Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2cccnc2)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2cccnc2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-3-ylmethyl-ethylamine (326 mg.; 1 mmol, from Example 3) in dichloromethane (15 mL) at 0° C. was added triethylamine (0.28 mL; 2 mmol) and 1-methyl-1-cyclohexanecarbonyl chloride (160 mg.; 1 mmol). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (5% methanol/chloroform) to yield the free base of the title compound as a clear oil (132 mg.; 29%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as an off-white amorphous solid, m.p. 150–152° C.; MS (+) FAB, [M+H]+ @ m/z 451, [M+Na]+ @ m/z 473; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2.C4H4O4.0.5H2O Calculated: C, 64.68; H, 7.53; N, 9.73 Found: C, 64.89; H, 7.18; N, 9.64.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15](O)([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Yield: 97.8 %

Procedure:
A suspension of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 73-2, 300 mg, 0.864 mmol) in DCM (2 mL) was treated with triethylsilane (1.380 mL, 8.64 mmol) and then slowly with TFA (0.666 mL, 8.64 mmol) and the mixture was stirred at rt for 40 min. The resulting suspension was diluted with DCM and the resulting solution was washed with NaHCO3 (aq). The organic phase was washed with water and brine, and dried and concentrated to give 4-bromo-7-isopropyl-9H-carbazole-1-carboxamide as a white solid (280 mg, 98%). 1H NMR (400 MHz, chloroform-d) δ 10.50 (1H, br. s.), 8.63 (1H, d, J=8.1 Hz), 7.32-7.40 (3H, m), 7.22 (1H, dd, J=8.4, 1.3 Hz), 5.97 (2H, br. s.), 3.02-3.18 (1H, m), 1.35 (6H, d, J=6.8 Hz). Mass spectrum m/z 331, 333 (M+H)+.
Reaction SMILES: C(C1C=[CH:47][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:46])([C:42]([F:45])([F:44])[F:43])[C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#N.[OH-:49].[K+].Cl.[CH2:52]([OH:55])[CH2:53][CH3:54]>O>[C:52]([C:53]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:46])([C:38]([F:41])([F:39])[F:40])[C:42]([F:45])([F:43])[F:44])=[CH:33][CH:32]=2)[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[CH:47][CH:54]=1)([OH:49])=[O:55]
Reactant: CCCO
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2)Cc2ccc(C#N)cc2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A solution of 170 mg (0.25 mmol) of methyl 4-{(4E)-3-(4-cyanobenzyl)-5-[2-({4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]benzyl}oxy)phenyl]pent-4-en-1-yl}benzoate in 3 ml of 1-propanol and 2 ml of water is mixed with 427 mg (7.6 mmol) of potassium hydroxide and stirred at 110° C. for 12 h. After cooling, the mixture is acidified with 1 M hydrochloric acid, and the crystals which have separated out are filtered off with suction, washed several times with water and dried. 135 mg (0.2 mmol, 79% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([CH:25]=[O:26])=[CH:10][N:9]=1.[CH2:27]([Li])[CH2:28][CH2:29][CH3:30].C(=O)([O-])O.[Na+]>OC[C@@H]1CCCN1C1N=C(NCC2C=CC(OC)=C(Cl)C=2)C(C(=O)C)=CN=1.CCCCCC>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C@@H:25]([OH:26])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:10][N:9]=1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Reactant: [Li]CCCC
Agent: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(C)=O)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CCCC[C@H](O)c1cnc(N2CCCC2CO)nc1NCc1ccc(OC)c(Cl)c1

Procedure:
A solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (10.0 mg) in tetrahydro-furan (1.0 ml) obtained in Example 2 (3) is treated with a 1.6M solution of n-butyl lithium in hexane (83 μl) at −78° C. for 3 minutes, and thereto is added an aqueous sodium hydrogen carbonate solution. The reaction mixture is extracted with ethyl acetate to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxypentyl)pyrimidine (13.7 mg) as oil.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].C([Mg]Cl)C(C)C.CN(C)[CH:32]=[O:33].[Cl-].[NH4+]>O1CCCC1>[F:23][C:3]1[C:2]([CH:32]=[O:33])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Br)c2F)CC1
Reactant: CN(C)C=O
Agent: CC(C)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C=O)c2F)CC1
Reaction time: 2 h

