Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC(OC)=C([N+]([O-])=O)C=1.[O:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[F:20][C:21]1[CH:46]=[CH:45][C:24]([C:25]([NH:27][C:28]2[S:29][C:30]3[C:36](N4CCOCC4)=[CH:35][CH:34]=[C:33]([O:43][CH3:44])[C:31]=3[N:32]=2)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:27][C:28]2[S:29][C:30]3[C:36]([N:16]4[CH2:17][CH2:18][CH2:19][O:13][CH2:14][CH2:15]4)=[CH:35][CH:34]=[C:33]([O:43][CH3:44])[C:31]=3[N:32]=2)=[O:26])=[CH:45][CH:46]=1
Reactant: C1CNCCOC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: COc1ccc(Br)cc1[N+](=O)[O-]
Product: COc1ccc(N2CCCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-methoxy-2-nitro-benzene and [1.4]Oxazepane as described for 4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a light yellow solid in about 10% overall yield, MS: m/e=402 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[S:54][C:55]2[CH:61]=[C:60]([O:62][S:63]([C:66]3[CH:71]=[CH:70][C:69]([NH:72][CH2:73][CH2:74][N:75]([CH:79]([CH3:81])[CH3:80])[CH:76]([CH3:78])[CH3:77])=[CH:68][CH:67]=3)(=[O:65])=[O:64])[CH:59]=[CH:58][C:56]=2[N:57]=1>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:52][C:53]1[S:54][C:55]2[CH:61]=[C:60]([O:62][S:63]([C:66]3[CH:71]=[CH:70][C:69]([NH:72][CH2:73][CH2:74][N:75]([CH:79]([CH3:81])[CH3:80])[CH:76]([CH3:77])[CH3:78])=[CH:68][CH:67]=3)(=[O:65])=[O:64])[CH:59]=[CH:58][C:56]=2[N:57]=1)=[O:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1)C(C)C
Reactant: CC(C)(C)OC(=O)NCCCCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CCCCCCCNC(=O)OC(C)(C)C)sc3c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
175 mg of 8-tert-butoxycarbonylaminooctanoic acid, 256 mg of HBTU and 235 μl of DIEA are added to a solution of 4-(2-diisopropylaminoethylamino)-benzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 34) (100 mg, 0.225 mmol) in 5 ml of dimethylformamide. The solution obtained is stirred for 20 hours at room temperature. After addition of 50 ml of water, the reaction mixture is extracted with 3 times 25 ml of ethyl acetate. The extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 338 mg of crude oil. This oil is purified by elution in a 95/5 dichloromethane/methanol mixture at a flow rate of 10 ml/minute, on 10 g of silica, to give 153 mg of 4-(2-diisopropylaminoethylamino)benzenesulfonic acid 2-(8-tert-butoxycarbonylaminooctanoylamino)benzothiazol-6-yl ester.
Reaction SMILES: C(OC(=O)/C=[C:11](/[C:13]1C=CC=C[N:14]=1)\C)C1C=CC=CC=1.C([O:27]C(=O)/C=C(\C1C=CC=CN=1)/C)C1C=CC=CC=1.[CH2:39]1[CH2:43][O:42][CH2:41][CH2:40]1>[Pd]>[N:14]1[CH:13]=[CH:11][CH:43]=[CH:39][C:40]=1[C:41]([OH:27])=[O:42]
Reactant: C/C(=C\C(=O)OCc1ccccc1)c1ccccn1
Reactant: C1CCOC1
Reactant: C/C(=C/C(=O)OCc1ccccc1)c1ccccn1
Agent: [Pd]
Product: O=C(O)c1ccccn1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution under N2 of (E)-3-pyridin-2-yl-but-2-enoic acid benzyl ester (1.40 g, 5.53 mmol, 1.00 eq.) and (Z)-3-pyridin-2-yl-but-2-enoic acid benzyl ester (320 mg, 1.26 mmol, 0.23 eq.) in THF (50 mL), palladium on activated carbon (10 wt. %, 200 mg) was added. The flask was evacuated and refilled with H2 (3×). The black suspension was stirred at 50° C. under an H2-atmosphere for 16 hours. The black suspension was filtered through Celite. The Celite was rinsed with THF and the filtrate was concentrated in vacuo. The residue was dissolved in water (3 mL), MeCN (1 mL) and formic acid (0.5 mL). The solution was directly purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions, extremely polar method) and concentrated in vacuo to give the desired acid as a white solid.
