Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][C:2]12[CH2:10][OH:11].[F:12][C:13]([F:47])([F:46])[C:14]1[CH:15]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32](Cl)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:16]([C:24]([CH3:45])([CH3:44])[C:25]([N:27]([C:29]2[CH:30]=[N:31][C:32]([N:6]3[CH2:5][CH2:4][N:3]4[CH2:7][CH2:8][CH2:9][C:2]4([CH2:10][OH:11])[CH2:1]3)=[CH:33][C:34]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[CH3:42])[CH3:28])=[O:26])[CH:15]=[C:14]([C:13]([F:47])([F:12])[F:46])[CH:19]=1
Reactant: OCC12CCCN1CCNC2
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCCC3(CO)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 10.5 %

Procedure:
To a solution of hexahydropyrrolo[1,2-a]pyrazin-8a(6H)-ylmethanol (D67, 35 mg) in methyl sulfoxide (1.5 mL), 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (60 mg) and potassium carbonate (63 mg) were added. The resulting mixture was heated at 150° C. for 24 hours. The mixture was allowed to cool down to r.t and further D67 (17 mg) and potassium carbonate (15 mg) were added. The resulting mixture was heated at 150° C. for further 8 hours and then it was allowed to cool to r.t. and diluted with water (2 mL). The aqueous phase was extracted with ethyl acetate (3×2.5 mL). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified twice by flash chromatography (first purification: EtOAc/Cycl from 80/20 to 100:0 then DCM/MeOH 95:5. Second purification: DCM/MeOH 98:2) to give the desired compound (7.7 mg) as yellow foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:8]=1[C:9]#[N:10].C1CCCCC=1>CCO.[Pd]>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:8]=1[C:9]#[N:10]
Reactant: COCCCNc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COCCCNc1cccc(N)c1C#N
Temperature: 100 °C
Yield: 84.5 %

Procedure:
To a solution of 2-(3-methoxypropylamino)-6-nitrobenzonitrile (Example 258c) (0.58 g, 2.48 mmol) in EtOH (20 mL) was added cyclohexene (1.26 mL, 12.4 mmol). Then 10% Pd/C (1.32 g) was added, and the reaction mixture was refluxed at 100° C. for 20 minutes, cooled to room temperature, filtered trough Celite which was washed with EtOH (3×20 mL), and evaporated to give 2-amino-6-(3-methoxypropylamino)benzonitrile (0.43 g, 84%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 1.71-1.77 (m, 2H), 3.10 (q, J=6.8 Hz, J=6.8 Hz, 2H), 3.22 (s, 3H), 3.37 (t, J=3.2 Hz, 2H), 5.55 (t, J=5.2 Hz, NH), 5.63 (s, NH2), 5.79 (d, J=7.6 Hz, 1H), 5.93 (d, J=8.0 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H). MS 206 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]([OH:21])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]([O:21][CH2:22][CH3:23])=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Sodium hydride (60%, oily, 1.20 g) was added to a solution of ethyl 1-benzyl-3-hydroxy-1H-pyrazol-4-ylacetate (7.81 g) in N,N-dimethylformamide (100 ml) at 0° C., which was stirred at room temperature for 15 minutes. Ethyl iodide (2.40 ml) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-benzyl-3-ethoxy-1H-pyrazol-4-ylacetate (7.52 g, yield 87%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[NH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:28]1([S:34]([CH2:37][C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[CH2:40]Br)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH2:40][C:39]2[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=2[CH2:37][S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[N:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]2[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n[nH]c21
Reactant: O=S(=O)(Cc1ccccc1CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n(Cc3ccccc3CS(=O)(=O)c3ccccc3)nc21
Yield: 41.8 %

Procedure:
3-[(3-Hydroxypropyl)thio]-5-methyl-7-(2-methylpropyl)-1H-pyrazolo[3,4-d]-pyrimidine-4,6(5H,7H)-dione (94 mg), potassium carbonate (90 mg) and 2-(phenylsulfonylmethyl)benzyl bromide (105 mg) were combined in dimethylsulfoxide (11 ml). After 5 hours at room temperature the reaction mixture was diluted with ethyl acetate and washed thrice with water, twice with dilute hydrochloric acid, once with brine, then dried over magnesium sulfate and then concentrated in vacuo. Chromatography on silica gel (isohexane:isopropanol 4:1) gave the title compound (70 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[CH3:1][C:2]1([CH3:12])[CH2:7][S:6](=[O:9])(=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH+:3]1[O-:18]
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CS(=O)(=O)CC(C)(C)[NH+]1[O-]
Temperature: 25 °C