Procedure:
194 mg of tert-butyl 4-(3-bromo-2-fluorobenzoyl)piperazine-1-carboxylate was dissolved in 5.0 ml of tetrahydrofuran, and 1.25 ml of a solution of isobutyl magnesium chloride in tetrahydrofuran (2.0 M) was added thereto at −78° C. After stirring at the same temperature for 2 hours, 0.39 ml (5.0 mmol) of N,N-dimethylformamide was added thereto. The resulting mixture was stirred at the same temperature for 30 minutes and further stirred at 0° C. for 30 minutes. To the reaction mixture was added saturated ammonium chloride, and the mixture was extracted with chloroform. The organic layer was washed with brine and then concentrated. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=9/1 to 1/1) to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[CH3:19][C:17]([CH3:20])([O:16][C:14]([N:12]([CH3:13])[CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:15])[CH3:18]
Reactant: COC(=O)C1(CCN(C)C(=O)OC(C)(C)C)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(CCC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of 1-[2-[[(1,1-dimethylethoxy)carbonyl](methyl)amino]ethyl]cyclopentane carboxylic acid methyl ester (4.00 g, 14.0 mmol) in THF/MeOH (2:1, 24 mL) was added a solution of LiOH (1.50 g, 35.0 mmol) in water (8 mL). The mixture was stirred overnight at 50° C. and then cooled to room temperature. The reaction mixture was poured into a round bottom flask and concentrated in vacuo. The mixture was diluted with H2O (50 mL) and acidified with 1M HCl. The aqueous phase was extracted with ethyl acetate (3×1 50 mL) and the combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography, using hexane-ethyl acetate (5:1), afforded (3.60 g, 95%) of a white powder. HR MS (C14H25NO4): Calcd mass, 272.1862. Obs mass, 272.1872 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]2[N:16]([C:17](=[O:27])[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14][O:13][C:12]2([CH3:29])[CH3:28])=[O:8])#[CH:2].[N+:35]([CH3:38])([O-])=[O:36].[Cl-].[CH3:40]OC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CS(C)=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:34][C:32]1[CH:31]=[CH:30][C:4]([CH2:5][NH:6][C:7]([C:9]2[N:10]=[C:11]3[N:16]([C:17](=[O:27])[C:18]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14][O:13][C:12]3([CH3:29])[CH3:28])=[O:8])=[C:3]([C:1]2[O:36][N:35]=[C:38]([CH3:40])[CH:2]=2)[CH:33]=1
Reactant: C[N+](=O)[O-]
Reactant: C#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)on1
Temperature: 22 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A solution of intermediate 179, N-(2-ethynyl-4-fluorobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.150 g, 0.32 mmol) in dimethyl sulfoxide (5 ml) was treated with nitromethane (0.14 ml, 1.92 mmol), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (0.241 g, 1.0 mmol) (M. Kunishima et al., Tetrahedron, 55, 1999, 13159–13170) and 4-(dimethylamino)pyridine (DMAP) (0.010 g) and the resulting mixture stirred at 22° C. for 16 h. Identical quantities of nitromethane, DMTMM and DMAP were then added and the mixture was stirred for another 24 h. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in dichloromethane) gave 0.122 g (73% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.62 (6H, s, 2×CH3), 2.39 (3H, s, CH3), 4.04 (4H, m, 2×CH2), 4.69 (2H, d, J=6.1 Hz, NCH2), 5.31 (2H, s, OCH2), 6.36 (1H, m, CH), 7.13 (1H, m, aromatic), 7.30–7.35 (4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.58 (1H, dd, J=5.5 Hz and J=8.6 Hz, aromatic), 8.06 (1H, broad t, NH). HRMS (ESI+) calculated for C28H28FN4O5 [M+H+]: 519.2044. Found: 519.2059.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([CH3:13])[C:9](=O)[O:10]C)=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[CH:19]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:16]=2)[N:3]=1.[H-].[Na+]>CN(C=O)C.O.CCOCC>[NH2:1][C:2]1[N:3]=[C:4]([C:15]2[CH:19]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][N:24]=3)[N:17]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:16]=2)[N:5]=[C:6]2[C:7]=1[N:8]([CH3:13])[C:9](=[O:10])[NH:14]2
Reactant: COC(=O)N(C)c1c(N)nc(-c2cc(-c3ncco3)n(Cc3ccccc3F)n2)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Cn1c(=O)[nH]c2nc(-c3cc(-c4ncco4)n(Cc4ccccc4F)n3)nc(N)c21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
To a solution of methyl 4,6-diamino-2-(1-(2-fluorobenzyl)-5-(oxazol-2-yl)-1H-pyrazol-3-yl)pyrimidin-5-yl(methyl)carbamate (82 mg, 0.19 mmol) in DMF (3.7 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 15 mg, 0.37 mmol). The solution was immediately warmed to ambient temperature and stirred for 45 min. Water (3 mL) was added, and after stirring for 5 minutes, the crude reaction mixture was diluted with ethyl acetete (100 mL) and water (75 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were combined, washed with water (2×50 mL) and brine (50 mL), dried over magnesium sulfate, and filtered. The solvent was removed in vacuo to give the crude product as an orange solid. The crude material was brought up in ether (10 mL) and the orange solid was filtered off. The procedure was repeated to give 6-amino-2-(1-(2-fluorobenzyl)-5-(oxazol-2-yl)-1H-pyrazol-3-yl)-7-methyl-7H-purin-8(9H)-one (51 mg, 0.13 mmol, 67% yield) as a pink solid. 1H NMR (400 MHz, DMSO): δ 11.57 (s, 1H), 8.31 (s, 1H), 7.41 (s, 1H), 7.35-7.31 (m, 2H), 7.25-7.20 (m, 1H), 7.12 (t, 1H), 6.96-6.93 (m, 1H), 6.65 (s, 2H), 6.01 (s, 2H), 3.45 (s, 3H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH:15]([C:16]([OH:18])=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5].C(=O)=O.CC(C)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:16]1(=[O:18])[CH:15]2[N:6]([CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14]2)[C:4](=[O:5])[CH2:3][CH2:2][S:1]1
Reactant: O=C(O)C1Cc2ccccc2CN1C(=O)CCS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C1SCCC(=O)N2Cc3ccccc3CC12
Reaction time: 0.08 h

