Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[C:14]([NH:28][C:29]2[S:30][CH:31]=[C:32]([CH3:34])[N:33]=2)=[N:15][CH:16]=[C:17]([S:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH3:21])[CH:18]=1.C([Cl:40])(=O)OCC.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45].[OH-].[Na+].[ClH:49]>C(Cl)Cl.CCOCC>[ClH:2].[ClH:40].[ClH:49].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:45][CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])=[O:9])=[CH:5][C:4]=1[O:12][C:13]1[C:14]([NH:28][C:29]2[S:30][CH:31]=[C:32]([CH3:34])[N:33]=2)=[N:15][CH:16]=[C:17]([S:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH3:21])[CH:18]=1
Reactant: Cc1csc(Nc2ncc(SC(C)c3ccccn3)cc2Oc2cc(C(=O)[O-])ccc2Cl)n1
Reactant: CN(C)CCN
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1csc(Nc2ncc(SC(C)c3ccccn3)cc2Oc2cc(C(=O)NCCN(C)C)ccc2Cl)n1
Reaction time: 3 h
Yield: 14.8 %

Procedure:
4-chloro-3-(2-(4-methylthiazol-2-ylamino)-5-(1-(pyridin-2-yl)ethylthio)pyridin-3-yloxy)benzoic acid (prepared according to Example 73; 0.131 g, 0.263 mmol), TEA (d. 0.726) (0.0732 mL, 0.525 mmol), ethyl carbonochloridate (0.057 g, 0.525 mmol), and N1,N1-dimethylethane-1,2-diamine (0.0231 g, 0.263 mmol) were reacted according the method of Example 72. 1N NaOH was added and the reaction mixture was stirred for 3 hours. The reaction mixture was extracted with CH2Cl2. The combined extracts were concentrated and purified by silica gel chromatography (4% MeOH in CH2Cl2, using 2% 7N ammonia in MeOH) and then purified by reverse phase chromatography to give the compound as the free base. The free base was dissolved in CH2Cl2 and HCl in ether was added. The mixture was concentrated to give 4-chloro-N-(2-(dimethylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)-5-(1-(pyridin-2-yl)ethylthio)pyridin-3-yloxy)benzamide trihydrochloride (0.025 g, 14.8% yield). 1H NMR (d6-DMSO) δ 9.73 (s, 1H), 8.91 (m, 1H), 8.42 (m, 1H), 8.01 (d, 1H), 7.78 (m, 3H), 7.51 (s, 1H), 7.29 (m, 2H), 6.83 (s, 1H), 6.66 (m, 1H), 4.48 (q, 1H), 3.60 (m, 2H), 3.24 (m, 2H), 2.81 (d, 6H), 2.24 (s, 3H), 1.54 (d, 3H); Mass spectrum (esi) m/z=569.2 (100) (M+H-3HCl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH:14]=[CH2:15])[C:10](Cl)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:16]1([C:22](=[S:26])[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.I[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C(#N)C>[C:24]([C:23]1[C:10]([CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH:14]=[CH2:15])=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[S:26][C:22]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:25]
Reactant: C=CCC(C(=O)Cl)c1ccc(Cl)c(Cl)c1
Reactant: N#CCC(=S)N1CCOCC1
Reactant: CCOC(=O)CI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(c1ccc(Cl)c(Cl)c1)c1c(C(=O)OCC)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a solution of 2-(3,4-dichlorophenyl)pent-4-enoyl chloride (2.51 g, 9.53 mmol) and 3-morpholin-4-yl-3-thioxopropanenitrile (1.62 g, 9.53 mmol) in acetonitrile (40.0 mL) in a 100 mL round bottom flask was added N,N-diisopropylethylamine (1.82 mL, 10.5 mmol), and the resulting deep orange/red solution was stirred at room temp for 1 hr. To the resulting mixture was added N,N-diisopropylethylamine (4.15 mL, 23.8 mmol) and then ethyl iodoacetate (1.24 mL, 10.5 mmol). The flask was fitted with a reflux condenser and the reaction was heated to reflux over 48 hrs. The mixture was concentrated and distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined org layer was washed with brine, dried, and concentrated to provide a dark syrup. Purification on a silica gel column (gradient elution 3-30% EtOAc/hexanes) provided ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate (704 mg, 15.9% yield). LCMS: (AA) ES+ 465, 467, 469; 1H NMR (400 MHz, CDCl3) δ 7.49-7.42 (m, 1H), 7.41-7.33 (m, 1H), 7.31-7.27 (m, 1H), 5.82-5.66 (ddt, J=17.2, 10.1, 6.8 Hz, 1H), 5.62-5.50 (t, J=8.2 Hz, 1H), 5.16-5.08 (dd, J=17.1, 1.6 Hz, 1H), 5.04-4.94 (dd, J=10.2, 1.5 Hz, 1H), 4.35-4.27 (q, J=7.1 Hz, 2H), 3.86-3.78 (m, 4H), 3.59-3.48 (m, 4H), 3.10-2.99 (h, J=6.9 Hz, 2H), 1.40-1.31 (m, 