Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]3[N:16]=[N:17][NH:18][CH:19]=3)=[C:9]([O:20]C)[C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]3[N:16]=[N:17][NH:18][CH:19]=3)=[C:9]([OH:20])[C:8]2=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1c(O)c(CCc2c[nH]nn2)ccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.8 %

Procedure:
To a solution of 158a (0.10 g, 0.338 mmol) in dry CH2Cl2 (8 mL) was slowly added 1M BBr3 (1.2 equiv) at −30° C. under argon atmosphere. The reaction mixture was stirred for 48 h at room temperature. The mixture was again cooled to −30° C. and the MeOH (5 mL) was slowly added to the mixture. After evaporation of solvent, the residue was adjusted to pH 7 with 1M NaOH and then extracted with CHCl3 (30 mL×3). The combined organic layer dried over Na2SO4 to give 79 mg (83%) of 159a as slightly brownish solid without any further purification required. 1H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.51 (s, 1H), 7.78 (d, J=7.3 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.31 (t, J=7.3 Hz, 1H), 6.75 (d, J=5.9 Hz, 1H), 6.64 (d, J=6.0 Hz, 1H), 5.95 (t, J=7.0 Hz, 1H), 4.76 (t, J=5.5 Hz, 2H), 4.42 (t, J=5.6 Hz, 2H). 13C NMR (100 MHz, DMSO) δ 158.25, 147.17, 146.77, 131.11, 129.34, 128.41, 128.31, 125.54, 122.23, 115.38, 105.76, 49.42, 48.33. HRMS (EI) calcd for C15H14N4O2 [M]+ 282.1117. found 282.1120.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:23](=[O:24])[N:22]([CH:25]([F:27])[F:26])[C:21]([CH3:28])=[N:20]2)=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][CH:6]=1.S(Cl)([Cl:31])=O>>[Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:23](=[O:24])[N:22]([CH:25]([F:27])[F:26])[C:21]([CH3:28])=[N:20]2)=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([Cl:31])=[O:12])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nn(-c2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Product: Cc1nn(-c2cc(Oc3ccc(C(=O)Cl)cc3)c(Cl)cc2F)c(=O)n1C(F)F

Procedure:
A stirred solution of 1.7 g (0.0041 mole) of 4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]phenylcarboxylic acid in 75 mL of thionyl chloride was heated at reflux for four hours. The excess thionyl chloride was removed by distillation under reduced pressure to yield 4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]-phenylcarboxylic acid chloride as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:32]([Mg]Br)[CH2:33][CH3:34].Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11]([CH2:32][CH2:33][CH3:34])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC[Mg]Br
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 1 h

Procedure:
100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 3 ml of THF. 0.349 ml (0.90 mol/l, THF solution) of n-propyl magnesium bromide was added at 0° C. and stirred at the same temperature for 1 hour. 10% hydrochloric acid was added at the same temperature and stirred for 10 minutes. After the reaction mixture was diluted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=O)(C)(C)C.[ClH:34]>ClCCl.C(O)C>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1.[ClH:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reaction time: 1 h

