Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[CH2:43]Br>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]([CH2:43][C:34]2[CH:35]=[CH:36][C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]=[CH:9][NH:10][C:11]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CNc2ccc3c(c2)ncn3C(=O)OC(C)(C)C)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc3ccccc3c2)c2ccc3nc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N1-Boc-N-(4-methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K2CO3 (166 mg; 1.2 mmol; 1.2 eq.) and naphthalen-2-yl-methyl-bromide (265 mg; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH3 and stirred for 2 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.058 mg (14.8%); MS m/z: 394.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 3.70 (s, 3H); 4.68 (s, 2H); 4.80 (s, 2H); 6.76 (d, 1H, 4J=2.1 Hz); 6.82 (dd, 1H, 4J=2.3 Hz, 3J=8.9 Hz); 6.87-6.89 (m, 2H); 7.22-7.24 (m, 2H); 7.34 (d, 1H, 3J=8.9 Hz); 7.43-7.47 (m, 5H); 7.75 (br s, 1H); 7.79-7.81 (m, 1H); 7.85-7.87 (m 2H); 7.94 (s, 1H); HPLC (METHOD [A]): rt 18.12 min (95.6%)
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=3)[NH2:19])[C:10]=2[CH:9]=[CH:8]1.CCN(C(C)C)C(C)C.[CH3:34][C:35](=[CH2:39])[C:36](Cl)=[O:37]>ClCCl>[CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([NH:19][C:36](=[O:37])[C:35]([CH3:39])=[CH2:34])[CH:20]=[CH:21][CH:22]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: C=C(C)C(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cccc(N)c3)ncnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline (10.0 g, 29.4 mmol) in dichloromethane (200 mL), was added DIPEA (12.0 g, 92.9 mmol) followed by dropwise addition of a solution of 2-methylprop-2-enoyl chloride (4.60 g, 44.0 mmol) in dichloromethane (50 mL) at −5 to 0° C. The reaction was stirred overnight at room temperature, quenched by addition of water (150 mL), and extracted with dichloromethane (×3). The organic layers were combined, washed with water and HCl solution (0.5 M in water), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-33% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a yellow oil. LRMS (ESI) calc'd for C22H29N4O2Si [M+H]+: 409, found 409.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(CCN(C)C)C.[Li]C(CC)C.C1CCCCC1.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:31]([CH3:33])([CH3:32])[CH3:30])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc(Cl)c1C(=O)O
Temperature: -100 °C
Yield: 63 %

Procedure:
2-Chlorobenzoic acid (3.91 g, 25 mmol), THF (60 mL), and TMEDA (8.6 mL, 57 mmol) were stirred under nitrogen and cooled to −100° C. 1.3M s-BuLi in cyclohexane (0.055 mol, 42.3 mL) was added dropwise keeping the temperature below −80° C. After the addition was complete, TMSCl (2.7 g, 25 mmol) was added dropwise and the resulting mixture was allowed to stir and slowly warm to −30° C. 25% citric acid (100 mL) was added and the mixture was extracted with two 50 mL portions of ether, which were then combined and washed three times with water, dried (MgSO4) and concentrated. The crude product was purified by HPLC, eluting with 2:3 ethyl acetate/hexanes. The product was recovered as a white solid in 63% yield. m.p. 129-131° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O>CO>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[N:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]=[CH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=Cc1ccccn1
Solvent: CO
Product: C(=N[C@@H]1CCCC[C@H]1N=Cc1ccccn1)c1ccccn1
Temperature: 25 °C

