Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH3:16].[OH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[CH:24].O=O>N1C=CC=CC=1.CO.Cl[Cu]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[CH:8].[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:24]#[C:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][OH:17]
Reactant: CCCC#CCCO
Reactant: CCCCC#CCO
Agent: Cl[Cu]
Agent: C#CCCCCCO
Agent: O=O
Solvent: c1ccncc1
Solvent: CO
Product: OCCCCCC#CC#CCCCCCO

Procedure:
HO(CH2)5C≡CH was prepared by the KAPA-promoted isomerization of HOCH2C≡C(CH2)3CH3 (prepared according to Millar, J.G.; Oehlschlager, A. C. J. Org. Chem. 1984,49, 2332-2338) or HO(CH2)2C≡C(CH2)2CH3 (commercially available from GFS Chemicals; Powell, Ohio). Oxidative coupling of HO(CH2)5C≡CH was carried out in a glass reaction vessel by dissolving 6.95 grams of HO(CH2)5C≡CH in pyridine/methanol (2.0 milliliters/6.2 milliliters) and adding 307 grams of CuCl followed by stirring in the presence of oxygen until all the staring material was consumed. The reaction mixture was worked up with diethyl ether and 4N HCl, the combined organic layers were dried over MgSO4, filtered and concentrated. Recrystallization of the residue from 1/1 hexanes/tert-butyl methyl ether to yield 5.35 grams of HO(CH2)5C≡C—C≡C(CH2)5OH as a pink solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[S:28])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: S=C=Nc1cccc(Cl)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc(Cl)c1
Yield: 77.1 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.218 g, 0.90 mmol) and 3-chlorophenyl isothiocyanate (0.12 mL, 0.92 mmol) to give the product (0.286 g); m.p. 165-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:16][S:17]Cl.CSSC.ClCl>C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:17][CH3:16])=[C:9]([OH:13])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CSCl
Reactant: Oc1cccc(Oc2ccc(Br)cc2)c1
Agent: ClCl
Solvent: ClCCl
Solvent: CSSC
Product: CSc1ccc(Oc2ccc(Br)cc2)cc1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(4-Bromophenoxy)phenol (0.1 mole) and methylene chloride (200 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. The mixture is stirred until dissolved and cooled to about -20° C. A solution of methyl sulfenyl chloride freshly prepared by reacting dimethyl disulfide (0.15 mole) with chlorine (0.18 mole) in methylene chloride (100 ml) is then added dropwise to the reaction vessel over a period of about 40 minutes. After the addition is completed stirring is continued for 30 minutes with cooling and 30 minutes at room temperature. After this time the reaction mixture is washed with water (200 ml), with 5% aqueous sodium bicarbonate (200 ml) and again with water (200 ml). The washed solution is then dried by passing it through a phase separator. The dried solution is stripped of solvent under reduced pressure and the residue chromatographed using a clay column and hexane/ethyl acetate as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product 5-(4-bromophenoxy) 2-(methylthio)phenol as the residue.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:19](=[O:20])[O:21][CH3:22]
Reactant: COC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
A solution of 2-bromo-5-nitroaniline (500 mg, 2.30 mmol) in THF (40 mL) was treated with pyridine (0.19 mL, 2.3 mmol) and methyl chloroformate (0.27 mL, 3.5 mmol) at room temperature. After 4 hours, additional methyl chloroformate (0.27 mL, 3.5 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 3 hours. The reaction mixture was concentrated to dryness and then taken up in EtOAc (30 mL) and washed with 1 N HCl (3×25 mL), dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 0% ethyl acetate/hexanes to 30% ethyl acetate/hexanes, 40 g column, 30 min. gradient) to afford Intermediate 60A (390 mg, 61.5%). HPLC: Rt=3.215 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=274.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.39 (1H, s), 8.44 (1H, d, J=2.52 Hz), 7.92-7.96 (1H, m), 7.88-7.92 (1H, m), 3.71 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: COc1ccc(-c2csc(N)n2)cc1
Product: COc1ccc(-c2csc(NC(=O)c3cc(Cl)ccc3O)n2)cc1
Yield: 16.4 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(4-methoxyphenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C@@H:25](Cl)[CH3:26]>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C@@H:25]([C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])[CH3:26])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: C[C@H](Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(Br)cc21
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of 6-bromoindazole (3.4 g, 17.0 mmol) and Cs2CO3 (15.8 g, 48.5 mmol) in 1-methyl-2-pyrrolidinone (NMP, 11 mL) at 85° C. was added crude (S)-2,4-dichloro-1-(1-chloroethyl)benzene (3.2 g, 15.4 mmol) dropwise. The reaction mixture was heated for 10 min, and cooled to room temperature. The mixture was diluted with ethyl acetate (20 mL), washed with deionized water and brine, dried (Na2SO4), and concentrated in vacuo. The resulting crude material was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-indazole (2.2 g, 6.0 mmol, 39%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:5]([F:18])[CH:4]=1)#[N:2].[NH2:19][OH:20]>CO>[NH2:2][C:1](=[N:19][OH:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[C:5]([F:18])[CH:4]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)CNc1ccc(C#N)cc1F
Solvent: CO
Product: CC(C)(C)OC(=O)CNc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl N-(4-cyano-2-fluorophenyl)glycinate obtained in Step 1 (290 mg; 1.16 mmol; 1 eq.) was dissolved in MeOH (1 mL) and hydroxylamine (0.34 mL; 5.79 mmol; 5 eq.) was added. The mixture was stirred at RT overnight. Solvents were evaporated off, affording the title product as an off-white solid, which was used further without purification (302 mg, 92%). HPLC (Method A) Rt 2.23 min (Purity: 74.2%).
Reaction SMILES: N[C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:3]=1[C:4]([N:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7])=O.N([O-])=[O:22].[Na+]>C(O)C.Cl.O1CCCC1.O>[N+:18]([C:16]1[CH:17]=[C:4]2[C:3]([C:2](=[O:22])[NH:7][N:6]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:14][CH:15]=1)([O-:20])=[O:19]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)N(N)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=c1[nH]n(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Temperature: 72 °C
Reaction time: 0.67 h

