Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]([CH3:43])=[CH:10][C:11]1[N:12]([CH2:41][CH3:42])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:40])(=[O:39])[N:30]([CH2:35][CH2:36][O:37][CH3:38])C(C)(C)C)=[CH:25][CH:24]=3)[N:17]=2)=[CH:14][N:15]=1.C1(OC)C=CC=CC=1>>[CH3:8][C:9]([CH3:43])=[CH:10][C:11]1[N:12]([CH2:41][CH3:42])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([S:29](=[O:39])(=[O:40])[NH:30][CH2:35][CH2:36][O:37][CH3:38])=[CH:27][CH:28]=3)[N:17]=2)=[CH:14][N:15]=1
Reactant: CCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)N(CCOC)C(C)(C)C)cc3)n2)cnc1C=C(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)cnc1C=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Aqueous TFA (90%) was added to a mixture of 4-[2-(2-methylprop-1-enyl)-1-ethylimidazol-5-yl]-2-{4-[N-(2-methoxyethyl)-N-t-butylsulphamoyl]anilino}pyrimidine (Method 111; 70 mg, 0.14 mmol), and anisole (90 μl, 0.83 mmol), and the mixture stirred at ambient temperature for 1 hour. The volatiles were evaporated and the residue dissolved in water. The solution was neutralised (NaHCO3), and extracted with EtOAc. The extracts were dried, and the solvent evaporated to give the title compound (30 mg, 41%). NMR: 1.19 (t, 3H), 1.99 (s, 3H), 2.15 (s, 3H), 2.89 (q, 2H), 3.18 (s, 3H), 3.30-3.28 (m, 2H), 4.65 (q, 2H), 6.28 (s, 1H), 7.25 (d, 1H), 7.50 (t, 1H), 7.70 (d, 2H), 7.85 (s, 1H), 7.89 (d, 2H), 8.45 (d, 1H), 9.85 (s, 1H); m/z: 457.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26][S:27][CH3:28])[CH:6]=[CH:5][C:4]=1[C:29]1[NH:33][C:32](=[O:34])[O:31][N:30]=1.ClC1C=CC=C(C(OO)=[O:43])C=1.O>CN(C)C=O>[CH3:28][S:27]([CH2:26][C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)[S:15][C:11]=1[CH2:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:43]
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CSC)ccc1-c1noc(=O)[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CS(C)=O)ccc1-c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.7 %

Procedure:
To a solution of 32 mg of 3-{2-methoxy-4-[4-methylsulfanylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one in 4 mL of dimethylformamide was added 15 mg of metachloroperbenzoic acid. The resulting mixture was stirred for 45 min at room temperature, then poured into water and extracted with dichloromethane. The organic extracts were washed with a saturated aqueous solution if sodium bicarbonate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of methanol in dichloromethane) to give 25 mg of 3-{4-[4-methanesulfinylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-1,2,4-oxadiazol-5-one as a white solid which was further purified by trituration with diisopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=[O:14])=[O:4].C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.[N:41]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[C@@H:43](O)[CH2:42]2>C1COCC1.CC#N>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]([C:13]([O:15][C@@H:43]1[CH:44]2[CH2:47][CH2:48][N:41]([CH2:46][CH2:45]2)[CH2:42]1)=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1ccccc1NC(C(=O)O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine 2-(2-(methoxycarbonyl)phenylamino)-2-phenylacetate (I34) (611 mg, 1.47 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (559 mg, 1.47 mmol), and HOBT (226 mg, 1.47 mmol) are dissolved in THF (7 mL) and MeCN (3 mL). (R)-Quinuclidin-3-ol (375 mg, 2.95 mmol) is added and the mixture is stirred at RT for 1 hour. Solvents are evaporated, the residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated. The crude is purified by preparative HPLC and the collected fractions are evaporated, the residue is dissolved in EtOAc and washed with NaHCO3 and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated to afford compound the title compound as a colorless compound (95 mg, 16% yield, mixture of diastereoisomers).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8][N:9]([CH3:14])[C:10](=[O:13])[CH:11]=[CH2:12])[CH:2]([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:32]=[C:33]2[C:38](=[N:39][CH:40]=1)[NH:37][C:36](=[O:41])[CH2:35][CH2:34]2.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:5][C:6]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:7]=1[CH2:8][N:9]([CH3:14])[C:10](=[O:13])/[CH:11]=[CH:12]/[C:31]1[CH:40]=[N:39][C:38]2[NH:37][C:36](=[O:41])[CH2:35][CH2:34][C:33]=2[CH:32]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: O=C1CCc2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1cccc(OC)c1OCC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCC#N
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c1OCC(C)C
Yield: 32.2 %

