Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH2:25][OH:24])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: OCc1ccccc1B(O)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3CO)cc1OCC2

Procedure:
Following the procedures of Example 475, 8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 was reacted with 2-(hydroxymethyl)phenylboronic acid to give 478. MS(ESI+) 402.1. 1H NMR (400 MHz, DMSO) δ 8.46 (d, J=8.3 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.41 (td, J=7.4, 1.1 Hz, 1H), 7.38-7.32 (m, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.20 (dd, J=8.3, 1.6 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 6.02-5.83 (m, 1H), 5.16 (t, J=5.3 Hz, 1H), 4.56 (q, J=6.1 Hz, 4H), 4.45 (d, J=5.3 Hz, 2H), 1.50 (d, J=6.6 Hz, 6H)
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][C:43]=1[F:49].[CH2:51]([C:53]([C:76]1[CH:81]=[CH:80][C:79](B2OC(C)(C)C(C)(C)O2)=[C:78]([CH3:91])[CH:77]=1)([C:56]1[CH:61]=[CH:60][C:59]([C:62]#[C:63][C:64]2([O:70][Si:71]([CH3:74])([CH3:73])[CH3:72])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]2)=[C:58]([CH3:75])[CH:57]=1)[CH2:54][CH3:55])[CH3:52]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:79]2[CH:80]=[CH:81][C:76]([C:53]([CH2:54][CH3:55])([C:56]3[CH:61]=[CH:60][C:59]([C:62]#[C:63][C:64]4([O:70][Si:71]([CH3:73])([CH3:74])[CH3:72])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]4)=[C:58]([CH3:75])[CH:57]=3)[CH2:51][CH3:52])=[CH:77][C:78]=2[CH3:91])=[CH:44][C:43]=1[F:49]
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of palladium acetate (2.0 mg, 0.009 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (7.4 mg, 0.018 mmol) and potassium phosphate (38.4 mg, 0.181 mmol) in water (0.032 mL) and toluene (0.150 mL) was stirred for three minutes. A solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 19.6 mg, 0.097 mmol) and 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 35-(4); 37.1 mg, 0.0647 mmol) in toluene (0.18 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for one hour. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (3% ethyl acetate/hexane) to give the title compound (30.9 mg, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[Si]([O:30][CH2:31][CH2:32][N:33]([CH3:45])[C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38](F)=[C:37]([Cl:42])[C:36]=1F)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:42][C:37]1[C:36]2[O:30][CH2:31][CH2:32][N:33]([CH3:45])[C:34](=[O:44])[C:35]=2[CH:40]=[CH:39][C:38]=1[O:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4ccn(C)n4)c3)c2Cl)C1=O
Temperature: 140 °C
Yield: 31.9 %

Procedure:
A mixture of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (539 mg, 1.77 mmol), N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamide (539 mg, 1.77 mmol) and potassium carbonate (490 mg, 3.55 mmol) in acetonitrile (15 mL) was placed in a Smith Creator microwave reactor and heated to 140° C. for 6 hours. Distilled water was added to the reaction and the aqueous layer extracted with DCM (3×30 mL). The combined organic phase was washed with brine (30 mL), dried (MgSO4), filtered and evaporated to give a yellow oil. This was purified by column chromatography, eluting with 20-100% ethyl acetate in isohexane, to give the title compound (290 mg). 1H NMR δ (CDCl3): 2.09-2.15 (1H, m), 2.18-2.27 (1H, m), 3.23 (3H, s), 3.59 (2H, t), 3.76 (3H, s), 3.86-3.92 (1H, m), 3.94-4.00 (3H, m), 4.54 (2H, t), 4.95 (1H, d), 6.68 (1H, d), 6.78-6.81 (2H, m), 7.04-7.05 (1H, m), 7.16-7.17 (1H, m), 7.28 (1H, d), 7.70 (1H, d), 8.75 (1H, s); m/z 513 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.ClCCl.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].I[C:40]1[S:44][C:43]([NH:45][C:46](=[O:48])[CH3:47])=[N:42][C:41]=1[CH3:49].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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].C(O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:40]2[S:44][C:43]([NH:45][C:46](=[O:48])[CH3:47])=[N:42][C:41]=2[CH3:49])=[CH:3][C:4]=1[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1cc(Br)cnc1Cl
Reactant: CC(=O)Nc1nc(C)c(I)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(S(C)(=O)=O)c2)s1

