Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[Li]CCCC.CON(C)[C:26]([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[N:31]2)=[O:27]>C1COCC1>[F:1][C:2]1[C:7]([C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[N:31]3)=[O:27])=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CON(C)C(=O)c1ccc2nccnc2c1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3nccnc3c2)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
To a solution of tert-butyl (2,4,5-trifluorophenyl)carbamate (2.72 g, 11 mmol, 1.1 eq.) in THF (150 mL) cooled at −78° C. was added n-BuLi (9.17 mL, 22 mmol, 2.2 eq.) dropwise. The resulting mixture was stirred at −78° C. for 30 min, then a solution of N-methoxy-N-methylquinoxaline-6-carboxamide (2.17 g, 10 mmol, 1.0 eq.) in THF (50 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, then quenched by the addition of NH4Cl solution. The mixture was extracted with EA (100 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford tert-butyl (2,4,5-trifluoro-3-(quinoxaline-6-carbonyl)phenyl)carbamate as yellow foam (600 mg, 14.9%)
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)C.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[SH:4][CH2:5][CH:6]([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(CC)CSC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CC)CS
Temperature: 0 °C

Procedure:
To a solution of the thioester of Step 1 (5.00 g, 24.5 mmol) in MeOH (15 mL) at 0° C., under nitrogen, was added K2CO3 (9.67 g, 73.5 mmol). The resulting mixture was stirred at 0° C. for a half hour, and then AcOH (8.82 g, 147 mmol) and 25% aq NH4OAc were added. The title compound was extracted with EtOAc, dried over Na2SO4 and purified by distillation on a Kugelrohr apparatus (200° C., 760 mm Hg). Yield: 1.700 g, 45%. 1H NMR (CD3COCD3): δ 0.86 (3H, t), 1.25 (3H, t), 1.65 (2H, quintet), 1.78 (1H, t), 2.45 (1H, quintet), 2.68 (2H, m), 4.15 (2H, q).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[CH:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:38]3[CH2:39][CH2:40][N:35]([CH:33]=[O:34])[CH2:36][CH2:37]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: O=CN1CCNCC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCN(C=O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 1-formylpiperazine. A yellow solid 99 was obtained (0.0159 g, 34%). 1H-NMR (CDCl3, 400 MHz) δ 3.62–3.65 (m, 2H), 3.68–3.72 (m, 2H), 3.75–3.78 (m, 2H), 3.83 (s, 3H), 3.86–3.89 (m, 2H), 6.95 (s, 1H), 7.02 (m, 3H), 7.08 (d, J=8.4 Hz, 1H), 7.46–7.52 (m, 3H), 7.86 (d, J=1.5 Hz, 1H), 8.16 (s, 1H), 8.30 (d, J=6.2 Hz, 1H); MS (APCI) m/z 474 (M+H)+.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[C:5]([F:11])[CH:4]=1.[OH2:13]>CCO.[N+]([O-])([O-])=O.[Ag+]>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[O:13])=[CH:4][C:5]=1[F:11])#[N:10]
Reactant: N#Cc1ccc(C(Br)Br)cc1F
Reactant: O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: N#Cc1ccc(C=O)cc1F
Reaction time: 18 h

Procedure:
To a solution of α,α-dibromo-4-cyano-3-fluorotoluene, as described above in Step A, (5.60 g, 19.1 mmol) in EtOH (255 mL) and water (45 mL) was added AgNO3. The mixture was heated to reflux for 3 hours, then stood at ambient temperature for 18 hours, then the solid was removed by filtration and the filtrate was concentrated under reduced pressure to a volume of approximately 20 mL. Water (30 mL) was added, and the mixture was concentrated to dryness in vacuo. The residue was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dried for several days at ca. 0.5 mm Hg to yield the desired aldehyde as a pale solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccccc3C(F)(F)F)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and 2-(trifluoromethyl)phenylboronic acid (190 mg, 1.0 mmol) to afford after chromatographic purification the title compound (175 mg, 79%). 1H NMR (CDCl3, 300 MHz) δ7.69 (d, 1H, J=7.7 Hz), 7.50 (dd, 1H, J=7.3, 7.7 Hz), 7.40 (dd, 1H, J=7.7, 7.3 Hz), 7.31 (d, 1H, J=7.3 Hz), 6.89 (s, 1H), 6.85 (s, 1H), 3.82-4.30 (m, 2H), 3.66-3.71 (m, 1H), 2.88-3.50 (m, 7H), 1.80-1.90 (m, 2H), 1.47 (s, 9H) ppm. MS-ApCI: 445 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26]([NH:29][CH2:30][CH2:31][CH3:32])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.O.C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26]([NH:29][CH2:30][CH2:31][CH3:32])(=[O:27])=[O:28])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCCNS(=O)(=O)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: CCCNS(=O)(=O)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Reaction time: 0.5 h

