Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-].[K+].[Cl-].[K+]>C(O)C>[CH2:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH:9]1[O:11][CH2:10]1
Reactant: ClCC1CO1
Reactant: C1CNCCN1
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C1CN(CC2CO2)CCN1

Procedure:
Piperazine (86.15 g., one mole) and ethanol (150 g. plus 1.5 g. water) were placed in a one liter 3-neck flask equipped with a stirrer, thermometer, dropping funnel and condenser. The mixture was stirred until a complete solution was obtained and then epichlorohydrin (92.53 g., one mole) was added dropwise while maintaining the temperature below 25° C., by means of an ice bath. After addition of the epichlorohydrin was complete, the temperature was maintained below 25° C. for an additional 30 minutes. Then a solution of 56.11 g. (1 mole) of potassium hydroxide in 225 g. of ethanol was added over a period of 30 minutes while maintaining the temperature below 25° C. After cooling to 15° C. the potassium chloride which had formed during the reaction was filtered from the mixture and the filtrate concentrated to 1/2 its volume by stripping under vacuum. One liter of ethyl acetate was then added to the residual filtrate. The N-glycidylpiperazine oligomer precipitated as a white solid. The resultant slurry was filtered after standing several hours. The N-glycidylpiperazine oligomer collected on the filter after drying in vacuo at room temperature amounted to 119 grams, 83.8% of the theoretical yield. Elemental analysis indicated: %C, 56.09; %H, 9.55; %N, 18.55; %O 15.77. The number average molecular weight as determined by vapor pressure osmometry was 705. This data corresponds to the formula: ##STR5##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29].O>C1COCC1>[CH2:29]([O:14][C@@H:13]1[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 26 g (77 mmol) of benzyl 3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate in 120 mL of THF was added 5 g (211 mmol) of sodium hydride at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then 10 mL (115 mmol) of allyl bromide was added. The reaction mixture was warmed up to room temperature and continuously stirred at room temperature overnight. Water (50 mL) was added to quench the reaction. The organic phase was separated, and the aqueous layer was extracted with ethyl acetate twice (100 mL×2). The combined extracts were washed with brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel column with 25% EtOAc-hexane provided the title compound (21.3 g, 73%). MS (M+H)+ 377.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:22][NH2:23])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Reactant: NN
Solvent: CCO
Product: NNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1

Procedure:
A mixture of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (4.8 g, 0.015 mol) in hydrazine (20 ml, 0.41 mol) is refluxed for 90 minutes. The reaction is poured into ethanol (300 ml) with efficient stirring. The resulting precipitate is filtered with suction to yield the title compound, m.p. 201–203° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH2:21].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Yield: 25.8 %

Procedure:
A mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (1 g, 3.90 mmol), 2-methyl-5-nitroaniline (890 mg, 5.90 mmol), and 2N HCl (3 ml) in water:ethanol (1:1, 200 ml) was refluxed for 48 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The mixture was extracted with ethyl acetate (200 ml), washed with water (2×100 ml), with aqueous saturated NaCl (1×100 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness to give a tan solid (377 mg, 30%). 1H NMR (CDCl3): 8.90 (s, 1H), 8.80 (dd, J=1.8, 4.8 Hz, 2H), 8.30 (dd, J=1.5, 4.5 Hz, 2H), 8.09 (dd, J=2.4, 8.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:9]=[C:8](Cl)[N:7]=1)=[O:5])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:9]=[C:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: CCOC(=O)c1nc(Cl)nc(N2CCOCC2)c1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1nc(-c2cccc(O)c2)nc(N2CCOCC2)c1OCC
Yield: 55.4 %

Procedure:
A mixture of 2-chloro-5-ethoxy-6-morpholine-4-yl-pyrimidine-4-carboxylic acid ethyl ester (152 mg, 1 eq.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (137.9 mg, 1.3 eq.), dioxane (6 ml), H2O (1 ml), Pd(PPh3)4 (56 mg, 0.1 eq.) and sodium carbonate (102 mg, 2 eq.) was heated to reflux overnight. The solvent was removed in vacuo. The residue was extracted with EA, and the organic layer washed with brine and dried. The crude was purified by chromatography to give a product (99.6 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:17]([C:3]1[CH:4]=[C:5]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:19])=[O:18]
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 65 °C
Yield: 90.5 %