Procedure:
5.7 g (0.03 mole) of 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is dissolved in 100 ml of methylene chloride. To this solution there is then added dropwise at 20°C in ca. 90 minutes a solution of 11.2 g of m-chloroperoxybenzoic acid in 100ml of methylene chloride. The reaction is slightly exothermic. Stirring is subsequently maintained for 15 hours at room temperature, and the precipitated m-chlorobenzoic acid filtered off. The reddish coloured methylene chloride solution is extracted twice with 50 ml of 2N sodium hydroxide solution each time, and then with 50 ml of 2N hydrochloric acid, and subsequently dried over sodium sulphate. After the solvent has been distilled off, the residue is crystallised from ethanol to obtain 2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-1,4,4-trioxide (8) of the formula ##SPC12##
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[CH3:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH3:5])=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(C(C)=O)cc1

Procedure:
A mixture of 12.3 g. of 1-propyl bromide, 13.6 g. of 4-hydroxyacetophenone, 27.6 g. of potassium carbonate and 200 ml. of acetone was refluxed overnight. The mixture was then cooled, filtered, the filtrate concentrated and distilled in a Kugelrohr. The distillate was dissolved in ethyl acetate, treated with charcoal, filtered through diatomaceous earth, concentrated and dried, giving the desired intermediate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:9]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:17]=[N:16]2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[C:9]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:17]=[N:16]2)[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Temperature: -80 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 3.5 g (8.2 mmoles) of ethyl 3,3-bis-(4-fluorophenyl)-2-(5-phenyl-1H-tetrazol-1-yl)-2-propenoate in 75 mL of dry methylene chloride at -80° C. under argon was added dropwise 18 mL (1.0M, 18 mmoles) of diisobutylaluminum hydride in methylene chloride. The clear solution was stirred at -80° C. for 10 minutes then monitored by TLC. An additional 5 mL of diisobutylaluminum hydride in methylene chloride was added to the mixture and stirring was continued for 30 minutes. The reaction mixture was quenched with 2M HCl and the product was extracted into ethyl acetate. The organic layers were combined, dried over MgSO4 and evaporated to a semi-solid. Recrystallization from ethyl acetate-hexanes mixture gave 3.2 g (99%) of the title compound; m.p.=196.6°-197.6° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:23])[CH:4]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[CH2:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Solvent: C1COCCO1
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Reaction time: 6.5 h

Procedure:
To a suspension of 3-(3,5-dimethoxy-phenyl)-2-(4-hydroxy-phenyl)-acrylic acid methyl ester (2.1 g) in dioxane (60 mL) 10% palladium on carbon (50% wet, 2.1 g) was added. Hydrogenation was carried out in a Parr shaker at 70 psi for 6.5 h. Catalyst was filtered through a bed of Celite and solvent was evaporated. Yield: quantitative. Analysis: 1HNMR (CDCl3): δ7.15 (d, J=8.7 Hz, 2H), 6.74 (d, J=8.7 Hz, 2H), 6.29 (t, J=2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 2H), 3.78 (t, J=8.7 Hz, 1H), 3.72 (s, 6H), 3.62(s, 3H), 3.31(dd, J=13.5 & 8.4 Hz, 1H), 2.93 (dd, J=13.5 & 6.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[H-].[Na+].[C:14]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24](SC)[S:25][CH3:26])(=[O:22])=[O:21].O>CN(C)C=O>[C:14]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:24](=[N:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1)[S:25][CH3:26])(=[O:21])=[O:22]
Reactant: CSC(=NS(=O)(=O)c1ccccc1-c1ccccc1)SC
Reactant: COc1nc(N)nc(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(N=C(NS(=O)(=O)c2ccccc2-c2ccccc2)SC)nc(OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine were suspended in 300 ml of dimethylformamide, and 4 g of sodium hydride (oily, 60%) were added to the suspension. The mixture was stirred at room temperature for 1 hour. Furthermore, 33.7 g of dimethyl N-(2-biphenylylsulfonyl)carbonimidodithioate were added, and the mixture was stirred at room temperature for a day and night. The reaction mixture was poured into 2 liters of water and filtered. The filtrate was made weakly acidic to precipitate white crystals. The crystals were collected by filtration and recrystallized from ethanol to give 36.2 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl) 2-methylisothiourea (compound No. II-1), the same compound as obtained in Example 5. The melting point of the product was 135° to 137° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19]>ClCCl>[C:18](=[O:19])([O:20][CH3:21])[O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:9]
Reactant: COC(=O)Cl
Reactant: Cc1cc(Br)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(Br)cc1C
Temperature: 25 °C
Yield: 86.2 %