Procedure:
3-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)-N-propylpropane-1-sulfonamide (260 mg, 0.547 mmol) was dissolved in methanol (5 mL) and water (0.2 mL). Sodiumborohydride (41.4 mg, 1.095 mmol) was added in small portions at room temperature and the reaction mixture was stirred over night. 5N Hydrochloric acid in isopropanol was added until the reaction mixture became acidic. Stirring was continued for 30 min at room temperature. The reaction mixture was concentrated in vacuo. The crude product was dissolved in dichloromethane. Aqueous saturated NaHCO3 solution (10 mL) and water (10 mL) were added and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, first dichloromethane, then dichloromethane:methanol=80:1). The purified product was treated with 2N hydrochloric acid in diethylether. The diethylether was removed by destillation. Yield: 120 mg (0.234 mmol, 42.7%, colorless foam).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:34])[CH2:37][CH2:36]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)C5(O)CC5)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[CH2:19]([O:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]C.[CH2:48](OC(=O)C)C>>[C:44]1([CH3:47])[CH:43]=[CH:42][C:41]([S:38]([O-:40])(=[O:37])=[O:39])=[CH:46][CH:45]=1.[CH2:18]([N+:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=1)([CH3:48])[CH3:1])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(C)=O
Reactant: CN(C)CCCNC(=O)c1ccc(N(C)C)cc1
Product: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCNC(=O)c1ccc(N(C)C)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(3-dimethylaminopropyl)-p-dimethylaminobenzamide (77 g, 0.31 mole) from Example 1 and 131.5 g of stearyl-p-toluenesulfonate (0.31 mole) was heated to 110° C. under a blanket of nitrogen with continuous stirring for 2 hours. The resulting melt was dissolved in 800 ml of hot ethylacetate and then crystallized by cooling to ambient temperature. The crystals were recovered by filtration, dried in air and then under vacuum at 50°-60° C. The resulting whitish crystals of stearyl-[3-(p-dimethyl-aminobenzamido)propyl]dimethyl ammonium p-toluenesulfonate were found to have a melting point of 122°-125° C. and the yield 191.8 g, was 92% of theoretical. The structure and purity of the product were confirmed by elemental analysis, NMR, FTIR and UV spectra.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(=O)=O.CO.C(OP([CH2:22]/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])(OCC)=O)C.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1>C1COCC1.C(O)(=O)C>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH:30]=[CH:22][CH:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:32]=1
Reactant: O=Cc1cccnc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C=CC=Cc1cccnc1
Yield: 89098.4 %

Procedure:
A solution of LDA (16.5 ml of 2M solution, 3.5 g, 0.03 mol) in THF (100 ml) was cooled to −70° C. or below (dry ice-methanol bath) under a nitrogen flow and treated dropwise with ethyl 4-diethylphosphonocrotonate (8.6 g, 0.037 mmol) while stirring. The mixture was further stirred for 15 minutes, treated dropwise with nicotinaldehyde (3.2 g, 0.030 mol), and then stirred at 0° C. for 1.5 hours. Next, the mixture was treated with acetic acid and evaporated. To the residue was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was treated according to conventional techniques. Evaporation of solvent yielded ethyl 5-(pyridin-3-yl)penta-2,4-dienoate as an oil (6.7 g).
Reaction SMILES: N1[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH:4]=[N:3][CH:2]=1.[N+:12]([CH:15]=[C:16](SC)SC)([O-:14])=[O:13].[CH3:21]S>C(O)C>[N:3]1[CH:4]=[C:5]([CH2:7][N:8]2[CH2:9][CH2:10][NH:11][C:16]2=[CH:15][N+:12]([O-:14])=[O:13])[CH:6]=[CH:21][CH:2]=1
Reactant: NCCNCc1cncnc1
Reactant: CS
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: O=[N+]([O-])C=C1NCCN1Cc1cccnc1
Temperature: 25 °C

