Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][C:14]2[O:15][C:16]3[C:21]([C:22](=[O:25])[C:23]=2[CH3:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:8][CH:7]=1.N1C=CC=C[CH:27]=1.[C:32]1(C)[C:33]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=1.O>C(OCC)(=O)C>[S:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][S:13][C:14]2[O:15][C:16]3[C:21]([C:22](=[O:25])[C:23]=2[CH3:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:8][CH:7]=1)([C:33]1[CH:32]=[CH:37][C:36]([CH3:27])=[CH:35][CH:34]=1)(=[O:39])=[O:40]
Reactant: c1ccncc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Cc1c(SCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CSc3oc4ccccc4c(=O)c3C)cc2)cc1

Procedure:
A 50 mL round bottom flask is charged with 2-(4-(4-hydroxybutyl)phenyl methyl)thio 3-methyl chromen-4-one (6.0 g, 16.9 mmol) and pyridine (15 mL) is added to it. Toluenesulfonyl chloride (25.4 mmol) is then added in one lot and the mixture is stirred for 8 hours after which water and ethyl acetate are added to it. The contents are poured into a separatory funnel and the layers separated. The organic layer is washed with 5% CuSO4 (2×10 mL) and then with water and brine. It is then dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue obtained is purified by silica gel flash chromatography (ethyl acetate:hexanes) to afford the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([O:12][CH3:13])[CH:6]=[CH:5][C:4]=1I.[C:15]([C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1)#[CH:16].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([O:12][CH3:13])[CH:6]=[CH:5][C:4]=1[C:16]#[C:15][C:17]1[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=1
Reactant: C#Cc1cnn(C)c1
Reactant: COc1ccc(I)c(OC)c1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2cnn(C)c2)c(OC)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 71 %

Procedure:
To a mixture of 2,4-dimethoxy-3-nitro-iodobenzene (0.95 mmol), 0.122 g (1.15 mmol) of 4-ethynyl-1-methyl-1H-pyrazole, 0.028 g (0.04 mmol) of dichlorobis (triphenylphosphine)palladium (H) and 8 mg (0.042 mmol) of copper (I) iodide 4 mL of anhydrous acetonitrile and 2 mL of triethylamine were added under nitrogen atmosphere at room temperature. The resulting mixture was stirred for 1 hour, when TLC indicated a consumption of the iodobenzene. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography (silica gel; dichloromethane:ethyl acetate 9:1) to give the title compound in 71% yield as creamy crystals. H1 NMR (CDCl3) 3.88(s, 3H, Me); 3.9 (s, 3H, OMe); 4.07 (s, 3H, OMe); 6.7 (d, 1H, CH, J=8.9 Hz); 7.44 (d, 1H, CH, J=8.9 Hz); 7.56 (s, 1H, CH pyr); 7.62 (s, 1H, CH pyr).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH:14]=[CH:13][S:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17]N1C(=O)CCC1=O>ClCCl.C(Cl)(Cl)(Cl)Cl>[CH2:1]([S:8][C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[Cl:17])[CH:14]=[CH:13][S:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CSc2cn3ccsc3n2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1c(SCc2ccccc2)nc2sccn12
Temperature: 25 °C
Yield: 87.7 %

Procedure:
6-Benzylthioimidazo[2,1-b]thiazole (2.0 g) is dissolved in a mixture of 8 ml of dichloromethane and 40 ml of carbon tetrachloride. N-Chlorosuccinimide (1.2 g) is added to the solution during 10 minutes and stirred for an hour at room temperature. The insoluble product is filtered off and the filtrate is purified by silica gel chromatography (eluent: ethylacetate) to give 2.0 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH2:20][N:21](C)C)([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].[CH:30]1C=CC=CC=1>>[CH3:1][C:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7]([CH2:18][CH2:19][CH2:20][NH:21][C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26])([OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc2c1C=Cc1ccccc1C2(O)CCCN(C)C
Reactant: c1ccccc1
Product: CCCOC(=O)NCCCC1(O)c2ccccc2C=Cc2c(C)cccc21
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution containing 30 g. of 1-methyl-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene in 100 ml. of dry benzene is added dropwise with stirring at 20° C. to a mixture of 31.8 g. of ethyl chloroformate in 100 ml. of dry benzene. Subsequently, the mixture is vigorously boiled under reflux conditions for 20 hours. After cooling, the benzene solution is washed with water, dilute hydrochloric acid and once again with water, dried over sodium sulfate and evaporated. The 1-methyl-5-(3-methylcarbethoxyaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene obtained has a melting point of 157°-159° C. after recrystallization from ethanol.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:41])[C:17]([CH2:39][CH3:40])=[C:18]([C:37]#[N:38])[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26](O)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)=[CH:22][CH:21]=1)=[O:14])[CH3:11].O>C(Cl)Cl>[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:41])[C:17]([CH2:39][CH3:40])=[C:18]([C:37]#[N:38])[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([F:7])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)=[CH:22][CH:21]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1c(-c2ccc(C(O)Cc3cccc(C#N)c3)cc2)c(C#N)c(CC)n1C
