Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(=O)(O)[O-].[Na+].[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1F)([O-:20])=[O:19]>O.C(O)C>[N+:18]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([O-:20])=[O:19]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(NCCc2c[nH]c3ccccc23)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1 mMole of tryptamine was dissolved in 100 ml of water and the pH was adjusted to pH 8.3 with 2.5 moles of sodium bicarbonate (NaHCO3), A 1.5% solution of 2,4-dinitrofluorobenzene in 200 liters ethanol was added and the mixture was stirred during 2 hours at room temperature. The desired product precipitates out, it is washed and dried. The product is obtained in 90% yield, and TLC (chloroform, silica-gel plates, reveals one yellow spot (Rf=0.84) which is well resolved from the starting materials under the same conditions.
Reaction SMILES: [C:1]([N:8]1[CH2:25][CH2:24][C@@:15]23[C:16]4[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:1]([N:8]1[CH2:25][CH2:24][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of N-Boc-3-hydroxymorphinan 2 (20 mg, 0.058 mmol) and triethylamine (9 μL, 0.064 mmol) in dry CH2Cl2 (1 mL) was slowly added pivaloyl chloride (8 μL, 0.064 mmol) at 0° C. and the mixture stirred for 1 h. Solvent was removed under reduced pressure. The crude product was purified on a silica gel column chromatography (5:1 n-Hexane/EtOAc) to give a colorless oil (23 mg, 92% yield): 1H NMR (300 MHz, CDCl3) 0.9˜1.7 (m, 29H); 2.34 (d, J=9.9 Hz, 1H); 2.52˜2.73 (m, 2H); 3.09˜3.17 (m, 1H); 3.73˜3.84 (m, 1H); 6.83˜6.87 (m, 1H); 6.95 (s, 1H); 7.09˜7.12 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:10][Si:11]([CH3:19])([CH3:18])[O:12][Si:13]([CH2:16]I)([CH3:15])[CH3:14].C(#N)C.CCCCC>O>[CH2:1]([N:8]1[CH2:14][Si:13]([CH3:16])([CH3:15])[O:12][Si:11]([CH3:19])([CH3:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: C[Si](C)(CI)O[Si](C)(C)CI
Solvent: CC#N
Solvent: O
Solvent: CCCCC
Product: C[Si]1(C)CN(Cc2ccccc2)C[Si](C)(C)O1
Reaction time: 1 h

Procedure:
An amount of 33.6 g. (0.315 mole) of benzylamine is added over a period of approximately 5 minutes to 41.4 g. (0.1 mole) of 1,3-bis-iodomethyl-1,1,3,3-tetramethyl-disiloxane with stirring in a bath at room temperature. Stirring is continued at room temperature for one hour. (A slurry resulted). Addition of 50 ml. of acetonitrile gives a clear solution which is then heated to reflux for 2 hours. The cooled solution is distributed between approximately 0.5 l. of pentane and 1.5 l. of water. The aqueous layer is then extracted with one more approximately 200 ml. portion of pentane, and the combined organic layer is washed twice with approximately 300 ml. of water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to provide a clear yellow mobile liquid. This product is then vacuum distilled to give 4-benzyl-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6-disilacyclohexane; b.p. 134° to 135° C., at 13 mm Hg.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:43]([OH:47])[CH2:44][CH:45]=[CH2:46]>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[OH:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH:46]=[CH:45][CH2:44][CH2:43][OH:47])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[NH:12][C:13](=[O:20])[C:14]=1[C:18]#[N:19]
Reactant: N#Cc1c(O)c2c(-c3ccc(I)cc3)csc2[nH]c1=O
Reactant: C=CCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: N#Cc1c(O)c2c(-c3ccc(C=CCCO)cc3)csc2[nH]c1=O
Temperature: 150 °C