3H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CO>[Br:27][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CCO)c3c2)c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CCBr)c3c2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 3-[3-(2-hydroxyethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.690 g, 0.00185 mol) in methylene chloride is added carbon tetrabromide (0.655 g, 0.00197 mol) followed by triphenylphosphine (0.517 g, 0.00197 mol). The mixture is stirred three hours at ambient temperature and treated with additional carbon tetrabromide (0.328 g, 0.000988 mol) and triphenyl phosphine (0.259 g, 0.000987 mol). The resultant mixture is stirred 85 minutes, diluted with methanol, and concentrated in vacuo. The resultant solid is taken up in methylene chloride, washed with saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a yellow solid. The yellow solid is chromatographed on silica gel with methylene chloride to give the title product as an off-white solid (0.530 g, 66.0%) which is identified by NMR and elemental analyses.
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=O)[CH:23]=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH:30]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:40][O:39][C:37](=[O:38])[CH2:36][N:30]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:27](=[O:29])[CH2:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:21]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(CC(=O)O)c1
Reactant: COC(=O)CNCC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cccc(CC(=O)N(CC(=O)OC)CC(=O)OC)c1
Reaction time: 17 h
Yield: 64.9 %

Procedure:
A solution of 1.9 g (4.78 mmol) of 3-(octadecyloxy)phenylacetic acid in 40 ml of thionyl chloride was refluxed for 1.5 hours. The excess thionyl chloride was removed at reduced pressure and the resultant acid chloride was dissolved in 40 ml of anhydrous methylene chloride. This solution was added dropwise to an ice bath cooled mixture of 1.0 g (6 mmol) of dimethyl iminodiacetate and 1.4 ml (10 mmol) of triethylamine in 25 ml of methylene chloride. The reaction mixture was kept at room temperature for 17 hours and then was washed with 1N HCl, dried and concentrated to a solid. Purification by chromatography on 150 g of silica gel using 40% ethyl acetate-hexane gave 1.7 g (65% yield, mp 52°-55°) of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)phenylacetyl]glycine methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[S:12]1[CH2:16][C:15](=[O:17])[NH:14][C:13]1=[O:18].[C:19]1([CH3:31])[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(O)C>[CH3:11][O:10][C:4]1[N:3]=[C:2]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:31])=[CH:20][CH:21]=3)[CH2:26][CH2:27]2)[N:7]=[C:6](/[CH:8]=[C:16]2/[C:15](=[O:17])[NH:14][C:13](=[O:18])[S:12]/2)[CH:5]=1
Reactant: COc1cc(C=O)nc(Cl)n1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Product: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCN(c3ccc(C)cc3)CC2)n1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Crude 2-chloro-6-methoxypyrimidine-4-carbaldehyde (sad105-058, 76 mg) was dissolved in ethanol (2 mL) and was added to a 10 mL vial containing the thiazolidine-dione (42.8 mg, 0.37 mmol., 1 equiv.) and the 1-(p-tolyl)piperazine (70.8 mg, 0.40 mmol, 1.1 equiv.). The mixture was shaken for 45 h at 80° C. and for 15 h at 90° C. producing a precipitate. LC-MS of the solution showed some product at (M+1=412) and some intermediate at (M+1=430). The desired product crashed out of the solution and the LC-MS of the solution does not reflect well the conversion of the reaction. The yellow solid was filtered using a Pasteur pipette through a pad of glass wool and the solid was rinsed with EtOH (4×0.5 mL). The ethanol filtrate contains some desired product. The solid was re-dissolved in CH2Cl2 and the insoluble solid was filtered off. The filtrate was concentrated under reduced pressure to provide 20 mg of the desired product (Z)-5-((6-methoxy-2-(4-(p-tolyl)piperazin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (97.3% pure). The insoluble solid was partitioned between saturated NaHCO3 (3 mL) and CH2Cl2 (2×5 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide an additional 13.4 mg of the desired product (total 33.4 mg, 150 mg theoretical, 22%). LC-MS m/z: 412 (M+1).
