Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:8]=1>[Pd]>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:16]([F:18])([F:17])[F:19])[CH:8]=1
Reactant: C[C@H]1CCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Pd]
Product: C[C@H]1CCCN1c1ccc(N)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A flask charged with (S)-2-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (2.45 g, 8.9 mmol) and palladium on carbon (245 mg, 10 wt %) was flushed with N2 followed by evacuating under vacuum. Methanol (15 mL) was added under inert atmosphere followed by evacuating under vacuum. The reaction mixture was stirred overnight under an atmosphere of H2. The palladium catalyst was removed by filtration and solvent was removed under reduced pressure to give (S)-4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethyl) aniline in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 6.78 (d, J=8.8 Hz, 1H), 6.70-6.67 (m, 1H), 6.47 (d, J=2.7 Hz, 1H), 4.68 (s, 2H), 3.76-3.69 (m, 1H), 3.32-3.27 (m, 1H), 3.02-2.96 (m, 1H), 2.05-1.94 (m, 2H), 1.93-1.84 (m, 1H), 1.64-1.58 (m, 1H), 1.05 (d, J=6.1 Hz, 3H). LC/MS: m/z 245.1 (M+H)+ at 0.48 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C@H:7]([OH:9])[CH3:8])[CH2:4][O:3]1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:13]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(OC(CO)CO)N=1>C1COCC1.[H-].[Na+]>[Cl:11][C:12]1[CH:17]=[C:16]([O:9][C@@H:7]([C@@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)[CH3:8])[N:15]=[C:14]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:13]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C[C@@H](O)[C@@H]1COC(C)(C)O1
Agent: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iii) using (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (prepared according to Liebigs, Ann. Chem. 1987, 7-14) (0.25 g) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step (0.53 g) in THF (20 mL) and 60% sodium hydride (80 mg). Crude material was purified by column chromatography on silica gel using EtOAc/isohexane (1:3) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.37 g.
Reaction SMILES: [S:1]1[C:5]2[C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.[BH4-].[Na+].O>O1CCCC1>[S:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1NCCCc2ccsc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1cc2c(s1)CNCCC2
Yield: 66.8 %

Procedure:
To a mixture of 6.7 g of 4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one and 4.5 g of sodium borohydride in 70 ml of tetrahydrofuran was added boron trifluoride-ether complex dropwise under ice-cooling and the mixture was refluxed under heating for an hour. The mixture was poured into water, washed with chloroform, made alkaline with 10% potassium hydroxide solution and extracted with chloroform. The extract was washed with water, dried and concentrated to give 4.1 g of 5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH3:5].C(Cl)[C:7](=[CH2:9])[CH3:8]>>[CH3:5]/[CH:4]=[CH:3]/[CH2:2][C:2]#[C:3][CH2:4][CH2:5][CH2:8][CH2:7][CH3:9]
Reactant: CC=CCBr
Reactant: C=C(C)CCl
Product: C/C=C/CC#CCCCCC

Procedure:
Obtained in 74% yield (as a 92:8 E/Z mixture) from 1-heptyn using 1-bromo-but-2-en and using methallylchloride according to the procedure described under a).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13]CC2C=CC(OC)=CC=2)[CH2:10][C@@H:9]1[C@H:23]1[O:27][C:26]([CH3:29])([CH3:28])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[C@H:23]1[O:27][C:26]([CH3:28])([CH3:29])[N:25]([C:30](=[O:32])[CH3:31])[C@H:24]1[CH2:33][C:34]1[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CO[C@@H]2C[C@H]([C@H]3OC(C)(C)N(C(C)=O)[C@H]3Cc3cc(F)cc(F)c3)N(C(=O)OC(C)(C)C)C2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)OC1(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To an ice cold solution of (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluorobenzyl)-2,2-dimethyloxazolidin-5-yl]-4-(4-methoxy-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.48 g, 13.0 mmol) in 20:1 dichloromethane:water (130 mL) add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.71 g, 20.74 mmol). Stir 4 h in an ice bath and wash with saturated aqueous sodium bicarbonate (3×300 mL), saturated aqueous sodium chloride, dry magnesium sulfate and purify on silica gel with dichloromethane/ethyl acetate mixtures to give the title compound as a foam (5.288 g, 89%).
Reaction SMILES: C[C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[Br:9].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:17]12[CH2:22][CH:21]1[CH2:20][NH:19][CH2:18]2>CN(C=O)C>[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:7][C:5]1[S:6][CH:2]=[C:3]([Br:9])[N:4]=1)[CH2:18]2
Reactant: C1NCC2CC12
Reactant: Cc1sc(CBr)nc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1csc(CN2CC3CC3C2)n1
Yield: 78 %