Procedure:
A solution of N-(2-isobutoxy-3-methoxybenzyl)-N-methyl-acrylamide (0.475 g, 1.71 mmol) in propionitrile (6 mL) and DMF (1.2 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.48 mL, 2.77 mmol) and 6-bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.300 g, 1.32 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.029 g, 0.13 mmol) and P(o-tol)3 (0.080 g, 0.26 mmol) were then added and the mixture was deoxygenated with Ar for 20 min. The mixture was heated to reflux for 18 h. Upon cooling, a precipitate formed. The solids were collected by filtration and washed with water. Purification by column chromatography (silica gel, CH2Cl2/MeOH 9:1) gave an orange solid. The solid was dissolved in CH2Cl2 and the solution was diluted with hexanes. The resulting precipitate was collected by filtration, washed with Et2O (50 mL) and dried to yield the title compound (0.18 g, 32%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.66-10.64 (m, 1H), 8.36-8.32 (m, 1H), 8.09-8.00 (m, 1H), 7.53-7.47 (m, 1H), 7.27-7.20 (m, 1H), 7.04-7.96 (m, 2H), 6.66-6.60 (m, 1H), 4.79-4.64 (m, 2H), 3.79 (s, 3H), 3.72-3.67 (m, 2H), 3.10-2.85 (m, 5H), 2.56-2.49 (m, 2H), 2.03-1.97 (m, 1H), 1.00-0.97 (m, 6H); MS (ESI) m/e 424 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8](F)(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].C(=O)([O-])[O-:17].[K+:20].[K+]>O>[F:1][C:2]1[C:7]([S:8]([O-:17])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[K+:20]
Reactant: O=S(=O)(F)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 9 h

Procedure:
25 Grams (93.8 mmols) of pentafluorobenzenesulfonyl fluoride was charged in a flask, and 13.0 g (93.8 mmols) of potassium carbonate and 100 ml of water were added under cooling with ice, followed by stirring at room temperature for 9 hours. Then, 1.3 g (9.4 mmols) of potassium carbonate was further added and the mixture was stirred at 60° C. for 1 hour. A white solid produced was filtered off and purified by recrystallization with water. The resulting white solid was subjected to 19F-NMR measurement and it was confirmed that the resulting white solid was potassium pentafluorobenzenesulfonate (c).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8]([C:12]3[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=3[O:23][CH3:24])=[N:9]2)=[CH:5][N:4]=1.[CH3:25][NH2:26]>>[CH3:1][O:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8]([C:12]3[CH:17]=[C:16]([S:18]([NH:26][CH3:25])(=[O:20])=[O:19])[C:15]([Cl:22])=[CH:14][C:13]=3[O:23][CH3:24])=[N:9]2)=[CH:5][N:4]=1
Reactant: COc1ncc2[nH]c(-c3cc(S(=O)(=O)Cl)c(Cl)cc3OC)nc2n1
Reactant: CN
Product: CNS(=O)(=O)c1cc(-c2nc3nc(OC)ncc3[nH]2)c(OC)cc1Cl