Procedure:
To a stirred suspension of 3-(4-iodo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (60 mg, 0.15 mmol), triethylamine (0.1 mL), Pd(OAc)2 (3 mg), P(o-Tol)3 (9 mg), and MgO (18 mg, 0.45 mmol) was added 0.1 mL of but-3-en-1-ol in a single portion. The resulting mixture was heated to 150° C. using microwave reactor for 20 min, then filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 399 (M+H)+; 1H NMR (500 MHz, DMSO-d6): δ 2.35 (q, J=5 Hz, 2H), 3.53 (t, J=5 Hz, 2H), 6.28 (dt, J=15.91, 7.02 Hz, 1H), 6.45 (d, J=15.91 Hz, 1H), 6.60 (s, 1H), 7.27 (d, J=8.42 Hz, 2H), 7.39 (d, J=8.11 Hz, 2H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:35](I)[CH3:36]>O>[CH2:35]([O:22][C:21]([C:19]1[S:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23])[CH3:36]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 10.6 g (0.031 mole) of 5-tetradecyloxy-2-thiophene carboxylic acid, 4.3 g (0.034 mole) of potassium carbonate, and dimethylformamide is stirred at room temperature after which 15.6 g (0.10 mole) of ethyl iodide is added. The mixture is heated at 50° C with stirring overnight and poured into water and extracted with the ether. The ether layer is washed with water and salt water and then dried over sodium sulfate, filtered, and the ether is distilled off to give 5-tetradecyloxy-2-thiophenecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[CH:26][CH:27]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:28](=[O:29])[C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and p-toluic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:54])[C@@H:15]([NH:40][S:41]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)(=[O:43])=[O:42])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[NH2:39]/[C:20](=[N:21]\[S:22]([C:25]1[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]2[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=2[C:35]=1[CH3:36])(=[O:24])=[O:23])/[NH:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:40][S:41]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)(=[O:43])=[O:42])[C:14](=[O:54])[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCNCC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of compound C (36.6 g, 46.2 mmol) in dioxane (60 mL) was added 4M HCl in dioxane (58 mL) dropwise. The reaction mixture was stirred at room temperature for 1.5 h. Et2O (600 mL) was added to the reaction mixture, precipitated product was filtered off, washed with Et2O and finally dried under vacuum to afford compound D (34.5 g, 46.2 mmol). LC-MS [M+H] 685.4 (C33H44N6O6S2+H, calc: 685.9). Compound D was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[Br:10]Br.S(=O)(O)[O-].[Na+]>C(Cl)Cl.[Fe]>[Br:10][C:6]1[CH:7]=[C:2]([F:1])[C:3]([OH:9])=[C:4]([F:8])[CH:5]=1
Reactant: BrBr
Reactant: Oc1c(F)cccc1F
Agent: [Fe]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1c(F)cc(Br)cc1F
Temperature: 0 °C

Procedure:
A stirred mixture of 2,6-difluorophenol (20.0 g, 0.154 mole), bromine (25.57 g, 0.16 mole) and powdered iron (1 g) in methylene chloride (250 ml) was heated at reflux overnight. The cooled reaction mixture was poured into ice-water (300 ml) containing sodium bisulfite (5 g) and the organic phase separated. The aqueous phase was washed with additional methylene chloride. The organic phase was combined, dried (MgSO4) and the solvent evaporated to give a light yellow oil which solidified upon standing. NMR (CDCL3) of this material was consistent with the assigned structure. No additional analysis or purification was attempted. This material was used directly in the next step.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C@H:9]([N:26]1[CH2:30][C:29]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])=[CH:28][C:27]1=[O:39])[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH2:18][C@@H:19]2[CH2:23][O:22]C(C)(C)[O:20]2)[N:14]=1)=[O:11])(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[O:31][C:29]1[CH2:30][N:26]([C@@H:9]([CH2:8][CH2:7][OH:6])[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH2:18][C@@H:19]([OH:20])[CH2:23][OH:22])[N:14]=2)=[O:11])[C:27](=[O:39])[CH:28]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](CCO)N1CC(Oc2ccccc2Cl)=CC1=O
Yield: 45.4 %

Procedure:
In a round bottom flask was placed (S)-4-(t-butyl-dimethyl-silanyloxy)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-butyramide (128 mg, 0.21 mmol), methanol (5 mL) and p-toluenesulfonic acid monohydrate (10 mg) and stirred at 25° C. for 16 h. The mixture was then concentrated and treated with ethyl acetate and methanol to solubilize the material and concentrated in vacuo with silica gel (1 g). Purification by Biotage flash chromatography (AnaLogix, 25 g column, 100% ethyl acetate to 20% methanol/ethyl acetate) afforded material that was not pure. A second purification by Biotage flash chromatography (AnaLogix, 25 g column, 100% ethyl acetate to 20% methanol/ethyl acetate) afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-4-hydroxy-butyramide (43 mg, 45%) as a white foam: HR-ES-MS m/z calculated for C20H23N4O6Cl [M+H]+ 451.1379, observed 451.1379; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-2.06 (m, 2H), 3.23-3.31 (m, 2H), 3.37-3.50 (m, 2H), 3.72-3.81 (m, 1H), 3.86 (dd, J=13.9, 7.9 Hz, 1H), 4.09 (dd, J=13.5, 3.9 Hz, 1H), 4.29 (d, J=18.3 Hz, 1H), 4.50-4.60 (m, 2H), 4.71 (t, J=5.6 Hz, 1H), 4.80 (s, 1H), 4.84 (dd, J=8.4, 5.4 Hz, 1H), 4.94 (d, J=5.3 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.34-7.41 (m, 1H), 7.43-7.57 (m, 2H), 7.66 (dd, J=8.0, 1.2 Hz, 1H), 10.59 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.ClCCCl.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>N1C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]4[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:6][CH:7]=2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)sc2c1
Yield: 98.8 %

