Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]([Br:25])=[CH:15][N:14]=2)=[O:12])([C:6](=[NH:9])[NH:7][OH:8])[CH3:5])[CH2:3][CH2:2]1.[CH2:26](N(CC)CC)[CH3:27].C(OC(=O)C)(=O)C>CN(C=O)C>[CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[C:16]([Br:25])=[CH:15][N:14]=2)=[O:12])([C:6]2[N:9]=[C:26]([CH3:27])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)(C(=N)NO)C1CC1
Reactant: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)C2CC2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(N-hydroxycarbamimidoyl)-ethyl]-amide (Example 78f, 800 mg, 1.88 mmol) in dry DMF (10 ml) was added triethylamine (190 mg, 262 μl, 1.88 mmol) followed by addition of acetic anhydride (192 mg, 1.88 mmol). The reaction mixture was stirred at room temperature for 1 hours and was then stirred at 125° C. for 30 min under microwave radiation. DMF was removed in vacuo and the residue was dissolved in ethylacetate which was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (492 mg, 47%) as a light yellow oil. MS (ESI, m/z): 449.3 (M+H+).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:8]([O:15][N:16]1[C:22](=[O:23])[N:21]2[CH2:24][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C:25]1[O:29][C:28]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)=[N:27][N:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH2:32][CH2:31][CH2:30][C:28]1[O:29][C:25]([C@@H:20]2[CH2:19][CH2:18][C@@H:17]3[CH2:24][N:21]2[C:22](=[O:23])[N:16]3[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:26][N:27]=1
Reactant: CC(C)(C)OC(=O)NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
TFA (0.5 mL) was added to a 0° C. solution of tert-butyl 2-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethylcarbamate (85 mg, 0.192 mmol) in CH2Cl2 (2.0 mL). The reaction mixture was stirred at 0° C. for 2 hrs and was then concentrated under vacuum to provide (2S,5R)-2-(5-(2-aminoethyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one TFA salt as a sticky oil, which was used directly in the next step. ESI-MS (EI+, m/z): 344.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Yield: 75.2 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.150 g; 0.415 mmol), LHMDS 1N in THF (0.462 mL; 0.462 mmol), 1-iodopropane (0.066 mL; 0.677 mmol) in DMF (6 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-30%) in heptane furnished 0.126 g (75%) of the title compound as a colorless oil.
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5](=[CH:7][CH2:8][CH2:9]/[C:10](=[CH:12]/[CH:13]=[O:14])/[CH3:11])[CH3:6].[NH4+].[Cl-].[CH3:17]CCCCC>COC(C)(C)C.O>[CH3:11][C:10]([CH2:9][CH2:8][CH:7]=[C:5]([CH3:4])[CH3:6])=[CH:12][CH:13]([OH:14])[CH3:17]
Reactant: CCCCCC
Reactant: CC(C)=CCC/C(C)=C/C=O
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)=CCCC(C)=CC(C)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
1 l of t-butyl methyl ether and 1.05 l of 3N methyl magnesium chloride solution were placed under N2 in a 41/2 l sulphonation flask having a thermometer, stirrer and dropping funnel and 456 g of geranial in 500 ml of t-butyl methyl ether were added dropwise at 0° C. The mixture was stirred at 10° C. for 1 hour and poured on to 3 kg of ice and 500 g of NH4Cl and treated with 1 l of hexane. After mixing well the H2O phase was separated and washed neutral 3 times with 500 ml of NH4Cl solution, dried and evaporated.