Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CCl)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CN2CCN(C)CC2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (1.0 g, 2.1 mmol) in DMF (40 mL) at 0° C. was added 1-methylpiperazine (1.2 mL, 1.1 g, 11 mmol), and the mixture stirred for 0.5 hours at 0° C., then warmed to ambient temperature. After 7 hours the reaction mixture was poured into water (150 mL) and the resulting solid collected by filtration, washed with water (50 mL) and acetonitrile (10 mL). Purification by flash chromatography on silica gel afforded 0.77 g (64% yield) of N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, as a white foam: NMR (DMSO-d6/TFA) 10.4 (s, 1), 9.4 (s,1), 7.2-8.1 (m, 7), 4.4 (s, 2), 3.8 (s, 3), 3.0-3.8 (br m, 8), 2.8 (s, 3) ppm.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:8][CH2:9][CH:10]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:11]1[CH:12]=[CH:13][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:16]=1
Reactant: CC(C)(C)c1ccc(C(CO[Si](C)(C)C(C)(C)C)OC2CCCCO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC(C)(C)c1ccc(C(CO)OC2CCCCO2)cc1

Procedure:
To 1-tert-butyldimethylsilyloxy-2-tetrahydropyranyloxy-2-(4-tertbutylphenyl) ethane (0.4 g, 1.01 mmol) is added tetrabutylammonium fluoride solution (1M TBAF in THF, 5 ml, 5.0 mmol). The solution is stirred for 2 hours after which water is added to the reaction and this is extracted in ethyl acetate. The organic layer is then washed with water, dried and concentrated. The residue obtained is purified by flash chromatography (silica gel; ethyl acetate/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:16])=[N:7]2.[C:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:16])=[N:7]2
Reactant: Cc1ccc2c(Cl)cc(C(=O)O)c(O)c2n1
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(Cl)cc(C(=O)NCCCc3ccccc3)c(O)c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-chloro-8-hydroxy-2-methyl-7-quinolinecarboxylic acid (0.500 g) and 3-phenylpropylamine (0.33 mL) in 20 mL DMF is added EDC hydrochloride (0.444 g) and hydroxybenzotriazole hydrate (0.312 g). The reaction is stirred at room temperature for 48 h. The mixture is then partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine (1×), dried over sodium sulfate and condensed. The residue is stirred in 20 mL 1:1 THF/1N HCl overnight. The solution is neutralized with saturated aqueous NaHCO3. The reaction is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine (1×), dried and condensed. The crude product is chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and condensed. The residue taken up in a minimal amount of CH2Cl2. Toluene is added to the solution and the mixture is sonicated while adding hexanes until a white solid formed. The solid is collected and dried to yield 0.310 g of the title product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][C@H:9]([C:11]2[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH:9]([C:11]2[CH:12]=[C:13]([C:17]([NH:35][CH3:34])=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33]
Reactant: C[C@H](Sc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N)c1cccc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(C(C)Sc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
33 mg (0.072 mmol) of rac-3-[(1S)-1-({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-pyridin-2yl}sulfanyl)ethyl]benzenecarboxylic acid (Example 16) were initially charged in 0.66 ml of DMF. At 0° C., 54.5 mg (0.143 mmol) of HATU were added, and the reaction solution was stirred at 0° C. for 20 min. After addition of 6.7 mg (0.215 mmol) of methylamine (2N in tetrahydrofuran) and 18.5 mg (0.143 mmol) of N,N-diisopropylethylamine, the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:23][N:24]=[C:25]=[O:26]>C(O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[N:8]([C:25](=[O:26])[NH:24][CH3:23])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Reactant: CN=C=O
Solvent: CCO
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Br)ccc2CC1C
Yield: 84 %

Procedure:
0.84 g (2.33 mmoles) of 8-bromo-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 22, Step D) are reacted with methyl isocyanate according to the method of Example 3. The crude product is suspended in 5 ml of hot ethanol. After filtration and drying, 0.82 g (84%) of the title compound are obtained. M.p.: 197°-200° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:13][CH2:12][CH2:11][O:10][CH3:9]