Procedure:
3-(4-((3S)-3-t-Butoxycarbonylamino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (2.1 g, 4.54 mmol) was suspended by stirring in dichloromethane (10 ml) under nitrogen and treated with a solution of hydrogen chloride in ethanol (4M, 50 ml) at ambient temperature. The mixture was stirred 1 hour, evaporated to a small volume, and treated with a mixture of dichloromethane (30 ml) and diethyl ether (30 ml). The precipitate was filtered and washed with diethyl ether to give the title compound as its hydrochloride (2.0 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:38])C=CC=CC=1>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([OH:38])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCCc1nn2cccc2c(=O)n1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(O)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-benzyl-2-propyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (2.0 g, 7.48 mmol) in THF (45 mL) at −78° C. was added KHMDS (0.5 M in toluene, 17.2 mL, 8.6 mmol) dropwise. After stirring at −78° C. for 10 min, the orange solution was charged with a solution of racemic 2-benzenesulfonyl-3-phenyloxaziridine (2.15 g, 8.23 mmol) in THF (5 mL). The pale yellow solution was stirred at −78° C. for 25 min and was then quenched with 50 mL of saturated NaHCO3 solution. The mixture was extracted with EtOAc (3×50 mL) and the pooled organic extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Purification of the crude product by flash column chromatography (SiO2, EtOAc/Hexane 1:4) gave the title compound as a colorless viscous oil which solidified upon standing (1.40 g, 66%): 1H NMR (CDCl3) δ 7.25 (m, 5H), 7.12 (t, 1H, J=1.4 Hz), 7.01 (m, 1H), 6.49 (m, 1H), 5.34 (d, 1H, J=16.1 Hz), 5.18 (d, 1H, J=16.2 Hz), 4.45 (m, 1H), 2.55 (brs, 1H), 1.78 (m, 1H), 1.63 (m, 1H), 0.88 (t, 3H, J=7.36 Hz); 13C NMR (CDCl3) δ 155.4, 150.7, 136.7, 129.4, 128.2, 126.7, 121.4, 118.5, 111.5, 109.6, 71.0, 44.8, 29.8, 10.3; MS (ESI+) 284.17 (M++H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[C:25]([CH3:29])([CH3:28])[CH2:24][O:23]5)[C:9]2=[O:30])C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:28][C:25]1([CH3:29])[CH2:24][O:23][C:22]2=[CH:21][C:18]3[O:19][CH2:20][C:10]4([C:17]=3[CH:27]=[C:26]12)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]4=[O:30]
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Yield: 66.4 %

Procedure:
To a solution of 1′-(diphenylmethyl)-5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.23 g, 0.49 mmol) in methanol (50.0 mL) was added palladium on carbon (0.10 g). The mixture was hydrogenated under 120 psi of hydrogen at ambient temperature overnight. The reaction mixture was filtered through celite, washed with methanol. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/2) to give the title compound (0.10 g, 68%): mp 95-100° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 7.28-7.20 (m, 1H), 7.15 (d, 1H), 7.03 (t, 1H), 6.95 (d, 1H), 6.43 (s, 1H), 6.40 (s, 1H), 4.94 (d, 1H), 4.66 (d, 1H), 4.19 (s, 2H), 1.20 (s, 3H), 1.16 (3H); 13C NMR (75 MHz, CDCl3) δ 180.4, 161.3, 161.0, 140.3, 133.0, 130.1, 128.8, 124.2, 123.4, 120.0, 116.6, 110.1, 93.4, 85.5, 80.6, 58.3, 41.4, 27.7, 27.6; MS (ES+) m/z 308.6 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19])[C:6]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=[O:21])=[CH:5]2.C(N(CC)CC)C.[CH3:37][C:38]([CH3:44])([CH3:43])[CH2:39][C:40](Cl)=[O:41]>ClCCl>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:40](=[O:41])[CH2:39][C:38]([CH3:44])([CH3:43])[CH3:37])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)=[O:21]
Reactant: Cc1cccc(NC(=O)c2cc3cc(N)ccc3n2Cc2c(F)cccc2F)c1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)c2cc3cc(NC(=O)CC(C)(C)C)ccc3n2Cc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
59 mg (0.150 mmol) of the compound from Example XIV and 0.04 ml (0.30 mmol) of triethylamine are initially-charged in 5 ml of dichloromethane. At 0° C., a solution of 26 mg of 3,3-dimethylbutyryl chloride (0.195 mmol) in 1 ml of dichloromethane is added dropwise, and the mixture is stirred at RT for 30 min. The reaction solution is concentrated and the residue is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane→cyclohexane:ethyl acetate 2.5:1). The resulting product is taken up in a little ethyl acetate, precipitated by addition of n-pentane, filtered off with suction and dried. This gives 35 mg (45% of theory) of a light-beige solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([OH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])=[O:19]>O>[C:7]([O:15][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])=[O:19])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(OCC(=O)c1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 0.25 h

