Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][NH:57][CH2:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][N:64]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65]2)=[CH:61][CH:60]=1>C(Cl)Cl>[OH:69][CH:66]1[CH2:67][CH2:68][N:64]([CH2:63][C:62]2[CH:70]=[CH:71][C:59]([CH2:58][N:57]([CH3:56])[C:21]([C:19]3[N:20]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:17][CH:18]=3)=[O:22])=[CH:60][CH:61]=2)[CH2:65]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-oxazole-4-carboxylic acid (35 mg, 0.10 mmol), EDCI (26 mg, 0.14 mmol), HOBt (19 mg, 0.15 mmol), DIPEA (0.03 mL, 0.19 mmol), 1-(4-methylaminomethyl-benzyl)-pyrrolidin-3-ol hydrochloride (30 mg, 0.11 mmol) and DCM (10 mL).
Reaction SMILES: [CH3:1][C:2]1([CH2:14][C:15]([OH:17])=O)[CH2:6][C:5]2[C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:30]([N:32]=[C:33]=NCCCN(C)C)C.CNC>CN(C)C=O.O>[CH3:30][N:32]([CH3:33])[C:15](=[O:17])[CH2:14][C:2]1([CH3:1])[CH2:6][C:5]2[C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CC(=O)O)C2
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(CC(=O)N(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl acetic acid (3.0 g, 12.8 mmol) in dimethylformamide (30 ml) were added 1-hydroxy-1H-benzotriazole monohydrate (HOBt) (2.1 g, 14.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (3.7 g, 19.2 mmol). The mixture was stirred at room temperature for 1 hour. Then, 50% dimethylamine aqueous solution (3 ml) was added and the resulting mixture was stirred for additional 30 minutes. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (isopropyl ether) to obtain the desired compound (3.1 g, yield: 92.6% yield) as oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from [5-(isobutyl-methyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example C9) (3.88 g, 9.91 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a orange oil (2.70 g, 75%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[Na+]>CCO.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1[nH]c2ccccc2c1Br
Yield: 96.7 %

Procedure:
A solution of ethyl 3-bromoindole-2-carboxylate (54.40 g, 203 mmol) in EtOH (600 ml) and water (50 ml) with NaOH (20.20 g, 505 mmol) was refluxed for 1 h. The mixture was cooled and the sodium salt of the title compound was removed by filtration. This was acidified (aqueous 3N HCl) and extracted with ethyl acetate. The organic extract was washed with water then brine, dried (sodium sulfate) and concentrated. Crystallization from ethyl acetate afforded the product (47.1 g, 88%). mp 201°-203° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH:26]1[CH2:31][CH2:30][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27]1)[C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=2[N:15]=1)[C:5]([O:7]C)=[O:6].[Li+].[OH-].CCOC(C)=O.Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH:26]1[CH2:27][CH2:28][CH:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:30][CH2:31]1)[C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=2[N:15]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(CN(c2nc3cc(OC)ccc3n2C)C2CCC(C(C)(C)C)CC2)c(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(c1)nc(N(Cc1ccc(C(=O)O)cc1Br)C1CCC(C(C)(C)C)CC1)n2C
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To the title compound of Example 224 Step D (0.07 mmol, 40 mg) in 2 mL of dioxane was added a solution of LiOH (1 mmol, 24 mg) in 1 mL of H2O. The reaction was allowed to stir at 40° C. for 1.5 h. The crude reaction mixture was poured into pH 7 buffer/EtOAc, which was acidified with 2 N HCl until two clear layers formed after agitation. The organic phase was collected and the aqueous phase was extracted twice with EtOAc. The combined organic phase was dried over Na2SO4, then concentrated under reduced pressure to afford the product as a slightly yellow-green foam. HPLC A: 2.32 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH:22][C:23](=O)[CH2:24][CH2:25][C:26]2[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]4)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]4)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCNC(=O)CCc2ccc3[nH]ccc3c2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNCCCc2ccc3[nH]ccc3c2)cc1OC
Temperature: 77 °C
Reaction time: 5.5 h
Yield: 55 %