Procedure:
A mixture of N-(5-pyrimidinylmethyl)ethylenediamine (15.2 g), 1-nitro-2,2-bis(methylthio)ethylene (14.9 g) and ethanol (100 g) was refluxed with stirring until the generation of methylmercaptan ceased (for about 3 hours). The reaction mixture was cooled to room temperature, and the resultant crystals were collected by filtration. The crystals were washed with ethanol, and dried to give 1-(5-pyridylmethyl)-2-(nitromethylene)imidazolidine (12.7 g) as pale yellow crystals. This product decomposes at 236° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Cl-].[Na+].[OH2:15].[OH2:16]>CN(C=O)C>[O:15]=[C:1]1[NH:5][CH2:4][C@H:3]([CH2:2][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[O:16]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC[C@H](CN2C(=O)c3ccccc3C2=O)O1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of Example IA (22.16 g) in DMF (163 mL) at room temperature was treated with potassium phthalimide (16.7 g), heated to 80° C., stirred for 5 hours, poured into 1:1 brine/water (200 mL), and extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was treated with ethyl acetate (200 mL), cooled to 5° C., and filtered. The mother liquor was concentrated, treated with ethyl acetate (100 mL), cooled to 5° C., filtered, and combined with the first crop to provide the desired product. MS (ESI(+)) m/e 247 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.88 (m, 2H), 7.75 (m, 2H), 4.98 (m, 1H), 4.10 (dd, 1H), 3.90 (dd, 1H), 3.73 (t, 1H), 3.49 (dd, 1H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[F:20][C:21]1[C:22](=[O:28])[NH:23][C:24](=[O:27])[NH:25][CH:26]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:25]2[CH:26]=[C:21]([F:20])[C:22](=[O:28])[NH:23][C:24]2=[O:27])=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: Cl
Product: O=c1[nH]c(=O)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)cc1F

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 5-fluoropyrimidine-2,4(1H,3H)-dione. M/e+ 371 for C18H13ClFN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J=6.9 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.36 (m, 1H), 6.96 (m, 1H), 6.69 (d, J=5.5 Hz, 1H), 5.45 (s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[NH:12][CH2:13][CH2:14][O:15][Si](C)(C)C.[H-].[Na+].[CH2:29]([N:31]([CH2:45][CH3:46])[C:32](=[O:44])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH3:30].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:40]([C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:32]([N:31]([CH2:45][CH3:46])[CH2:29][CH3:30])=[O:44])=[CH:39][CH:38]=1)(=[O:42])=[O:41])[C:6](=[O:11])[C:5]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[NH:12][CH2:13][CH2:14][OH:15]
Reactant: C[Si](C)(C)OCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCO)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Reaction time: 0.42 h
Yield: 32.2 %

Procedure:
A solution of 1.084 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[[2-(trimethylsilyloxy)ethyl]-amino]indol-2-one in 20 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.111 g of sodium hydride as a 60% dispersion in oil is added. After stirring for 25 minutes, 0.78 g of 4-(N',N'-diethylureido)-benzenesulfonyl chloride is added and the reaction mixture is stirred for 3 hours at RT. It is poured into water and extracted with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (70/30; v/v) as the eluent to give 0.505 g of the expected product after crystallization and then recrystallization from a DCM/iso ether mixture. M.p.=192°-193° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10](SC)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:14]1(C)C=CC(S(OC)(=O)=O)=CC=1.CC#N.[CH2:29]([N:36]1[C:40](=[O:41])[CH2:39][S:38][C:37]1=[N:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[NH:51][CH2:52][CH3:53])[C:46]#[N:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(OC)C=CC=CC=1>[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:10]2[N:9]([CH3:14])[C:8]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[S:11]2)[S:38][C:37]1=[N:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][C:50]=1[NH:51][CH2:52][CH3:53])[C:46]#[N:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cccc2sc(SC)nc12
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Solvent: COc1ccccc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cccc(OC)c3N2C)C(=O)N1Cc1ccccc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 68.6 %

Procedure:
To a suspension of the 4-methoxy2-methylthiobenzothiazole (0.60 g, 2.8 mmol) in anhydrous anisole (8 mL) was added methyl p-toluenesulfonate (1.4 mL, 9.0 mmol) and the suspension was heated at 130° C. for 3.5 h. After cooling to 20° C., MeCN (5 mL), 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile (119 mg, 0.34 mmol) and TEA (2.0 mL, 14 mmol) were added. The suspension was stirred for 5 h at 80° C. After cooling to ambient temperature, yellow solids were collected by filtration, washed with MeCN and dried under high vacuum to afford the title compound (123 mg, 69%). 1H-NMR (CDCl3): δ 7.45-7.11 (9H, m), 6.88-6.85 (1H, m), 6.48 (1H, d), 5.17 (2H, s), 4.08 (3H, s), 3.92 (3H, s), 3.02-2.97 (2H, m), 1.02 (3H, t); MS(ESI): 528 (MH+).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH2:36][C:37]([O-])=[O:38])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1)(=O)C.[CH2:40]([CH2:42][NH2:43])[OH:41]>C(Cl)Cl.CO.CCOCC>[OH:41][CH2:40][CH2:42][NH:43][C:37](=[O:38])[CH2:36][C:29]1[C:28]2[C:33](=[CH:34][C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[CH:26][CH:27]=2)[O:32][C:31](=[O:35])[CH:30]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccc3c(CC(=O)[O-])cc(=O)oc3c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: NCCO
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: O=C(Cc1cc(=O)oc2cc(O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)ccc12)NCCO
Temperature: 25 °C
Reaction time: 60 h
Yield: 37.1 %