Reaction SMILES: CO.[ClH:3].Cl.Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:11][NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC)=[NH:17])=[NH:14].[CH3:36][C:37]([CH3:39])=O>>[ClH:3].[CH3:36][C:37]1([CH3:39])[N:14]=[C:13]([NH:12][CH2:11][C:10]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:8]([O:7][CH3:6])[CH:9]=2)[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:17]1
Reactant: CCCCCCCCCCCCNC(=N)NC(=N)NCc1ccc(OC)c(OC)c1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(OC)c(OC)c2)N1

Procedure:
75 ml of methanol, 120 ml of acetone and 0.2 ml of concentrated hydrochloric acid were added to 3.5 g (7.5 mmol) of N1-(3,4-dimethoxybenzyl)-N5-dodecyl-biguanide dihydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.2)), and dissolved in 70% aqueous acetonitrile. The solution was concentrated under reduced pressure to remove the solvent, and the residue was sufficiently dried under reduced pressure to obtain 2.2 g of a colorless resinous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[C:9]2/[CH:10]([N:15]3[CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:12][CH2:13][CH2:14]/2)[CH:5]=[CH:6][CH:7]=1.N1CCC1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[N:15]2[CH2:18][CH2:17][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(/C=C2\CCCCC2N2CCC2)c1
Agent: C1CNC1
Product: Oc1cccc(C=C2CCCCC2N2CCC2)c1
Reaction time: 8 h

Procedure:
A mixture of 1.1 g of (±)-(E)-N-[2[(3-methoxyphenyl)methylene]cyclohexyl]azetidine, prepared by analogy to the preparation of the 4-methoxy compound of Example 5, and 5 ml of 48% hydrogen bromide in water solution was stirred and heated at 95° C. for 2.75 hr. The resulting mixture was cooled and extracted with diethyl ether. The ether extract was dried with magnesium sulfate and evaporated to give 0.8 g of N-[2-[(3-hydroxyphenyl)methylene]cyclohexl]azetidine as an oil which deposited as crystals upon standing overnight. Filtration with diethyl ether gave 0.21 g of this 3-hydroxyphenyl compound as a pale yellow solid. The UV, IR, mass spectrum and NMR analysis indicated the named product was present. Gas chromatography (GC) analysis indicated that this product was a mixture containing about 92% of (±)-(E)-1-[2-[(3-hydroxyphenyl)methylene]cyclohexyl]azetidine, mp 160°-165° C. and 8% of the starting 1-[2-(3-methoxyphenyl)methylene]cyclohexyl]azetidine, mp 136°-137° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.[N:18]1([C:23](=N)[NH2:24])C=CC=N1.CCOCC>CN(C=O)C>[OH:7][C@H:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:23]([NH2:24])=[NH:18])[CH2:3]1
Reactant: N=C(N)n1cccn1
Reactant: N[C@H]1CC[C@H](O)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)N[C@H]1CC[C@H](O)C1
Reaction time: 0.17 h
Yield: 164.8 %

Procedure:
To a stirred solution of (1S,3S)-3-aminocyclopentanol (9.00 g, 89.0 mmol) (obtained from ASID pharmaceuticals) in DMF (45 mL) at RT under nitrogen was added DIPEA (31.0 mL, 178 mmol) followed by 1H-pyrazole-1-carboximidamide hydrochloride (14.7 g, 133 mmol). After stirring overnight Et2O (150 mL) was added and the reaction was stirred for 10 min. The Et2O was decanted and concentrated under high vacuum to afford 21 g (99%) of 1-((1S,3S)-3-hydroxycyclopentyl)guanidine (164) as a dark orange oil: MS m/z (APCI-pos) M+1=144.1
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-:7].[Na+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[CH2:17][C:18](=O)[CH:19]=[CH2:20]>CS(C)=O>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C@@H:17]1[CH2:2][C@H:18]1[C:19](=[O:7])[CH3:20]
Reactant: C=CC(=O)Cc1c(F)cccc1F
Reactant: C[S+](C)(C)=O