Procedure:
To a solution of N-{2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl}-3-(1H-indol-5-yl)propionamide (60 mg in 2.0 mL dry tetrahydrofuran) at 0° C. was added 26 mg lithium aluminum hydride and the mixture heated to 77° C. on an oil bath. After 5.5 hours, the mixture was cooled to 0° C. and quenced by the addition of 0.025 mL water and stirred vigorously for 30 minutes at which time the suspension was filtered through a pad of sodium sulfate and the filtrate concentated in vacuo. Purification by flash chromatography (methylene chloride:methanol, 92:8) gave the title compound (32 mg). m/e=454 (M+H)
Reaction SMILES: [CH:1]1([N:4]([CH3:24])[C:5]2[C:6]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=4[S:17][C:7]=3[N:8]=[C:9]([CH2:11][C:12]([O:14]CC)=[O:13])[N:10]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([N:4]([CH3:24])[C:5]2[C:6]3[C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=4[S:17][C:7]=3[N:8]=[C:9]([CH2:11][C:12]([OH:14])=[O:13])[N:10]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1nc(CC(=O)O)nc2sc3c(c12)CCCC3)C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate (1.0 gm, 0.00289 mol) in THF (9 ml) and water (1 ml) was added lithium hydroxide hydrate (0.24 gm, 0.00578 mol). The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was diluted with water. The aqueous layer was made acidic to pH 1 with 2N HCl and then extracted with ethyl acetate (25 ml×3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to get crude compound. It was purified by column chromatography by using 100-200 mesh silica gel and 2% MeOH: DCM as eluent to get 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetic acid as an off white solid. Yield: (0.4 gm, 43.57%); 1H-NMR: (400 MHz, DMSO-d6); δ=12.46 (s, 1H), 3.70 (s, 2H), 2.99 (s, 3H), 2.96-2.91 (m, 1H), 2.90-2.87 (m, 2H), 2.83-2.80 (m, 2H), 1.88-1.84 (m, 2H), 1.71-1.66 (m, 2H), 0.78-0.65 (m, 2H), 0.43-0.31 (m, 2H); LC-MS [M+H]=317.9; HPLC purity=99.72%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)O1.C(=O)(O)[O-].[Na+].C(Cl)Cl.CO>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]c(=O)[nH]c4c3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 130 °C
Yield: 38.1 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (100 mg, 0.24 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (93 mg, 0.36 mmol) in dioxane/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 (9.8 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (60.4 mg, 0.72 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 130° C. for 20 min. DCM/MeOH (1:1) was added, it was pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOH was added, it was sonicated and the solids that precipitated were filtered, washed with EtOH and DCM and dried to afford the title compound (43 mg, 37%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H) 10.78 (s, 1H) 10.74 (s, 1H) 8.64 (t, J=4.80 Hz, 1H) 8.35 (s, 1H) 8.02 (s, 1H) 7.81 (s, 1H) 7.44 (dd, J=8.08, 1.77 Hz, 1H) 7.36-7.39 (m, 1H) 7.03 (d, J=8.08 Hz, 1H) 5.89 (s, 1H) 5.16 (quin, J=6.57 Hz, 1H) 4.39 (d, J=4.80 Hz, 2H) 2.21 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.49 (s, 3H). MS (ES) [M+H]+ 471.3
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[C:22]2[C:29]([I:30])=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:46][CH2:47][C@@H:48]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH:49]=[CH2:50]>COCCOC>[Cl:20][C:21]1[C:22]2[C:29]([I:30])=[CH:28][N:27]([CH2:50][CH2:49][C@@H:48]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH:47]=[CH2:46])[C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: C=C[C@@H](CCO)NC(=O)OC(C)(C)C
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: C=C[C@@H](CCn1cc(I)c2c(Cl)ncnc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Triphenylphosphine (3.25 g) was added to and dissolved in a solution of (R)-tert-butyl (5-hydroxypent-1-en-3-yl)carbamate (2.5 g) obtained in Step 3 and 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.31 g) obtained in Step 1 of Example 1 in DME (23 ml) under ice-cooling. Thereafter, diisopropyl azodicarboxylate (2.44 ml) was gradually added thereto. The reaction mixture was stirred under ice-cooling for 30 minutes and at room temperature for 1 hour, and the solvent was then distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow solid (3.49 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[CH3:2].[CH2:24]=[O:25]>CS(C)=O.C(Cl)Cl>[OH:25][CH2:24][CH:1]([C:3]1[CH:4]=[C:5]([C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[CH3:2]
Reactant: C=O
Reactant: CCc1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(CO)c1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 110.2 %

Procedure:
A suspension of 2-(3-ethyl-4-nitrophenyl)-2-phenyl-1,3-dioxane (17) (20.0 g, 63.8 mmol), paraformaldehyde (6.5 g, 72.6 mmol) and a methanolic solution of Triton B (35%, 17 mL) in DMSO (100 mL) was stirred for 2 hours at 85° C. The reaction mixture was then cooled to ambient temperature, diluted with CH2Cl2 (200 mL), washed with water (2×200 mL), partially concentrated in vacuo (for azeotropic drying) and filtered over silica gel (35 g). The filtrate was then evaporated in vacuo to give 24.15 g (approx. 70.3 mmol, 110%) of the crude product as a yellow oil.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O>[I:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:4]2[CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)=[CH:14][CH:13]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Nc1ccc(I)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: Ic1ccc(NC2CN3CCC2CC3)cc1
Reaction time: 0.33 h

