Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][S:5][N:6]=1.[CH3:13][I:14]>CC(C)=O>[I-:14].[Cl:1][C:2]1[C:3]([C:7]2[CH:8]=[N+:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][S:5][N:6]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc(-c2nsnc2Cl)c1
Product: [I-]
Yield: 100.1 %

Procedure:
A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (1.98 g, 10 mmol) and methyl iodide (4.25 g, 30 mmol) in acetone (10 ml) was stirred at room temperature for 16 h. The precipitate was collected by filtration to yield 3.40 g (100%) of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH-].[K+].[O:12]1[CH2:24][CH:13]1[CH2:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>C(O)C>[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[O:15][CH2:14][CH:13]([OH:12])[CH2:24][NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:19]
Reactant: CCOC(=O)CCN
Reactant: N#Cc1ccccc1OCC1CO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCNCC(O)COc1ccccc1C#N

Procedure:
15.36 g of the hydrochloride of ethyl 3-aminopropanoate and 6.2 g of potassium hydroxide were stirred in 150 ml of abs. ethanol until neutral reaction, ca 1 h. Under reflux was added 8.7 g of 2-(2,3-epoxypropoxy)benzonitrile in 125 ml of abs. ethanol. The mixture was refluxed for 8 h, filtered and evaporated. The residue was dissolved in ether, washed twice with water and extracted with 25 ml of 2-n hydrochloric acid. The aqueous phase was extracted with methylene chloride. The methylene chloride phase was dried over Na2SO4, filtered and evaporated to dryness. The hydrochloride of ethyl N-[3-(2-cyanophenoxy)-2-hydroxypropyl]-3-aminopropanoate crystallized. Yield 5.75 g. Melting point 120° C. (HCl). The structure was determined using NMR and equivalent weight.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1>O.ClCCl.O.[Ru](Cl)(Cl)Cl>[F:7][CH2:8][CH2:9][O:10][CH:11]1[C:15](=[O:2])[N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:12]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)C1CC(OCCF)CN1C(=O)OC(C)(C)C
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CC(OCCF)C(=O)N1C(=O)OC(C)(C)C
Reaction time: 72 h
Yield: 17 %

Procedure:
A solution of 4.3 g (20.0 mmol) of sodium periodate and 1.7 g (0.6 mmol) of ruthenium(III) chloride hydrate in 50 ml of water was added to 1.45 g (5 mmol) of 1-tert-butyl 2-methyl 4-(2-fluoroethoxy)pyrrolidine-1,2-dicarboxylate in 80 ml of dichloromethane. The mixture was left at room temperature for three days with vigorous stirring. Subsequently, the phases were separated, the aqueous phase was extracted twice with ethyl acetate (25 ml) and the combined organic phases were stirred with 10 ml of isopropanol for 30 min. The mixture was dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate). 0.26 g (17%) of 1-tert-butyl 2-methyl 4-(2-fluoroethoxy)-5-oxopyrrolidine-1,2-dicarboxylate (26) was obtained as.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH:15]=[N:14][N:13]=[N:12]1.C(N(CC)CC)C.O>CN(C=O)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: c1nnn[nH]1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(-n2cnnn2)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-chloro-5-nitropyrimidine (1.6 g, 10 mmol), 1H-tetrazole (24.44 mL, 11 mmol, 0.45M in MeCN) were added in DMF (20 mL), cooled to 0° C., then triethylamine (1.67 mL, 12 mmol) was added drop-wise. After 15 minutes, water (100 mL) was added, extracted with ethyl acetate (100 mL×1, 50 mL×6). The organic phase were combined and dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 100 gram Biotage SNAP KP-Sil™silica gel cartridge eluting with 30% ethyl acetate/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2](=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33](=[O:35])[CH3:34])[C:22]1=[O:36])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:5][CH:4]=1.[C:37]([O:41][C:42]([NH:44][CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C>ClCCl>[C:37]([O:41][C:42]([NH:44][CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH:50]/[C:2](=[C:21]2\[C:22](=[O:36])[N:23]([C:33](=[O:35])[CH3:34])[C:24]3[C:29]\2=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)/[C:3]2[CH:8]=[CH:7][C:6]([CH2:9][N:10]3[C:14](=[O:15])[C:13]4=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]4[C:11]3=[O:20])=[CH:5][CH:4]=2)=[CH:48][CH:47]=1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C(=O)/C(=C(\Nc2ccc(CNC(=O)OC(C)(C)C)cc2)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 2c from 3-[1-chloro-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone, 4-tert.butoxycarbonylaminomethyl-aniline and triethylamine in dichloromethane.
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>O1CCCC1.CO>[CH3:3][O:4][C@@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O