Procedure:
Prepared as described in the Amide Coupling section using 1,2-dichloroethane 2-(4-aminophenyl)-6-methylbenzothiazole (2.5 g, 10.4 mmol) and 4-nitrobenzoyl chloride (2.12 g, 11.4 mmol) in dry pyridine (30 ml) to give the title compound (4.0 g, 99%) as small tan-coloured needles after recrystallisation from DMF/water.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(=O)C)[CH2:14][C@H:13]2[C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[O:11])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
40 mg of (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidine was dissolved in 4 ml of methanol, and 0.1 ml of a 1N sodium hydroxide aqueous solution was added thereto, followed by stirring at room temperature for 15 minutes. 0.11 ml of a 1N hydrochloric acid aqueous solution was then added thereto, followed by concentration under reduced pressure. The concentrate was diluted with ethyl acetate, washed with water, dried over sodium sulfate and distilled off to remove the solvent to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-mercaptopyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C@@H:23]([OH:26])[CH2:24][OH:25])[CH:16]=1.[CH3:28][C:29]([CH3:31])=O>[Cl-].[Zn+2].[Cl-]>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:27])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C@@H:23]2[O:26][C:29]([CH3:31])([CH3:28])[O:25][CH2:24]2)[CH:16]=1
Reactant: CC(C)=O
Reactant: Nc1c(C(=O)c2cccc(OC[C@@H](O)CO)c2)cnn1-c1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1(C)OC[C@H](COc2cccc(C(=O)c3cnn(-c4ccc(F)cc4)c3N)c2)O1
Reaction time: 13 h

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-4-[3-{2(S),3-dihydroxypropoxy}benzoyl]pyrazole (0.6 g, 1.6 mmol) in 30 ml acetone was added zinc chloride (0.34 g, 2.6 mmol). The reaction mixture was stirred and heated at reflux. After 13 hours, the reaction mixture was concentrated to dryness and the product was purified by flash column chromatography on silica gel using 40% EtOAc/Hexane as elutent. The product was stirred with 1:1 ether/hexane and 125 mg of 5-amino-1-(4-fluorophenyl)4-{3-[(2,2-dimethyl-1,3-dioxolan-5(S)-yl)methoxy]benzoyl}pyrazole was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:24]=[CH:23][C:22]([N+]([O-])=O)=[C:21](/[CH:28]=[CH:29]/[N:30](C)C)[CH:20]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]2[C:19]2[CH:20]=[C:21]3[C:22](=[CH:23][CH:24]=2)[NH:30][CH:29]=[CH:28]3)=[CH:6][CH:7]=1
Reactant: CN(C)/C=C/c1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: O=c1c2ccccc2nc(-c2ccc3[nH]ccc3c2)n1-c1ccc(Cl)cc1
Yield: 39 %

Procedure:
Zn dust (0.220 g, 3.35 mmol) was added to a solution of (E)-3-(4-chlorophenyl)-2-(3-(2-(dimethylamino)vinyl)-4-nitrophenyl)quinazolin-4(3H)-one in AcOH (15 mL). After heating and stirring at reflux temperature for 4 hours, the mixture was basified with 1N NaOH and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 20% to 90% EtOAc in heptane, afford the title compound as a white solid (0.048 g, 39%). 1H-NMR (300 MHz, DMSO-d6): δ11.19 (s, 1H), 8.18-8.21 (m, 1H), 7.88-8.00 (m, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.47-7.70 (m, 2H), 7.30-7.44 (m, 5H), 7.20 (d, J=8.4 Hz, 1H), 7.06 (d, J=6.8 Hz, 1H), 6.40 (d, J=2.0 Hz, 1H). MS (APCI) m/z: 372 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)CCC>C1(C)C=CC=CC=1.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:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(-c4ccco4)cc3C(F)(F)F)[C@@H]2C1

