Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:17]1([P:23](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>N1CCCC1=O.C(O)C.C(Cl)(Cl)Cl>[C:17]1([P:23]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: NC(=O)c1ccc(N)nc1
Agent: Cl
Agent: O=C1CCCN1
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NC(=O)c1ccc(NP(=O)(c2ccccc2)c2ccccc2)nc1

Procedure:
6-Aminonicotinamide 1.37 g (0.01 mole) is dissolved in 10 ml of 2-pyrrolidinone and 3 ml of pyridine by gentle warming of the mixture. Diphenylphosphoryl chloride 6 ml (0.024 mole) is then slowly added to the mixture. After 1 hour of reaction at room temperature, the mixture is poured into 300 ml of 0.2 N HCl. A reddish syrup, 2.2 g which is formed in the bottom of the flask is isolated by decantation. The product may be purified as follows. The reddish syrup obtained above is dissolved in 3 ml of ethanol and the solution is admixed with 200 ml of 0.2 N HCl. Chloroform, 100 ml is added to the mixture to extract the product. After dried over anhydrous sodium sulfate the chloroform solution which contains the product is evaporated at 35° C. in vacuum to give a practically pure 6-diphenylphosphorylamino nicotinamide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=[O:12].[O-2].[Ca+2].[CH2:15]([OH:17])C>>[CH2:7]([C:8]([CH2:15][OH:17])([CH2:11][OH:12])[CH2:9][OH:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1ccccc1
Reactant: C=O
Reactant: CCO
Agent: [Ca+2]
Agent: [O-2]
Product: OCC(CO)(CO)Cc1ccccc1

Procedure:
A solution of 3-phenylpropanal (100 g, 0.7 mol), formaldehyde (540 mL, 7.5 mol) and calcium oxide (56 g, 1 mol) in ethanol (1 L) was stirred at 40° C. under nitrogen for 18 h. The reaction mixture was filtered and the filtrate was concentrated. Water (1 L) was added to the residue. The mixture was extracted with ethyl acetate (1 L×3), the combined organic layers were concentrated and purified via silica gel chromatography (petroleum ether/ethyl acetate 3:1) to afford 2-benzyl-2-(hydroxymethyl)propane-1,3-diol as a white solid (90 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[Cl:10][C:11]1[C:12]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4]2)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: O=C1CCCC(CO)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CCCC(=O)C2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a solution of 3-(hydroxymethyl)cyclohexanone (575 mg) and tert-butyl 5-chloro-2,4-difluoro-benzoate (1.23 g) in DMSO (13.5 mL) at 14° C. (bath) was added potassium tert-butoxide (604 mg) gradually. After 5 min, the mixture was stirred at rt for 30 min. Diluted with EtOAc, the contents were washed with dilute NaHCO3 (3×) and brine, and dried (Na2SO4). After filtration and concentration, the crude was purified with flash chromatography (0->40% EtOAc/heptane) to give the product (445 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH3:13])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[CH2:14]([OH:16])[CH3:15].CO.C([C:31]1[CH:36]=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC.CO[Si](OC)(OC)OC>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11].[Cl:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH3:13])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11].[CH2:14]([O:16][Si:5]([O:12][CH2:36][CH3:31])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH3:15]
Reactant: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Reactant: CCO
Agent: CCO[Si](CCCCl)(OC)OCC
Agent: CO[Si](OC)(OC)OC
Solvent: CO
Product: CCO[Si](CCCCl)(OCC)OCC
Product: CCO[Si](OCC)(OCC)OCC
Yield: 7 %

Procedure:
Similar product, containing less than 0.3% 3-chloropropylmethoxydiethoxysilane, was prepared under similar conditions except that an ethanol/methanol mixture (96% ethanol) was fed at midpoint of the first column with pure ethanol being fed to its bottom flask and dodecylbenzenesulfonic acid (0.2 wt-% relative to starting silane) was used as the transesterification catalyst. This demonstrates the effective use of a less pure recycle stream, which is significant, since 100% molar excess of ethanol is used. 3-Chloropropyltriethoxysilane of similar relative purity (low 3-chloropropylmethoxydiethoxysilane content) was prepared when the feed contained several percent tetramethoxysilane, providing 7% tetraethoxysilane in the product stream.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:26][CH2:27][N:28]4[C:29](=[O:38])[C:30]5[C:31](=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:32]4=[O:33])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 80 °C
Yield: 67.5 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (290 mg, 0.81 mmol), prepared as described in Example 1, N-(2-bromoethyl)phthalimide (215 mg, 0.84 mmol) and K2CO3 (337 mg, 2.44 mmol) in DMF (3 ml), was heated at 80° C. for 2.5 hours. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified using silica gel column chromatography using an automated system eluting with a 1:1 mixture of ethyl acetate:hexane to give the title compound, 2-(2-(7,8-bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)ethyl)isoindoline-1,3-dione as a yellow solid (290 mg, 68%). MS M+H=530.
Reaction SMILES: Cl.[N:2]1[C:3]([NH2:11])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12>C(O)C.[Pd]>[N:2]1[C:3]([NH2:11])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: Nc1nc2ccccn2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1nc2n(n1)CCCC2
Reaction time: 72 h