Procedure:
A solution of methyl 4-bromo-2-(bromomethyl)thiazole (prepared according to the procedure reported in US 2010/298388, 0.60 g, 2.33 mmol) in DMF (5 ml) was added to a potassium carbonate (0.48 g, 3.50 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride (0.33 g, 2.80 mmol) at 0° C. under stirring. The reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (5 ml). The mixture was then extracted with ethyl acetate (2×25 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; the crud product was further purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.47 g, 78%). MS: m/z 261 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[N:19]1(C(OCC)=O)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH-].[K+]>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(CCBr)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(C(CCN2CCNCC2)c2ccc(F)cc2)cc1
Yield: 84.7 %

Procedure:
31.1 g (0.100 mol) of 3,3-bis(4-fluorophenyl)propyl bromide, 20.6 g (0.130 mol) of ethyl piperazine-1-carboxylate, 27.6 g (0.200 mol) of powdered potassium carbonate and 4.15 g of potassium iodide were heated at the reflux temperature in 400 ml of toluene for 31 hours; the precipitate was then filtered off and the filtrate was concentrated. The material thus obtained was dissolved in 450 ml of ethanol, 450 ml of 4N KOH were added and the mixture was heated under reflux for 9 hours. After customary working up (compare Example 3d), 26.8 g of product, melting point 58°-64° C., were obtained.
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][C@@H:15]([NH:24]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:16]1[CH:21]=[C:20]([I:22])[CH:19]=[C:18]([F:23])[CH:17]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.N1CCCCC1.C(N1CCCCC1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>C(OCC)(=O)C>[P:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])([O:13][CH2:14][C@@H:15]([NH2:24])[C:16]1[CH:21]=[C:20]([I:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:7]
Reactant: CC(C)(C)OP(=O)(OC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc(F)cc(I)c1)OC(C)(C)C
Agent: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(OC[C@@H](N)c1cc(F)cc(I)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (S)-(9H-fluoren-9-yl)methyl (2-((di-tert-butoxyphosphoryl)oxy)-1-(3-fluoro-5-iodophenyl)ethyl)carbamate (6450 mg, 9.27 mmol) was added DMF (Volume: 90 mL) followed by piperidine (25 mL, 253 mmol) and stirred at room temperature for 30 minutes, followed by LCMS. To the crude reaction mixture was added 750 ml of ethyl acetate, washed with saturated sodium bicarbonate (2×), water (5×), saturated salt solution, dried sodium sulfate, and filtered. The solvent was concentrated off to constant mass under high vacuum to give the desire crude product which includes FMOC piperidine impurity, used as is. LCMS (m/z): 474.2 (MH+), 0.80 min.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][C:7]1[N:16]([CH2:17][C@H:18]2[CH2:20][C@@H:19]2[CH3:21])[C:10]2[C:11](=O)[NH:12][N:13]=[CH:14][C:9]=2[C:8]=1[CH3:22].[OH-].[Na+]>>[Cl:3][C:11]1[N:12]=[N:13][CH:14]=[C:9]2[C:8]([CH3:22])=[C:7]([CH3:6])[N:16]([CH2:17][C@H:18]3[CH2:20][C@@H:19]3[CH3:21])[C:10]=12
Reactant: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(=O)[nH]ncc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(Cl)nncc12
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 91.8 %