Procedure:
4-Amino-3-nitrophenylboronic acid pinacol ester (1.60 g, 6.06 mmol), 3-bromopyridine (1.10 g, 6.96 mmol), cesium carbonate (3.33 g, 10.22 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride DCM complex (491 mg, 0.60 mmol) were suspended in dimethylformamide (20 mL). The solution was degassed by vacuum several times and placed in an argon atmosphere. It was then heated to 65° C. for 6 hr. After cooling, EA (100 mL) and water (40 mL) were added. When additional water (50 mL) was added to the organic layer, a precipitate was formed in the separatory funnel. The biphasic solution was filtered, and the filtrate was transferred to the separatory funnel and separated. The organic phase was washed twice with water (50 mL each), then with brine, and then dried with sodium sulfate and concentrated under reduced pressure to give 2-nitro-4-(pyridin-3-yl)benzenamine (1.18 g). 2-Nitro-4-(pyridin-3-yl)benzenamine (700 mg, 3.26 mmol) in 1:1 ethanol/EA (40 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (90 mg, 0.08 mmol) at room temperature for 2 days. Filtration and concentration under reduced pressure gave 4-(pyridin-3-yl)-benzene-1,2-diamine (621 mg).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35][CH2:36][CH2:37]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:37][CH2:36][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: CCc1oc(-c2ccccc2)nc1CCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1oc(-c2ccccc2)nc1CCCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 79 %

Procedure:
Intermediate 60 was prepared as described above for the preparation of intermediate 52. From 266 mg of N-(Boc)-L-Tyrosine methyl ester and 208 mg of Intermediate 8F was prepared 360 mg of BOC-protected intermediate methyl ester (79% yield; 1H NMR (CDCl3, 300 MHz) δ8.06-8.03 (m, 2H), 7.46-7.44 (m, 3H), 7.04 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.4), 4.97 (d, 1H, J=7.6), 4.57 (m, 1H), 3.99 (t, 2H, J=6.0), 3.74 (s, 3H), 3.05 (m, 2H), 2.77-2.65 (m, 4H), 2.19 (t, 2H, J=6.6), 1.45 (s, 9H), 1.24 (t, 3H, J=7.5); From 352 mg of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 60. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield intermediate 60; 1H NMR (DMSO-d6, 400 MHz) δ7.88-7.85 (m, 2H), 7.48-7.43 (m, 3H), 7.11 (d, 2H, J=8.5), 6.82 (d, 2H, J=8.5), 3.92 (t, 2H, J=6.2), 3.55 (m, 1H), 3.0 (dd, 1H, J=14.3, 4.8), 2.8 (dd, 1H, J=14.3, 7.7), 2.67-2.56 (m, 4H), 2.02-1.96 (m, 2H), 1.13 (t, 3H, J=7.4); low resolution MS (ES+)m/e 392.9 (MH+); TLC Rf=0.44 (4/1, DCM/MeOH).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9](CS([O-])(=O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)N1CCC(CS(=O)(=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 63.2 %