Procedure:
In a glove box (O2 content≦2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 5.40 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 (0.0046 mmol, S/C 1,000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run at 60° C. for 20 h and subsequently 80° C. for 2 h under 10 bar of hydrogen. After the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 89.7% (91.1% conversion) and an enantiomeric purity of 99.8%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:7]([OH:9])=O)([O-:3])=[O:2].C(Cl)Cl.ClC(N(C)C)=C(C)C.[Br:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:7]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([Br:26])=[CH:28][CH:29]=1)=[O:9])([O-:3])=[O:2]
Reactant: Nc1ccc(Br)cc1
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]

Procedure:
A mixture of 3-Nitro-4-methylaminobenzoic acid (196 mg, 1.00 mmol), 20 ml DCM, 0.15 ml pyridine and 160 mg 1-Chloro-N,N,2-trimethylprop-1-enylamine was stirred until a clear solution was obtained. 4-Bromoaniline (172 mg, 1.0 mmol) was added and the mixture was stirred for 16 h. The mixture was filtered through a pad of ALOX B and concentrated. 5 ml DMF and 20 ml H2O were added and the precipitate was collected and dried. Yield: 240 mg (68%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Br[C:20]1[CH:21]=[CH:22][C:23]([C:26]#[C:27][CH2:28][O:29][CH3:30])=[N:24][CH:25]=1.O.C(OCC)(=O)C>C(=O)([O-])[O-].[K+].[K+].O1CCCC1.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>[CH3:30][O:29][CH2:28][C:27]#[C:26][C:23]1[N:24]=[CH:25][C:20]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[CH:21][CH:22]=1
Reactant: COCC#Cc1ccc(Br)cn1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCC#Cc1ccc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 80 °C
Yield: 78.9 %

Procedure:
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (37, 0.998 g, 4.09 mmol), 5-bromo-2-(3-methoxy-prop-1-ynyl)-pyridine (42, 0.616 g, 2.72 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.157 g, 0.136 mmol) were mixed in 8.2 mL of 1.00 M potassium carbonate in water (8.2 mmol) and 22 mL of tetrahydrofuran. The resulting mixture was heated at 80° C. Ethyl acetate and water were added, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the filtrate concentrated under vacuum. The crude material was purified by silica gel flash chromatography. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (43, 565 mg). MS (ESI) [M+H+]+=264.3.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: COC(=O)c1ccc(Cl)cc1Br
Product: COC(=O)c1ccc(Cl)cc1Nc1cc(C(C)(C)C)nn1-c1ccccc1C

Procedure:
This compound was prepared using the procedure described in Example 234 and Intermediate C and methyl 2-bromo-4-chlorobenzoate as starting materials. 1H NMR (300 MHz, CD2Cl2) δ 9.33 (s, 1H), 7.84 (d, 1H), 7.20-7.30 (m, 4H), 7.15 (s, 1H), 6.68 (d, 1H), 6.13 (s, 1H), 3.72 (s, 3H), 2.06 (s, 3H), 1.31 (s, 9H). ES-MS m/z 398.3 (MH)+; HPLC RT (min) 4.27.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1>>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:20]=2)=[O:12])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(C(=O)O)cs1
Reactant: CCOC(=O)COc1ccc(N)cc1
Agent: Cl
Product: CCOC(=O)COc1ccc(NC(=O)c2csc(NC(=N)N)n2)cc1