Procedure:
Prepared analogously to Example 11 from 2-methoxy-8-(2-methoxy-4-chloro-5-chlorosulfonyl-phenyl)-purine and aqueous methylamine solution.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11]([O:16][CH3:17])=[CH:12][C:13](Cl)=[O:14])=[CH:7][CH:6]=1.CS.N1C=CC=CC=1.CC[O:39]CC>O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH:10]([CH3:18])[C:11]([O:16][CH3:17])=[CH:12][C:13]([OH:39])=[O:14])=[CH:7][CH:6]=1
Reactant: COC(=CC(=O)Cl)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: CCOCC
Agent: CS
Solvent: O
Solvent: c1ccncc1
Product: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoyl chloride (10 mm.) and ether (10 ml.) is added methyl mercaptan (12 mm.) and pyridine (1 ml.) at about -20°. The mixture is stirred for about 30 minutes and then allowed to rise to about 0° and stand for about 2 hours. The mixture is then diluted with ether and water and the ether phase separated, washed, dried and solvent removed to give the methylthiol ester of 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[Cl:17])[N:3]=1
Reactant: NCc1ccccc1Cl
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2ccccc2Cl)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[(2-chlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5]Br.CN1CCCC1=[O:17]>O>[Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5][OH:17]
Reactant: CN1CCCC1=O
Reactant: FC(F)(Br)C(F)(Cl)CCBr
Solvent: O
Product: OCCC(F)(Cl)C(F)(F)Br
Temperature: 130 °C
Yield: 49 %

Procedure:
A mixture of 1,4-dibromo-2-chloro-1,1,2-trifluorobutane (XVI) (7.5 g, 24.6 mmol), 1-methyl-2-pyrrolidinone (14 mL) and water (2.5 mL) was heated at 130° C. for 16 hours. The mixture was cooled to room temperature, diluted with water (80 mL) and extracted with ether (2×75 mL). The ether extract was washed with water (3×40 mL,), brine, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was chromatographed over silica gel to give 2.9 g (49%) of the desired alcohol as a clear off.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14]/[N:15]=[C:16](\[CH3:24])/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:4](OC)=[O:5].[CH3:25][NH2:26].CO>>[CH3:1][O:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14]/[N:15]=[C:16](\[CH3:24])/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:4]([NH:26][CH3:25])=[O:5]
Reactant: COC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Reactant: CN
Solvent: CO
Product: CNC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of methyl (E)-α-methoxy-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetate (0.48 g, 1.3 mmol) and 40% monomethylamine-methanol solution (10 ml) was stirred in a sealed tube at 80° C. for 15 hours. The mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. Water was added, the mixture was adjusted to pH 1 with 1N hydrochloric acid, extracted with methylene chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/2) to give the desired compound (E)-α-methoxy-N-methyl-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetamide (0.41 g, 86%) as an oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)(=[O:12])=[O:11].[SH:23][C:24]1[C:33]([C:34]([NH:36][CH2:37][C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[O:35])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C(Cl)Cl>CC(C)=O>[S:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[CH2:37][NH:36][C:34]([C:33]1[C:24]([S:23][CH2:8][CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)(=[O:12])=[O:11])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:35]
Reactant: O=S(=O)(CCCl)c1cccc(C(F)(F)F)c1
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(NCc1cccs1)c1cc2ccccc2nc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 30 %

Procedure:
151 mg (1.1 mmol) K2CO3 and 300 mg (1.1 mmol) 1-(2-chloroethylsulfonyl)-3-(trifluoromethyl)benzene were added to a solution of 300 mg (1.0 mmol) 2-mercapto-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV02) in acetone (10 ml) at RT and the mixture was heated for 3 h at 70° C. Then it was filtered and the filtrate was concentrated to small volume under vacuum. The residue was taken up with EE and washed with water and brine, dried over MgSO4, filtered and concentrated to small volume under vacuum. Column chromatography (DCM/EE 20:1) of the residue yielded 163 mg (0.3 mmol, 30%) N-(2-thienylmethyl)-2-[2-[3-(trifluoromethyl)-phenyl]sulfonylethylthio]-3-quinoline carboxamide. MS: m/z 537.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](Cl)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:12](=[O:13])[CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCc2ccc([N+](=O)[O-])cc2)cc1
Yield: 81.3 %

