Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:18][Mg]Cl.COC1C=C(C=CC=1OC)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>[Pd]>[CH3:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc(C[Mg]Cl)cc1C
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Agent: [Pd]
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(OC)c(OC)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(C)c(C)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) was reacted with 3,4-dimethyl-benzylmagnesium chloride (0.25 M in THF, 28.0 mL, 7.0 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3,4-dimethylbenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane to afford the title compound. 0.050 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.02-2.19 (m, 1H) 2.19-2.35 (m, 6H) 2.44-2.62 (m, 1H) 2.62-2.87 (m, 4H) 3.19-3.38 (m, 1H) 3.82 (s, 3H) 6.46 (d, J=1.56 Hz, 1H) 6.95 (d, J=7.52 Hz, 1H) 7.00 (s, 1H) 7.07 (d, J=7.42 Hz, 1H) 8.93 (br. s, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.[C:10]([CH2:13][N:14]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][N:20]([CH2:26][C:27]([OH:29])=[O:28])[CH2:19][CH2:18][N:17]([CH2:30][C:31]([OH:33])=[O:32])[CH2:16][CH2:15]1)([OH:12])=[O:11].[OH-].[K+]>O1CCOCC1.O>[OH:4][CH:2]([CH2:1][O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][N:23]1[CH2:24][CH2:25][N:14]([CH2:13][C:10]([OH:12])=[O:11])[CH2:15][CH2:16][N:17]([CH2:30][C:31]([OH:33])=[O:32])[CH2:18][CH2:19][N:20]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:22]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CC(C)(C)OCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OCC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
11.27 g (86.58 mmol) of glycidyl-tert-butyl ether and 10 g (28.86 mmol) of 1,4,7-tris-carboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6 N potassium hydroxide solution. It is stirred for 24 hours at 70° C. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl-methyl ether. The aqueous solution is adjusted to pH 1 with 5 N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent =gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.38 g (71% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [N-]=C=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([CH2:36][C@@H:37]2[CH2:41][CH2:40][C:39](=[O:42])[NH:38]2)[CH:33]=[CH:32][C:31]=1[N:43]1[S:47](=[O:49])(=[O:48])[N:46](CC[Si](C)(C)C)[C:45](=[O:56])[CH2:44]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.O>[CH2:22]([O:29][C:30]1[CH:35]=[C:34]([CH2:36][C@@H:37]2[CH2:41][CH2:40][C:39](=[O:42])[NH:38]2)[CH:33]=[CH:32][C:31]=1[N:43]1[S:47](=[O:49])(=[O:48])[NH:46][C:45](=[O:56])[CH2:44]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCC(=O)N3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [N-]=C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC[C@@H](Cc2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of PS-isocyanate resin (0.500 g) in THF is added TBAF (1M in THF, 2.5 mL) and the mixture is stirred at RT for 2 h. The resin is filtered off and the TBAF solution is added to a stirring solution of 5-[2-benzyloxy-4-((S)-5-oxopyrrolidin-2-ylmethyl)-phenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.660 g, 1.28 mmol) in THF (20 mL). The mixture is stirred at 50° C. for 18 h. The mixture is allowed to cool to RT then is diluted with water and extracted with EtOAc (3×). The organic layer is washed with brine, dried over Na2SO4 and concentrated. The residue is purified on a reverse phase silica cartridge eluting with EtOH/H2O (10-60%) to provide the title compound: (M−1)−=414.