Reaction SMILES: [CH2:1]=[O:2].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][CH:12]([CH3:16])[C:13](=O)C.Cl.C=O.[CH2:20](N)[C:21]1C=CC=CC=1.[OH-].[K+]>C(O)C.O>[CH2:3]([N:10]1[CH2:21][CH2:20][C:1](=[O:2])[C:12]([CH3:16])([CH3:13])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)C(C)C
Reactant: NCc1ccccc1
Reactant: C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 10 °C

Procedure:
In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution was cooled in an ice-water bath to 10° C., and benzylamine (109 mL, 1 mole) was added dropwise over a one hour period. In a separate 3 liter 3-necked flask equipped with mechanical stirring, addition funnel and two condensers is added 3-methyl-2-butanone (113 mL, 1.06 mole) dissolved in 500 mL of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution is brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution is refluxed overnight, and then cooled to ambient temperature. Diisbpropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL, 0.3 mole) are added and the resulting solution is heated to reflux for six hours, and then cooled to ambient temperature. The solution was quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted with 500 mL ethyl acetate three times. The organics were concentrated under vacuum to give 225 g of red oil. The crude oil was dissolved in 1 liter of methylene chloride. This solution was carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel was washed with 4 L of methylene chloride. The methylene chloride was concentrated under vacuum to provide 142 g of a yellow oil which crystallizes in the freezer overnight. Yield=65.4%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([CH2:23][CH3:24])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.Cl.C(=O)([O-])[OH:27].[Na+].[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1[C:40](Cl)=[O:41]>C(Cl)(Cl)Cl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]([C:9]1[CH:20]=[C:21]([CH2:23][CH3:24])[S:22][C:8]=1[N:7]1[C:6]([CH2:12][NH:11][C:40]([C:32]2[NH:31][C:39]3[C:34]([CH:33]=2)=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:41])=[N:5][N:4]=[C:3]1[CH2:2][OH:1])=[O:27]
Reactant: CCc1cc2c(s1)-n1c(CO)nnc1CN=C2c1ccccc1Cl
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CO)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1

Procedure:
9-Hydroxymethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (0.5 g) which can be synthesized by a known method (Japanese Patent Unexamined Publication No. 102698/1974) was stirred with 5% hydrochloric acid (10 ml) at 60° C. overnight. Then, sodium hydrogencarbonate was added to the reaction mixture to make the mixture alkaline. Chloroform and indole-2-carbonyl chloride (0.35 g) were added, and the mixture was stirred under ice-cooling for 3 hours. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin-layer chromatography (developing solvent:ethyl acetate) and recrystallized from ethyl acetate-hexane to give 0.015 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-3-hydroxymethyl[1,2,4]triazol-5-ylmethyl)indole-2-carboxamide.