Procedure:
15.0 g (0.13 mol) of trans-1,2-diaminocyclohexane are dissolved in 80 ml of methanol and, at room temperature, 28.1 g (0.26 mol) of pyridine-2-aldehyde are added a little at a time. The solution is refluxed for one hour and then cooled to room temperature. The precipitated solid is filtered off and dried in an oil pump vacuum. The product is obtained in the form of a light-yellow powder in a yield of 23 g (79 mmol, 60%). 1H-NMR (400 MHz, CDCl3): δ=8.55 (m, 2H, Py), 8.31 (s, 2H, ═C—H), 7.88, 7.63, 7.21 (3×m, 6H, Py), 3.52 (m, 2H, NC—H), 1.90–1.49 (m, 8H, (CH2)4) ppm.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH:15]([C@:18]1([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)([CH3:17])[CH3:16].[CH3:42][O:43][CH:44]1[C:49](=O)[CH2:48][CH2:47][O:46][CH2:45]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:15]([C@:18]1([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][C@@H:20]([NH:23][CH:49]2[CH2:48][CH2:47][O:46][CH2:45][CH:44]2[O:43][CH3:42])[CH2:19]1)([CH3:17])[CH3:16]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}carbonyl)cyclopentanamine bis(trifluoroacetate) (140 mg, 0.23 mmol), 3-methoxytetrahydro-4H-pyran-4-one (90 mg, 0.69 mmol) and triethylamine (0.096 mL, 0.69 mmol) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (97 mg, 0.46 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated and purified on silica gel eluting with EtOAc to 1% Et3N/EtOAc affording 105 mg (92%) of the desired product. The product was separated by chiral HPLC to give two major isomers. MS calculated for C26H38F3N3O3: (M+H) 498; found 498.2 for both isomers.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[Cl:56][C:57]1[CH:67]=[CH:66][C:60]([O:61][CH:62]2[CH2:65][NH:64][CH2:63]2)=[CH:59][CH:58]=1>ClCCl>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12]([N:64]1[CH2:65][CH:62]([O:61][C:60]2[CH:59]=[CH:58][C:57]([Cl:56])=[CH:67][CH:66]=2)[CH2:63]1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(OC2CNC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CC(Oc2ccc(Cl)cc2)C1)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
A solution of (S)-2-tert-butoxycarbonylamino-succinic acid 1-benzyl ester (5.0 g, 13.99 mmol) in dichloromethane (50 ml) is treated with diisopropylethylamine (7.51 ml, 41.97 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (4.49 g, 13.99 mmol). To the reaction mixture is added 3-(4-chloro-phenoxy)-azetidine hydrochloride (3.06 g, 13.99 mmol) and stirring continued for 3 hours. The dichloromethane is evaporated and residue partitioned between ethylacetate and saturated NaHCO3 solution. The ethylacetate phase is washed with 1M HCl solution and brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 1:1 ethylacetate/hexane) to afford (S)-2-tert-butoxycarbonylamino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]4-oxo-butyric acid benzyl ester. [M-BOC] 389.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2O[C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:5][CH:4]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C1(C)C(C)=CC=CC=1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:26]1[C:15](=[O:17])[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[C:11]1[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(CCc2nc3ccccc3c(=O)o2)cc1
Reactant: CN(C)CCN
Solvent: Cc1ccccc1C
Product: COc1ccc(CCc2nc3ccccc3c(=O)n2CCN(C)C)cc1
Yield: 74 %

Procedure:
A mixture of 295 mg (1 mmol) of 2-{2-(4-methoxyphenyl)ethyl}-4H-3,1-benzoxazin-4-one synthesized in the same manner as in Synthesis example 2 and 88 mg (1 mmol) of 2-dimethylaminoethylamine in xylene (5 ml) was heated under reflux for 2 hours. After the xylene was distilled off under reduced pressure, the crude crystals obtained were purified by silica gel column chromatography (eluent; 3% methanol/methylene chloride) to obtain 260 mg (76%) of 3-(2-dimethylaminoethyl)-2-{2-(4-methoxyphenyl)ethyl}- 4(3H)-quinazolinone.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[CH:9]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)[CH2:11][CH2:10]1>C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH:9]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:7])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(OCCC2CC2)cc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCCC2CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
A solution of 2,2′-azobis(isobutyronitrile) (0.122 g), N-bromosuccinimide (3.19 g) and 4-(2-cyclopropylethoxy)-1-methyl-2-nitrobenzene (3.30 g) in ethyl acetate (100 mL) was refluxed for 8 hr. The reaction mixture was allowed to cool to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The obtained solution was filtered with a short silica gel pad, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (150 mL), and molecular sieves 4A (10 g) and 4-methylmorpholine N-oxide (2.02 g) were added thereto at 0° C. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 3 hr, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.90 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C>[Zn].O1CCCC1.CO>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product of Example 28A (1.6 g, 4.9 mmol), zinc dust (3.2 g, 49 mmol) and acetic acid (5.4 mL) in 1/1 tetrahydrofuran/methanol (100 mL) was stirred at ambient temperature for 1 hour. The mixture was filtered and the filtrate was diluted with water and adjusted to pH 9. The mixture was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 99/1 dichloromethane/methanol to give the title compound. MS: 296 (M+H+).
Reaction SMILES: [Cl-].ClC1N(C)CC[NH+]1C.[F:10][C:11]([F:23])([F:22])[S:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(N(CC)CC)C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[C:45]([O:52][C:53](=[O:55])[CH3:54])[CH:44]=2)[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:51]=[CH:50][C:46]([C:47]([NH:19][C:18]3[CH:20]=[CH:21][C:15]([S:12]([C:11]([F:22])([F:10])[F:23])(=[O:13])=[O:14])=[CH:16][CH:17]=3)=[O:48])=[C:45]([O:52][C:53](=[O:55])[CH3:54])[CH:44]=2)[C:37](=[O:41])[C:38]=1[O:39][CH3:40]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(OC(C)=O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c(OC(C)=O)c2)=C(C)C1=O
Reaction time: 2 h
Yield: 39.2 %