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(C(F)Cc3cccc(C#N)c3)cc2)c(C#N)c(CC)n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Add (diethylamino)sulfur trifluoride (145 uL, 1.1 mmol) to 4-cyano-3-{4-[2-(3-cyano-phenyl)-1-hydroxy-ethyl]-phenyl}-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.427 g, 1.0 mmol, prepared in example E-163) in methylene chloride with stirring at −78° C. After 30 minutes, gradually allow the reaction mixture to warm to ambient temperature. After 2 hours, pour the reaction mixture into water and extract with methylene chloride. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 430.0 (M+1).
Reaction SMILES: N1C=CC=CC=C1.[Cl:8][CH:9]([CH3:37])[CH:10]([NH:22][C:23]([CH:25]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][C:35]#[N:36])[CH2:28][CH2:27][NH:26]1)=[O:24])[CH:11]1[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH:13]([S:20][CH3:21])[O:12]1.CCN(C(C)C)C(C)C.Br[CH2:48][C:49]1[O:50][C:51](=[O:55])[O:52][C:53]=1[CH3:54]>CN(C=O)C.CCOC(C)=O>[Cl:8][CH:9]([CH3:37])[CH:10]([NH:22][C:23]([CH:25]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH2:34][C:35]#[N:36])[CH2:28][CH2:27][N:26]1[CH2:48][C:49]1[O:50][C:51](=[O:55])[O:52][C:53]=1[CH3:54])=[O:24])[CH:11]1[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH:13]([S:20][CH3:21])[O:12]1
Reactant: CSC1OC(C(NC(=O)C2CCC(CCCC#N)CCN2)C(C)Cl)C(O)C(O)C1O
Reactant: Cc1oc(=O)oc1CBr
Agent: C1=CC=CNC=C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSC1OC(C(NC(=O)C2CCC(CCCC#N)CCN2Cc2oc(=O)oc2C)C(C)Cl)C(O)C(O)C1O

Procedure:
To a solution of azepine compound prepared in example 7′ (5-(3-cyano-propyl)-azepane-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide, 100 mg) in DMF (2.0 mL) was added DIEA (181 μL) followed by 4-bromomethyl-5-methyl-[1,3]-dioxol-2-one (194 mg, prepared as described in J. Alexander, et al. J. Med. Chem, 1996, 39, 480-486). After stirring overnight EtOAc (30 mL) was added, the organic solution washed with brine (20 mL), dried over Na2SO4 and the solvents removed under reduced pressure. The resulting residue was purified by semi-preparative HPLC (Waters Nova-Pak® HR C18, 6 μm particle size, 60 Å pore size, 20 mm ID×100 mm) to provide the title compound (6 mg) of as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=2[O:24][CH2:25][CH3:26])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([N:38]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[N:33][CH:32]=[CH:31]2.O.[C:54]([OH:58])(=[O:57])[CH:55]=O>>[C:49]([O:48][C:46]([N:38]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[C:34]1[C:35]2[C:30](=[CH:29][C:28]([NH:27][CH:55]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][O:12][C:10](=[O:11])[NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)=[C:16]([O:24][CH2:25][CH3:26])[CH:17]=3)[C:54]([OH:58])=[O:57])=[CH:37][CH:36]=2)[CH:31]=[CH:32][N:33]=1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: CCOc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Reactant: O=CC(=O)O
Solvent: O
Product: CCOc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Yield: 64 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 62G (250 mg, 0.0706 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 63A (329 mg, 64%) as a solid. MS (ESI) m/z 726.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[O:10][CH3:11].[Cl:12]CCOCCCl>C(O)(=O)C.O>[CH3:11][O:10][C:3]1[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[C:7]([Cl:12])[C:2]=1[CH3:1]
Reactant: COc1cccc(C)c1OC
Reactant: ClCCOCCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cl)c(C)c1OC
Yield: 67980.1 %

Procedure:
To a mixture of 25 g (0.16 mmol) of 1-methyl-2,3-dimethoxybenzene in 25 mL of acetic acid, was slowly added 26.4 g (0.33 mmol) of 1-chloromethylmethylether. The resultant reaction mixture was reacted overnight at 30° C. and then diluted with cold water, resulting in the formation of a precipitate. This precipitate was purified by recrystallization from hot hexanes and then reduced to dryness under reduced pressure to provide 20.3 g of a white solid (m.p. 69°-70° C. ).