Procedure:
A solution of 5-bromo-2-chloro-3-methylsulfonylpyridine (0.135 g, 0.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (24 mg, 0.03 mmol), bis(pinacolato)diboron (0.135 g, 0.53 mmol) and potassium acetate (0.147 g, 1.5 mmol) in 1,4-dioxane (4 mL) was heated at 80° C. for 18 hours. The reaction mixture was cooled and N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide (100 mg, 0.35 mmol), 2M aqueous sodium carbonate (1.25 mL, 2.5 mmol), ethanol (0.6 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (12 mg, 0.015 mmol) were added. The resultant mixture was heated again at 80° C. for 8 hours. The resultant mixture was filtered through a plug of celite and purified with preparative HPLC (Method A) to give the title compound (30 mg, 17%; retention time
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9](S(C2C=CC(C)=CC=2)(=O)=O)[C:10]#[N:11])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[N+:33]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])#[C-:34].O>C1COCC1.CCOC(C)=O>[CH2:39]([O:38][C:36]([C:35]1[NH:33][CH:34]=[C:9]([C:10]#[N:11])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:37])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)C(C#N)=Cc2ccc(Br)cc2)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc(C#N)c1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-(4-bromo-phenyl)-2-(toluene-4-sulfonyl)-acrylonitrile (38.76 g, 0.107 mol, prepared directly above) in anhydrous THF (500 mL) is treated with DBU (65.00 mL, 0.434 mol), followed by ethyl isocyanoacetate (25.00 g, 0.214 mol). The resulting dark-brown reaction mixture is allowed to stir at room temperature for 3 hours. The reaction mixture is poured into water (1,000 mL) and extracted with EtOAc (3×250 mL each). The combined organics are washed with 1 N HCl (250 mL), water (250 mL), brine (250 mL), dried over anhydrous Na2SO4, filtered, then concentrated in vacuo to afford an off-white solid. The solid is dissolved in a minimum amount of EtOAc, then treated with excess hexanes, causing a solid to crash out. The solid is recovered by vacuum filtration, washed with hexanes, and dried under vacuum filtration to afford the title compound (23.90 g, 69.9% crude yield) as a off-white solid: 1H NMR (500 MHz; CDCl3) δ 1.22 (t, 3H), 4.26 (q, 2H), 7.39 (d, 2H), 7.45 (d, 1H), 7.55 (d, 2H), 9.70 (bs, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([OH:8])[CH:4]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[OH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([O:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cc(O)n[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(CO)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a stirred suspension of 5-hydroxymethyl-1H-pyrazol-3-ol (J. Heterocycl. Chem., 1979, 16, 505-508) (1.0245 g, 8.98 mmol) in anhydrous dichloromethane (50 ml), under nitrogen, was added p-toluenesulfonyl chloride (1.8825 g, 9.87 mmol), then, dropwise over 5 min, anhydrous triethylamine (1.50 ml, 10.8 mmol). The mixture was stirred at room temperature for 16.5 h under nitrogen, then washed with brine (50 ml). The aqueous layer was further extracted with dichloromethane, and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 5-7% MeOH/CH2Cl2) to afford 1.3067 g (54%) of the title compound as a pale green solid; 1H NMR (360 MHz, d6-DMSO) δ 2.42 (3H, s), 4.38 (2H, d, J=5.7 Hz), 5.32 (1H, t, J=5.7 Hz), 5.82 (1H, d, J=2.2 Hz), 7.47 (2H, d, J=8.3 Hz), 7.77 (2H, d, J=8.3 Hz), 12.55 (1H, s).
Reaction SMILES: [P:1]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:2]CCCCCCCCCCCCCCCCCC.[C:59]([C:63]1[C:68]([OH:69])=[C:67]([CH3:70])[C:66]([CH2:71]Cl)=[C:65]([CH3:73])[CH:64]=1)([CH3:62])([CH3:61])[CH3:60]>>[C:59]([C:63]1[CH:64]=[C:65]([CH3:73])[C:66]([CH2:71][P:1](=[O:2])([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[C:67]([CH3:70])[C:68]=1[OH:69])([CH3:62])([CH3:61])[CH3:60]
Reactant: CCCCCCCCCCCCCCCCCCOP(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Product: CCCCCCCCCCCCCCCCCCOP(=O)(Cc1c(C)cc(C(C)(C)C)c(O)c1C)OCCCCCCCCCCCCCCCCCC