Procedure:
2-Chloro-1,3-dimethylimidazolinium chloride (130 mg, 0.77 mmol), 4-(trifluoromethylsulfonyl)aniline (173 mg, 0.77 mmol) and triethylamine (78 mg, 0.77 mmol) were added to a methylene chloride solution (8 ml) of 4-[(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl]-2-acetoxybenzoic acid (240 mg, 0.64 mmol) in a nitrogen atmosphere and the resulting solution was stirred for 2 hours. The reaction solution was diluted with chloroform, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (methylene chloride:methanol=60:1) to obtain the titled compound (146 mg, 0.251 mmol, 39%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>>[NH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(N)cccc1F
Reactant: OCCCOc1ccccc1
Product: N#Cc1c(N)cccc1OCCCOc1ccccc1

Procedure:
Prepared as in Example 22b from 3-phenoxy-1-propanol and 2-amino-6-fluorobenzonitrile as a yellow oil (93%). 1H NMR (400 MHz, DMSO-d6) δ 2.14 (m, 2H), 4.10-4.16 (m, 4H), 5.98 (s, 2H), 6.23 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 6.89-6.94 (m, 5H), 7.16 (t, J=8.0 Hz, 1H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]4[S:44][CH:45]=[C:46]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[N:47]=4)[CH2:39][CH2:38]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:54][C@@H:25]([CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:43]3[S:44][CH:45]=[C:46]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[N:47]=3)[CH2:39][CH2:38]2)=[CH:34][CH:35]=1)[CH2:24][O:23][C:22]1[CH:55]=[CH:56][C:19]([OH:18])=[CH:20][CH:21]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(c4nc(-c5ccccc5)cs4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(c4nc(-c5ccccc5)cs4)CC3)cc2)cc1