Procedure:
A procedure similar to step 2 of Example 1 was used, the 3-(4-nitro-phenyl)-propionyl chloride prepared in the step 2 and methylphenyl ether were used as starting materials, and anhydrous AlCl3 was used as catalyst, the obtained product was white solid in a yield of 81.3%, mp: 123-125 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.18 (2H, t, J=7.00 Hz), 3.30 (2H, t, J=7.00 Hz), 3.87 (3H, s, OCH3), 6.93 (2H, d, J=8.96 Hz, ArH), 7.42 (2H, d, J=8.60 Hz, ArH), 7.93 (2H, d, J=8.96 Hz, ArH), 8.15 (2H, d, J=8.60 Hz, ArH); EI-MS m/e (%): 285.0 (M+, 62), 134 (100).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH3:10].I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:10]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23.0 mL of 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-chloro-phenyl)-acetic acid ethyl ester (1.28 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 mg, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.65 g, 90.9%) as a yellow oil: EI-HRMS m/e calcd for C16H21Cl2O2(M+) 280.1230, found 280.1227.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5](OCC)=[O:6])#[N:3].S(O)(O)(=O)=O.[C:15]([NH2:20])(=[NH:19])[CH:16]([CH3:18])[CH3:17]>C(O)C>[NH2:3][C:2]1[N:19]=[C:15]([CH:16]([CH3:18])[CH3:17])[NH:20][C:5](=[O:6])[CH:4]=1
Reactant: CCOC(=O)CC#N
Reactant: CC(C)C(=N)N
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: CC(C)c1nc(N)cc(=O)[nH]1
Temperature: 0 °C