Procedure:
3-Quinuclidinone hydrochloride (Aldrich, 3.22 g, 20 mmol) was treated with 4-iodo-aniline (Aldrich, 2.19 g, 10 mmol), Na2SO4 (anhydrous, Aldrich, 7.40 g, 50 mmol) and NaBH(OAc)3 (Aldrich, 3.16 g, 15 mmol) in HOAc (25 mL) at ambient temperature for 15 h. After the reaction was complete, the reaction mixture was slowly poured into a flask containing 75 mL of saturated NaHCO3 and stirred for 20 min. It was then extracted with EtOAc (3×100 mL). The extracts were combined and washed with brine (2×20 mL). The organic solution was concentrated under reduced pressure and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.10) as oil (3.24 g, yield, 98%). 1H NMR (300 MHz, CD3OD,) δ 1.70-1.81 (m, 1H), 1.93-2.04 (m, 2H), 2.08-2.24 (m, 2H), 2.89 (ddd, J=12.9, 5.1, 2.7 Hz, 1H), 3.12-3.28 (m, 4H), 3.64 (ddd, J=12.9, 9.5, 2.4 Hz, 1H), 3.79-3.85 (m, 1H), 6.46 (dt, J=9.0, 2.7 Hz, 2H), 7.39 (dt, J=9.1, 2.7 Hz, 2H) ppm. MS (DCI/NH3) m/z 329 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10]O)[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=O)=O)=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].C(N(CC)CC)C.C1(C)C=CC(S)=CC=1>N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)O[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO
Agent: Cc1ccc(S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CSc1ccc(C)cc1
Reaction time: 16 h

Procedure:
A solution of 3'-O-acetylthymidine 26 (0.511 g, 1.8 mmol) and toluene-4-sulfonyl chloride (0.514 g, 2.7 mmol) in dry pyridine (3 cm3) was stirred at room temperature. After 16 h, saturated aqueous sodium hydrogen carbonate (2 cm3) was added and, after a further 10 min, the products were partitioned between chloroform (50 cm3) and saturated aqueous sodium hydrogen carbonate (50 cm3). The dried (MgSO4) organic layer was concentrated under reduced pressure. The residue was fractionated by short column chromatography on silica gel: the appropriate fractions, eluted with chloroform-methanol (99:1 v/v), were combined and evaporated under reduced pressure. The residue was dissolved in acetonitrile (2.5 cm3) at room temperature and triethylamine (0.90 cm3, 6.5 mmol) and toluene-4-thiol (0.805 g, 6.5 mmol) were added to the stirred solution which was kept under an atmosphere of argon. After 60 h, the products were concentrated under reduced pressure and the residue was fractionated by short column chromatography on silica gel: the appropriate fractions, eluted with chloroform-methanol (99:1 v/v) were combined and evaporated under reduced pressure to give 3'-O-acetyl-5'-S-(4-methylphenyl)-5'-thiothymidine 31 as a colourless glass (0.60 g, 85% based on 3'-O-acetylthymidine) (Found: M+ =390.1249. 12C191H2214N216 O532S requires: 390.1249); Rt 12.05 min (programme 1); δH [(CD3)2SO] 1.76 (3 H, d, JO.9), 2.05 (3 H, s), 2.25 (1 H, m), 2.26 (3 H, s), 2.49 (1 H, m), 3.32 (2 H, m), 4.02 (1 H, m), 5.18 (1 H, m), 6.13 (1 H, dd, J 6.0, 8.6), 7.14 (2 H, d, J7.9), 7.29 (2 H, d, J 8.2), 7.51 (I H, m), 11.38 (1 H, br s); δC [(CD3)2 SO] 12.1, 20.5, 20.8, 35.2, 35.4, 75.7, 81.9, 83.9, 110.0, 129.1, 129.7, 131.6, 135.7, 136.0, 150.5, 163.6, 169.9.
Reaction SMILES: C(S[C:5]1[NH:6][C:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:9]=1[CH2:10][CH:11]=[CH2:12])(=O)C.CC(C)=O>[Ni].C(O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:8]2[C:9]([CH2:10][CH2:11][CH3:12])=[CH:5][NH:6][C:7]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: C=CCc1c(SC(C)=O)[nH]c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Agent: [Ni]
Solvent: CC(C)=O
Solvent: CCO
Product: CCCc1c[nH]c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Yield: 22.8 %