Reactant: COCCCO
Reactant: Oc1ccccc1I
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCOc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a stirred solution of 2-iodophenol (3.00 g, 13.6 mmol), 3-methoxy-1-propanol (1.57 ml, 16.4 mmol) and triphenylphosphine (4.29 g, 16.4 mmol) in THF (15 ml) was added dropwise diisopropyl azodicarboxylate (3.22 ml, 16.4 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure: The residue was purified by silica gel chromatography (EA/HEP 1:5). 4.00 g of the title compound were obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F-].[Cs+].[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].Br[C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH:32]3[CH3:36])=[N:26][C:25]=2[CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:31]1[CH2:30][CH2:29][C:27]1[S:28][C:24]2[CH:23]=[CH:22][C:21]([C:14]3[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=3)=[CH:37][C:25]=2[N:26]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1CCCN1CCc1nc2cc(Br)ccc2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1CCCN1CCc1nc2cc(-c3ccc(C#N)cc3)ccc2s1
Temperature: 90 °C
Yield: 31.5 %

Procedure:
To a reaction flask containing K2CO3 (0.326 g, 1.5 mmol), CsF (0.233 g, 1.5 mmol), and (0.19 g, 1.3 mmol) of 4-cyanophenyl boronic acid was added a solution of 5-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole (0.25 g, 0.77 mmol) in 3 mL of toluene. The resulting mixture was purged with nitrogen, and then 2-dicyclohexylphosphinobiphenyl (54 mg, 0.15 mmol) and Pd2(dba)3 (70 mg, 0.08 mmol) were added. The resulting reaction mixture was then heated at 90° C. for 2 hr. At completion, the reaction was washed with water, then diluted with with CH2Cl2, and purified by column chromatography (silica gel, 10% MeOH/CH2Cl2), to give 4-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazol-5-yl}-benzonitrile in an isolated yield of 31.5%. The hydrochloride salt of the product was formed by adding 6N HCl (2 equivalents) in isopropanol solution and then diluting with 1 mL of isopropanol, followed by removal of solvent. 1H NMR (400 MHz, Methanol d4) δ 1.47 (d, J=6.45 Hz, 3 H) 1.72 (dd, J=12.76, 8.37 Hz, 1 H) 2.29 (m, 2 H) 3.23 (m, 3 H) 3.36 (t, J=7.14 Hz, 1 H) 3.62 (m, 3 H) 3.99 (m, 1 H) 7.68 (dd, J=8.44, 1.72 Hz, 1 H) 7.77 (m, 4 H) 8.01 (d, J=8.37 Hz, 1 H) 8.17 (d, J=1.51 Hz, 1 H) [M+H]+ at m/z 348.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:6]1)=[O:4].[OH-].[Li+].Cl>CO>[O:30]=[C:11]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[CH2:10][N:7]1[CH2:8][CH2:9][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 18 h

Procedure:
1-{2-Oxo-2-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethyl}-pyrrolidine-3-carboxylic acid methyl ester (compound 11 from Step 8, 3.3 gm, 8.06 mmol) was dissolved in methanol and 10 ml of 1 N lithium hydroxide added. The reaction mixture was stirred for 18 hrs. 10 ml of 1 N HCl was added to the reaction mixture and evaporated to a white solid (3.94 gm)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([NH2:9])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](=[S:19])[NH2:9]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCOCC(N)=O
Solvent: C1CCOC1
Product: COCCOCC(N)=S
Temperature: 25 °C
Yield: 134.9 %

Procedure:
A solution of 2-(2-methoxyethoxy)acetamide (Example 6A, 3.39 g, 25.5 mmol) in THF (40 mL) was treated with Lawesson's reagent (6.55 g, 16.19 mmol) and the reaction was refluxed for 18 hours. The reaction was then allowed to cool down to RT and was concentrated under vacuum, diluted with ethyl acetate, washed with sat. NaHCO3 (1×) and brine (1×). The aqueous phases were extracted with ethyl acetate (2×200 mL) and the organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3.5×11 cm, 30% AcOEt/CH2Cl2) to give the title material (3.26 g, 86%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.58 (very broad s, 1H), 7.50 (very broad s, 1H), 4.36 (s, 2H), 3.66-3.69 (m, 2H), 3.53-3.56 (m, 2H), 3.39 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:31][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCCC1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 71 at rt but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cycloheptylamine (1.0 mL) as a white powder (8 mg, 13%). HPLC, Rt: 3.85 min. (purity 95.9%). LC/MS, M+(ESI): 419.3, M−(ESI): 417.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)=[CH:4][CH:3]=1.[CH3:16][O-:17].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:17][CH3:16])=[CH:4][CH:3]=1