Procedure:
To a stirred solution of sodium (1.15 g.) in dry ethanol (20 ml.) was added ethyl cyanoacetate (1.8 ml.) followed after 15 minutes by isobutyramidine sulphate (2.25 g.). The mixture was refluxed for 20 hours, evaporated to dryness, the residue triturated with water (30 ml.) and the pH adjusted to 6 by the addition of hydrochloric acid. After cooling to 0° C, 4-amino-2-isopropylpyrimid-6-one (1.7 g.), m.p. 248°-250° C, was filtered off and recrystallised from ethanol to give 4-amino-2-isopropylpyrimid-6-one (0.95 g.), m.p. 254° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:25]=[CH:24][C:11]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][CH2:15][O:16][C:10]=2[CH:9]=1.C(OCC)(=O)C.[ClH:32]>C(OCC)(=O)C>[ClH:32].[ClH:32].[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:25]=[CH:24][C:11]2[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:10]=2[CH:9]=1
Reactant: C[C@H]1COCCN1c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H]1COCCN1c1ccc2c(c1)OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
A mixture of tert-butyl 8-[(3S)-3-methylmorpholin-4-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.15 mmol), ethyl acetate (4 ml) and 4N hydrogen chloride-ethyl acetate solution (8 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (300 mg, 81.3%) as a solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:21][C@@H:22]([CH2:25][CH3:26])[CH2:23][OH:24])[S:19][CH:20]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[C:18]([NH:21][C@@H:22]([CH2:25][CH3:26])[CH2:23][OH:24])[S:19][C:20]=2[Cl:1])=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC[C@@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: ClCCl
Product: CC[C@@H](CO)Nc1nc(-c2ccc(Br)cc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
A solution of N-chlorosuccinimide (975.0 mg, 7.30 mmol) in 50 mL of methylene chloride was added under nitrogen at room temperature dropwise over 45 min to a solution of (2S)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}butan-1-ol (2.1611 g, 6.60 mmol), prepared in step 1 of Example 7, in 50 mL of methylene chloride. After the addition, the reaction was stirred at room temperature for 3 h. The reaction was poured directly onto a column of silica gel (230-400 mesh). Elution of the column with 5% ethyl acetate-methylene chloride to 15% ethyl acetate-methylene chloride gave (2S)-2-{[4-(4-bromophenyl)-5-chloro-1,3-thiazol-2-yl]amino}butan-1-ol (1.5371 g, 64%) as a yellow foam, MS (ES) m/z 358.8 [M+H]+.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[CH:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH:6]1[NH:15][C:16]([C:18]1[C:19](Cl)=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[O:17])[CH2:12]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:5]12[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH:6]1[NH:15][C:16]([C:18]1[C:19]([S:4][CH2:1][CH2:2][CH3:3])=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[O:17])[CH2:14]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCSc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
Propanethiol (1.45 mL, 16 mmol) was added to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (5.2 g, 16 mmol), and sodium carbonate (5.09 g, 48 mmol) in DMF (50 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with EtOAc (400 mL) and washed with water (3×50 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was recrystallised from 15% ethyl acetate/hexane to give N-(2-adamantyl)-6-chloro-2-propylsulfanyl-pyridine-3-carboxamide (4.9 g, 84%)
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=3)[NH:16][CH:15]=2)=[CH:10][CH:9]=1.[NH2:24]OS([O-])(=O)=O.[K+].NOS(O)(=O)=O>CN(C=O)C>[NH2:24][N:16]1[C:17]2[C:22](=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:14]([C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)=[CH:15]1
Reactant: NOS(=O)(=O)[O-]
Reactant: Cc1ccc2[nH]cc(-c3ccc(F)cc3)c2c1
Agent: CC(C)(C)[O-]
Agent: NOS(=O)(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2N

Procedure:
Potassium tert-butoxid (7.5 g) was added to a solution of 3-(4-fluorophenyl)-5-methyl-1H-indole 1c (15 g) in DMF during 15 min at 0°-5° C. Then a suspension of potassium hydroxylamine-O-sulphonate in DMF (prepared by addition of potassium tert-butoxid (7.5 g) to a suspension of hydroxylamine-O-sulphonic acid (7.6 g) in DMF (100 ml) during 0.5 h at 0°-5° C.) was added slowly at 0°-5° C. After reaction at 0° C. for 1 h the mixture was poured into ice, and extracted with diethyl ether (2×250 ml). The combined organic phases were washed with brine (3×250 ml) and dried (Na2SO4). Evaporation of the solvents afforded the title compound which was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:3) and crystallized from diethylether. Yield: 4.3 g, mp 116°-120° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:14][C:13]=2[CH:21]=1.C(=O)(O)[O-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH2:6]([O:5][C:3]([CH2:2][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([S:17](=[O:19])(=[O:20])[NH2:18])[S:14][C:13]=2[CH:21]=1)=[O:4])[CH3:7]
Reactant: NS(=O)(=O)c1cc2ccc(O)cc2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 36 h
Yield: 38.1 %

Procedure:
To a solution of ethyl bromoacetate (1.2 ml, 11 mmol) and 6-hydroxy-2-sulfamoylbenzo[b]thiophene (2.29 g, 10 mmol) in DMSO (10 ml) was added dropwise a solution of potassium bicarbonate (1.0 g, 10 mmol) and potassium carbonate (0.13 g, 1 mmol) in water (7 ml). The mixture was stirred for 1-2 days, then diluted with water. The precipitated product was collected dissolved in ethyl acetate, dried (Na2SO4) and evaporated to dryness. The residue was recrystallized from hot ethyl acetate, boiling off solvent until crystallization began, to give 1.2 g of product, m.p. 182°-184° C.