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[C:4]1([Mg]Br)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1[CH2:17][CH2:16]OCC1>C1COCC1>[C:4]1([Zn:2][C:17]2[CH:16]=[CH:6][CH:5]=[CH:4][CH:9]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Br[Mg]c1ccccc1
Reactant: [Zn+2]
Reactant: C1COCCO1
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1ccc([Zn]c2ccccc2)cc1
Reaction time: 2 h

Procedure:
The zinc chloride solution was charged to the flask by syringe and diluted with 60 ml THF all under a nitrogen atmosphere. The stirrer was started and phenylmagnesium bromide introduced using a dry 20 ml syringe dropwise over 5 min initially forming a precipitate which dissolved by the end of the addition. The reaction mixture was held at 20-25° C. during addition and stirred for a total of 2 hours. The dioxan was then added by syringe causing a fine, white solid to precipitate. The slurry was stirred a further 45 min at 25° C., then filtered via the in-line sintered glass filter. The filter cake was washed with 10 ml THF and blown dry with nitrogen. The filtrate was a pale yellow solution in THF of diphenylzinc (57 mol % Zn, 10.2 mol % Mg). The flask was sealed and stored in a refrigerator.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.C(N(CC)CC)C.[C:19]1([C:25](Br)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1c[nH]cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 72 h

Procedure:
To a suspension of 1H-imidazole-4-acetic acid methyl ester hydrochloride (1, 7.48, 42.4 mmol) in methylene chloride (200 ml) was added triethylamine (17.7 ml, 127 mmol) and triphenylmethyl bromide (16.4 g, 50.8 mmol) and stirred for 72 h. After this time, reaction mixture was washed with sat. aq. sodium bicarbonate (100 ml) and water (100 ml). The organic layer was evaporated in vacuo and purified by flash chromatography (30-100% ethyl acetate/hexanes gradient elution) to provide 23 as a white solid.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]=2[CH:15]=1.CC(C)=[O:19]>O.[N+]([O-])([O-])=O.[Ag+]>[CH3:13][C:9]1([CH3:14])[O:8][C:7]2[CH:15]=[C:3]([CH:2]=[O:19])[CH:4]=[CH:5][C:6]=2[C:11](=[O:12])[O:10]1
Reactant: CC(C)=O
Reactant: CC1(C)OC(=O)c2ccc(C(Br)Br)cc2O1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CC1(C)OC(=O)c2ccc(C=O)cc2O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
To a solution of 7-(dibromomethyl)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (6.0 g, 17 mmol) in acetone (20 mL) and water (40 mL) under nitrogen was added AgNO3 (6.0 g, 35 mmol). The reaction mixture was stirred at rt for 14 hours, then filtered through a pad of Celite. The solvents were removed under reduced pressure. The residue was purified by chromatography (pet ether/EtOAc 9/1) to give 2.0 g (57%) of the titled compound as a solid. TLC-Pet Ether/EtOAc (7/3): Rf=0.7.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:5][C@@H:6]2[C@@H:23]([CH2:24][CH3:25])[C:22](=[O:26])[N:7]2[C:8]=1[C:9]([O:11]CC1C=CC([N+]([O-])=O)=CC=1)=[O:10])=[O:3].C([O-])(O)=O.[Na+:31]>C1COCC1.CCO.O.[Pd]>[CH3:1][S:2]([C:4]1[S:5][C@@H:6]2[C@@H:23]([CH2:24][CH3:25])[C:22](=[O:26])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10])=[O:3].[Na+:31]
Reactant: CC[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(C)=O)S[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC[C@H]1C(=O)N2C(C(=O)[O-])=C(S(C)=O)S[C@H]12
