Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][NH:18][C@@H:8]([C@@H:9]3[CH2:10][C@H:11]([CH3:20])[C:12](=[O:19])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:21][CH3:22].C([O-])(O)=O.[Na+].[CH:28]1([CH2:31]Br)[CH2:30][CH2:29]1>CN(C=O)C>[CH:28]1([CH2:31][N:18]2[CH2:17][CH2:16][C@@:14]34[C:15]5[C:2]([OH:1])=[C:3]([O:21][CH3:22])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@@H:9]3[CH2:10][C@H:11]([CH3:20])[C:12](=[O:19])[CH2:13]4)[CH2:30][CH2:29]1
Reactant: COc1ccc2c(c1O)[C@]13CCN[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1O)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3

Procedure:
A mixture of 18a (5.00 g, 16.6 mmole), NaHCO3 (2.90 g, 34.6 mmole) and cyclopropylmethyl bromide (2.80 g, 20.8 mmole) in DMF (50 ml) was heated at 100° under argon for 2 hours. The mixture was cooled, filtered from insoluble material and the filtrate evaporated in high vacuum. The residue was dissolved in dilute NH4OH and extracted with three portions of toluene. The toluene was evaporated to give 4.89 g (83%) of crystalline 19a-CPM. Two recrystallizations from ethanol gave analytically pure 19a-CPM, mp 176.5°-178°. NMR: δ 6.56, s, 2H (aromatic); 6.17, S, 1H, (hydroxy proton); 4.23, d, 1H, (H-5α, J=12.5 Hz); 3.78 (CH3O--); 1.30, d, (H-5β); 0.87, d, 3H (7α-CH3, J=6.5 Hz),
Reaction SMILES: Br[CH2:2][C:3]([NH:5][CH:6]1[C:28](=[O:29])[N:8]2[C:9]([C:25]([OH:27])=[O:26])=[C:10]([CH2:13][NH:14][C:15](=[O:24])[C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH2:11][S:12][C@H:7]12)=[O:4].[SH:30][C:31]1[S:32][CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:35]=1>>[C:36]1([C:34]2[N:35]=[C:31]([S:30][CH2:2][C:3]([NH:5][CH:6]3[C:28](=[O:29])[N:8]4[C:9]([C:25]([OH:27])=[O:26])=[C:10]([CH2:13][NH:14][C:15](=[O:24])[C:16]5[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=5[Cl:23])[CH2:11][S:12][C@H:7]34)=[O:4])[S:32][CH:33]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Sc1nc(-c2ccccc2)cs1
Reactant: O=C(CBr)NC1C(=O)N2C(C(=O)O)=C(CNC(=O)c3c(Cl)cccc3Cl)CS[C@H]12
Product: O=C(CSc1nc(-c2ccccc2)cs1)NC1C(=O)N2C(C(=O)O)=C(CNC(=O)c3c(Cl)cccc3Cl)CS[C@H]12
Yield: 62 %