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:30][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH:27]([CH3:28])[CH3:29])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CC(C)Oc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-isopropoxy-1H-pyrrolo[2,3-b]pyridine (236 mg, 0.55 mmol) and 10% palladium on activated carbon (40 mg) in methanol (200 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb pressure for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-isopropoxy-1H-pyrrolo[2,3-b]pyridine (180 mg, 76%) as a white solid: LC/MS m/e calcd for C24H30N2O3S [M+H]+ 427.58, observed 427.2; 1H NMR (400 MHz, CD3OD) δ ppm 7.88-7.92 (m, J=8.3 Hz, 2H), 7.81 (d, J=2.3 Hz, 1H), 7.58-7.63 (m, J=8.3 Hz, 2H), 7.51 (d, J=2.5 Hz, 1H), 6.33 (s, 1H), 4.53 (dt, J=12.1, 6.1 Hz, 1H), 4.30 (t, J=7.8 Hz, 1H), 3.10 (s, 3H), 2.24-2.32 (m, 1H), 2.07-2.15 (m, 1H), 1.61-1.88 (m, 5H), 1.46-1.57 (m, 2H), 1.18-1.35 (m, 8H).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[F:36]>>[F:36][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:28]=1[CH2:27][N:3]1[C:2]([I:1])=[CH:6][N:5]=[CH:4]1)[C:32]#[N:33]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(Cn2cncc2I)c(F)c1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-iodo-1-trityl-1H-imidazole (17.1 g, 39.2 mmol) and 4-bromomethyl-3-fluorobenzonitrile (9.65 g, 45.08 mmol) in 150 mL of dry actetonitrile is stirred at room temperature for 7 days. After concentration, the residue is mixed with methanol, and heated to reflux for 1.5 h. The solvent is subsequently removed and the residue is treated with 1M HCl (300 mL). The resulting suspension is filtered and the washed with HCl (1M). The combined solution is adjusted to PH 9-10 by saturated NaHCO3 solution. The resulting precipitation is collected by filtration, dried in vacuum oven. MS (ESI) m/z (M+H) 328.1.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=[S:8].[Br:9][CH2:10][CH2:11][NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:41])[CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29]([OH:36])=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:27]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(OC)(C)(C)C>C(O)CC.C(OCC)(=O)C>[Br-:9].[C:32]([C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([S:13]([NH:12][CH2:11][CH2:10][S:8][C:3]3[N:4]=[CH:5][CH:6]=[CH:7][N+:2]=3[CH3:1])(=[O:14])=[O:15])=[CH:17][CH:18]=2)=[O:41])[CH:27]=[C:28]([C:37]([CH3:39])([CH3:40])[CH3:38])[C:29]=1[OH:36])([CH3:33])([CH3:34])[CH3:35]
Reactant: Cn1cccnc1=S
Reactant: CC(C)(C)c1cc(CCC(=O)Nc2ccc(S(=O)(=O)NCCBr)cc2)cc(C(C)(C)C)c1O
Solvent: COC(C)(C)C
Solvent: CCCO
Solvent: CCOC(C)=O
Product: C[n+]1cccnc1SCCNS(=O)(=O)c1ccc(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Product: [Br-]

Procedure:
A stirred mixture of 1-methyl-1H-pyrimidine-2-thione (2.76 g, 0.0219 mol) and N-[4-(2-bromo-ethylsulfamoyl)-phenyl]-3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-propionamide (9.98 g, 0.0185 mol) in 1-propanol (25 ml) was heated at reflux for 2.5 hours. The mixture was spin-evaporated in vacuo to give a solid residue. The residue was dissolved in ethyl acetate (200 g) and mixed with tert.-butyl-methyl ether (20 g) to give two liquid phases. The lower phase was concentrated in vacuo to give2-(2-{4-[3-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-propionylamino]-benzenesulfonylamino} -ethylsulfanyl)-1-methyl-pyrimidin-1-ium bromide.