Procedure:
Into a 1000-mL 4-necked round-bottom flask, was placed a solution of 2-amino-4-nitro-N-phenylbenzohydrazide (23 g, 84.56 mmol, 1.00 equiv) in ethanol (250 mL), 1N hydrogen chloride (250 mL), tetrahydrofuran (100 mL). To the resulting mixture was then added a solution of NaNO2 (17.5 g, 253.62 mmol, 3.00 equiv) in water (45 mL) dropwise with stirring at 72° C. in 40 min. The resulting solution was heated to reflux for 1 hr. The resulting mixture was then cooled to 25° C. The solids were collected by filtration to yield 6-nitro-1-phenyl-1,2-dihydroindazol-3-one as a brown solid. MS: 256 (MH+).
Reaction SMILES: [O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12]Cl)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].C(N(CC)CC)C.O>CS(C)=O>[O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12][NH:27][CH2:26][CH2:25][CH2:24][C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=4)[NH:20][CH:19]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Reactant: ClCCOc1cccc2c1OCC2
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4c3OCC4)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 77.2 %

Procedure:
A solution of 2-(2,3-dihydrobenzofuran-7-yloxy)ethylchloride (0.38 g, 1.9 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.93 g, 4.8 mmol), triethylamine (0.48 g, 4.8 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 90° C. for 12 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.52 g (77%) of product as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:11][CH2:10][C:9]([OH:13])=[O:12])[CH:2]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: C=CC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)CC=Cc1cccnc1
Product: O=C(O)CC=Cc1cccnc1

Procedure:
The target compound 4-pyridin-3-yl-but-3-enoic acid (Compound 2035) was prepared by two steps starting from the commercial available 3-Pyridinecarboxaldehyde. Reaction of this aldehyde with ethyl acrylate and triphenylphosphine in a sealed tube for 4 hr at 140° C. gave ethyl 4-pyridin-3-yl-3-butenoate in a 55% yield. Kirby, Anthony J.; Walwyn, David R. Effective molarities for intramolecular hydride transfer. Reduction by 1,4-dihydropyridines of the neighboring α-ketoester group. Gazzetta Chimica Italiana (1987), 117(11), 667-80. This reaction is a self-priming Wittig reaction and the yield was not optimized. Gilbert Stork, R. A. Kretchmer, R. H. Schlessinger. The Stereospecific Total Synthesis of dl-Lycopodine. J. Am. Chem. Soc. (1968), 90, 1647. Hydrolysis of the ester using the routine condition and the subsequent purification with preparative HPLC afforded the target compound 2035 with almost quantitative yield.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.Cl[C:18]1[O:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][N:22]=1>C1COCC1>[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:18]3[O:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][N:22]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Clc1ncc(-c2ccccc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccccc4)o3)cc2)CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Sodium hydride (60% in mineral oil, 0.51 g, 0.013 mol) was suspended in dry THF (8 mL) under an atmosphere of nitrogen. The suspension was treated with 4-(4-methylpiperazin-1-yl)-aniline (0.23 g9 1.0 mmol) and 2-chloro-5-phenyl-1,3-oxazole (0.19 g, 1.0 mmol) and heated to 60° C. and stirred for 18 h. The reaction was cooled to RT and quenched with methanol (10 drops). Silica gel was added and the solvent was evaporated under reduced pressure to dryness and purified by silica gel chromatography using 10% methanol in dichloromethane to elute the title compound (0.10 g, 31%). 1H NMR (400 MHz, d6-DMSO): δ 2.21 (s, 3H), 2.45 (m, 4H), 3.04 (m, 4H), 6.91 (d, J=8.97, 2H), 7.24 (t, J=7.32, 1H), 7.41 (m, 3H), 7.47 (d, J=8.97, 2H), 7.55 (d, J=7.51, 2H), 9.99 (s, 1H). MS (ES+, m/z)=335 (m+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[F:10][C:11]([F:18])([F:17])[C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([N:14]2[CH:13]=[C:12]([C:11]([F:18])([F:17])[F:10])[CH:16]=[N:15]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Cc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1-n1cc(C(F)(F)F)cn1
Temperature: 107.5 °C
Yield: 30 %