Procedure:
The compound produced in Example 2 is dissolved in about 500 milliliters methylene chloride and the solution is chilled under nitrogen to 15° C. in a dry ice-acetone mixture. 4-Dimethylaminopyridine is added and the mixture is stirred for five minutes. A slight excess of dicyclohexylcarbodiimide dissolved in methylene chloride is added with stirring. The chilling source is removed after 15 minutes and the solution is stirred overnight at room temperature. The volume of the reaction mixture is reduced on a rotary evaporator under reduced pressure to about 100 milliliters. A precipitate is removed by filtration and the filter residue is washed several times with methylene chloride. The filtrate and combined washings are washed successively with 1 N, HCl, saturated aqueous NaHCO3, water and saline and the solution is dried over MgSO4. Evaporation of the methylene chloride with a rotary evaporator under reduced pressure yields a white solid which is recrystallized from diethyl ether to yield the title compound.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C(OC(=O)C)(=O)C>O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[CH:17][C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccncc1
Reactant: COc1ccc(C=O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(C=Cc2ccncc2)cc1
Yield: 54.9 %

Procedure:
The photo-bleachable compound expressed by the structural formula (II-14) was prepared in the following manner. Thus, a reaction mixture was prepared by dissolving 6.81 g (0.05 mole) of p-anisaldehyde and 4.66 g (0.05 mole) of γ-picoline in 10.21 g (0.10 mole) of acetic anhydride and the mixture was heated under reflux for 16 hours to effect the reaction. After acetic acid and the unreacted acetic anhydride were evaporated from the reaction mixture, the residual reaction mixture was poured into water so that a crystalline material was precipitated therein. The reaction mixture was filtered and the collected precipitates were washed with water. Recrystallization of the precipitates from a mixture of methyl alcohol and water gave 5.80 g of 4-[2-(4-methoxyphenyl)ethenyl]pyridine, the yield of which was 55% of the theoretical value.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[S:17][C:16]([S:18]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8](=[O:9])(=[O:10])[NH2:11])(=[O:20])=[O:19])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)s1
Temperature: 60 °C
Yield: 57 %

Procedure:
To a solution of 2-aminobenzenesulfonamide (172 mg) in pyridine (3 ml) was added 5-chlorothiophene-2-sulfonyl chloride (217 mg) and the resulting mixture was heated at 60° C. for 18 h. The mixture was concentrated and then partitioned between DCM (20 ml) and 2N HCl (10 ml). The organics were separated, dried (MgSO4) and evaporated to a gum which was purified by silica chromatography eluting with a gradient of ethyl acetate/hexane to give the title compound as a solid (201 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:11][C@@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][OH:10].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH3:18][S:19]([O:10][CH2:9][C@H:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:11][C@@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC[C@H](C)C[C@H](CO)OC1CCCCO1
Solvent: c1ccncc1
Product: CCCC[C@H](C)C[C@H](COS(C)(=O)=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of 1.51 g of (2R,4S)-2-tetrahydropyranyloxy-4-methyloctanol obtained in Step 9 and 15 ml of pyridine was kept at -5° C., and 1.06 g of methanesulfonyl chloride was added thereto, followed by stirring at that temperature for 1 hour. The reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was adjusted to pH 5 with 1% hydrochloric acid, washed with water, dried, and distilled to remove the solvent to obtain 1.74 g (77.81%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:25])[CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:27]\[OH:28])=[C:4]([F:25])[CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2F)C2CCCC2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2F)C2CCCC2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-2-fluoro-phenyl)-3-cyclopentyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=421.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([O:13]C(C3C=CC=CC=3)=O)[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C@@H:3]1[C@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@H:8]2[O:7][C@H:4]1[O:5][CH3:6]
Reactant: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2OC(=O)c2ccccc2)[C@H]1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CO[C@@H]1O[C@H]2[C@H](OC[C@H]2O)[C@H]1OC
Yield: 85 %