Procedure:
(2S)-1-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-3-[(4-{[1-(4-phenyl-1,3-thiazol-2-yl)-4-piperidinyl]amino}phenethyl)amino]-2-propanol (0.25 g, 0.319 mmol) was reacted following general Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound as the hydrochloride salt (0.12 g, 0.22 mmol).
Reaction SMILES: [OH:1]O.[OH-].[Na+].[CH3:5][O:6][C:7]1[CH:28]=[CH:27][C:10]([CH2:11][N:12]([CH2:22][CH2:23][CH2:24][C:25]#[N:26])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:12]([CH2:22][CH2:23][CH2:24][C:25]([NH2:26])=[O:1])[CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:28][CH:27]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(CN(CCCC#N)Cc2ccc(OC)cc2)cc1
Reactant: OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN(CCCC(N)=O)Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrogen peroxide (30% w/v; 5.67 ml ), tetra-n-butylammonium hydrogensulphate (1.70 g) and 5N aqueous sodium hydroxide (4 ml) were added successively to a stirred solution of 4-[N,N-bis-(4-methoxybenzyl)amino]butyronitrile (3.24 g) in dichloromethane (10 ml), with water cooling. The mixture was stirred vigorously at room temperature for 18 hours and dichloromethane (100 ml) was added. The layers were separated and the organic phase was washed with saturated aqueous sodium chloride (1×10 ml), dried (Na2SO4) and concentrated in vacuo to give an oil (4.71 g). The product was chromatographed on silica with eluant 20% ethyl acetate/toluene →ethyl acetate, and crystallised from diisopropyl ether at room temperature to give the title compound (2.21 g), m.p. 53°-54° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)[C:11]([O:13][CH3:14])=[O:12].Cl.[F:25][C:26]1[C:27]([C:33](=[NH:35])[NH2:34])=[N:28][CH:29]=[C:30]([F:32])[CH:31]=1.C([O-])(=O)C.[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][S:20][CH2:19]2)[NH:35][C:33]([C:27]2[C:26]([F:25])=[CH:31][C:30]([F:32])=[CH:29][N:28]=2)=[N:34]1
Reactant: COC(=O)C(=Cc1ccc(F)cc1Cl)C(=O)CCN1CCSC1
Reactant: N=C(N)c1ncc(F)cc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)C1=C(CCN2CCSC2)NC(c2ncc(F)cc2F)=NC1c1ccc(F)cc1Cl

Procedure:
A solution of 0.20 g (0.56 mmol) of the compound from Example IX in 5 ml of isopropanol is heated together with 0.11 g (0.56 mmol) of the compound from Example VI and 0.06 g (0.67 mmol) of sodium acetate under reflux for 2 hours. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and extracted with dilute hydrochloric acid. The aqueous phase is made alkaline with dilute sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (5:1→3:1) as mobile phase.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][C:4]2[CH:18]=[CH:19][S:20][C:3]1=2.CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[OH:1][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)c3sccc3C2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Oc1cncc2ccsc12
Yield: 72 %

Procedure:
A solution of 7-oxo-5-tosyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (19.6 g; 0.064 mole; obtained in (b) above) and potassium tert-butoxide (28.6 g; 0.255 mole) in tert-butanol (300 ml) is refluxed for 2 hours under a nitrogen atmosphere. Evaporation of the solvent in vacuo leaves a residue which is taken up into 2N hydrochloric acid. The aqueous phase is extracted with ether, made basic by addition of concentrated ammonia, and evaporated to dryness. The residue is extracted four times with boiling ethyl acetate. The organic extracts are filtered through a silica bed and evaporated to dryness. The solid residue is recrystallized from ethanol-acetonitrile. Greyish crystals; M.P.=180° C.; Yield: 72%.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5].P(=O)(O)(O)O>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1
Yield: 84.7 %

Procedure:
3.00 Grams of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone were dissolved in 50 ml to toluene, and 0.50 g of 85% phosphoric acid, was added thereto. The resulting mixture was refluxed for 1 hour with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 2.83 g of 6-(4-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis=28 : 1) (purity: 84.2%). The yield was 84.7%.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](O)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([Cl:23])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Yield: 92.9 %

Procedure:
2-Butyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (444 mg, 1.58 mmol) was dissolved in dry DCM (15 mL) at rt and under an atmosphere of nitrogen. Oxalyl chloride (0.15 mL, 1.73 mmol) was added dropwise and the reaction mixture was refluxed for 1.5 h. DMF (0.08 mL) was added followed by oxalyl chloride (0.15 mL, 1.73 mmol) in 2 portions and the reaction mixture was refluxed for another 6 h. The solvents were evaporated and the residue was partitioned between water and DCM. The combined organic layers were washed with water and the two phases were separated using a phase separator. Evaporation of the organic phase gave the title compound (440 mg, 88%) as a brown oil with approximately 95% purity according to 1H-NMR and was used without further purification; 1H-NMR (400 MHz, CDCl3): δ 7.96-8.00 (m, 2H), 7.53-7.62 (m, 3H), 3.74-3.80 (t, 2H), 1.78-1.87 (m, 2H), 1.39-1-50 (m, 2H), 0.98 (t, 3H); 13C-NMR (100 MHz, CDCl3): δ 156.3, 137.1, 132.7, 129.6, 129.2, 127.6, 123.7, 40.9, 30.1, 20.1, 13.7.