10]2I)[CH3:6].[CH2:27]([O:31][C:32]1[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][C:35]([CH:41]([CH3:43])[CH3:42])=[CH:34][C:33]=1B(O)O)[CH2:28][CH2:29][CH3:30].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCCCCC.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:11]=[C:10]2[C:33]1[CH:34]=[C:35]([CH:41]([CH3:43])[CH3:42])[CH:36]=[C:37]([CH:38]([CH3:39])[CH3:40])[C:32]=1[O:31][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:6]
Reactant: CCCCOc1c(B(O)O)cc(C(C)C)cc1C(C)C
Reactant: COC(=O)C=C(C)c1ccc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOc1c(-c2cn(S(=O)(=O)c3ccccc3)c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Temperature: 80 °C
Reaction time: 6 h
Yield: 151.2 %

Procedure:
3-(1-Benzenesulfonyl-3-iodo-1H-indol-5-yl)-but-2-enoic acid methyl ester (653 mg, 1.35 mmol) and (2-butoxy-3,5-diisopropylphenyl)-boronic acid (415 mg, 1.49 mmol) were dissolved in toluene (8 mL) under a nitrogen atmosphere. Tetrakis(triphenylphosphine) palladium (172 mg, 0.15 mmol) and 2N Na2CO3 (2.7 mL) was added and the biphasic mixture stirred at 80° C. for 6 h. The reaction was judged complete by TLC (9:1) in hexane:ethyl acetate but was allowed to stir overnight at room temperature. The reaction was diluted with water (5 mL)/ethyl acetate (15 mL). The layers were separated and the aqueous washed with ethyl acetate (10 mL). The organic portions were passed through a pad of Celite, dried (MgSO4), filtered and concentrated in vacuo to provide 1.20 g of a dark brown oil. Chromatography (SiO2, hexanes/ethyl acetate) provided 294 mg (37%) of a yellow foam. 1H NMR (250 MHz, CDCl3): δ 8.06 (d, 1H, J=8.7), 7.94 (m, 2H), 7.80 (s, 1H), 7.75 (d, 1H, J=1.7), 7.56-7.45 (m, 4H), 7.13 (m, 2H), 6.14 (d, 1H, J=1.2), 3.75 (s, 3H), 3.39 (sep, 1H, J=6.9), 3.29 (t, 2H, J=6.3), 2.93 (sep, 1H, J=6.9), 2.60 (d, 3H, J=1.2), 1.29 (d, 7H, J=6.9), 1.27 (d, 7H, J=6.9), 1.22 (m, 2H), 0.62 (t, 3H, J=7.2). MS [EI+] 588 (M+H)+.
Reaction SMILES: [C:1]([O:9]CC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[K+:22]>CCOCC>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+:22]
Reactant: O=C(OCc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])c1ccccc1
Yield: 73.7 %

Procedure:
The procedure of Example 1 was followed using benzyl benzoate (9.6 mL, 50 mmol), potassium trimethylsilanolate (6.42 g, 50 mmol), dry ether (150 mL), and a 2 h reaction mixture. Potassium benzoate (5.9 g, 73% yield) was isolated as a white solid: 1H NMR (D2O) δ 7.1-8.0 ppm (m, Ar--H's, 5H). Anal. Calcd. for C7H5KO2 : C, 52.48; H, 3.15; K, 24.61. Found: C, 50.53, 50.76; H, 3.40, 3.21; K, 25.60, 25.50.