Procedure:
1.0 g. of 7-bromoacetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-4-carboxylic acid and 0.39 g. of 2-mercapto-4-phenyl-1,3-thiazole were reacted and worked up according to the method of Example 15. Thus 0.78 g. o(62%) of 7-(4-phenyl-1,3-thiazole-2-ylthio)acetamido-3-(2,6-dichlorobenzoylamino)methylceph-3-em-4-carboxylic acid were obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1nc2ccc(C(F)(F)F)cc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C(F)(F)F)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-trifluoromethyl-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH:16]=O.Cl.O>CO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: O=C1COc2cc(O)ccc21
Reactant: Cc1cc(C=O)ccc1O
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc(C=C2Oc3cc(O)ccc3C2=O)ccc1O
Temperature: 25 °C
Yield: 68.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methyl-4-hydroxybenzaldehyde 1.00 g were dissolved in methanol 70 ml, concentrated hydrochloric acid 60 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and water 250 ml was added. Precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.22 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH2:11].[CH2:12]([OH:14])[CH3:13]>[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:11][C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CCO
Agent: [Pd]
Product: CC(=O)Nc1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-5-nitrophenylamine (2.0 g), palladium, 10 wt. % on activated carbon (0.10 g) and ethanol (20 mL) were stirred at room temperature for 2 hours under an atmosphere of hydrogen. The mixture was filtered through hyflo, washing with ethanol and the solvent removed under reduced pressure to afford title compound as a white solid, 1.7 g.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:39]([NH2:45])[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>>[O:44]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:39][NH:45][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:29])=[O:28])[CH:31]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: NCc1ccco1
Product: O=C(NCc1ccco1)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 90.2 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 55 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 610 [M+H]+.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([F:30])[C:28]=1[F:29])[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[CH:34]([CH:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1)=O.O>C1COCC1>[F:30][C:27]1[CH:26]=[C:5]([CH:6]=[CH:34][CH:36]2[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]2)[CH:4]=[C:3]([F:2])[C:28]=1[F:29]
Reactant: Fc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(F)c1F
Reactant: O=CC1CCC(=O)CC1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC(C=Cc2cc(F)c(F)c(F)c2)CC1
Yield: 70.5 %

Procedure:
A suspension of 3,4,5-trifluorobenzyltriphenylphosphonium bromide (234 g) in THF (500 ml) was stirred in a nitrogen gas stream, followed by adding sodium methoxide (32.4 g) little by little at room temperature, stirring the reaction solution at room temperature for one hour, dropwise adding a solution of 4-formylcyclohexanone (50 g) in THF (250 ml), stirring the mixture at room temperature for 2 hours, adding it to water (1 l) extracting with ethyl acetate (1 1), washing the organic layer with water, drying over anhydrous MgSO4, concentrating the solvent under reduced pressure, to obtain 4-(2'-(3",4",5"-trifluorophenyl)ethenyl)cyclohexanone (71 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C>[C:12]1([CH2:11][N:18]2[CH2:19][CH:20]=[C:21]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:22][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Oc1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: Oc1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1

Procedure:
A mixture of 5-hydroxyindole (0.66 g) and 1-benzyl-4-piperidone (0.95 g) in glacial acetic acid was purged with nitrogen and heated to reflux for 50 min. The mixture was concentrated in vacuo, treated with toluene and concentrated in vacuo, and the residue was purified by chromatography (silica gel, 20-30% ethanol/dichloromethane) to afford the title compound which was recrystallized from ethanol (0.4 g). mp 223-227° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:13]Br>CO>[Br:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1ccc(C=O)cc1OC
Reactant: BrBr
Solvent: CO
Product: COc1cc(Br)c(C=O)cc1OC