Procedure:
21.7 Grams of trioctadecyl phosphite and 5.75 grams 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol was stirred together as a melt at 110° to 120° for 2 hours and at 120° to 125° for 7 hours. The reaction mixture was dissolved in 100 ml. of toluene and the colorless, slightly turbid solution was successively washed with 3 N aqueous hydrochloric acid, water, 2 N aqueous sodium carbonate solution and water until the wash waters were neutral. After drying over anhydrous sodium sulfate and filtering free of drying agent, the clear filtrate was concentrated by distillation of the solvent at reduced pressures. The residual oil was topped in the "ASCO 50" Rota-Film Molecular Still at a wall temperature of 210° to 215° and a pressure of 1 to 5 microns. After crystallization from methylethyl ketone, the desired product was obtained as white crystals melting at 70° to 72.5°. (compound 4)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[N+:19]([O-])([OH:21])=[O:20]>O>[CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][C:11]([N+:19]([O-:21])=[O:20])=[C:5]([CH:4]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCOC)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)c1cc(OC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
Ethyl 3-methoxy-4-(2-methoxyethoxy)benzoate (9.5 g, 37 mmol) was added portionwise to stirred concentrated nitric acid (75 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for a further 90 minutes. The mixture was diluted with water and extracted with methylene chloride, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with hexane to give ethyl 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzoate (10.6 g, 95%) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]([CH:17]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:19]=2)[C:13](OC)=[O:14])=O)=[CH:4][CH:3]=1.B.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C1COCC1.CO.CCOC(C)=O>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][CH2:8][C:10]2[CH:11]=[C:12]([CH2:13][OH:14])[CH:17]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:19]=2)=[CH:4][CH:3]=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]
Reactant: COC(=O)c1cc(Oc2ccc(F)cc2)cc(C(=O)NCc2ccc(F)cc2)c1
Agent: B
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: OCc1cc(CNCc2ccc(F)cc2)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3-(4-fluorobenzylcarbamoyl)-5-(4-fluorophenoxy)benzoate (2.7 g, 6.79 mmol) in 10 mL of THF at ice bath temp was added borane (40 mL of 1 M solution in THF) slowly. After 10 min, the mixture was warmed to rt, stirred for 30 min and heated at 50° C. for 10 h. The mixture was cooled to rt and treated with 10 mL of 1M solution of LiAlH4 in THF. The mixture was stirred for 2 h and treated with EtOAc. The resulting mixture was treated with MeOH and TFA slowly, stirred for a while, mostly concentrated. Water and MeOH were added to the residue and the insoluble material was filtered. The filtrate was concentrated. Purification of the residue using prep HPLC provided the desired product as a white solid of TFA salt (1.74 g, 54.6%). 1H NMR (CD3OD): δ 7.49˜6.97 (m, 11H), 4.56 (s, 2H), 4.19 (s, 2H), 4.16 (s, 2H); MS (ESI): (M+H)+=356.24.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=2)[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].CO>C1COCC1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:16]=2)[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OC2CCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 3-(cyclopentyloxy)-5-[(phenylmethyl)oxy]benzoate (9.25 g, 28.34 mmol) was dissolved in THF (120 mL) and a solution of lithium hydroxide mono hydrate (3.49 g, 85.0 mmol) in water (60 mL) added. The bi-phasic solution was stirred at RT for 16 hours (LCMS indicated reaction 80% complete), methanol (15 mL) added and the mixture stirred for a further 4 hours. The THF was removed in vacuo then water (40 mL) added and the pH adjusted to 7 with hydrochloric acid. The solid was collected and washed thoroughly with cold water (8.85 g).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:20]=4[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:20]=4[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2c1CCCCC2
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2c1CCCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To a solution of 2-(1-methyl-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (40 mg, 0.08 mmol) in CH2Cl2 (2 mL) was added TFA (1.0 mL, 13.0 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (2 mL) and ethylenediamine (0.1 mL, 1.48 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h then concentrated and directly purified by silica gel chromatography with 0% to 3% MeOH/EtOAc to isolate 20 mg (68%) of 2-(1-methyl-1,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as an off-white solid. MS: (M+Na)+=389; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.63 (br. s., 1H), 8.80 (s, 1H), 8.27 (s, 1H), 7.83 (s, 1H), 3.81 (s, 3H), 3.02-3.12 (m, 2H), 2.74-2.83 (m, 2H), 1.82 (br. s., 2H), 1.57-1.73 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:34][C:35]([O:38][C:39]([NH:41][C@H:42]([C:54]([OH:56])=O)[CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:40])([CH3:37])[CH3:36].Cl.CN>CC(N(C)C)=O.C(Cl)Cl>[CH3:34][C:35]([O:38][C:39]([NH:41][C@H:42]([C:54](=[O:56])[NH:4][CH3:1])[CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:40])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.3 %