Procedure:
Potassium carbonate (19 g) was added to a stirred suspension of benzoic acid (34 g) in water (600 ml) and the mixture was warmed gently on a steam bath. After 15 minutes, 2-bromo-2'-nitroacetophenone (68 g) and industrial methylated spirit (1 1) were added. The resultant mixture was heated under reflux for 2 hours, stirred without external heating for 1 0 minutes and then rapidly cooled to 0°-5° in an ice/salt bath with agitation. The mixture was kept at this temperature for 90 minutes and the product was collected by filtration and washed with water to give the novel compound 2-(2-nitrophenyl)-2-oxoethyl benzoate, m.p. 77-80°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21]NC.C=O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH2:21])[C:12]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Product: C=C1COc2ccc(OCc3ccccc3)cc2C1=O

Procedure:
A solution of 9.2 g of 6-benzyloxy-4-chromanone, dimethylamine hydrochloride and 1.3 g of paraformaldehyde in 100 ml of acetic acid was heated on a steam bath for 5 hours. The volatiles were evaporated in vacuo and the residue was purified on silica gel, eluting with CH2Cl2, to give 3.7 g of product, Rf (CH2Cl2)=0.5.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Product: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[I:22]N1C(=O)CCC1=O.O>CN(C)C=O>[I:22][C:18]1[O:17][C:16]([S:15][CH2:14][C:5]2[C:6]([C:10]([F:12])([F:13])[F:11])=[N:7][N:8]([CH3:9])[C:4]=2[O:3][CH:2]([F:1])[F:21])=[N:20][CH:19]=1
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSc2ncc(I)o2)c1OC(F)F

Procedure:
2-({[5-(Difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (0.700 g, 2 mmol) is initially charged in 10 ml of dimethylformamide. N-Iodosuccinimide (0.750 g, 3.3 mmol) is then added a little at a time with stirring. The mixture is stirred at 40° C. for a further 16 hours. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 8:2). This gives 0.25 g of product (24.5% of theory).
Reaction SMILES: [CH2:1]([N:5]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:38])(=[O:37])[NH:32]C(C)(C)C)=[CH:21][CH:20]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[CH2:1]([N:5]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:37])(=[O:38])[NH2:32])=[CH:23][CH:24]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCCc2ccccc21