Reactant: BrCCCCCCOc1ccc(Br)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCCCCOc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 1-bromo-4-(6-bromohexyloxy)benzene (6.0 g) and sodium methylate (28% in methanol) (10.3 ml) in methanol (30 ml) was stirred for 2 hours at 70° C. (bath temp.), and then the solvent was evaporated. The residue was neutralized by 1N-hydrochloric acid and extracted with ethyl acetate (100 ml), and washed with water and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (20:1-10:1 hexane-ethyl acetate) to give 1-bromo-4-(6-methoxyhexyloxy)benzene (15.61 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.O>C(O)CCC.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:24]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(S(N)(=O)=O)c4)nc(Cl)nc32)cc1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
A mixture of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.58 mmol), 3-aminobenzenesulfonamide (111 mg, 0.65 mmol) and triethylamine (0.200 mL, 1.44 mmol) in nBuOH (6 mL) was heated at 80° C. overnight. The mixture was then heated at 110° C. for another 24 h. After cooling down, H2O and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, and it was dried over Na2SO4, concentrated in vacuo to give 2-chloro-N-(3-aminosulfonyl-phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (210 mg).
Reaction SMILES: [CH2:1]([CH:8]([NH:31][C:32]([C:34]1[CH:43]=[N:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[CH:9]([O:23][Si](C(C)(C)C)(C)C)[CH2:10][CH:11]([C:18]1[O:19][CH:20]=[CH:21][N:22]=1)[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([CH:8]([NH:31][C:32]([C:34]1[CH:43]=[N:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[CH:9]([OH:23])[CH2:10][CH:11]([C:18]1[O:19][CH:20]=[CH:21][N:22]=1)[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)c1ncco1
Solvent: C1CCOC1
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)c1ncco1
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid [1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-7-methyl-4-oxazol-2-yl-octyl]-amide (133 mg, 0.220 mmol) in tetrahydrofuran (2 mL) was added tris(dimethylamino)sulfur (trimethylsilyl)difluoride (180 mg, 0.660 mmol). The reaction was stirred for 1 hour then quenched with methanol and concentrated. Chromatography on silica gel gave the title compound (73 mg, 68%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:2]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26](=[O:28])[CH3:27])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[N:11]=2)[CH:2]=1
Reactant: NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
A mixture of 4-[2-(pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.36 mmol), acetic anhydride (0.42 g, 4.1 mmol), 4-dimethylaminopyridine (DMAP) (0.083 g, 0.68 mmol) and triethylamine (0.17 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.5 g (90%) of N-[[4-[2-(3-pyridinyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC): 244-246° C. Anal. Calc'd. for C17H13F3N4O3S: C, 49.76; H, 3.19; N, 13.65; S, 7.81. Found: C, 49.66; H, 3.06; N, 13.53; S, 8.11.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9]([CH3:25])([CH3:24])[C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[O:13].C(O)(C(F)(F)F)=O>>[OH:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[N:7][C:8]=2[C:9]([CH3:25])([CH3:24])[C:10](=[O:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cccnc21
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A solution of tert-butyl 2-(5-hydroxy-8,8-dimethyl-7-oxo-7,8-dihydroquinoline-6-carboxamido)acetate (15 mg) and TFA (1 mL) was stirred at room temperature. After 20 minutes, LCMS showed that the reaction was complete. The reaction was concentrated in vacuo to give a yellow oil. The sample was lyophilized to give a white solid (10 mg, 60%). MS (m/z)=291 (M+H)+. Calculated for C14H14N2O5 290.3.