Procedure:
N,N-Diisopropylethylamine (15.10 g, 116.8 mmol) and HATU (10.77 g, 28.34 mmol) were added to a suspension of Boc-Asp-(OBzl)-OH (7.61 g, 23.54 mmol) and methylamine hydrochloride (5.03 g, 74.50 mmol) in DMA (31 mL). After stirring at room temperature for 18 h, the reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3. The organic layer was washed with H2O several times, dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 4% MeOH in CH2Cl2 to afford the titled product (6.2 g, 78%) as a white solid. 1H-NMR (CDCl3) δ: 1.471 (9H, s), 2.730 (1H, m), 2.818 (3H, d, J=4.8 Hz), 3.120 (1H, m), 4.520 (1H, s), 5.156 (2H, m), 5.660 (1H, s), 6.430 (1H, s), 7.378 (5H, m). LC-MS (ES) m/e 337.2 (M+H)+.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[SH:12])[CH:5]=[CH:4][CH:3]=1.CO.Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C(N(CC)CC)C>[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[S:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[N:2]=[CH:3][CH:4]=[CH:5]2
Reactant: Clc1ncccn1
Reactant: Sc1cccc2cccnc12
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: c1cnc(Sc2cccc3cccnc23)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 210 mg. (1.06 m mole) of quinoline-8-thiolhydrochloride in 5 ml. of dry methanol was added 128 mg. (1.05 m mole) of 2-chloropyrimidine in 2 ml. of the same solvent followed by 148 ul (1 m mole) of dry triethylamine. The reaction mixture was allowed to stir at room temperature overnight followed by the removal of the methanol in vacuo. The residue was partitioned between a saturated sodium bicarbonate solution and ethyl acetate. The organic phase was separated, dried and concentrated. The residue was redissolved in chloroform and concentrated without heat. The residue was triturated with ethyl acetate, filtered and dried, 170 mg., m.p. 165°-168° C.
Reaction SMILES: Cl[CH:2]([F:12])[C:3](=O)[C:4](=[N:9][OH:10])[C:5]([O:7][CH3:8])=[O:6].[NH2:13][C:14]([NH2:16])=[S:15].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.O>[NH2:16][C:14]1[S:15][C:2]([F:12])=[C:3](/[C:4](=[N:9]/[OH:10])/[C:5]([O:7][CH3:8])=[O:6])[N:13]=1
Reactant: COC(=O)C(=NO)C(=O)C(F)Cl
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)/C(=N\O)c1nc(N)sc1F
Temperature: 300 °C
Reaction time: 12 h
Yield: 25.1 %

Procedure:
To a solution of methyl 4-chloro-4-fluoro-2-(hydroxyimino)-3-oxobutyrate (7.8 g) in N,N-dimethylacetamide (80 ml) was added thiourea (15 g) under stirring at 300° C. and then the stirring was continued for 12 hours at the same temperature. The resulting solution was powered into a mixture of ethyl acetate (300 ml) and water (400 ml), and adjusted to pH 3.0 with saturated aqueous sodium hydrogencarbonate. The separated organic phase was washed with water (400 ml), and brine (400 ml), and dried with magnesium sulfate and evaporated in vacuo to give methyl 2-(2-amino-5-fluorothiazol-4-yl)-2-(Z)-(hydroxyimino)acetate (2.17 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:25])[C:22](O)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.CN(C)CCCN=C=NCC>C(Cl)Cl.C(O)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22]1[N:9]([CH:10]([CH3:12])[CH3:11])[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:25])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)Nc1cc(F)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Product: CC(C)n1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
4-Fluoro-N2-isopropylbenzene-1,2-diamine (0.7 g, 5.07 mmol) was dissolved in DCM (10 mL) and (S)-2-tert-butoxycarbonylaminopropionic acid (1.06 g, 5.58 mmol) added. To the resultant dark red solution was added HOAt (0.76 g, 5.58 mmol), followed by N-methyl morpholine (1.23 mL, 11.15 mmol) and N-(3-dimethylaminopropyl)-N′ ethylcarbodiimide (1.07 g, 5.58 mmol). The resultant blue/black solution was stirred at RT overnight, under an atmosphere of nitrogen. The mixture was diluted with DCM (40 mL) and washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo to afford a dark red oil. This was purified by column chromatography (silica gel, gradient 0-20% EtOAc in DCM) to afford a red oil which solidified on standing. This was dissolved in acetic acid (20 mL) and heated at 70° C. overnight. The resultant mixture was allowed to cool to RT and was concentrated in vacuo to afford the title compound as a dark red gum (1.0 g, 88%). This material was used in the next step without any purification. LCMS (Method B): RT 2.78 min [M+H]+ 322.2
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].[H-].[Na+].Br[CH2:16][CH:17]=[CH:18][CH3:19].O>C1(C)C=CC=CC=1>[CH2:16]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:11][CH3:12])[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:17]=[CH:18][CH3:19]
Reactant: CC=CCBr
Reactant: CCOC(=O)NCC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC=CCN(CC(OC)OC)C(=O)OCC
Reaction time: 1 h

Procedure:
89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)carbamate are added dropwise to 17.5 g (0.58 mol) of NaH (80% strength in paraffin oil) in 500 ml of absolute toluene at 80° C. The mixture is then stirred for one hour and 80 g (0.59 mol) of 1-bromo-2-butene are subsequently added dropwise at 80° C. The mixture is stirred at 80° C. overnight and cooled, the salts are dissolved with water and the aqueous phase is separated off and extracted with toluene. The toluene solutions are dried over K2CO3 and concentrated and the residue is distilled.