Reaction SMILES: [O-2].C[Si](C)(C)[O:4][V+2:5]([O:11][Si](C)(C)C)O[Si](C)(C)C.Br[C:19]1[CH:24]=[CH:23][C:22]([Si](C2C=CC(Br)=CC=2)(C2C=CC(Br)=CC=2)[OH:26])=[CH:21][CH:20]=1.C1(O)CCCCC1>>[O-2:4].[CH:19]1([O:11][V+4:5])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[O-2:26]
Reactant: O[Si](c1ccc(Br)cc1)(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: C[Si](C)(C)O[V+2](O[Si](C)(C)C)O[Si](C)(C)C
Agent: [O-2]
Solvent: OC1CCCCC1
Product: [V+4]OC1CCCCC1

Procedure:
tris-(trimethylsiloxy)-vanadium oxide is reacted with tri-(p-bromophenyl)-silanol and cyclohexanol in a molar ratio of 1:2:1 to produce bis-[tri-p-bromophenyl)-siloxy]-cyclohexyloxy-vanadium oxide [mol peak = 1184 ref to 79Br]; and
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=S(=O)=O)[C:7]([O:12][CH3:13])=[N:6][C:5](C)=[N:4]1.[OH:15][CH:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:12][CH3:13])[N:6]=[C:5]([O:15][CH:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])[N:4]=1
Reactant: COC1=NC(C)=NC(OC)C1=S(=O)=O
Reactant: COC(=O)C(O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(C)C
Reaction time: 3 h

Procedure:
2.18 g (10.0 mmol) of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine and 1.62 g (11.0 mmol) of methyl (+/-)-2-hydroxy-3,3-dimethylbutanoate were heated in the presence of 2.07 g (15.0 mmol) of potassium carbonate in 20 ml of N,N-dimethylformamide to 60° with stirring. After 3 hours, the solvent was removed in a rotary evaporator at 60° C./20 mbar. The residue was taken up in 40 ml of water and 40 ml of ethyl acetate. After the organic phase had been separated off, the aqueous phase was again extracted with 40 ml of ethyl acetate. The combined organic phases was washed with water, dried over magnesium sulfate and evaporated. The title product was obtained in a yield of 2.76 g (93.8 percent of theory) in the form of pale yellowish crystals (GC content 96.6 percent).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[CH3:11].[C:13]1(/[C:19](=[C:21]2/[C:22](=[O:30])[NH:23][C:24]3[C:29]/2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:21](=[C:19](\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[CH3:20])/[C:22]2=[O:30])[CH:7]=[CH:6][C:5]=1[CH3:11]
Reactant: C/C(=C1\C(=O)Nc2ccccc21)c1ccccc1
Reactant: COC(=O)c1cc(Br)ccc1C
Product: COC(=O)c1cc(N2C(=O)/C(=C(\C)c3ccccc3)c3ccccc32)ccc1C

Procedure:
The title compound was prepared in analogy to Example 1 starting from 5-bromo-2-methyl-benzoic acid methyl ester (commercially available) and 3-[1-phenyl-eth-(E)-ylidene]-1,3-dihydro-indol-2-one. 1H NMR (400 MHz, chloroform-d) δppm 2.71 (s, 3H) 2.86 (s, 3H) 3.91 (s, 3H) 6.24 (d, J=7.83 Hz, 1H) 6.67-6.75 (m, 2H) 7.08 (t, J=7.83 Hz, 1H) 7.34-7.37 (m, 2H) 7.43-7.47 (m, 1H) 7.49-7.56 (m, 4H) 8.05 (d, J=2.27 Hz, 1H).
Reaction SMILES: [Cr:1].[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([OH:8])=[O:7])[OH:5]>O>[C:2]([O-:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([O-:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5].[Cr+3:1]
Reactant: [Cr]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [Cr+3]

Procedure:
222 g of chromium III chloride were dissolved in 3 liters of distilled water. 160 g of citric acid were added. This produces a concentration of 14.4 million ppb of chromium citrate. After 10 minutes of stirring at room temperature, the green color changed to purple, signifying that chromium citrate has been formed. Then, 3 ml of the resulting chromium citrate were added to 1 gallon of distilled water. The following amounts of the above solution were prepared:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-:11].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:5]([CH3:6])([CH3:4])[C:8]([OH:10])=[O:11])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
2-(p-Acetylphenoxy)-2-methylpropionic acid was prepared from 545 g. of p-hydroxyacetophenone, 960 g. of sodium hydroxide and 715 g. of chloroform in 11 liters of acetone according to the procedure described above in Example 1, part (d). The product was recrystallized from carbon tetrachloride and from isopropyl acetate to give 2-(p-acetylphenoxy)-2-methylpropionic acid as a pale cream solid, m.p. 108°-110°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:21])=[O:16].[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:32](=[O:34])[CH3:33])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:21])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCN(C)CCNC(=O)Cc1cc(=O)oc2cc(O)c(Cl)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCN(C)CCNC(=O)Cc1cc(=O)oc2cc(OC(C)=O)c(Cl)cc12