Procedure:
Bromination of 3,4-dimethoxybenzaldehyde using bromine in methanol to afford 2-bromo-4,5-dimethoxybenzaldehyde (B1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:23]([CH3:31])([CH3:30])[O:24][SiH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([N:8]2[CH:17](O)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:19]4[CH2:21][CH2:20]4)[CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:23]([CH3:31])([CH3:30])[O:24][SiH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:19]4[CH2:20][CH2:21]4)[CH:14]=3)[C:9]2=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1N1C(=O)c2ccc(C3CC3)cc2CC1O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[SiH2]OC(C)(C)c1c(Br)cccc1-n1ccc2cc(C3CC3)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 2-[3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-cyclopropyl-3-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (3.52 g, 7.00 mmol) and triethylamine (4.0 mL, 29 mmol) in 50 mL of anhydrous CH2Cl2 was added 0.85 mL of methanesulfonyl chloride. Purged the flask with nitrogen and stirred at room temperature overnight. Added 25 mL of CH2Cl2 and 50 mL of water and separated phases. Washed the organic phase with 50 ml brine. Dried the solution over MgSO4 and concentrated in vacuo. Purified the residue by flash chromatography (gradient elution, 0 to 50% EtOAc/hexane) to obtain 2-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one as an amber resin (2.90 g, 5.99 mmol). MS (ESI) 484, 486 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[F:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([Cl:43])=[O:42])=[C:39]([C:46]([F:49])([F:48])[F:47])[CH:38]=1>ClCCl>[ClH:43].[C:25]([C:24]1[CH:27]=[CH:28][C:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([N:8]3[CH2:7][CH2:6][CH:5]([N:4]([CH3:3])[C:41](=[O:42])[C:40]4[CH:44]=[CH:45][C:37]([F:36])=[CH:38][C:39]=4[C:46]([F:49])([F:48])[F:47])[CH2:10][CH2:9]3)=[N:12][N:13]=2)=[CH:22][CH:23]=1)#[N:26]
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: CNC1CCN(c2nnc(-c3ccc(C#N)cc3)c3ccccc23)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccc(F)cc1C(F)(F)F)C1CCN(c2nnc(-c3ccc(C#N)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Charge a 4 mL reaction vial with 4-(4-(4-(methylamino)piperidine -1-yl)phthalazin -1-yl)benzonitrile dihydrochloride (44.7 mg, 0.107 mmol), dichloromethane (1 mL), and triethylamine (0.0598 mL, 0.429 mmol). Flush the reaction vial with nitrogen and add 4-fluoro-2-(trifluoromethyl)benzoyl chloride (033 g. 0.14 mmol). Cap the vial and allow the reaction to stir at room temperature overnight. Evaporate to a residue and purify using silica gel chromatography (40:60, ethyl acetate:hexane, then ethyl acetate). Add 1 N HCl in diethyl ether to a solution of the isolated product in dichloromethane/methanol and remove the solvents by placing under a stream of nitrogen gas. Dry in a vacuum oven at 50° C. to obtain the title compound (36.0 mg. 59%). ES/MS m/z 533.8 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCC[C@H]1C(O)=O.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cu]I.CS(C)=O>[C:15]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCNC1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: c1ccc(N2CCCC2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 59.6 %

Procedure:
Pyrrolidine (21.6 g, 304.23 mmol), L-proline (1.12 g, 9.74 mmol), and CuI (960 mg, 5.05 mmol) were added sequentially to 1-iodobenzene (10.0 g, 49.02 mmol). DMSO (40 mL) was then added, and the resulting solution was stirred at 60° C. for 20 hours. The reaction mixture was then quenched by adding 400 mL of iced water. The resulting solution was extracted with ethyl acetate (3×150 mL), and the organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to afford 4.3 g (57%) of 1-phenylpyrrolidine as brown oil.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:6][C@@H:5]1[OH:34])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)(Cl)Cl.C(O)C>[C:46]([O:34][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:6]1)(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 0.33 h

Procedure:
Ethyl 2β-ethoxy-3α-hydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (200 mg) in chloroform (2.15 ml) containing dry toluene-4-sulphonic acid (PTSA; 172 mg) was stirred for 20 min, then treated with acetic anhydride (0.5 ml) and the mixture left for 18 h. The reaction mixture was diluted with ethanol and evaporated. The residue in ethyl acetate was washed with dilute ammonia solution (2×) and water (1×), dried and evaporated to give the title compound as an oil (220 mg), [α]D +25.8° (CHCl3C=1%), νmax 1720 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O.CN(C)C=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([Cl:26])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)Cl)C(F)(F)F
Yield: 91.9 %