Reaction time: 2 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-methylsulfinyl-6-ethyl-pen-2-em-3-carboxylate (50 mg) in THF (9 ml) is diluted with EtOH (4.5 ml) and H2O (7.0 ml) containing NaHCO3 (10.6 mg). The resulting solution is added to a prereduced mixture of 10% Pd/C (100 mg) in EtOH (4.5 ml) and the resulting mixture is rapidly stirred under a H2 atmosphere for 2 hours. The mixture is filtered to remove the catalyst which is washed with H2O (2×25 ml). The combined filtrate is extracted with Et2O (2×50 ml) concentrated under vacuum to ca. 10 ml volume, and lyophilized to yield the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8](C)[N:9]=1)(=[O:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O>C(Cl)Cl>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([S:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:8]=2)(=[O:13])=[O:12])[CH2:18][CH2:17]1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ncc(S(=O)(=O)N2CCN(C)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (3 g, 11.8 mmol) in DCM (50 mL) and TEA (3.2 mL, 23.6 mmol) was slowly added N-methylpiperazine (1.2 g, 12.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, and the organic phase was isolated. The water phase was extracted with DCM (3×75 mL). The combined organic phase was dried with anhydrous magnesium sulphate, filtered, and evaporated in vacuo to give 2.6 g of yellow, impure crystals. Purification on a silica gel column (Eluent: DCM:MeOH (9:1)) gave N-[5-(4-methylpiperazine-1-sulfonyl)-thiazol-2-yl]-acetamide as light yellow crystals of N-[5-(4-methylpiperazine-1-sulfonyl)-thiazol-2-yl]-acetamide. Yield: 1.52 g (41%). 1H-NMR (CDCl3): δ3.20 (m, 4H); 2.55 (m, 7H); 2.32 (s, 3H); 2.29 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[C:6](=[O:9])([O-])[O-].[K+].[K+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:5]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:9][CH3:6])=[CH:15][CH:16]=2)[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][CH:15]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a solution of methanesulfonamide (5 g) in N,N-dimethylformamide (75 mL), potassium carbonate (29.1 g) was added and the resultant reaction mixture was stirred at room temperature for 5 hours. To the solution, p-methoxybenzyl chloride (18.1 g) was added and the resultant reaction mixture was stirred at room temperature for 19 hours. To the reaction solution, water was added and the mixture was extracted with ethyl acetate. The obtained organic phase was dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure to give the title compound (17.1 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:21])=[C:12]3[CH:18]=[C:17]([CH2:19][OH:20])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[CH:18]=[C:17]([CH2:19][OH:20])[S:16][C:13]=3[N:14]([CH3:24])[CH:15]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CO)cc2c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carboxamide (0.955 g) from Example No. 34 in DMF (20 mL) is added potassium carbonate (0.567 g) followed by iodomethane (0.20 mL). The reaction is stirred at rt for 1 h. The reaction mixture is partitioned between water (50 mL) and CH2Cl2 (100 mL). The aqueous layer is extracted with CH2Cl2 (100 mL). The organic layer is removed in vacuo and insoluble material in the aqueous layer is filtered off. The resulting solid is recrystallized from ethanol to yield 0.825 g (83%) of the title compound as a white, crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15](O)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15]([NH:24][CH3:22])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(OCc2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Product: CNC(=O)COc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1c), the (4-benzyloxy-phenoxy)-acetic acid was reacted with methylamine using 1,1′-carbonyl-diimidazole as the condensation reagent. 