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A sample of this 2-(6-Chloro-7-hydroxycoumarin-4-yl)-N-[2-(N-decyl-N-methyl-amino)ethyl]acetamide (26 mg, 0.06 mmole) was dissolved in anhydrous dichloromethane (5 mL) and acetic anhydride (0.5 mL, 5.3 mmole) and dry pyridine (0.5 mL, 6.2 mmole) added. This mixture was allowed to stir overnight, and the resulting solution, diluted with dichloromethane (30 mL) and extracted with water (1×25 mL), saturated sodium bicarbonate solution (1×25 mL), 1N HCl (1×25 mL) and water (1×25 mL). The resulting dichloromethane layer was dried over anhydrous sodium sulfate, filtered and evaporated. Drying in vacuo provided an off-white solid (22 mg, 79%). A biocompatible solution of this substrate was prepared by dissolving 22 mg in dry DMSO (0.446 mL) for staining live cells for esterase activity.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[CH2:13]([N:15](CC)[CH2:16]C)C.CNC>C(#N)C>[CH3:13][N:15]([CH3:16])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(CCBr)c1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CC#N
Product: CN(C)CCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 250 mL round bottom flask was charged with 1-(2-bromoethyl)-3-nitrobenzene (10 g, 43.5 mmol) and acetonitrile (36 mL). The suspension was treated with triethylamine (18.1 mL, 130 mmol) and dimethylamine (2 M in tetrahydrofuran, 65.2 mL, 130 mmol). The resulting solution was stirred at ambient temperature for 48 hours. The reaction was concentrated. The residual solid was partitioned between ethyl acetate (130 mL) and 60 ml saturated aqueous sodium bicarbonate. The aqueous layer was washed with ethyl acetate (75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The concentrate was purified by flash chromatography on an 80 g silica gel column using an AnaLogix IntelliFlash 280 system eluting with a gradient of from 0% to 7% methanol in CH2Cl2 to provide the title compound. MS (DCI(+)) m/e 195.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[CH:25]2[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=CCc1ccccc1
Reactant: Oc1cccc(CCNc2ccc(Cl)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCN(c1ccc(Cl)cc1)C2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 3-{2-[(4-chlorophenyl)amino]ethyl}phenol (0.20 g, 0.8 mmol) and phenylacetaldehyde (0.194 g, 1.6 mmol) in CH2Cl2 (6 mL) was added trifluoroacetic acid (0.148 g, 1.6 mmol). After stirring at room temperature overnight, the reaction was quenched with saturated sodium bicarbonate and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.203 g, 72% yield): 1H NMR (CDCl3) 7.19-7.24 (m, 4H), 7.16 (m, 1H), 7.14 (m, 1H), 6.70 (m, 2H), 6.71 (m, 2H), 6.61 (m, 2H), 6.54 (dd, 1H), 4.77 (t, 1H), 3.58 (ddd, 1H), 3.47 (ddd, 1H), 3.17 (dd, 1H), 2.86-2.99 (m, 2H), 2.67 (m, 1H); ES-MS (m/z) 350 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:8]=[CH:9][CH:10]=1)C=C.[BH4-].[Na+]>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>[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[CH:11]([O:21][CH:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1)[C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=1
Reactant: C=CCOc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(OC(c2cccc(O)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-[(3-allyloxyphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 22) (2.35 g) in tetrahydrofurane (40 mL) is added tetrakistriphenylphosphinepalladium (0.344 g). The mixture is stirred for 5 min at room temperature, then sodium borohydride (0.576 g) is added. The mixture is stirred for 20 h at room temperature, filtered over a clarcel pad. The pad is rinsed with ethyl acetate. Pooled organic phases are washed with aqueous ammonium chloride solution, then sodium hydrogenocarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by three column chromatographies over silica gel (twice gradiant heptane/ethyl acetate from 95/5 to 80/20, third eluant heptane/dichloromethane 5/1). Pooled fractions are concentrated under reduced pressure. The residue is dissolved in methanol, refluxed for 5 h and concentrated under reduced pressure. The residue is purified by column chromatography (gradiant dichloromethane/methanol/ammonia from 100/0 to 90/10/1) to give 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenol as a beige solid melting at 201° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1)#[N:20].[NH2:36][CH2:37][CH:38]([C:40]1[CH:41]=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=1)[OH:39]>>[OH:39][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=1)[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:19]#[N:20])=[CH:32][CH:31]=1)=[O:7])=[O:18]