Procedure:
4-Bromo-2-methyl-phenol (3.63 g, 19.41 mmol) was dissolved in dichloromethane (18 mL) and triethylamine (5.41 mL, 38.80 mmol), cooled to 0° C., then treated with methyl chloroformate (2.25 mL, 29.12 mmol) and allowed to warm to room temperature over 2 h. The reaction was quenched with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined organic extracts was dried over Na2SO4, filtered, and concentrated in vacuo to yield an oil that was purified by silica gel chromatography (10% ethyl acetate/hexane) to yield 4-bromo-2-methylphenyl methyl carbonate (4.1 g, 86% yield) as a white solid. 1H NMR (400.0 MHz, DMSO-d6) δ 7.56 (d, J=2.1 Hz, 1H), 7.44 (dd, J=2.3, 8.6 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 3.84 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C.C(OCC)(=O)C>[O:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:19][CH2:18][CH:17]=[CH2:16])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12]
Reactant: C=CCCBr
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc2ccc(=O)oc2c1
Temperature: 60 °C
Yield: 63.7 %

Procedure:
A suspension of 7-hydroxycoumarin (3 g, 19.6 mmol) in DMF (20 ml) is treated with NaH (60% suspension in oil, 1.03 g, 25.9 mmol), then with 4-bromo-1-butene (2.65 g, 19.6 mmol). It is heated to 60° C. for 24 hours, then it is diluted with ethyl acetate (400 ml), and it is washed with water (3×300 mL) then with 1 M NaOH (3×200 ml). The residue is chromatographed with the mixture (ethyl acetate-hexane) to obtain 4-(7-coumarinyloxy)-1-butene (2.7 g, 67%).
Reaction SMILES: [NH2:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31](Cl)=[O:32])[CH:29]=1>ClCCl>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31]([NH:1][C:2]2([C:12]([O:14][CH3:15])=[O:13])[CH2:3][CH2:4][C:5]3([O:9][CH2:8][CH2:7][O:6]3)[CH2:10][CH2:11]2)=[O:32])[CH:29]=1
Reactant: COC(=O)C1(N)CCC2(CC1)OCCO2
Reactant: Cc1ccc(Br)cc1CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, 5.47 g (25.41 mmol) of methyl 8-amino-1,4-dioxaspiro[4.5]decane-8-carboxylate [T. Satoh et al., Tetrahedron 63 (2007), 4806-4813], 3.86 g (38.12 mmol) of triethylamine and 155 mg (1.27 mmol) of N,N-dimethylaminopyridine were dissolved in 45 ml of dichloromethane. A solution of 6.29 g (25.41 mmol) of (5-bromo-2-methylphenyl)acetyl chloride (Example 3A) in 45 ml of dichloromethane was then added dropwise to the mixture. The resulting reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution. After drying over sodium sulphate, the mixture was concentrated by evaporation and the residue was purified by chromatography on silica gel (mobile phase: hexane/ethyl acetate gradient/1% triethylamine) Evaporation and drying gave 3.64 g (34% of theory) of the title compound which was used without further characterization in the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][C:10]3[C:11]([CH:21]=[CH2:22])(O)[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:25]>C(O)(=O)C>[C:1]1([C:7]2[CH:24]=[CH:23][C:10]3[C:11](=[CH:21][CH2:22][Br:25])[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br
Reactant: C=CC1(O)c2ccccc2CCc2cc(-c3ccccc3)ccc21
Solvent: CC(=O)O
Product: BrCC=C1c2ccccc2CCc2cc(-c3ccccc3)ccc21
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
A suspension of the above alcohol (1.56 g, 5.06 mmol) in acetic acid (15 mL) was stirred and treated at 15° C. with 15% solution of hydrogen bromide in acetic acid (10 mL) over 15 min. The mixture was stirred at 15° C. for 30 min and then at laboratory temperature for 1.5 h and evaporated in vacuo. The rest of acetic acid was removed by addition of 40 mL xylene and evaporation in vacuo and the residue was chromatographed in a short column of silica gel Fluka 60 (75 g, benzene). The benzene solutions were evaporated in vacuo to yield 1.58 g (87.5%) of 2-phenyl-5-(2-bromo-ethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:9]=1)=[O:7])[CH3:4].[CH3:36]I>[Ag]=O.CC#N>[CH3:36][O:1][CH2:2][C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COC[C@@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 40 °C
Yield: 44.5 %