Reaction SMILES: Cl[C:2]1[C:3](=[O:26])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=2)[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>CC#N>[F:24][CH:23]([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:4]2[C:3](=[O:26])[C:2]([NH:37][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:39][CH:38]=3)=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:5]2(=[O:14])=[O:13])=[CH:17][CH:18]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C1C(Cl)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Solvent: CC#N
Product: O=C1C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Temperature: 150 °C
Yield: 25.9 %

Procedure:
4-Chloro-2-[4-(difluoromethoxy)benzyl]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (40 mg, 0.1 mmol) and 4-morpholinoaniline (36 mg 0.2 mmol) were mixed in MeCN (1 ml). The reaction mixture was heated in a microwave reactor at 150° C. for 15 mins and then evaporated to dryness. The residue was purified by column chromatography (ISOLUTE SI, 5 g/25 ml), eluting with DCM, then MeOH/DCM (1:99) and a product mixture was obtained. It was further purified by re-chromatography (ISOLUTE SI, 5 g/25 ml), eluting with EtOAc/heptane (10:90, then 25:75), to give the title compound (14 mg, 26%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.96-2.99 (m, 4H), 3.78-3.81 (m, 4H), 4.86 (s, 2H), 6.47-6.51 (m, 2H), 6.50 (t, J=74 Hz, 1H), 6.57-6.60 (m, 2H), 7.09-7.13 (m, 7H), 7.17-7.22 (m, 1H), 7.52-7.57 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 42.8, 49.4, 66.6, 109.7, 115.3, 115.8 (t, J=259 Hz), 119.6, 123.5, 124.7, 127.9, 128.9, 129.3, 130.6, 131.2, 131.5, 149.1, 151.2, 159.3; Mass Spectrum: M−H+ 540.
Reaction SMILES: COC(=O)CC1CC2C(=CC(OCCNC(OC(C)(C)C)=O)=CC=2)NC1=O.[CH3:28][O:29][C:30](=[O:63])[CH2:31][C:32]1[C:33](=[O:62])[N:34]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[CH:36]=2>>[CH3:28][O:29][C:30](=[O:63])[CH2:31][C:32]1[C:33](=[O:62])[N:34]([CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[C:37]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:36]=2
Reactant: COC(=O)Cc1cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2n(Cc2ccccc2)c1=O
Agent: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2NC1=O
Product: COC(=O)Cc1cc2ccc(OCCCCN)cc2n(Cc2ccccc2)c1=O

Procedure:
The title compound is prepared according to the procedure of Example 78 except that [7-(2-tert-butoxycarbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester is replaced with [7-(4-tert-butoxycarbonylaminobutoxy)-1-benzyl-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[CH2:14][N:13](CC2C=CC(OC)=CC=2)[C:12]1=[O:24])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[K+].[K+]>C(#N)C.O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[CH2:14][NH:13][C:12]1=[O:24])[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN2C[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C2=O)cc1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CNC1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A mixture of (3S)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(4-methoxybenzyl)azetidin-2-one (2.45 g), potassium persulfate (4.73 g) and dipotassium hydrogen phosphate (3.66 g) in acetonitrile (35 ml) and water (30 ml) was stirred at 70° C. for 2 hours. The mixture was evaporated and the residue was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The resultant solution was evaporated and the residue was column-chromatographed on silica gel (eluent : a mixture of hexane and ethyl acetate, 3:1) to give (3S)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]azetidin-2-one (0.71 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[N:35][CH:36]=1>CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([O:1][C:31]2[CH:36]=[N:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)[CH:3]=[C:4]([CH3:23])[C:5]=1[C:9]1[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])nc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 50 °C
Yield: 66.6 %

Procedure:
A solution of 5-3 (1.92 g, 5.91 mmol) in DMF (15 mL) was added with cesium carbonate (2.41 g, 7.39 mmol). The reaction mixture was heated at 50° C. for 60 min and added with 5-bromo-2-nitropyridine (24-1, 1.80 g). The reaction mixture was heated at 50° C. for 4.0 h. The solution was quenched with water (40 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 24 (1.76 g) in 67% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, 2 H), 8.42 (d, 1 H), 8.33 (d, 1 H), 7.96 (d, 2 H), 7.63 (m, 1 H), 7.21 (s, 1 H), 7.01 (s, 2 H), 2.08 (s, 6 H), ESI-MS=m/z 447.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=[O:4].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To a solution of product from step 2 (500 mg, 1.11 mmol) in methylene chloride (10 ml) was added 4M HCl (2 ml) and the resulting mixture was stirred for 2 hours at room temperature. The solid was filtered, washed with ether to obtain 410 mg(95%) of the product as a solid. 1H NMR(300 MHz, CDCl3): δ1.86(m, 3H), 2.52(m, 4H), 2.89(m, 2H), 3.52(m, 2H), 3.74(s, 3H), 4.74(m, 2H), 7.10(d, 2H, J=8.7 Hz), 7.69(d, 2H, J=8.7 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:9](O)[CH2:8][CH2:7][O:6][P:5]1(=[O:15])[NH:11][CH2:12][CH2:13][Cl:14].[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[SH:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27].ClC(Cl)(Cl)C(O)=O>O>[CH:16]1([NH3+:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl:1][CH2:2][CH2:3][N:4]1[CH:9]([S:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27])[CH2:8][CH2:7][O:6][P:5]1([NH:11][CH2:12][CH2:13][Cl:14])=[O:15]
Reactant: O=P1(NCCCl)OCCC(O)N1CCCl
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: O
Product: O=P1(NCCCl)OCCC(SCCS(=O)(=O)[O-])N1CCCl
Reaction time: 20 h

Procedure:
277 mg (1 mmol) of 3-(2-chloroethyl)-2-(2-chloroethylamino)-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2oxide and 240 mg (1 mmol) of cyclohexylammonium-2-mercaptoethanesulphonate were dissolved in 4 ml of water, mixed with a trace of trichloroacetic acid and stored for 20 hours at 0° C. The reaction mixture which was concentrated under vacuum was dissolved twice in ethanol and re-concentrated. It was then taken up in ethanol and precipitated with ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][CH:15]=[CH2:16])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CCC(C(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 2-(3,4-dichlorophenyl)pent-4-enoate (2.47 g, 9.53 mmol) in tetrahydrofuran (15.0 mL) was added a solution of lithium hydroxide monohydrate (2.00 g, 47.6 mmol) in water (15.0 mL). The mixture was vigorously stirred at rt for 12 hrs. The resulting mixture was acidified by addition of 12.0 M of hydrochloric acid in water (3.97 mL, 47.6 mmol) at 0° C., and extracted with EtOAc (×3). The combined organic layer was dried and concentrated to provide 2-(3,4-dichlorophenyl)pent-4-enoic acid as a yellow syrup (2.65 g, quantitative). 1H NMR (400 MHz, CDCl3) δ 7.45-7.35 (m, 2H), 7.21-7.11 (dd, J=8.3, 2.1 Hz, 1H), 5.76-5.59 (ddt, J=17.0, 10.2, 6.8 Hz, 1H), 5.14-4.99 (m, 2H), 3.65-3.56 (t, J=7.7 Hz, 1H), 2.88-2.74 (dt, J=14.8, 7.5 Hz, 1H), 2.58-2.43 (dt, J=14.3, 6.9 Hz, 1H).
Reaction SMILES: CC[O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[C:21]3[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[CH:25][C:20]=3[O:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5].[OH-].[K+]>C1COCC1.C(O)C.O>[CH2:27]([O:26][C:24]1[CH:23]=[CH:22][C:21]2[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:13]=3[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]4)=[CH:18][O:19][C:20]=2[CH:25]=1)[CH3:28]
Reactant: CCOC(=O)c1cc2c(OCc3coc4cc(OCC)ccc34)cccc2n1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
4-(6-Ethoxy-benzofuran-3-ylmethoxy)-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (29a) (7.5 g, 15.6 mmol) is dissolved in 150 ml of a 1:1:1 mixture of THF, ethanol and water. And after addition of KOH pellets (4.4 g, 78.2 mmol) the mixture is stirred for 2 h (TLC control) at 85° C. Then the organic solvent is removed under reduced pressure. The residue is cooled to 0° C. and treated with 2M HCl. The crude product is filtered off and dried under high vacuum. The crude product is recrystallized from ethyl acetate.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[C:24]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[C:25]#[N:26])=[CH:19][CH:18]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)C>[C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[C:24]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[C:25]#[N:26])=[CH:19][CH:18]=3)[N:14]=2)[NH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)c4nccs4)cc3)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)c4nccs4)cc3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