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:42][CH2:43][O:44][CH3:45])(=O)=O)=CC=1>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:42][CH2:43][O:44][CH3:45])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1c(C(=O)N2CCC(C(=O)N(C)Cc3ccccc3)CC2)cc2ccccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (50 mg, 0.133 mmol) dissolved in 0.5 mL of DMF was added to a suspension of sodium hydride (7.99 mg, 0.200 mmol) in 1.0 mL of DMF. The reaction was heated at 70° C. for ten minutes before adding 2-methoxyethyl 4-methylbenzenesulfonate (0.144 mL, 0.266 mmol). The reaction was allowed to stir overnight. After 18 hours, the reaction was cooled to room temperature before diluting with water and ethyl acetate. The organic phase was washed with water followed by saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified via column chromatography using 50-80% ethyl acetate/hexanes. The purification provided product as a white solid 1H-NMR (400 MHz, DMSO-d6) 7.63-7.49, 7.43-7.14, 7.12-7.03, 6.67-6.58, 4.68, 4.63-4.06, 3.53, 3.20-3.13, 3.10-2.92, 2.79, 1.92-1.50
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[C:9](C)[CH:10]=[C:11](C(C3C=NN(CC)C=3OS(CCC)(=O)=O)=O)[C:12]=2[CH3:14])[S:7](=O)(=O)[CH2:6][CH2:5]1.[Mg].C([Br:37])C.CON=C1C2C(=CC=C(C3C=NN(CC)C=3OS(CCC)(=O)=O)C=2C)S(=O)(=O)C(=C=O)C1>C1COCC1>[CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:37])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1
Reactant: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(=NOC)CCS3(=O)=O)cnn1CC
Reactant: CCBr
Agent: CCCS(=O)(=O)Oc1c(-c2ccc3c(c2C)C(=NOC)CC(=C=O)S3(=O)=O)cnn1CC
Agent: [Mg]
Solvent: C1CCOC1
Product: CON=C1CCSc2ccc(Br)c(C)c21

Procedure:
3.0 Grams (12 mmol) of 5-methyl-6-bromothiochroman-4-one and 1.9 g (23 mmol) of O-methylhydroxylamine hydrochloride were refluxed in a solvent mixture of 10 ml of ethanol and 10 ml of pyridine under heat for 30 minutes. The solvents were distilled off under reduced pressure, 50 ml of 5% hydrochloric acid was added, and a formed solid was recovered by filtration, washed with water and then dried to give 3.2 g (yield 93%) of 4-methoxyimino-5-methyl-6-bromothiochroman. (2) 1.1 Grams (46 mmol) of magnesium was dispersed in 10 ml of THF, and 2.2 g (20 mmol) of ethyl bromide was dropwise added under nitrogen current. The mixture was allowed to react for 10 minutes, and then a THF solution of 2.9 g (10 mmol) of the 4-methoxyimino-5-methyl-6-bromothiochroman obtained in the above (1) was gradually added at room temperature. The mixture was refluxed for 3 hours and then cooled to room temperature, and carbon dioxide gas was bubbled in for 1 hour. To the reaction mixture was added 5% hydrochloric acid, and the mixture was extracted with ether. An ether layer was extracted with a 5% potassium carbonate aqueous solution, and an aqueous layer was neutralized with concentrated hydrochloric acid. The neutralization product was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride aqueous solution. The washed extract was dried over sodium sulfate, and then the solvent was distilled off to give 1.6 g (yield 63%) of 4-methoxyimino-5-methylthiochroman-6-carboxylic acid.