Procedure:
A solution of methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-D-glucofuranoside (820 mg, 3.1 mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (10 mL) was stirred at room temperature for 30 minutes. The material was adsorbed on silica gel (5 g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to give methyl 3,6-anhydro-2-O-methyl-β-D-glucofuranoside as a colorless oil, 420 mg, 85% yield. 1H NMR (400 MHz; CDCl3): 5.04 (s, 1H), 5.84-5.81 (tr, 1H), 4.44-4.42 (tr, 1H), 4.25-4.19 (m, 1H), 3.85-3.75 (m, 1H), 3.49 (s, 3H), 3.43 (s, 3H), 2.75-2.72 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1)=[O:4].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:36]=[CH:35][C:30]([CH2:31][NH:32][CH2:33][CH3:34])=[CH:29][CH:28]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH2:33]([N:32]([CH2:31][C:30]1[CH:35]=[CH:36][C:27]([C:26]([F:25])([F:37])[F:38])=[CH:28][CH:29]=1)[C:20](=[O:22])[CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][S:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:24][CH:23]=1)[CH3:34]
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Reactant: CCNCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
[4-(2-{[2-(methoxycarbonyl)phenyl]thio}ethyl)phenoxy]acetic acid (0.200 g, 0.577 mmol) was dissolved in DMF (10 ml), N-[4-(trifluoromethyl)benzyl]ethanamine (0.129 g, 0.635 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.204 g, 0.635 mmol) and N-ethyl-N,N-diisopropylamine (0.157 g, 1.212 mmol) was added. The solution was stirred overnight at room temperature. Water (100 ml) was added and the water phase was extracted with diethyl ether (3×20 ml). The organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by flash chromatography (started with isocratic heptane/EtOAc 30/70 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the solvent was removed by evaporation to give 0.085 g of methyl 2-({2-[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethyl}thio)benzoate (yield 27.7%).
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH2:26].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>C(O)C.C(O)(C)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:4]1[NH:5][CH:6]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCCCc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Reactant: Cc1[nH]cnc1CSCCN
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: CCCCc1c[nH]c(NCCSCc2nc[nH]c2C)c1[N+](=O)[O-]
Yield: 9.7 %

Procedure:
2-Methylsulphinyl-3-nitro-4-n-butylpyrrole (2.78 g) was dissolved in ethanol and added to a solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (2.08 g) in ethanol (total 100 ml). The mixture was heated under reflux for nine days. The solution was evaporated to dryness, and the residue was chromatographed on a silica gel column using chloroform and ethyl acetate to give 0.65 g of crude product as a brown oil. The crude product was dissolved in isopropanol (30 ml) and reacted with a solution of maleic acid (0.5 g) in 2-propanol. The mixture was warmed on a steam bath for a few minutes and then allowed to cool, yielding bright yellow crystals of 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-nitro-4-n-butylpyrrole maleate (0.19 g), m.p. 94°-95°.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:13](#[N:16])[CH:14]=[CH2:15].CCCCCCCC>>[C:13]([C:14]1[CH2:15][O:12][C:3]2[C:4]([CH:5]=1)=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=2[F:1])#[N:16]
Reactant: COc1ccc(F)c(O)c1C=O
Reactant: C=CC#N
Solvent: CCCCCCCC
Product: COc1ccc(F)c2c1C=C(C#N)CO2
Yield: 13.6 %

Procedure:
Crude 3-fluoro-hydroxy-6-methoxybenzaldehyde (8.0 g) from above, acrylonitrile (13 mL; 193 mmol) and 1.4.diazadicyclo [2,2,2] octane (0.66 g; 5.9 mmol) were refluxed in a three-necked round-bottom flask (50 mL) under nitrogen for 4 h. Rotary-evaporation of the volatiles left a thick, red oil which was flash-chromatographed on a silica column eluted with methylene chloride/n-hexane (4:5). Concentration of relevant fractions gave an impure product (91% GC) which was crystallized form EtOAc to give 1.31 g of the title compound as colourless bars. Mp. 133°-135° C.