Procedure:
A solution of (±)-2-[4-(4-chlorophenyl)phenoxy]-3,3,3-trifluoro-2-methylpropionic acid (414 mg.), thionyl chloride (1.0 g.) and dimethylformamide (0.05 g.) in benzene (10 ml.) is heated under reflux for 1 hour. The solvent is evaporated in vacuo, and light petroleum (10 ml., b.p. 60°-80° C.) is added, and the mixture is re-evaporated. A further 10 ml. of light petroleum are added, and the mixture re-evaporated. The residue is dissolved in light petroleum, and the solution is filtered and evaporated to give (±)-2-[4-(4-chlorophenyl)-phenoxy]-3,3,3-trifluoro-2-methylpropionyl chloride (401 mg.).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([OH:12])=[O:11])[CH:4]=1.[CH3:13][NH:14][CH3:15]>C(O)CCC>[CH3:13][N:14]([CH3:15])[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([OH:12])=[O:11])[CH:4]=1
Reactant: Cc1cc(Br)cc(C(=O)O)n1
Reactant: CNC
Agent: Cl
Solvent: CCCCO
Product: Cc1cc(N(C)C)cc(C(=O)O)n1
Yield: 142.9 %

Procedure:
To a solution of 4-bromo-6-methyl-pyridine-2-carboxylic acid hydrochloride (100 mg, 0.396 mmol) in butanol (6 mL), dimethylamine (162 mg, 1.19 mmol) is added and the mixture is refluxed for 2 days. The solvent is removed in vacuo and the residue is dried under HV to give 4-dimethylamino-6-methyl-pyridine-2-carboxylic acid (102 mg) as dimethylammonium salt in form of a yellow oil; LC-MS: tR=0.48 min, [M+1]+=181.07. This material is dissolved in DCM (5 mL), methanol (0.5 mL) and triethylamine (5 mL). The solution is stirred for 5 min at rt before it is concentrated and dried under HV to give the title compound (125 mg) as triethylammonium salt in form of a pale yellow oil. 1H NMR (D6-DMSO): δ 1.20 (t, J=7.3 Hz, 18H), 3.08 (q, J=7.0 Hz, 12H), 3.17 (s, 6H), 6.80 (s, 1H), 7.14 (s, 1H), 9.75 (s br, 2H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[N:12]=[N:11][C:10]([CH2:13][N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]([CH2:25][C:26]4[N:27]=[N:28][N:29](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:30]=4)[C:17](=[O:50])[CH:16]([NH:51][C:52]([NH:54][C:55]4[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=4)=[O:53])[C:15]3=[O:62])=[N:9]2)C=CC=CC=1.Cl.O>CO>[NH:30]1[C:26]([CH2:25][N:18]2[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]([CH2:13][C:10]3[NH:9][N:8]=[N:12][N:11]=3)[C:15](=[O:62])[CH:16]([NH:51][C:52]([NH:54][C:55]3[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=3)=[O:53])[C:17]2=[O:50])=[N:27][N:28]=[N:29]1
Reactant: Cc1cccc(NC(=O)NC2C(=O)N(Cc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c3ccccc3N(Cc3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2=O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cccc(NC(=O)NC2C(=O)N(Cc3nnn[nH]3)c3ccccc3N(Cc3nnn[nH]3)C2=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.5 %

Procedure:
To a solution of Compound 8k (353 mg, 0.363 mmol) in methanol (20 ml) is added 10% HCl (5 ml) and the mixture is stirred for 15 hr at room temperature. After the addition of water (150 ml), the mixture is extracted with ethyl acetate. The organic layer is washed with water and extracted with 10% aqueous sodium carbonate. The aqueous layer is acidified with 10% HCl and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and distilled under reduced pressure to remove the solvent. Crystallization from methanol/benzene gives Compound 81 (118 mg, 66.7%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[N:14][OH:15])[NH2:13])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].[Na].[CH:19]1([C:25](OCC)=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[N:13]=[C:25]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[O:15][N:14]=3)[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17]
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2CC(N)=NO
Reactant: CCOC(=O)C1CCCCC1
Agent: [Na]
Solvent: CCO
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1noc(C2CCCCC2)n1
Reaction time: 10 h
Yield: 76 %