Procedure:
A flask was charged with 5-bromo-2-chloro-3-methylpyridine (250 mg, 1.21 mmol), 4-(trifluoromethyl)-1H-pyrazole (165 mg, 1.21 mmol), potassium carbonate (512 mg, 3.63 mmol), and anhydrous dimethylformamide (1.21 mL). The reaction was heated at 85 to 130° C. for 36 h. The reaction was concentrated to give 690 mg of crude material. Purification by silica gel flash chromatography (0-5% ethyl acetate in heptane) afforded 5-bromo-3-methyl-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine (containing approximately 30% starting material) was carried forth to the next reaction. MS (M+1) 308.1.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:20]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:4]=1[C:2]#[N:3])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CC(C)(C)C(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared as in Example 165b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride and pivaloyl chloride in 99%. 1H NMR (400 MHz, DMSO-d6) δ 1.16 (s, 9H), 1.91 (m, 3H), 2.13 (m, 1H), 3.70 (m, 2H), 4.35 (m, 3H), 7.81 (dd, J=7.5, 2.1 Hz, 1H), 7.92 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1.[Br:30]C1C=CC(C2N=C3C=CC=CN3C=2CN)=CC=1>>[Br:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1
Reactant: NCc1c(-c2ccc(Br)cc2)nc2ccccn12
Reactant: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Product: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Br)cc3)nc3ccccn23)C1

Procedure:
The title compound was prepared according to the experimental for compound 237 from (2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl)methanamine. m/e+=454 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.51 (d, 1H, D, J=5.8 Hz), 7.63 (m, 5H), 7.26 (m, 1H), 6.85 (t, 1H, D, J=6.6 Hz), 5.06 (s, 2H), 4.88 (m, 1H), 4.67 (s, 1H), 3.55 (s, 1H), 2.99 (m, 2H), 2.42 (m, 2H), 2.16 (s, 6H).
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]([N:12]=[C:13]=[O:14])=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH:16]([NH2:19])[CH:17]=[O:18].[CH:20]1C=CC=CC=1>>[CH3:20][N:19]([CH2:16][CH:17]=[O:18])[C:13]([NH:12][C:10]1[S:11][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:8][N:9]=1)=[O:14]
Reactant: c1ccccc1
Reactant: O=C=Nc1nnc(C2CCCCC2)s1
Reactant: CC(N)C=O
Product: CN(CC=O)C(=O)Nc1nnc(C2CCCCC2)s1

Procedure:
A mixture of 5-cyclohexyl-1,3,4-thiadiazol-2-yl isocyanate dimer (12 grams), the dimethyl acetal of 2-methyl-aminoacetaldehyde (6.9 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized from methanol to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde having a melt point of 133° to 134° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:12][C:13]#N)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.CI.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([S:12][CH3:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(SC#N)c[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CI
Product: COc1ccc2c(SC)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a solution of 6-methoxy-3-thiocyanato-1H-indole (0.336 g, 1.64 mmole) and methyl iodide (0.700 g, 4.93 mmole) in methanol (10 ml) was added potassium hydroxide solution (0.164 ml, 10N) at 0° C. The reaction mixture was stirred for 1 h at room temperature. Silica gel (5 g) was added to the reaction mixture and the solvent was removed under reduced pressure. The residue was purified on a column of silica gel, eluting the product with mixtures of ethyl acetate:hexane (1:9 to 1:1). The first product which was eluted was the desired 6-methoxy-3-methylsulfanyl-1H-indole (0.120 g, 37% yield) followed by 6-methoxy-1H-indole-3-thiol (0.126 g). Step 3
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>O>[N:1]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1CCNC1
Solvent: O
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a solution of pyrolidine (17 mL, 237 mmol) in 20 mL of H2O at room temperature was added p-flourobenzenesulfonyl chloride (15 g, 79 mmol) in portions over a 5 minute period. After 1 hour, the solution was diluted with 100 mL of H2O and extracted with ethyl acetate (3×50 mL). The organic was dried Na2SO4) and concentrated in vacuo to give 12.3 g (72%) of 4-(pyrrolidinosulfonyl)flourobenzene as a colorless oil that solidified on standing. This material was used in the following reaction without further purification. MS.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:25][CH2:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([CH:1]3[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]3)[S:9][C:10]=2[CH:16]=1
Reactant: Cc1ccc2nc(Cc3ccccc3)sc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(C3CCCCC3)sc2c1
Temperature: 25 °C
Yield: 53.3 %