Procedure:
A mixture of 5 g Raney nickel, 0.8 g (2 m moles) of 2-acetylthio-3-allyl-4,5-bis(4-chlorophenyl)pyrrole and 50 ml acetone was heated at reflux under nitrogen for two hours. The mixture was diluted with ethanol and the catalyst was removed by filtration. The filtrate was concentrated by rotary evaporation. The residue was purified by chromatography on 50 g Silic AR CC-7, eluting with hexane/toluene (90/10), to give 0.15 g of white crystals, m.p. 90°-93°.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19]([S:21][CH3:22])[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>ClC(Cl)C.ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19]([S:21]([CH3:22])=[O:31])[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC(C)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl)S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.25 g (30 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-5-chloro-6-(1-methylthioethyl)pyrimidine were placed in 120 ml of dichloroethane, and a solution of 7.40 g (30 mmol) of 70% 3-chloroperbenzoic acid in 50 ml of dichloromethane was added dropwise at 0° C. The mixture was stirred at room temperature for 8 hours and extracted by stirring with sodium bicarbonate solution and water. The organic phase was dried and concentrated, to give 10.5 g (98% of theory) of a colorless resin (diastereomer mixture).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[N:20][OH:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1C(=NO)c2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a suspension of 7.11 g of N-benzylisatin in 75 ml of ethanol was added a solution of 3.84 g of hydroxylamine hydrochloride and 3.84 g of sodium acetate in 500 ml of water. The mixture was stirred at room temperature for 1 hour, followed by concentration. The residue was washed with water and recrystallized from ethanol to give 6.11 g (81%) of the title compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][S:6][CH2:7][C:8](O)=[O:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:11]([C:8](=[O:9])[CH2:7][S:6][CH2:5]2)=[CH:12][CH:13]=1
Reactant: O=C(O)CSCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C1CSCc2cc(Cl)ccc21
Yield: 51.1 %

Procedure:
3-Chlorobenzylmercaptoacetic acid (Step 2) (3.35 g) was dissolved in trifluoroacetic acid (50 mL). Trifluoroacetic acid anhydride (25 mL) was added and the reaction was heated at reflux, under nitrogen, for 16 hours. The solution was carefully poured into 10% Na2CO3 solution (500 mL) which was stirring vigorously. The organics were extracted into ether (500 mL) and washed with brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting brown solid was purified by SiO2 chromatography, eluting with a 0-10% gradient of ethyl acetate in hexane to yield 7-chloroisothiochroman-4-one, (1.57 g, 51%): 1H NMR (CDCl3 300 MHz) 3.49 (d, 2H, J=0.8 Hz), 3.8 (s, 2H), 7.16 (m, 1H), 7.3 (dd, 1H, J=2.0, 8.4 Hz), 7.96 (d, 1H, J=8.5 Hz).
Reaction SMILES: [N+](C1C=C(C(C)=CC=1)C(O)=O)([O-])=O.[N+:14]([C:17]1[CH:18]=[C:19]([C:24]([CH3:27])=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])([O-:16])=[O:15].Cl.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C.CO>[Br:29][CH2:27][C:24]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1CBr

Procedure:
3-Nitro-6-methylbenzoic acid (2-1) (Aldrich) was converted into methyl 3-nitro-6-methylbenzoate (2-2) using the standard procedure of MeOH and HCl gas. To a mixture of methyl 3-nitro-6-methylbenzoate (2-2) (2.0 g, 10.3 mmol) and N-bromosuccinimide (1.64 g, 9.23 mmol) in CHCl3 was added AIBN (20 mg) and this was then photolysed at reflux for 4 hours. The reaction was cooled, filtered and the filtrate evaporated to dryness. Chromatography of the residue (silica, hexane/EtOAc 92:8) afforded 2-3 as a solid (1.56 g). Rf (silica; hexane/EtOAc 10:1)=0.25. ##STR57##
Reaction SMILES: N[C:2]1[CH:11]=[C:10](S(O)(=O)=O)[CH:9]=[C:8]2[C:3]=1[C:4]([OH:20])=[CH:5][C:6](S(O)(=O)=O)=[CH:7]2.ClC1N=C(Cl)N=C(Cl)N=1.NC1C=CC=CC=1>>[CH:10]1[CH:11]=[CH:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[OH:20])[CH:9]=1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: Nc1ccccc1
Product: Oc1cccc2ccccc12

Procedure:
In an aqueous solvent, 31.9 parts of 5-amino-4-hydroxynaphthalene-2,7-disulfonic acid was condensed with 18.4 parts of 2,4,6-trichloro-s-triazine according to a normal method and the resultant condensate was condensed with 28.1 parts of 3-(2-sulfate ethylsulfonyl)aniline according to a normal method. The product thus obtained was condensed with 9.3 parts of aniline according to a normal method to obtain a naphthol derivative.