Procedure:
Phosphorus oxychloride (55 ml, 590 mmol) was added to 2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]-6,7-dihydropyrrolo[2,3-d]pyridazine-7-one (6.95 g, 30.1 mmol) and the mixture was stirred at 90° C. for 3.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and poured into ice-water. The aqueous solution was neutralized with a 5N aqueous sodium hydroxide solution and extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated in vacuo. Hexane was added to the residue and the precipitate was collected by filtration to afford the desired compound (6.90 g, 92.0%) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C@H:6]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:7][OH:8])=[O:4].[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>O1CCCC1>[C:24]([O:8][CH2:7][C@@H:6]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[NH:5][C:3](=[O:4])[C:2]([F:19])([F:20])[F:1])(=[O:25])[CH2:23][C:22]([CH3:21])=[O:26]
Reactant: C=C1CC(=O)O1
Reactant: O=C(OCc1ccccc1)[C@H](CO)NC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1

Procedure:
A solution of benzyl trifluoroacetyl-L-serinate (500 mg) and diketene (0.1 ml) in tetrahydrofuran (10 ml) was heated with reflux overnight. The solvent was distilled off and the residue was diluted with ethyl acetate and washed successively with water and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was chromatographed on silica gel eluting successively with methylene chloride and a 4:1 mixture of methylene chloride and acetone to give benzyl O-acetoacetyl-N-trifluoroacetyl-L-serinate (320 mg).
Reaction SMILES: Cl.O1CCOCC1.[C:8]1([CH:14]([C:16]2[N:17]=[CH:18][C:19]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][C:20]=3[N:33]=2)[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([CH:14]([C:16]2[N:17]=[CH:18][C:19]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21][C:20]=3[N:33]=2)[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(c1ccccc1)c1ncc2c(n1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(c1ccccc1)c1ncc2c(n1)CCNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of HCl in dioxane (1.0 mL, 4M, 4.0 mmol) was added to a solution of tert-butyl 2-(1-phenylethyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate of Preparation 2, Step D, (150 mg, 0.40 mmol) in CH2Cl2 (2.0 mL). The mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of sat sodium bicarbonate and extracted into CH2Cl2. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the crude product as a brown gum (45 mg). The title compound was purified by reverse phase HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[O-2].[Mg+2].[Cl:24][CH2:25][C:26](Cl)=O>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:26]([CH2:25][Cl:24])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Cl)c2C1=O
Reactant: O=C(Cl)CCl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.0 g 7-Chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime and 1.0 g magnesium oxide were suspended under stirring and argon atmosphere in 160 ml 1,4-dioxane. 2.7 ml Chloracetyl chloride were added in one portion and the white thick gel obtained was stirred 4 hours at r.t. and then 17 hours at reflux to give a lightly orange fluid suspension. 100 ml Dioxane were distilled off and the reaction mixture was cooled to room temperature. 180 ml Deionized water were added within 15 minutes and the suspension was stirred 1 hour at r.t. The precipitate was filtered off, washed with 50 ml deionized water twice and dried under vacuum at 80° C. for 18 hours. Crude product: 8.3 g as a light pink powder. This crude product was dissolved in 120 ml tetrahydrofuran at reflux and 0.83 g active charcoal Darco G 60 were added. The system was refluxed 1 hour, then filtered on 25 g Dicalit-Speedex and the filter cake was washed with three portions of 50 ml warm tetrahydrofuran. The filtrate was concentrated at 40° C. under reduced pressure. The residue was digested in 80 ml ethanol 1 hour at reflux, then stirred 16 hours at r.t. and finally 2 hours at 2° C. The precipitate (7-chloro-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo [1,5-a][1,4]benzo-diazepin-6-one (IX)) was filtered off, washed with 2 portions of 25 ml cold tert-butyl methyl-ether and dried under vacuum 5 hours at 80° C. Crude product: 7.6 g as a light beige powder. m.p. 234-238° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.F[C:14]1[N:19]=[CH:18][C:17]([N:20]2[C:24](=[O:25])[C:23]([CH3:27])([CH3:26])[NH:22][C:21]2=[O:28])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:26][C:23]1([CH3:27])[NH:22][C:21](=[O:28])[N:20]([C:17]2[CH:18]=[N:19][C:14]([O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)=[CH:15][CH:16]=2)[C:24]1=[O:25]
Reactant: CC1(C)NC(=O)N(c2ccc(F)nc2)C1=O
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc(OC(F)(F)F)c3)nc2)C1=O
Temperature: 120 °C
Reaction time: 22 h
Yield: 53.9 %