Procedure:
Combine 2-benzyl-6-methyl-benzothiazole (0.6 g, 2.42 mmol), NBS (0.5 g, 2.54 mmol), AIBN (40 mg, 0.24 mmol), carbon tetrachloride (10 mL) and reflux for 3 h. Cool the reaction mixture to ambient temperature, dilute with chloroform and wash with water. Dry the organic extracts over anhydrous Na2SO4, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the title compound as a white solid (0.4 g, 53%). MS (ES+) m/z: 311 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.S(Cl)(Cl)=O.[CH3:24][N:25]1[C:29]([NH2:30])=[CH:28][CH:27]=[N:26]1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C:29]2[N:25]([CH3:24])[N:26]=[CH:27][CH:28]=2)=[O:8])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:16])([CH3:17])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1nccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.0 g, 7.6 mmol) and thionyl chloride (14 ml, 191 mmol) and the reaction mixture was stirred at RT for 1 h. Excess thionyl chloride was evaporated under vacuum and the remaining trace amount was removed azeotropically by addition of toluene (5 mL) and repeated concentration under reduced pressure. To the resulting residue was added DCM (10 mL) followed by 1-methyl-1H-pyrazol-5-amine (1.1 g, 11 mmol) and pyridine (1.2 ml, 15 mmol). The reaction was stirred at reflux for 1 h then cooled to RT. The mixture was diluted with DCM, washed with water followed by sat. NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. The brown residue was loaded on an ISCO 40 g column (eluted with 25-65% EtOAc in Hexanes) and purified to provide the title compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 342.2 (M+1).
Reaction SMILES: [Cl-].[C:2]([C:4]1([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][NH2+:7][CH2:6][CH2:5]1)#[N:3].C(N(CC)CC)C.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>ClCCl>[CH2:24]([S:26]([N:7]1[CH2:8][CH2:9][C:4]([CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)([C:2]#[N:3])[CH2:5][CH2:6]1)(=[O:28])=[O:27])[CH3:25]
Reactant: CCS(=O)(=O)Cl
Reactant: N#CC1(CC2CCOCC2)CC[NH2+]CC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(C#N)(CC2CCOCC2)CC1
Reaction time: 1 h

Procedure:
In a dry round bottom flask was placed 4-cyano-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidinium chloride (9, 1 g, 3.1 mmol), dichloromethane (50 ml) and triethylamine (2.162 ml, 15.51 mmol). To this was added dropwise ethanesulfonyl chloride (0.317 ml, 3.1 mmol). The reaction was stirred 1 hour and quenched with water (100 ml). The mixture was extracted with dichloromethane (3×50 ml) and the combined organic fractions were dried (MgSO4), filtered, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1-(ethylsulfonyl)-4-(tetrahydro-2H-pyran-4-ylmethyl)piperidine-4-carbonitrile (10) as a white solid. MS 301 (M+1)
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[C:4]2[C:8]([C:10]3[C:15]([OH:16])=[CH:14][C:13]([CH2:17][OH:18])=[CH:12][C:11]=3[C:19](=[O:20])[C:3]=2[CH:2]=1)=[O:9].Cl>CS(C)=O.C(N(CC)CC)C>[OH:16][C:15]1[C:10]2[C:8](=[O:9])[C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[OH:7])[C:19](=[O:20])[C:11]=2[CH:12]=[C:13]([CH:17]=[O:18])[CH:14]=1
Reactant: O=C1c2cccc(O)c2C(=O)c2c(O)cc(CO)cc21
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O
Reaction time: 0.25 h

Procedure:
To aloe-emodin (5.0 g) in dry dimethyl sulphoxide (55 ml) and triethylamine (77 ml) was added a solution/suspension of sulphur trioxide-pyridine complex (29.4 g) in dry dimethyl sulphoxide (100 ml), dropwise with stirring, over 15 minutes. The addition was slightly exothermic and gave a dark brown solution, which was stirred at room temperature for 2-3 hours, then poured onto dilute hydrochloric acid (1000 ml, 0.5M), stirred for 15 minutes, then left to stand for 15 minutes. The suspension was filtered (slow), washed with water (400 ml) and pulled dry to leave a brown solid. Dried at 50° C. in a vacuum oven, m.p. 198°-200° C.