Procedure:
In the same manner as described in Example 3, from 2-guanidino-thiazole-4-carboxylic acid and ethyl 4-amino-phenyloxyacetate hydrochloride there is obtained ethyl {4-[(2-guanidino-thiazole-4-carbonyl)-amino]-phenoxy}-acetate, m.p. 206° C., MS: 364 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[N:8][C:7]=2[C:19]=1[N+:20]([O-])=O>[Pd].CO>[CH3:1][O:2][C:3]1[C:19]([NH2:20])=[C:7]2[N:8]=[C:9]([C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:12])[S:10][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2sc(C(=O)N3CCOCC3)nc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2sc(C(=O)N3CCOCC3)nc2c1N
Reaction time: 18 h
Yield: 90.7 %

Procedure:
20 mg of 10% palladium on activated carbon is added to 210 mg (0.65 mmol) of 5-methoxy-2-(morpholin-4-ylcarbonyl)-4-nitro-1,3-benzothiazole in solution in 10 ml of methanol. The reaction medium is then placed under stirring under a hydrogen atmosphere for 18 hours. The catalyst is then filtered out and the solvent is evaporated off. 173 mg of the expected product (gross yield=91%) is obtained in the form of a yellow oil and is used in the following stage without other purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC#N>[CH2:30]([O:29][C:27]([CH2:26][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)=[O:28])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2c(O)cccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of tert-butyl 3,4-dihydro-5-hydroxyisoquinoline-2(1H)-carboxylate (750 mg, 3.01 mmol) and K2CO3 (498 mg, 3.61 mmol) in MeCN was added ethyl 2-bromoacetate (603 mg, 3.61 mmol). The mixture was stirred at room temperature overnight, the mixture was then filtered and the filtrate was concentrated under vacuum to give the desired product (900 mg, 90%). LCMS (m/z): 336.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:37]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[C:38]=[S:39].[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48].C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[F:50][C:49]([F:52])([F:51])[C:47]([O-:53])=[O:48].[CH2:40]([NH:37][C:38]([NH:17][C:15]1[NH+:14]=[CH:13][C:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[N:9][NH:10][C:11]=2[CH:16]=1)=[S:39])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(N)ncc23)ccn1
Reactant: S=C=NCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(-c2n[nH]c3cc(NC(=S)NCc4ccccc4)[nH+]cc23)ccn1
Product: O=C([O-])C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h
Yield: 27 %

Procedure:
A suspension of 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (intermediate 5a; 25 mg, 0.05 mmol) in toluene (1 mL) was treated with (isothiocyanatomethyl)benzene (15 mg, 0.1 mmol) and the mixture was heated at 100° C. overnight. The volatiles were concentrated in vacuo and the residue was directly dissolved in DCM (0.8 mL), treated with TFA (0.2 mL) and triethylsilane (0.008 mL, 0.051 mmol) and left under stirring for 5 h, then concentrated in vacuo and purified by MS-directed reverse phase preparative-HPLC (C-18 stationary phase, eluting with a H2O/MeCN gradient with 0.1% TFA) to yield 6-[(benzylcarbamothioyl)amino]-3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-5-ium trifluoroacetate as a yellow solid (7 mg, 0.014 mmol, 27%). MS ESI calc'd. for C20H19N6S [M+1]+ 375, found 375.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc(-c2csc(Br)n2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Yield: 25 %