Procedure:
43 g (0.076 moles) of 7-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)coumarin-4-acetate (i.e. compound 1 prepared as described in Scheme 1) was dissolved in 430 ml of methylene chloride in a 1 liter RB flask. 43 ml (0.712 moles) of ethanolamine was dissolved in 43 ml of methanol and added to the above solution. The solution was stirred at room temperature for 60 hrs and the resulting solid residue was filtered and washed with 50 ml of methylene chloride. The solid was suspended in 250 ml of methanol and stored in the freezer for 12 hrs. The solid was filtered again and suspended in 700 ml of methanol and refluxed for 30 min. The cloudy suspension was cooled to room temperature, then further cooled in an ice bath and filtered. The wet solid thus obtained was suspended in 200 ml of ether and stirred for 30 min., then filtered and vacuum dried at room temperature to give 12 g of an off-white solid. The yield was 37%. The structure was confirmed by 1H NMR and MS (as in Example 1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[CH3:11][O:12][NH2:13].C(N(CC)CC)C>CO>[CH3:11][O:12][N:13]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1
Reactant: O=Cc1cccc(I)c1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=Cc1cccc(I)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-iodo benzaldehyde (1 g, 4.3 mmol) in methanol (25 ml), O-methyl hydroxyl amine hydrochloride (0.54 g, 6.5 mmol) was added followed by triethyl amine (0.9 ml, 6.5 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. Reaction mixture was concentrated under vacuum; residual mass was diluted with water (50 ml) and extracted with ethyl acetate (3×30 ml). Ethyl acetate layer was washed with water (2×30 ml) followed by brine solution, dried over anhydrous sodium sulfate and evaporated to obtain 3-Iodo-benzaldehyde O-methyl-oxime (crude), which was dissolved in glacial acetic acid (10 ml), followed by addition of sodium cyanoborohydride (0.54 g, 8.6 mmol) portion wise at 15° C. The mixture was stirred for 12 hrs at room temperature. Excess acetic acid was removed by distillation. Resulting reaction mass was basified with 10% aq. NaOH solution at 10-15° C. Aqueous layer was extracted with EtOAc (3×30 ml). The combined organic layer was washed with brine (2×30 ml) and dried over sodium sulfate. Organic layer was concentrated under vacuum to give crude mass, which was purified by chromatography to afford 1 g (89% of theory) of N-(3-Iodo-benzyl)-O-methyl-hydroxylamine
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:36])[C@H:6]([O:14][C:15]1[C:20]([Br:21])=[CH:19][C:18]([C:22]2[C:30]3[C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[S:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:17][C:16]=1[Br:35])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1.CO.O>[Br:35][C:16]1[CH:17]=[C:18]([C:22]2[C:30]3[C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[S:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH:19]=[C:20]([Br:21])[C:15]=1[O:14][C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:36])=[O:4]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Reaction time: 1.5 h
Yield: 80 %

Procedure:
1.0 N Aqueous potassium hydroxide (0.81 mL, 0.81 mmol) was added to a stirred solution of (R)-2-[2,6-dibromo-4-(dibenzothiophen-1-yl)-phenoxy]-3-phenyl-propionic acid methyl ester (0.242 g, 0.406 mmol) in THF (4 mL) and methanol (2.5 mL). After 1.5 h at ambient temperature, the reaction mixture was diluted with water, acidified with 10% aqueous HCl and filtered. The solid was washed with water and triturated with pet. ether. The solid was dried in vacuo at 70° C. to provide the title compound as a white solid (0.190, 80%): [a]D25=+19.73 (10.14 mg/mL CHCl3); NMR (CDCl3): δ 7.89 (dd, J=8, 1 Hz, 1H), 7.83 (ddd., J=8, 1, 1 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.62 (d, J=2 Hz, 1H), 7.45 (dd, J=8, 6 Hz, 2H), 7.41-7.154 (m, 8H), 5.33 (t, J=8 Hz, 1H), 3.54 (dd, J=5, 2 Hz, 1H), 3.52 (dd, J=8, 4 Hz, 1H); MS (EI): [M+], 2 bromine isotope pattern, 580 (20%), 582 (40%) 584 (25%); Anal. Calc. for C27H18Br2O3S: C, 55.69, H, 3.11, N, 0.00. Found: C, 55.23, H, 2.97, N, 0.07; Analytical HPLC :98.8%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH2:17][O:18][C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1
Reactant: OCc1cc(F)c(Oc2ccc(F)nc2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)c(Oc4ccc(F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((6-fluoropyridin-3-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.