To a 25 ml one necked round bottom flask, 3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)-2-(thiazol-2-yl)acrylonitrile (0.09 g, 0.000161 mol) was taken in CH2Cl2 (10 ml) followed by dropwise addition of TFA (2.0 ml) at 0°-5° C. and the reaction was allowed to stir at room temperature for 24 hr. After completion of the reaction, the pH of the solution was adjusted to neutral by the addition of saturated sodium bicarbonate solution and the product was extracted with CH2Cl2. The combined organic layer was dried over anhy. sodium sulphate and concentrated to obtain crude mixture which was dissolved in ethanol (10 ml) and NaOAc.3H2O (0.219 g, 0.00161 moles) was added and the reaction mixture was stirred it at room temperature for 20 hr. Ethanol was removed and the reaction mixture was diluted with water, followed by extraction with ethyl acetate. The combined organic layers were dried over sodium sulphate, concentrated to afford crude product which was purified using column purification by eluting the compound with 50% ethyl acetate in hexanes to yield 35.0 mg of 3-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)-2-(thiazol-2-yl)acrylonitrile.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:11]([O-])=[O:12].[Na+]>Cl.O>[N:11]([N:4]1[CH2:3][CH2:2][S:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]1=2)=[O:12]
Reactant: c1ccc2c(c1)NCCS2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCSc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
3,4-Dihydro-2H-benzo[1,4]thiazine (1.2 g, 7.94 mmol) was dissolved in 3N HCl at 0° C., and the reaction mixture stirred for 5 min. at 0° C. A solution of sodium nitrite (548 mg, 7.94 mmol) in water was added at the same temperature, and the reaction mixture stirred at 0° C. for 1 h. After completion of reaction water was added and extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, to provide 1 g desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:16]2[CH:9]([CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([NH:18][C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][N:22]=3)=[O:20])[C:15]2=[O:17])[CH2:8][N:7](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:6]1)=[O:4].SC1C=CC(O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[N:16]2[CH:9]([CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([NH:18][C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][N:22]=3)=[O:20])[C:15]2=[O:17])[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC2CC=CCC(NC(=O)c3nccc4ccccc34)C(=O)N21
Agent: O=C([O-])[O-]
Agent: Oc1ccc(S)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CNCC2CC=CCC(NC(=O)c3nccc4ccccc34)C(=O)N21
Temperature: 25 °C
Reaction time: 12 h
Yield: 112.3 %

Procedure:
To a solution of 6-[(isoquinoline-1-carbonyl)-amino]-2-(2-nitro-benzenesulfonyl)-5-oxo-1,3,4,5,6,7,10,10a-octahydro-2H-2,4a-diaza-benzocyclooctene-4-carboxylic acid methyl ester (1.5 g, 2.53 mmol) in DMF (55 mL) is added 4-mercaptophenol (1.28 g, 10.1 mmol) and K2CO3 (1.4 g, 10.1 mmol). The solution is stirred at rt for 12 hrs, diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered, and concentrated. The crude residue is purified by preparative reverse phase HPLC (CH3CN/H2O with 0.1% TFA) to yield 1.16 g of product as a TFA salt.
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:5]2[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:9](=[O:15])[CH2:8][O:7][C:6]=2[N:16]=1.CC1(C)C(C)(C)OB([C:31]2[CH:45]=[CH:44][C:34]([CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH:12]1([CH2:11][N:10]2[C:9](=[O:15])[CH2:8][O:7][C:6]3[N:16]=[C:2]([C:31]4[CH:45]=[CH:44][C:34]([CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:33][CH:32]=4)[C:3]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:5]2=3)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)N(CC2CC2)C(=O)CO3)cc1
Temperature: 50 °C
Yield: 73.9 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-(cyclopropylmethyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (80 mg, 0.223 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (89 mg, 0.267 mmol) and CESIUM CARBONATE (363 mg, 1.114 mmol) in a mixture of 1,4-Dioxane (3341 NI) and water (1114 μl) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of PdC12(dppf)-CH2Cl2Adduct (36.4 mg, 0.045 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50° C. under a nitrogen atmosphere for one hour. LC-MS analysis showed reaction completion. The reaction mixture was allowed to cool to room temperature, diluted with water (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give an off-white solid. The resulting residue was purified via Biotage (15-85% cyclohexane:EtOAc; 10 g column) to give the title compound (80 mg, 74%). 1H NMR (500 MHz, CDCl3): 7.39 (1H, s), 7.32-7.26 (5H, m), 7.20-7.18 (2H, dd), 7.12-7.10 (2H, d), 4.89 (2H, s), 4.80 (1H, br), 4.27 (2H, s), 3.87-3.86 (2H, d), 1.48-1.45 (9H, br), 1.18-1.15 (1H, m), 0.60-0.56 (2H, m), 0.48-0.45 (2H, m).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:32])([F:33])[C:28]([F:30])([F:31])[F:29])=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(C3=CCNCC3)ccn2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 179, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.