Reactant: [OH-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)[C@@H]1C[C@H]1c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a 500 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet and addition funnel was charged 2.47 g (11.2 mmoles) of trimethyl sulfoxonium iodide, 0.448 g (11.2 mmole) of powdered sodium hydroxide, and 50 mls DMSO. The mixture was stirred at room temperature for 0.5 hour, followed by the rapid addition of 2.04 g (11.2 mmole) 2,6-difluoro-phenyl-3-buten-2-one in 25 ml DMSO in one portion. The reaction was stirred for 15 minutes at ambient temperature, poured into 200 mls of ice water, and then extracted with 150 ml of ethyl ether. The ether extract was washed with 4×100 mls of water, dried over anhydrous MgSO4, filtered, and concentrated in vacuuo on a rotary evaporator to afford 1.3 g crude product as a yellow oil. This was combined with 1.6 g from a similar reaction and the total crude of 2.9 g was chromatographed on silica with CH2Cl2. Fractions (#5-9) were combined and concentrated in vacuuo on a rotary evaporator to afford 1.5 g (92% purity by GC) of trans-1-(2,6 difluorophenyl)-2-acetylcyclopropane as a free flowing pale yellow liquid, in 28.8% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].C[O-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22]Cl>C(O)C>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10]
Reactant: ClCOc1ccccc1Br
Reactant: O=CNc1ccccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=CNc1ccccc1OCOc1ccccc1Br
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
N-(2-Hydroxyphenyl)formamide (16.0 g, 130 mmol) was dissolved in 99.9% ethanol (65 ml). Sodium methoxide 7.0 g, 130 mmol) was suspended in 99.9% ethanol (70 ml) and added dropwise over 30 minutes. The resulting mixture was stirred for 30 minutes. 1-Bromo2-chloromethoxybenzene (26.1 g, 118 mmol, synthesis described in J. Heterocycl. Chem., 11, 1974, 331-337) was added dropwise over 15 minutes. The reaction mixture was stirred for 2.5 h at room temperature, heated at reflux temperature for 2 h, and stirred at room temperature overnight. The mixture was filtered and evaporated. The residue was dissolved in toluene (500 ml) and washed with a saturated sodium carbonate solution (2×200 ml). The organic phase was dried (MgSO4) and evaporated. The residue was suspended in ethanol (40 ml), filtered and washed with ethanol (3×10 ml). After drying, this afforded the product, N-(2-(2-bromophenoxymethoxy)phenyl)formamide (14.1 g, 37%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([O:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:23])=O>C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([O:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8]([Cl:23])=[O:9])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1c(I)c(OC(C)=O)c(I)c(C(=O)O)c1I
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(I)c(OC(C)=O)c(I)c(C(=O)Cl)c1I
Reaction time: 5 h
Yield: 88 %

Procedure:
To a solution of 3,5-diacetoxy-2,4,6-triiodobenzoic acid (9.5 g) in ethyl acetate (80 mL) at 55° C. was added thionyl chloride (5.5 mL) and stirred 5 h. The solution was evaporated and the dry residue crystallized from ethyl acetate to yield 8.6 g (88%) 3,5-diacetoxy-2,4,6-triiodobenzoic acid chloride.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37](Br)=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH2:60]CCC.IC>C1COCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:39]=[C:38]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[C:37]([CH3:60])=[C:36]3[C:32]=2[CH2:33][CH2:34][CH2:35]3)[O:11][C@@H:10]1[CH2:50][O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Br)CCC3)cc1
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2C)CCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the intermediate 17 (0.95 g, 1.13 mmol) in anhydrous THF (12.0 mL) were added dropwise n-BuLi (2.5M in hexane, 0.72 mL, 1.81 mmol) at −78° C. under nitrogen atmosphere, and the mixture was stirred for 0.5 h at the same temperature. Then a solution of iodomethane (0.13 mL, 2.03 mmol) in THF (1.0 mL) was added dropwise, and the mixture was slowly warmed up to 0° C. for 3 h. The reaction mixture was quenched with 1M HCl solution (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 20, which was used without further purification (0.88 g, 1.13 mmol, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]1[O:23][CH:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)N)cc1OC
Reactant: c1ccc(C2CO2)cc1
Solvent: c1ccccc1
Product: COc1ccc(CC(C)NCC(O)c2ccccc2)cc1OC