Procedure:
A solution of 2.38 g of 2-(3-methyl-xanthine-7-yl)acetamidoxime in 25 ml of ethanol is admixed with a solution of 0.46 g of metallic sodium in 25 ml of ethanol and 3.02 g of ethyl cyclohexane carboxylate. The reaction mixture is heated to boiling under stirring for 10 hours, then evaporated. The residue is admixed with water and the pH is adjusted to 7. The precipitate is crystallized from aqueous ethanol. Thus 2.51 g of 3,7-dihydro-3-methyl-7-([5-cyclohexyl-1,2,4-oxadiazole-3-yl]methyl)-1H-purine-2,6-dione are obtained, m.p.: 245°-248° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]2[CH2:17][CH:18]([CH3:20])[CH3:19].S([O-])(O[O-])(=O)=[O:33].[K+].[K+].OOS([O-])=O.[K+]>CO.O>[OH:1][CH2:2][CH2:3][S:4]([C:5]1[N:6]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:33]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCO)n(Cc3cccc4ccccc34)cc21
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)CCO)n(Cc3cccc4ccccc34)cc21
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(2-hydroxyethyl)thio-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg) in methanol (20 ml) was added potassium peroxymonosulphate (commercially sold under the trade mark "OXONE") (300 mg) in water (10 ml). After stirring for 10 minutes the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were dried over magnesium sulphate and concentrated in vacuo. Chromatography on silica gel (ethyl acetate) gave the title compound (70 mg) as a white foam.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][CH:13]([CH2:19][CH:20]=C)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([Cl:24])[CH:9]=1>C1COCC1.O.O=[Os](=O)(=O)=O>[Br:7][C:8]1[CH:23]=[CH:22][C:11]([CH2:12][CH:13]([CH2:19][CH:20]=[O:2])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:10]([Cl:24])[CH:9]=1
Reactant: C=CCC(Cc1ccc(Br)cc1Cl)C(=O)OCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CC=O)Cc1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 75.7 %

Procedure:
Add sodium periodate (41 g, 190 mmol) into a solution of ethyl 2-(4-bromo-2-chlorobenzyl)pent-4-enoate (21 g, 63 mmol), 2.5 wt % OsO4 (64 g, 6.3 mmol) in THF (400 mL) and water (160 mL) and stir for 2 hours. Extract the reaction mixture with ethyl acetate, wash the organic layer with sodium thiosulfate solution and brine. Dry over sodium sulfate, filter and concentrate. Purify the residue with silica gel column to afford the title compound (15.9 g, 75%) as colorless oil.
Reaction SMILES: O1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.C(C1C(=O)C2[CH:18]=[CH:19][S:20]C=2CC1)C>>[CH2:3]([CH:4]1[CH:9]([NH2:10])[C:8]2[CH:18]=[CH:19][S:20][C:7]=2[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCC1CCc2sccc2C1=O
Reactant: NC1CCCc2occc21
Product: CCC1CCc2sccc2C1N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 5-ethyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.10, 7.05, 6.99, 3.98, 3.65, 2.87-2.73, 2.06-1.90, 1.74-1.19, 1.05-0.97. (MS/CI) calcd for C10H15NS+H 182.3, found 181.9.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][C:11]1[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:17]=2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:27])[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=2
Reactant: CCCCNc1nc(N)c2ncn(Cc3cccc(CC(=O)OC)c3)c2n1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCNc1nc(N)c2nc(Br)n(Cc3cccc(CC(=O)OC)c3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
After 2-butylamino-9-(3-methoxycarbonylmethylbenzyl)adenine obtained by Reference example 36 (0.23 g, 0.61 mmol) was dissolved in chloroform (10 ml), bromine (0.15 g, 0.92 mmol) was added thereto and the mixture was stirred at room temperature for 1 hour. After removing the solvent, the residue was poured into water and extracted with chloroform. The organic layer was washed with saturated sodium hydrogencarbonate, saturated sodium hydrogensulfite and saturated brine in that order, dried over anhydrous magnesium sulfate and concentrated to give the captioned compound (0.23 g, 0.51 mmol, yield: 83%) as a pale yellow solid.