Procedure:
3-[(trifluoromethyl)oxy]phenol (19.95 mg, 0.112 mmol) was dissolved in 1 mL of dimethylformamide. 3-(6-fluoro-3-pyridinyl)-5,5-dimethyl-2,4-imidazolidinedione (Intermediate 106, 25 mg) and potassium carbonate (31.0 mg, 0.224 mmol) were added. The reaction mixture was stirred at 120° C. during 22 hours. Some diethylether (4 mL) and water (4 mL) were added. The aqueous layer was extracted 4 times with diethylether. The gathered organic layers were dried over sodium sulphate and evaporated giving a residue, which was purified by mass directed purification (METHOD I). After evaporation of the fraction, addition of a solution of saturated NaHCO3 (3 mL) and extraction with dichloromethane (four times 4 mL), evaporation afforded the title compound as a white solid (23 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:14][C:8]=2[C:7]=1[OH:19])=[O:5])[CH3:2].[Br:20]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:20])[C:9]2[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:14][C:8]=2[C:7]=1[OH:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2nc(C(C)(C)C)sc2c1O
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Yield: 68.6 %

Procedure:
A solution of 2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (3.87 g, 13.8 mmol, example 166(d)), N-bromosuccinamide (2.67 g, 15 mmol), and benzoyl peroxide (315 mg, 1.3 mmol) in 46 mL of carbon tetrachloride was heated at reflux temperature for 4 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography, eluting the desired product from silica gel with a gradient of 0-30% ethyl acetate in hexanes to give 3.4 g of the title compound. MS (ESI−): 356.99, 358.98 e/z (M−1, 79Br/81Br).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]([C:13]2[CH:17]=[CH:16][N:15]([C:18](=[O:20])[CH3:19])[N:14]=2)C(=O)C)=[N:6][C:5]=1[CH3:21])(=[O:3])[CH3:2].[BrH:22].BrBr>CC(O)=O>[BrH:22].[C:18]([N:15]1[CH:16]=[CH:17][C:13]([NH:9][C:7]2[S:8][C:4]([C:1](=[O:3])[CH2:2][Br:22])=[C:5]([CH3:21])[N:6]=2)=[N:14]1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1sc(N(C(C)=O)c2ccn(C(C)=O)n2)nc1C
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: CC(=O)n1ccc(Nc2nc(C)c(C(=O)CBr)s2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 1491.2 %