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 20 g. (0.102 mol) of 1-(3,4-dimethoxyphenyl)-2-aminopropane and 12.01 ml. (0.102 mol) of styrene oxide is heated and stirred at 100° C. under argon for 18 hours. The cooled reaction mixture is dissolved in a minimum amount of benzene and petroleum ether is then added to precipitate a solid which turned to a liquid upon standing. Fractional vacuum distillation yields N-[2-(3,4-dimethoxyphenyl)-1-methylethyl]-2-hydroxy-2-phenylethylamine, b.p. 205°-225° C./0.2 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13](O)(=[O:18])[CH2:14][C:15](O)=[O:16]>>[OH:18][C:13]1[C:6]2[C:7](=[C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]3=[CH:4][CH:5]=2)[O:12][C:15](=[O:16])[CH:14]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cccc2c(O)cccc12
Product: Cc1cccc2c1ccc1c(O)cc(=O)oc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
The mixture of 5-methyl-1-naphthol (6) (1.0 g, 6.33 mmol), malonic acid (658 mg, 6.33 mmol), and PPA (10 g) was heated at 75° C. for 3 h. After the reaction, ice-water was added to the black residue. The solid was filtered, dissolved in 10% Na2CO3 solution, and stirred overnight. The basic solution was filtered, and the filtrate was acidified with 2 N HCl solution until the pH was about 4. The precipitate was then filtered and purified by silica gel chromatography to yield 7 (620 mg, 43%) as a yellow solid. mp 223-225° C.; 1H NMR (DMSO-d6) δ 2.69 (s, 3H), 5.70 (s, 1H), 7.57-7.61 (m, 2H), 7.86 (d, J=9.0 Hz, 1H), 7.92 (d, J=9.0 Hz, 1H), 8.23 (d, J=7.5 Hz, 1H), 12.8 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH2:19]([NH:22][C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[N:27]([CH3:35])[C:26]=1[CH3:36])=[O:24])[CH2:20][CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:19]([NH:22][C:23]([CH:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][CH:32]=2)[N:27]([CH3:35])[CH:26]1[CH3:36])=[O:24])[CH2:20][CH3:21]
Reactant: CCCNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCNC(=O)C1c2ccc(Oc3ccnc4cc(C(=O)N5CCC(O)C5)sc34)cc2N(C)C1C

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbynyl]thieno[3,2,-b]pyridine 4a with 6-hydroxy-1,2-dimethyl-1H-indol-3-carboxylic acid propylamide 58b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.50 (1H, d, J=5.6 Hz), 7.96 (1H, d, J=17.3 Hz), 7.86 (1H, d, J=8.7 Hz), 7.40 (1H, s), 7.06 (1H, d, J=10.7 Hz), 6.72 (1H, d, J=5.6 Hz), 4.61–4.53 (1H, m), 4.15–4.00 (2H, m), 3.91–3.73 (3H, m), 3.73 (3H, s), 3.53–3.40 (2H, m), 2.67 (3H, s), 2.28–2.07 (2H, m), 1.78–1.69 (2H, m), 1,18–1.04 (3H, m). LCMS (ESI+) [M+H]1z Calc'd 493. found 493.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>C(C(C)=O)C>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])[CH:19]=[CH2:18]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.5 g of 2-hydroxyphenylsulfonamide, 5.5 g of potassium carbonate and 1.7 ml of allyl bromide in 100 ml of methyl ethyl ketone is stirred, under nitrogen, for 1 hour at reflux temperature. The reaction mixture is cooled to room temperature, filtered, and evaporated to dryness. Once recrystallisation from ethyl acetate yields 3.27 g of 2-allyloxyphenylsulfonamide with a melting point of 104°-105° C.
Reaction SMILES: C(O)C.[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=O)=[CH:7][CH:6]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>O>[Br:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](/[CH:15]=[N:18]/[OH:19])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Br)c2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O/N=C/c1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask, was placed ethanol (100 mL), water (40 mL), 4-bromonaphthalene-1-carbaldehyde (4.3 g, 18.29 mmol, 1.00 equiv), hydroxylamine hydrochloride (1.52 g, 21.87 mmol, 1.20 equiv), sodium acetate (2.25 g, 27.43 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The solids were collected by filtration and washed with enough water. The solid was dried in an oven under reduced pressure. This resulted in 4.5 g (98%) of (E)-N-[(4-bromonaphthalen-1-yl)methylidene]hydroxylamine as a white solid.