Procedure:
To a degassed solution of tetrakis(triphenylphosphine)palladium(0) (3 mg, 0.002 mmol) in toluene (2 mL) was added N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (50 mg, 0.12 mmol). The resulting solution was degassed by exposure to vacuum and then an argon atmosphere (×3). To this solution was added 2-(tributylstannyl)furan (0.038 mL, 0.12 mmol). The resulting solution was degassed a final time and was then warmed to reflux conditions. The light yellow solution was maintained at reflux conditions for 14 h and became gray in color. The reaction was cooled, diluted with ethyl acetate, aqueous hydrogen chloride (1N), and saturated aqueous sodium chloride. The layers were separated and the aqueous layer washed with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by radial chromatography (10-30% ethyl acetate in hexanes) to give the desired product as a clear residue (44 mg, 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:15]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)(=[O:22])=[O:21])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>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]>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[C:23]([S:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:21])=[O:22])=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:3][CH:4]=2)=[N:9][CH:10]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)cc1
Temperature: 70 °C

Procedure:
To a 5 mL sealable vial equipped with a stir bar were added 5-(4-bromophenyl)pyrazin-2-amine (40 mg, 0.16 mmol), (2-(N-(tert-butyl)sulfamoyl)phenyl)-boronic acid (62 mg, 0.24 mmol), K2CO3 (66 mg, 0.48 mmol) and Pd(dppf)Cl2.CH2Cl2 (12 mg, 0.016 mmol). The vial was then sealed, evacuated, backfilled with argon and charged with argon sparged DMSO (0.64 mL). The vial was heated at 70° Celsius for 15 hours. The reaction mixture was cooled to rt diluted with ethyl acetate (2 mL) and water (2 mL), the layers separated and the aqueous layer further extracted with ethyl acetate (3×10 mL). The combined organic extracts were then dried with Na2SO4 and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C20H22N4O2S, 382.15; m/z found, 383.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.48-8.39 (d, J=1.5, 1H), 8.23-8.18 (dd, J=8.0, 1.4, 1H), 8.18-8.15 (d, J=1.4, 1H), 7.99-7.95 (d, J=8.4, 1H), 7.65-7.61 (m, 2H), 7.61-7.55 (m, 1H), 7.55-7.46 (m, 1H), 7.38-7.31 (dd, J=7.5, 1.4, 1H), 3.70 (s, 1H), 1.25 (s, 1H), 1.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH3:8])=[O:6].[CH3:20][O:21][C:22](=[O:25])[CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:20][O:21][C:22](=[O:25])[CH2:23][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:7]([C:5](=[O:6])[C:4]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Br:1])[CH:3]=1)[CH3:8]
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A mixture of 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (442 mg, 1.3 mmol), methylbromoacetate (0.247 mL, 2.6 mmol) and K2CO3 (717 mg, 5.2 mmol) was heated in DMF (8 mL) at 80° C. for 5 hrs. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over Na2SO4, then purified by silica gel column chromatography eluted with ethyl acetate/hexane (1/4) to yield {2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-phenoxy}-acetic acid methyl ester (495 mg). MS [M+H]+: 413.9; tR=2.75 min. (method 1)
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][N:18]=[C:19]([C:23]1[N:24]=[C:25]([NH:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:26][CH:27]=1)[C:20]([OH:22])=O.[C:48]([O:52][C:53]([NH:55][CH2:56][CH2:57][N:58]1[C:63](=[O:64])[C:62](=[O:65])[NH:61][NH:60][C:59]1=[S:66])=[O:54])([CH3:51])([CH3:50])[CH3:49]>C(OCC)(=O)C>[C:48]([O:52][C:53]([NH:55][CH2:56][CH2:57][N:58]1[C:63](=[O:64])[C:62](=[O:65])[NH:61][N:60]=[C:59]1[S:66][C:20](=[O:22])[C:19](=[N:18][O:17][CH3:16])[C:23]1[N:24]=[C:25]([NH:28][C:29]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:26][CH:27]=1)=[O:54])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)NCCn1c(=S)[nH][nH]c(=O)c1=O
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CON=C(C(=O)Sc1n[nH]c(=O)c(=O)n1CCNC(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
N,N'-Dicyclohexylcarbodiimide (1.11 g) is added to a suspension, cooled to +4° C., of 2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetic acid, syn isomer (2.17 g) and 4-(2-tert.-butyoxycarbonylamino-ethyl)-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (1.05 g) in ethyl acetate (50 cc). The mixture is stirred for 4 hours at 20° C., filtered and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The residue is taken up in methylene chloride (20 cc) and the solution is poured into diisopropyl ether (250 cc). After filtration and drying, 4-(2-tert.-butoxycarbonylamino-ethyl)-5,6-dioxo-3-[2-methoxyimino-2-(2-tritylamino-thiazol-4-yl)-acetylthio]-1,4,5,6-tetrahydro-1,2,4-triazine (syn isomer) (0.73 g) is obtained in the form of a yellow powder.