Procedure:
A solution of 2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole (6.89 g, 22.3 mmol), tert-butyl piperazine-1-carboxylate (8.31 g, 44.6 mmol) and potassium carbonate (3.08 g, 22.3 mmol) in dimethylformamide (70 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.31 g (25.0%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[CH2:17][CH2:16]1)(C)(C)C.C(O)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[N:18]1[CH2:19][CH2:20][CH:15]([NH2:14])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccs2)CC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2nccs2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of 1.14 g (4.00 mmol) (1-thiazol-2-yl-piperidin-4-yl)-carbamic acid-tert-butyl ester in DCM (10 ml). The reaction solution was stirred for 1 h at RT and subsequently concentrated in vacuo. 1.02 g (0.34 mmol, 86%) 1-(thiazol-2-yl)piperidin-4-amine trifluoroacetate were obtained by crystallisation of the residue from an ethanol/EE-mixture.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:29])=O>>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([Cl:29])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
4'-n-Decyloxy-4-carboxybiphenyl (3.00 g) was heated under reflux for 6 hours together with an excessive amount of thionyl chloride, and the unaltered thionyl chloride was removed by distillation to give about 3 g of 4'-n-decyloxybiphenyl-4-carboxylic acid chloride.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]([CH3:39])[CH2:34][CH2:35][CH2:36][NH:37][CH3:38]>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:37]([CH2:36][CH2:35][CH2:34][N:33]([CH3:39])[CH3:32])[CH3:38])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: CNCCCN(C)C
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N(C)CCCN(C)C)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 27.9 mg (0.24 mmol) N,N,N′-trimethyl-1,3-propanediamine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 24 mg (36.6%) product as an orange powder. MS (ESI) m/z 547.3 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:7][C@H:6]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:5]1.F[C:18]1[C:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C.CCOC(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:8]([C@H:6]1[CH2:7][C@H:4]([O:3][C:18]2[C:23]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:5]1)=[O:9]
Reactant: Fc1ncccc1C1CCOCC1
Reactant: O=C(Nc1ccccn1)[C@H]1C[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccn1)[C@H]1C[C@H](Oc2ncccc2C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.073 g, 1.8 mmol, 60% dispersion in mineral oil) was added to a stirred solution of trans-3-hydroxy-N-(pyridin-2-yl)cyclobutanecarboxamide (0.18 g, 0.92 mmol) in DMF (3.5 mL) under an argon atmosphere. The mixture was stirred at RT for 1 h. 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.17 g, 0.92 mmol) was added, and the reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was diluted with EtOAc and washed with saturated ammonium chloride. The organic layer was separated, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified via silica gel chromatography to give trans-N-(pyridin-2-yl)-3-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutanecarboxamide as a white solid. [M+1]=354.0. IC50 (uM): 3.066.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1CC(O)=O.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)[CH2:35][CH2:34][O:33]1.N1C=CC=CC=1CC(O)=O>ClCCCl>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:34](=[O:33])[CH2:35][C:18]2[CH:19]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1cccnc1
Reaction time: 16 h

Procedure:
To a solution of methyl 2-amino-4-chlorobenzoate (2 g, 10.8 mmol) in 1,2-dichlorethane (60 ml) was added 2-pyridylacetic acid hydrochloride (1.9 g, 10.8 mmol), triethylamine (3.2 ml, 22.7 mmol) and bis (2-oxo-3-oxazolidinyl)phosphinic chloride and the reaction refluxed for 8 h. More 2-pyridylacetic acid (1.9 g, 10.8 mmol) and triethylamine (3.2 ml, 22.7 mmol) were added and refluxing continued for a further 16 h. The solvent was evaporated and the residue partitioned between saturated aqueous sodium bicarbonate solution (50 ml) and dichloromethane (50 ml). The organic phase was dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica (eluting with 50% ethyl acetate/60°-90° petrol) to afford methyl 4-chloro-2-(3-pyridyl)acetamidobenzoate as a green solid (2.5 g), m.p. 85°-87° C. To a solution of the foregoing amide (1 g, 3.3 mmol) in tetrahydrofuran (40 mml) was added a solution of potassium hexamethyldisilazide in toluene (0.5M, 16.6 ml, 8.3 mmol) and the reaction stirred for 2 h. Methanol (15 ml) was added and the solvent evaporated. The residue was partitioned between aqueous sodium hydroxide (1M, 40 ml) and diethyl ether (40 ml), and the aqueous layer acidified with hydrochloric acid (5M). The resultant precipitate was collected and recrystallised from dimethylformamide/water to afford the title compound as a yellow-green solid; m.p.>330° C. (from DMF/H2O) (Found: C, 61.48; H, 3.20; N, 10.20; C14H9ClN2O2 requires C, 61.66; H, 3.33; N, 10.27%); δH (DMSO-d6) 7.15 (1H, dd, J=8.5 Hz and 1.9 Hz, 5-H), 7.26 (1H, s, 8-H), 7.42 (1H, t, J=6.1 Hz, 5'-H), 8.02 (1H, d, J=8.5 Hz, 5-H), 8.16 (1H, t, J=7.3 Hz, 4'-H), 8.78 (1H, d, J=8.6 Hz, 6'-H), 9.38 (1H, d, J=8.8 Hz, 3'-H), 11.20 (1H, s, NH); m/z 272 (M+).