Procedure:
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N-(1-acetyl-1H-pyrazol-3-yl)acetamide (689.3 mg; 2.25 mmol; 1 eq.) is dissolved in AcOH (10 ml) and hydrobromic acid (39 μl; 0.22 mmol; 0.10 eq.). A solution of bromine (115 μl; 2.25 mmol; 1 eq.) in AcOH (2 ml) is added dropwise. The reaction mixture is stirred 3 h at rt and 2 h at 60° C. In order to complete the reaction, a solution of bromine (58 μl; 1.12 mmol; 0.50 eq.) in AcOH (2 ml) is added and the mixture is stirred 4 h at 60° C. It is cooled down to rt and the resulting precipitate is filtered, washed with cyclohexane and dried under reduced pressure to give, affording Intermediate 4 (695.7 mg; 73%). It is used in bis-thiazol synthesis as HBr salt or as parent, after 5 min treatment with Amberlyst A21 in DCM/MeOH mixture. 1H NMR (DMSO-d6, 300 MHz) δ 2.57 (s, 3H), 2.64 (s, 3H), 4.63 (s, 2H), 6.36 (d, J=6 Hz, 1H), 8.35 (d, J=6 Hz, 1H). M− (ESI): 342.96; M+ (ESI): 344.94. HPLC (Method A), Rt: 3.08 min (purity: 91.91%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>CC(C)=O.C([O-])(O)=O.[Na+].O>[Cl:1][C:2]1[N:7]=[C:6]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyrimidine (Compound 1a) (5.82 g; 30.0 mmol) in acetone (480 mL), cooled to 0° C., was added a solution of 4-methoxy-phenol (3.75 g; 30.0 mmol) in a mixture of 1 N NaHCO3(aq) (30 mL) and H2O (120 mL) dropwise by an addition funnel. After completion of addition, the reaction mixture was allowed to warm to ambient temperature, and was then stirred at room temperature for 3 h. The resultant mixture was evaporated in vacuo, and the residue was washed sequentially with EtOAc, 1 N NaOH(aq), and H2O. The organic phase was washed sequentially with H2O and brine, and dried over Na2SO4. The mixture was filtered and the solvent was evaporated under reduced pressure to give the crude material. The crude material was recrystallized from Et2O-hexanes to afford Compound 1b (7.70 g; 91% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 7.13-7.15 (m, 2H), 6.98-7.01 (m, 2H), 3.87 (s, 3H); MS: m/z 282.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1>>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[C:20]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: Nc1cc([N+](=O)[O-])cc(S(N)(=O)=O)c1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc([N+](=O)[O-])cc(S(N)(=O)=O)c3)nc21
Yield: 232.1 %

Procedure:
Starting from 2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (3.15 g; 4.502 mmol) and 3-amino-5-nitro-benzenesulfonamide (3.49 g; 14.502 mmol), 4.4 g (10.45 mmol; 72% yield) of the desired nitro-product were obtained as a powder.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH2:13][C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:14]1([OH:17])[CH2:13][CH2:12][CH2:11][CH:10]2[CH:15]1[CH2:16][NH:8][CH2:9]2
Reactant: COc1ccccc1C1(O)CCCC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C1(O)CCCC2CNCC21
Temperature: 60 °C
Yield: 48.8 %

Procedure:
A mixture of 16 g of (3aRS,4RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-4-perhydroisoindolol and 200 cm3 of anhydrous ethanol is heated at 60° C. with stirring; 2 g of 20% palladium hydroxide on charcoal are added and the reaction mixture is then hydrogenated, with stirring, at a temperature of 60° C. and at atmospheric pressure. After reaction for 6 hours the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). 5.72 g of (3aRS,4RS,7aSR)-4-(2-methoxyphenyl)-4-perhydroisoindolol are obtained in the form of a cream-coloured foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][S:10][C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)[CH:6]=[CH:7][CH:8]=1.[Se](=O)=[O:21].OO.O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][S:10]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: O=[Se]=O
Reactant: COc1cccc(CSc2nc3cnccc3[nH]2)c1
Agent: OO
Solvent: O
Solvent: CO
Product: COc1cccc(CS(=O)c2nc3cnccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[[(3-Methoxyphenyl)methyl]thio]-1H-imidazo[4,5-c]pyridine (9.88 g, 0.036 mol) was dissolved in 130 mL of methanol by heating. An oxidizing solution was prepared by dissolving 4.0 g (0.036 mol) of selenium dioxide in 150 mL of methanol with heating followed by the addition of 4.07 g (0.036 mol) of 30% hydrogen peroxide and 2.5 mL of water. The oxidizing solution was cooled to room temperature and was added dropwise to the sulfide solution. The reaction mixture was stirred overnight. The precipitate which had formed was collected on a filter and rinsed with petroleum ether giving 4.68 g of product. An analytical sample (m.p. 176°-179° C.) was obtained by recrystallization from ethanol.