Procedure:
To a mixture of N-(ethoxycarbonyl)-piperidine-4-methanesulphonate (10 g) and 4-hydroxy benzaldehyde (5.8 g) in dry DMF (75 ml), K2CO3 (11 g) was added and the mixture was stirred at 80° C. for 12 h. At the end of this time, the reaction mixture was cooled, added water and extracted with EtOAc. The EtOAc extract was washed with 5% aqueous Na2CO3 solution followed by brine and dried over anhydrous sodium sulphate. The solvent was then removed by distillation under reduced pressure to give 7 g (63.6%) of the title compound as a semi solid.
Reaction SMILES: [S:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].S(C1C=CC(C(Cl)=O)=CC=1)(=O)(=O)N.FC1C(O)=C(F)C(F)=C(F)C=1F.N1C=CC=CC=1.[NH2:56][C:57]([NH2:59])=[NH:58]>CO>[S:1]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([NH:58][C:57]([NH2:59])=[NH:56])=[O:10])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: N=C(N)N
Reactant: NS(=O)(=O)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Agent: NS(=O)(=O)c1ccc(C(=O)Cl)cc1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CO
Solvent: c1ccncc1
Product: N=C(N)NC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
is obtained analogously to the procedure given in Example 1 from pentafluorophenyl 4-sulfamoylbenzoate, prepared from 4-sulfamoylbenzoyl chloride and pentafluorophenol in the presence of 1 mol of pyridine, with guanidine in methanol as reaction medium.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:17])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2nccnc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of quinoxaline-6-carboxylic acid (438 mg, 2.51 mmol) in benzene (16 mL) was added oxalyl chloride (0.26 mL, 3.02 mmol) and anhydrous DMF (0.1 mL). The reaction was stirred at room temperature for 30 minutes after which the mixture was concentrated in vacuo. The resulting yellow solid was azeotroped 3× with toluene and the product was used immediately without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[CH3:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](Cl)=O.C(N(CC)CC)C.[Cl-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:10]([CH2:9][C:8]([CH3:14])([CH3:13])[CH3:7])[O:6][N:5]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: N=C(CCl)NO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1nc(CCl)no1
Temperature: 130 °C
Reaction time: 5 h
Yield: 8.1 %

Procedure:
2.0 g of 2-chloro-N-hydroxyacetoamidine and 2.6 g of 3,3-dimethylbutyryl chloride were dissolved in 30 ml of N,N-dimethylformamide, and 2.05 g of triethylamine was added dropwise under ice-cooling. After completion of the addition, the mixture was stirred at 130° C. for 5 hours and then cooled to room temperature. After aqueous saturated sodium chloride was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 3-(chloromethyl)-5-(2,2-dimethylpropyl)-1,2,4-oxadiazole.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>N1C=CC=CC=1>[C:25]1([CH3:26])[CH:27]=[CH:28][C:22]([S:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCCCCCCO)cc1

Procedure:
To a solution of 1.1 g of 1,16-dihydroxyhexadecane in 10 ml of dry pyridine 0.8 g of tosyl chloride was added. After 2 h mixture was concentrated diluted with 20 ml of acetone, 5 g of SiO2 was added and acetone was removed in vacuum. The solid was applied on SiO2 and eluted with pentane-ethyl acetate (2:1) to yield 748 mg (42%) of C-101.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([CH3:7])[N:6]=1.C[Mg+].[Br-].[CH3:13]COCC>C1COCC1>[Br:1][C:2]1[S:3][C:4]([CH:8]([OH:9])[CH3:13])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Br)sc1C=O
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a mixture of 2-bromo-4-methylthiazole-5-carbaldehyde of preparation 98 (1.8 g, 8.8 mmol) in dry THF (50 mL) was added dropwise MeMgBr in Et2O (3M, 2.9 mL, 8.8 mmol) at −40° C. under N2. After the addition, the mixture was stirred at room temperature for 1 hr. TLC (petroleum ether/EtOAc=5:1) showed most of the starting material was consumed. To the reaction mixture was added saturated NH4Cl (60 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate and concentrated in vacuum. The residue was purified by a Biotage silica gel cartridge (EA/PE 48%, Rf=0.5) to give the title compound as a yellow oil (1.7 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:34](=[O:37])[CH2:35][CH3:36])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.16 g, 0.33 mmol) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise propionyl chloride (0.09 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (80 mg, 45%) as white crystals.
Reaction SMILES: [C:1]1([OH:15])[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH:6]([CH:7]=[CH:8]3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:4]1([OH:14])[C:5]2[CH:6]3[CH2:13][CH2:12][CH2:11][CH:9]([CH2:8][CH2:7]3)[C:10]=2[C:1]([OH:15])=[CH:2][CH:3]=1
Reactant: Oc1ccc(O)c2c1C1C=CC2CCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(O)c2c1C1CCCC2CC1
Reaction time: 5 h