Reaction SMILES: [CH:1]1([N:4]([CH3:19])[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]#[C:14][Si](C)(C)C)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]#[CH:14])[CH:7]=2)[CH3:19])[CH2:3][CH2:2]1
Reactant: Cc1ccc(CN(C)C2CC2)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(CN(C)C2CC2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A solution of cyclopropyl-methyl-(4-methyl-3-trimethylsilanylethynyl-benzyl)-amine (Intermediate 98, 0.95 g, 3.5 mmol) in methanol (10 mL) was treated with potassium carbonate (2.3 g, 16.6 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1 h. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (0.67 g, 96%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[C:21]([O:33][CH3:34])[CH:20]=4)=[C:14]([CH2:35][CH2:36][CH3:37])[N:13]4[N:38]=[CH:39][CH:40]=[C:12]34)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl.[OH-:42].[Na+].O1CC[CH2:46][CH2:45]1>C(OCC)(=O)C>[CH2:45]([O:4][C:3](=[O:42])[CH2:2][O:1][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]#[N:32])=[C:21]([O:33][CH3:34])[CH:20]=3)=[C:14]([CH2:35][CH2:36][CH3:37])[N:13]3[N:38]=[CH:39][CH:40]=[C:12]23)[CH2:9][CH2:10]1)[CH3:46]
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(OC)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(OC)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methoxybiphenyl-2-carbonitrile (0.25 g) in tetrahydrofuran (3 mL) was added 3M hydrochloric acid (3 mL), and the mixture was stirred at 60° C. for 12 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 1 M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (3 mL)-tetrahydrofuran (3 mL). Thereto was added sodium borohydride (0.019 g) at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in methylene chloride (2 mL), rhodium acetate (dimer, 0.020 g) and then ethyl diazoacetate (0.86 mL) were added dropwise, and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.13 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[C:7](/[C:8](/O)=[CH:9]\[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20].C1C(=O)N(Br)C(=O)C1.[CH:38]1([C:42](=[S:44])[NH2:43])[CH2:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[C:7]([C:8]2[N:43]=[C:42]([CH:38]3[CH2:41][CH2:40][CH2:39]3)[S:44][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Reactant: NC(=S)C1CCC1
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (1.2 g, 2.5 mmol), NBS (0.45 g, 2.5 mmol) and cyclobutanecarbothioamide (0.29 g, 2.5 mmol) the title compound was obtained as a white solid (0.75 g, 1.6 mmol, 54% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92-10.69 (m, 1H), 8.32-8.85 (m, 1H), 7.83-7.57 (m, 1H), 7.59-7.31 (m, 3H), 7.33-7.07 (m, 2H), 6.49 (d, J=5.3 Hz, 1H), 3.89 (quin, J=8.5 Hz, 1H), 2.67-2.14 (m, 4H), 2.14-1.79 (m, 2H). MS (ESI): 553 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)=[N:7][N:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=12)=[O:4].[F-:25].[K+].O>CC(N(C)C)=O>[Br:24][C:20]1[CH:19]=[C:18]([C:6]2[C:5]([C:3](=[O:4])[CH2:2][F:25])=[C:9]3[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][N:8]3[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)c1c(-c2cccc(Br)c2)nn2cc(C(F)(F)F)ccc12
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(CF)c1c(-c2cccc(Br)c2)nn2cc(C(F)(F)F)ccc12
Yield: 49.9 %

Procedure:
A solution of 2-bromo-1-[2-(3-bromophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (300 mg, 0.65 mmol, obtained from composite batches), KF (190 mg, 3.27 mmol) in DMA (10 mL) was heated for 3 h at 80° C. Water (25 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined and purified by LC (2-10% EtOAc in hexanes) to yield the desired product (130 mg, 42%) as a pale yellow glass. ESIMS (M+H)+=401.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:22])([F:21])[C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[H][H].CS([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)(=O)=O>CN(C=O)C>[F:3][C:4]([F:21])([F:22])[C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1ccncc1