Procedure:
In a 25 mL round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide (70 mg, 0.136 mmol), silver oxide (51 mg, 0.22 mmol) and methyl iodide (100 μl, 1.6 mmol) were combined with MeCN to give a black suspension. The round bottom flask was wrapped in foil to exclude light. The system was placed in a sand bath and heated to 40° C. with stirring. The temperature was maintained for 2 days. Upon cooling, the reaction mixture was filtered through a pad a celite. The filtrate was concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0%-40% EtOAc) to afford 32 mg (45%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. [M+Na]+=551.
Reaction SMILES: O=O.[O:3]=[O+][O-].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:17]1([CH:23]([O:30][C:31]([C@@H:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=C)=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CSC>CO>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1.[C:24]1([CH:23]([O:30][C:31]([CH:33]2[N:38]3[C:39](=[O:42])[C@@H:40]([NH2:41])[C@H:37]3[S:36][CH2:35][C:34]2=[O:3])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[O+][O-]
Reactant: C=C1CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=O
Solvent: CO
Solvent: CSC
Product: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Temperature: -12 °C
Reaction time: 0.08 h

Procedure:
A stream of oxygen and ozone (containing 0.35 mmol of ozone per minute) is passed for 4 minutes through a solution, cooled to -60° C., of 0.553 g of the 4-methylphenylsulphonate of 7β-amino-3-methylene-cepham-4α-carboxylic acid diphenylmethyl ester in 50 ml of methanol. After a further 5 minutes, the pale blue-coloured solution is treated with 0.3 ml of dimethyl sulphide. The mixture is stirred for 15 minutes at -70° C., for one hour at -12° C. and for one hour in an ice bath and is then evaporated. The residue is taken up in a small amount of methylene chloride, diethyl ether is then added until the mixture turns cloudy, and the mixture is left to stand. The microcrystalline, reddish-coloured pulverulent precipitate is filtered off and yields the 4-methylphenylsulphonate of 7β-amino-cepham-3-one-4ξ-carboxylic acid diphenylmethyl ester which is mainly present in the enol form as the 4-methylphenylsulphonate of 7β-amino-3-cephem-3-ol-4-carboxylic acid diphenylmethyl ester, melting point=143° -145° C. (with decomposition); thin layer chromatogram (silica gel) Rf~0.28 (system: ethyl acetate/pyridine/water, 85:10:5); ultraviolet absorption spectrum (in ethanol): λmax =262 mμ (ε=3,050) and 282 mμ (ε=3,020); infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58μ, 5.77μ (shoulder), 6.02μ and 6.22μ.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1F)[C:22]#[N:23]>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[S:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2)[C:22]#[N:23]
Reactant: Sc1cccc2cnccc12
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2cccc3cnccc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
According to the method in Example 10, 5-isoquinolinethiol 1.00 g (6.2 mmol), DMF 30 ml, potassium carbonate 1.60 g (11.6 mmol) and 3-chloro-4-fluorobenzonitrile 0.90 g (5.8 mmol) were stirred at 100° C. for 30 minutes, and 3-chloro-4-(5-isoquinolylsulfanyl)benzonitrile 1.55 g (90.3%) was obtained.
Reaction SMILES: [N:1]1([C:7]2[C:12]3[CH:13]=[CH:14][O:15][C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>ClCCCl.CO>[O:15]1[C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]4)[CH2:5][CH2:6]3)[C:12]=2[CH:13]=[CH:14]1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2occc2c(N2CCNCC2)n1
Solvent: CO
Solvent: ClCCCl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of commercially available 4-piperazine-1-yl-furo[3,2-c]pyridine [CAS-Nr. 81078-84-4] (125 mg, 0.62 mmol) in 1,2-dichloroethane (1.25 ml) were added trans-N-[4-(2-oxo-ethyl)-cyclohexyl]-acetamide [CAS-Nr. 946599-01-5, WO 2007/093540] (124 mg, 0.68 mmol) and 3 drops of MeOH. The resulting yellow solution was stirred 18 h at room temperature before addition of Na(AcO)3BH (196 mg, 0.92 mmol). After stirring 18 h at room temperature the reaction mixture was partitioned between sat. aq. NaHCO3 sol. (50 ml) and EtOAc (50 ml). The aqueous layer was extracted with more EtOAc (2×25 ml). The combined organic layers were washed with H2O (40 ml) and brine (40 ml) and dried over MgSO4. After evaporation of the solvent, the crude product (yellow crystals) was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 95:5) to yield the title compound as light yellow crystals (95 mg, 42%), MS (ISP) m/z=371.2 [(M+H)+].