Procedure:
To a solution of the hydroquinone prepared in Step 1 in 100 mL ethanol was added Pd/C (250 mg) charged with hydrogen. The reaction was stirred under hydrogen for 5 h and the solid was removed through filtration. The solvent was removed and the residue was chromatographed to afford 5,6,7,8-tetrahydro-5,8-propano-naphthalene-1,4-diol as a light brown solid (3.9g). 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.51 (s, 2H), 3.33 (bs, 2 H), 1.96-1.89 (m, 2 H), 1.70-1.57 9 (m, 6 H), 1.18 (m, 2 H);
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]2[C:18]=1[CH:17]=[N:16][CH:15]=[CH:14]2.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:19][C:11]2[CH:12]=[C:13]3[C:18](=[C:9]([Br:8])[CH:10]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1cc(Br)c2cnccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc(Br)c3cnccc3c2)cc1
Reaction time: 15 h
Yield: 70.9 %

Procedure:
Triethylamine (0.137 mL) was added to a dichloromethane (5 mL) solution of Intermediate 7 (100 mg) and p-toluenesulfonic acid chloride (66 mg; WAKO) at room temperature and the resulting mixture was stirred as it was for 15 hours. The resulting mixture was diluted with dichloromethane and washed with water, the organic layer was dried, then the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (Yamazen; n-hexane/ethyl acetate) to give the title compound (92.9 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH:4]([NH2:7])[CH2:5][OH:6].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:7][CH:4]([CH2:5][OH:6])[CH:3]([C:8]([F:9])([F:10])[F:11])[C:2]([F:12])([F:13])[F:1])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NC(CO)C(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC(CO)C(C(F)(F)F)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.8 %

Procedure:
To a solution of 3,3,3-trifluoro-2-(trifluoromethyl)-1-(hydroxymethyl)propyl amine (79 mg, 0.374 mmol) in CH2Cl2 (1 mL) was added triethylamine (0.1 mL, 0.749 mmol) and 4-fluorobenzenesulfonyl chloride (80.5 mg, 0.4 mmol) in CH2Cl2 (1 mL). The solution was stirred for 20 hours at 25° C. and then concentrated. EtOAc (5 mL) was added and the solution was washed with 1M HCl (1 mL), brine (1 mL), dried over Na2SO4 and concentrated. The crude solid was purified by Biotage Flash™ chromatography, eluting with EtOAc/hexanes (1:4), to give 4-fluoro-N-[3,3,3-trifluoro-1-(hydroxymethyl)-2-(trifluoromethyl)propyl]benzene sulfonamide (2.5 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH:9]([CH2:10][O:11][C:12]2[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])=[O:18])=[CH:15][N:16]=2)[CH2:8]1.O1C(COC2SC(C(N)=O)=CN=2)C1>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([N:16]2[CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])=[O:18])[S:13][CH:12]2[O:11][CH2:10][CH:9]([OH:7])[CH3:8])[CH2:2][CH2:3]1
Reactant: CCC(C)CCCNC(=O)c1cnc(OCC2CO2)s1
Reactant: C1COCCN1
Agent: NC(=O)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: CCC(C)CCCNC(=O)C1=CN(N2CCOCC2)C(OCC(C)O)S1

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I to the invention. In this example 1 g. of morpholine is added to a solution containing 0.3 g. of 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol -2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20° C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of the 1,2-epoxy-3-(5-aminocarbonylthiazol -2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue of 1-(N-morpholino-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol which is then further purified by thin-layer chromatography on silica gel.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Fc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cccnc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 21 h
Yield: 82.4 %

Procedure:
2-Chloro-3-fluoropyridine (0.4380 g, 3.33 mmol), 4-chlorophenylboronic acid (0.6248 g, 3.996 mmol), palladium tetrakistriphenylphosphine (0.1924 g, 0.1665 mmol), sodium carbonate (0.4235 g, 3.996 mmol), toluene (10 mL), and water (1 mL) were placed in a teflon lined vial. The vial was sealed and stirred at 125° C. for 21 hour. The mixture was cooled to ambient temperature and the whole mixture was purified on silica gel (EtOAc-hexanes gradient) to provide 569.4 mg of the title compound as white solid (82%).