Procedure:
The title compound was prepared from 1-[N-butyl-N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]carbamoyl]-1,2,3,4-tetrahydroquinoline (from Step A) and TFA in the presence of anisole, according to the procedure of Example 4, Step B, to give a 97% yield of the desired material after flash chromatography as a foam, homogeneous by TLC in 95:5 CH2Cl2 --MeOH; FAB-MS m/e 478 (M+1)+.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[F:22]>C1COCC1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][C:14]=1[F:22]
Reactant: CC(=O)c1ccc(Cl)c(F)c1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC1(c2ccc(Cl)c(F)c2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-chloro-3-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]=2[N:10]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[F:27][C:28]([F:32])([F:31])[CH2:29][OH:30]>C(#N)C>[F:27][C:28]([F:32])([F:31])[CH2:29][O:30][C:5]1[N:6]=[CH:7][C:8]2[CH2:13][NH:12][CH2:11][C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cnc(S(C)(=O)=O)nc2C1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)COc1ncc2c(n1)CNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the tert-butyl 2-(methylsulfonyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (300 mg) in dry acetonitrile (20 mL), 2,2,2-trifluoroethanol (1.8 mL) and cesium carbonate (815 mg) were added. The resulting mixture was stirred at room temperature for 1 h. The precipitate was removed by filtration. The solution was evaporated, and the resulting residue was purified on a Biotage Horizon® system (silica, gradient 35-65% ethyl acetate in hexanes). After concentration, tert-butyl 2-(2,2,2-trifluoroethoxy)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate was treated with HCl (4M in methanol) for 1 h. The residue was passed through an ion exchange resin (Strata-X-C™) and eluted with methanol containing 10% ammonium hydroxide to yield 2-(2,2,2-trifluoroethoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine as the title compound. LC/MS 220.0 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C=Cc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A suspension of 4-formylcinnamic acid (1.76 g), p-methoxybenzyl chloride (1.63 ml) and potassium carbonate (2.76 g) in 20 ml dimethylformamide was stirred at 80° C. for 7 hours, and then allowed to cool. The reaction mixture was extracted with ethyl acetate and washed with water. The combined organic layers were dried over magnesium sulfate. The drying agent was filtered off and the filtrate was evaporated under reduced pressure and dried to give p-anisyl 4formylcinnamate of interest (2.96 g, 100%) as a pale yellow solid.
Reaction SMILES: [N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[O:6][CH2:5][CH2:4][N:3]3[C:2]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[O:6][CH2:5][CH2:4][N:3]4[C:2]2=[N:13][S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=S(=O)(Nc1nc2cccc3c2n1CCO3)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(N=c1n(Cc2ccc(C(F)(F)F)cc2)c2cccc3c2n1CCO3)c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of N-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide (125 mg, 0.40 mmol) in DMF (2.5 mL) was added 1-bromomethyl-4-trifluoromethyl-benzene (190 mg, 0.80 mmol) and potassium carbonate (55 mg). The resulting mixture was heated to 120° C. in a microwave reactor for 1 h and then diluted with EtOAc, washed with H2O and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamide (2nd compound to elute off the column); which was further purified by HPLC (reverse phase C-18 column, 45-100% acetonitrile/water containing 0.05% trifluoroacetic acid) to yield N-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamide trifluoroacetic acid salt. MS 474 (M+1)+.
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C/CO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC/C=C/COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6]1[N:7]=[C:8]2[N:12]([CH:13]=1)[CH:11]=[C:10]([CH3:14])[S:9]2)C.C(O)C.C(OCC)C.[ClH:24]>>[ClH:24].[CH3:14][C:10]1[S:9][C:8]2=[N:7][C:6]([CH2:5][C:4]([OH:15])=[O:3])=[CH:13][N:12]2[CH:11]=1
Reactant: CCOC(=O)Cc1cn2cc(C)sc2n1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1cn2cc(CC(=O)O)nc2s1
Temperature: 25 °C
Yield: 93 %

Procedure:
Ethyl(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)acetate (151.3 g, 0.67 mol) was dissolved in 10% aqueous HCl (435 mL) and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and was concentrated in vacuo to give a yellow oil. Ethanol (100 mL) and diethylether (200 mL) were added and the resulting white precipitate was collected by filtration and dried in a vacuum oven overnight to give 144.3 g (93%) of final product, (2-methylimidazo[2,1-b][1,3]thiazol-6-yl)acetic acid hydrochloride). MS (ES+) 197.1 (M+H)+. 1H NMR (CD3OD) δ 2.48 (s, 3H), 3.88 (s, 2H), 7.81 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C1(C)C=CC=CC=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>>[CH3:34][O:33][C:31](=[O:32])[CH2:30][O:1][C:2]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 3-hydroxy-3-phenylpyrrolidine-1-carboxylate (480 mg, 0.0018 mol) in toluene (20 mL, 0.2 mol) was added sodium hydride (80.2 mg, 0.00200 mol) and the solution was refluxed for 1 hour. Methyl bromoacetate (0.190 mL, 0.00200 mol) was then added and the mixture continued to be stirred under reflux overnight. The reaction mixture was allowed to cool to rt and the product was extracted with EtOAc. The combined organic layers were washed with water, dried with MgSO4, and concentrated in-vacuo. LC/MS: m/z 336.1 (M+H)+.