Reactant: [H][H]
Reactant: OCCc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2ccc(CCOc3ccncc3)cc2)cc1
Reaction time: 8 h

Procedure:
To a suspension of 0.2 g of 60% NaH (as an oil dispersion, 0.005 m) in 5 mL of DMF was added 1.41 g (0.005 m) of 2-[4-[4-(trifluoromethyl)phenoxy]phenyl]ethanol. The mixture was stirred at room temperature for 30 minutes, until hydrogen evolution ceased. To the mixture was then added 0.79 g (0.005 m) of 4-(methylsulfonyl)pyridine, and the mixture was stirred overnight am room temperature. Excess DMF was then removed in vacuo. The resulting material was diluted with water, and the product was extracted into CH2Cl2. The CH2Cl2 layer was separated and filtered through phase separating paper, then concentrated. The residue was adsorbed onto silica gel and chromatographed, eluting with CH2Cl2 →30% EtOAc/CH2Cl2. The resulting material was rechromatographed over fine-particle silica gel, eluting with CH2Cl2 →50% EtOAc/CH2Cl2. Yield 0.5 g.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[C:5]1([N:11]=[C:12]=[S:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[C:2]([NH:3][C:12]([NH:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[S:13])#[N:1]
Reactant: S=C=Nc1ccccc1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccccc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a suspension of monosodium cyanamide (6.4 g, 100 mmol) in absolute ethanol (170 mL), phenylisothiocyanate (12.5 mL, 104.5 mmol) was added slowly with stirring at room temperature. The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (13.6 g), m.p. >250° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24]>CN(C=O)C>[OH:1][CH2:2][CH2:3][S:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH:16][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=4)[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CSCCO)[C@@H](O)[C@H]1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CNc2ncnc3c2ncn3[C@@H]2O[C@H](CSCCO)[C@@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 38.9 %

Procedure:
A mixture of triol 1b (650 mg, 2.0 mmol), 4-nitrobenzyl bromide (2.16 g, 10 mmol), and powdered 4A molecular sieves (2.0 g) in dry DMF (15 mL was stirred for 4 days in a stoppered flask at ambient temperature, and filtered. The filtrate was concentrated under reduced pressure and the resulting crystalline mass was triturated with acetone (3×) and toluene (3×). The solid residue was dissolved in MeOH (10 mL) and treated with NH3 /MeOH (10 mL; w/v, 1:1, prepared at -10° C.). This solution was stirred for 5 h at ambient temperature and concentrated to a red gum. The gum was dissolved in hot MeOH and cooled to give a brown solid that was recrystallized from MeOH to give title compound 2 as red needles (360 mg, 39%). The mother liquors were concentrated and the residue subjected to flash chromatography (MeOH/CHCl3, 2:23) to give a red solid that was recrystallized to give further red needles (165 mg, 19%) of 2 (total 57%) with mp 157°-158° C.; UV (MeOH) max 270 nm (ε 24 700), HCl/MeOH) max 274 nm (ε 29 900), (NaOH/MeOH) max 271 nm (ε 24 500); IH NMR (Me2 SO-d6) δ 8.62 (br s, 1, NH), 8.46 (s, 1, H8), 8.26 (s, 1, H2), 8.20 (d, JAB =8.8 Hz, 2, Ar), (d, 2, Ar), 5.96 (d, J1'-2' =5.7 Hz, 1, H1'), 5.56 (d, JOH-2' =5.8 Hz, 1, OH2'), 5.39 (d, JOH-3' =5.0 Hz, 1, OH3'), 4.85 (br s, 2, CH2Ar), 4.81 (t, J2'-3' =5.4 Hz, 1, H2'), 4.18 (br q, J3'-4' =4.0 Hz, 1, H3'), 4.05 (m, J4'-5'a =6.0 Hz, J4'-5'b =7.2 Hz, 1, H4'), 3.54 (dt, J=5.5 Hz, 2, CH2OH2.97 (m, J5'a-5'b =13.8 Hz, 1, H5'a), 2.87 (m, 1, H5'b), 2.62 (t, 2, SCH2); 13C NMR (Me2SO-d6) δ 154.32 (C6), 152.56 (C2), 149.31 (Ar), 148.26 (C4), 146.35 (Ar), 140.13 (C8), 128.01 (Ar), 123.44 (Ar), 120.01 (C5), 87.44 (C1'), 84.04 (C4'), 72.71, 72.54 (C2',3'), 60.85 (CH2OH), 43.31 (CH2Ar), 34.63 (C5'), 34.30 (SCH2); MS m/z 417.0969 [C17H17N6 O5S (MC2H5O)=417.0981]. Anal. Calcd for C19 H22N6O6S (462.5): C, 49.34; H, 4.79; N, 18.17. Found: c, 48.99; H, 4.70; N, 18.04
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([CH2:16][OH:17])[N:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2=[N:29][N:30]=[C:31]([C:32]3[CH:36]=[C:35]([CH3:37])[O:34][N:33]=3)[N:21]2[N:20]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([CH2:16][O:17][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3=[N:29][N:30]=[C:31]([C:32]4[CH:36]=[C:35]([CH3:37])[O:34][N:33]=4)[N:21]3[N:20]=2)[N:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(CO)nn1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cn(CCO[Si](C)(C)C(C)(C)C)nn4)nn23)no1
Yield: 85.8 %

Procedure:
The reaction was carried out according to Example 1 step 4 using {1-[2-(tert-butyldimethylsilanyloxy)ethyl]-1H-[1,2,3]triazol-4-yl}methanol (1.67 g, 6.49 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.85 g, 6.49 mmol). The crude residue was purified by column chromatography on silica using 2-3% MeOH/CH2Cl2 containing 1% NH3 to yield the desired phthalazine (2.82 g, 86%). 1H NMR (400 MHz, CDCl3) δ 8.75-8.70 (2H, m), 8.23 (1H, d, J=8.5 Hz), 7.94 (1H, t, J=8.5 Hz), 7.80 (1H, t, J=8.5 Hz), 6.91 (1H, s), 5.79 (2H, s), 4.46 (2H, t, J=5.7 Hz), 3.99 (2H, t, J=5.2 Hz), 2.60 (3H, s), 0.67 (9H, s), −0.16 (6H, s). m/z (ES+) 507 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:5][C:4]1[C:3]([F:9])=[C:2](/[CH:12]=[CH:11]/[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1cccc(Br)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cccc(N)c1F
Temperature: 145 °C
Reaction time: 8 h

Procedure:
400 mg (2.10 mmol) of 3-bromo-2-fluoroaniline, 809.42 mg (6.32 mmol) of tert-butyl acrylate and 1.47 ml (10.53 mmol) of triethylamine were initially charged in 2.4 ml of DMF. The reaction vessel was evacuated three times and in each case vented with argon. 47.26 mg (0.21 mmol) of palladium(II) acetate and 128.14 mg (0.42 mmol) of tri-2-tolylphosphine were then added, and the reaction vessel was evacuated two more times and again vented with argon. The mixture was stirred at 145° C. overnight. The reaction mixture was then cooled, added to saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 210 mg (42% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27]C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)[CH3:26].[C:50]1(C)C=CC=C[CH:51]=1>>[CH2:18]([O:17][C:15]1[CH:16]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:51]=[CH:50][C:14]=1[CH:13]=[CH:10][C:11]([O:27][CH2:25][CH3:26])=[O:12])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
To a solution of 2,4-dibenzyloxybenzaldehyde (702 mg) in toluene (30 ml), ethoxycarbonylmethylenetriphenylphosphoran (1.0 g) was added, followed by reflux under heating for 2.5 hours. After the reaction mixture was allowed to stand for cooling, the solvent was distilled off and the residue was purified by a silica gel column chromatography. From the fraction eluted with dichloromethane was obtained ethyl 3-(2,4-dibenzyloxyphenyl)-2-propenoate (794 mg) as an oily product.