2-(4-benzyloxy-phenoxy)-N-methyl-acetamide was obtained as white crystals; MS: m/e=272 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.C([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:30])=[O:29])(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:40][C:37]([F:38])([F:39])[C:34]1[CH:33]=[CH:32][C:31]([S:28]([NH2:27])(=[O:29])=[O:30])=[C:36]([C:2]2[CH:22]=[CH:21][C:5]3[NH:6][C:7]([CH2:9][O:10][C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)=[N:8][C:4]=3[CH:3]=2)[CH:35]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: NS(=O)(=O)c1ccc(C(F)(F)F)cc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.100 g, 0.269 mmol, from Example 1.1), N-tert-butyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-benzenesulfonamide (0.165 g, 0.404 mmol), sodium carbonate (0.171 g, 1.61 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.035 g, 0.0538 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the product as a off-white solid. The obtained material was dissolved in TFA (2 mL) and the resulting solution was heated to 60° C. for 3 hours. The reaction mixture was concentrated in vacuo to provide a residue which was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the title compound as a brown solid (0.101 g, 73%). 1H NMR (400 MHz, CD3OD) δ (ppm): 0.33 (d, 1H, J=8.0 Hz), 7.89 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.82 (d, 1H, J=0.8 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.69-7.65 (m, 3H), 7.50 (dd, 1H, J=8.8 Hz, J=1.6 Hz), 7.28 (d, 2H, J=8.8 Hz), 5.62 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H16F6N3O3S: 516.4 (M+H), Found 516.3.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][C:11]#[CH:12])=[O:7])([CH3:4])[CH3:3].O.ON1C2C=CC=CC=2N=N1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][CH2:37][CH2:38][NH2:39].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][CH2:37][CH2:38][NH:39][C:13](=[O:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:10][C:11]#[CH:12]
Reactant: NCCNc1nc2ccccc2o1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A cold mixture of Boc-L-propargyl-glycine (128.2 mg, 0.602 mmol), N-hydroxybenzotriazole hydrate (84.5 mg, 0.625 mmol) and the hydrochloride salt of N1-(benzo[d]oxazol-2-yl)ethane-1,2-diamine (152.3 mg, 0.609 mmol) in dichloromethane (6 mL) was cooled in an ice bath, then treated with triethylamine (0.34 mL, 2.44 mmol) and 1-[3-dimethylaminopropyl]-3-ethyl carbodiimide hydrochloride (119.6 mg, 0.624 mmol). The resulting mixture was stirred for 40 h at room temperature, then diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered and concentrated to yield a residue The residue was purified by flash column chromatography, eluting with 8% methanol in chloroform to yield (S)-tert-butyl 1-(2-(benzo[d]oxazol-2-ylamino)ethylamino)-1-oxopent-4-yn-2-ylcarbamate as a solid.
Reaction SMILES: [N+](C1C=C[C:7]([CH:10]=[C:11](C(=O)C)[CH2:12][C:13]([O:15][CH2:16][CH2:17][C:18]#[N:19])=[O:14])=CC=1)([O-])=O.C(CC(OCC)=O)(=[O:26])CC.OCCC#N>C(O)C>[C:11]([CH2:12][C:13]([O:15][CH2:16][CH2:17][C:18]#[N:19])=[O:14])(=[O:26])[CH2:10][CH3:7]
Reactant: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)CC(=O)OCCC#N
Reactant: CCOC(=O)CC(=O)CC
Agent: N#CCCO
Solvent: CCO
Product: CCC(=O)CC(=O)OCCC#N
Temperature: 202.5 °C
Yield: 73.4 %

Procedure:
2-Cyanoethyl 3-{(4-nitrophenyl)methylene}-4-oxopentanoate. A mixture of ethyl propionylacetate (25 g, 0.173 mol) and 3-hydroxypropionitrile (18.48 g, 0.26 mol) was stirred and heated at 200-205° C. for 2 hours and the ethanol formed was removed by distillation. The residue was subjected to high vacuum distillation and the fraction distilling at 120-125° C. at 0.4 mm Hg was collected to get 2-cyanoethyl propionylacetate (21.5 g, 73.4%). A mixture of 4-nitrobenzaldehyde (14.46 g, 0.957 mol), 2-cyanoethyl propionylacetate (17.0 g, 0.1005 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 24 h. The white solid, 2-cyanoethyl 3-{(4-nitrophenyl)methylene}-4-oxopentanoate, was filtered, washed with 2-propanol (2×50 mL) dried and used without further purification (Yield: 28.34 g, 97%); m.p. 98-100° C.