Reactant: NCC(O)c1cccc(O)c1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2cccc(O)c2)N(C(=O)c2ccc(-c3ccccc3C#N)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-cyano[1,1′-biphenyl]-4-carboxylic acid, and 3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 86% purity by HPLC. MS(ESI+): m/z=499.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-])=O)=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:24])[N:15]3[CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:10]=2)[CH:7]=1.C(O)(=O)C.O.[OH-].[NH4+]>[Fe].C(O)C>[NH2:31][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][C:14](=[O:24])[N:15]2[CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:11]([C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[N:10]=1
Reactant: O=c1[nH]c2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3[N+](=O)[O-])nc2n1C1CCOCC1
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a vial containing 2-(5-chloro-2-nitrophenylamino)-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (7 mg, 0.015 mmol) was added glacial acetic acid (0.5 mL), water (1.25 mL) and ethanol (2.5 mL), followed by iron powder (8.4 mg, 0.15 mmol, 10 equiv.) and the resulting mixture heated at 90° C. for 15 min (HPLC monitoring). The reaction mixture was left to cool down to room temperature, concentrated ammonium hydroxide solution was added to bring the pH to basic, and the mixture was stirred for 10 min. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with brine, dried (anhydrous Na2SO4), and the solvent removed in vacuo to give the desired product as a pale yellow solid (yield quantitative). This material was used in the next step without further purification. MS (EI) m/z 438.3 (MH)+.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([O:18]/[N:19]=[C:20](\[C:32]1[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][N:33]=1)/[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[OH:31])([CH3:17])([CH3:16])[CH3:15].O>C(Cl)(Cl)Cl>[C:14]([O:18]/[N:19]=[C:20](\[C:32]1[C:37]([O:38][C:7](=[O:9])[CH3:8])=[CH:36][CH:35]=[CH:34][N:33]=1)/[C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[OH:31])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)O/N=C(/c1cc(C(F)(F)F)ccc1O)c1ncccc1O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccnc1/C(=N\OC(C)(C)C)c1cc(C(F)(F)F)ccc1O
Reaction time: 0.83 h

Procedure:
Pyridine (0.30 ml) was dissolved in chloroform (10 ml). To the solution was added acetic anhydride (0.18 ml), and the mixture was stirred for 50 minutes. To the reaction mixture was then added (Z)-2-(2-hydroxy-5-trifluoromethylbenzoyl)-3-hydroxypyridine O-t-butyloxime (0.21 g), and the mixture was stirred for 3 hours at room temperature. To the reaction mixture were added water and chloroform for extraction. The organic layer was dried (anhydrous magnesium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane, then with ethyl acetate/THF) to give (Z)-3-acetoxy-2-(2-hydroxy-5-trifluoromethylbenzoyl)pyridine O-t-butyloxime (0.20 g) (Compound 46).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[C-]#N.[Na+]>CS(C)=O.O>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(cc1O)CCC2=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 54 %

Procedure:
5,6-Dimethoxy-1-indanone (1 g, 5.20 mmol) and NaCN (2.55 g, 52 mmol) were combined in DMSO (10 mL). The reaction was stirred at 100° C. for two days, cooled, diluted with water and extracted with dichloromethane. The aqueous solution was acidified with concentrated HCl, and extracted with dichloromethane. The organic layer was dried over MgSO4 and evaporated to give the title compound (500 mg). MS (DCI/NH3) m/z: 178.99 (M+H)+. 1H NMR (500 MHz, CD2Cl2) δ ppm 2.59 (t, J=5.62 Hz, 2H) 3.01 (t, J=5.62 Hz, 2H) 3.93 (s, 3H) 6.33 (s, 1H) 6.95 (s, 1H) 7.17 (s, 1H).