Procedure:
The 12.7% solution of HCl in ethanol (5.35 mL) and 10% Pd—C (50% wet) (2.5 g) were added to the mixture of [1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2.5 g) in ethanol (72 mL). The reaction mixture was hydrogenated at 400 KPa of H2 for 3 days at room temperature. The mixture was filtered and concentrated under reduced pressure. The residue was treated with saturated potassium carbonate solution and extracted with chloroform. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a pale yellow solid (2.31 g, 90%). 1H-NMR (400 MHz, CDCl3) δ 1.88-1.94 (m, 2H), 1.98-2.05 (m, 2H), 2.77 (t, 2H, J=6.2 Hz), 3.95 (t, 2H, J=6.2 Hz), 4.09 (brs, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25](Br)([CH2:27][CH3:28])[CH3:26]>CN(C)C=O>[CH:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)([CH2:27][CH3:28])[CH3:26]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc2c(=O)c(-c3ccccc3)coc2c1
Yield: 80.9 %

Procedure:
12 g of 7-hydroxy-isoflavone are boiled for 2 hours under reflux condenser with 10 g of potassium carbonate and 9 g of sec-butyl bromide in 40 ml of dimethyl formamide. On pouring the reaction mixture on water, the separated product is recrystallized from acetone, yielding 12 g of 7-sec-butyloxy-isoflavone, m.p. 87°-89° C. In a similar way, also 7-sec-butyloxy-2-methyl-isoflavone, m.p. 107°-109° C., and all the other isoflavone derivatives described in Example 7 can be prepared.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:12].[Na+:13].Cl>O1CCOCC1.O>[Na+:13].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)([O-])c1ccc(Cl)nc1

Procedure:
A solution of 6-chloro-3-pyridinesulfonyl chloride (5.0 g, 24 mmol) (C. Rath. Annalen. 1931, 487, 105-119) in dioxane (10 ml) and the solution cooled to 0° C. A solution of sodium hydroxide (1.88 g, 47 mmol) in water (20 ml) was added drop-wise to the stirred solution over 10 mins. After another 10 mins 0.5 pellet of NaOH was added and after a further 15 minutes the pH was adjusted to pH 7 with 2M hydrochloric acid and the solvent was vacuumed down. The material was dried on a Dean and Stark trap to give the title compound. MS (ES−) 192/194 [M−H]−.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:7][C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:27])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:12](=[O:21])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]2=[O:20])=[CH:7][C:6]=1[O:22][CH3:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2C(=O)c3ccccc3C2=O)cc1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(N2C(=O)c3ccccc3C2=O)ccc1C(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 2-(4-tert-butyl-3-hydroxy-phenyl)isoindoline-1,3-dione (450 mg, 1.52 mmol), dimethyl sulfate (385 mg, 288 μL, 3.05 mmol), K2CO3 (632 mg, 4.57 mmol) in acetone (10 mL) was stirred at 50° C. for 3 h. The reaction was cooled to room temperature, filtered and washed with acetone (10 mL). The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography (20% ethyl acetate/hexane) to provide 2-(4-tert-butyl-3-methoxyphenyl)isoindoline-1,3-dione (420 mg, 89% yield). 1H NMR (400.0 MHz, CDCl3) δ 7.72 (m, 2H), 7.55 (m, 2H), 7.15 (d, J=8.3 Hz, 1H), 6.72 (dd, J=2.1, 8.2 Hz, 1H), 6.68 (d, J=2.0 Hz, 1H), 3.61 (s, 3H), 1.15 (d, J=3.4 Hz, 9H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH:7]([CH3:9])[NH:6][CH2:5][CH2:4][NH:3]1.[Cl:10][S:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[C:16]([CH3:24])=[CH:17][N:18]=[CH:19]2)(=[O:13])=[O:12]>>[ClH:10].[CH3:1][CH:2]1[CH2:8][CH:7]([CH3:9])[N:6]([S:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([CH3:24])=[CH:17][N:18]=[CH:19]3)(=[O:12])=[O:13])[CH2:5][CH2:4][NH:3]1
Reactant: CC1CC(C)NCCN1
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Product: Cc1cncc2cccc(S(=O)(=O)N3CCNC(C)CC3C)c12
Product: Cl
Yield: 68.1 %

Procedure:
Using 0.77 g of 5,7-dimethyl-hexahydro-1H-1,4-diazepine and 0.48 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.50 g of the objective compound (white crystals).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)=[O:35])[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:39]2[CH:38]=[CH:37][C:36]([C:34]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[O:35])=[CH:41][CH:40]=2)[CH:3]=1)=[O:15]
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv), (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired compound (33% yield). LCMS: 542.20 (M+1)+; HPLC: 98.72% (@ 254 nm), (Rt; 5.034); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.96 (bs, 1H), 8.39 (s, 1H), 8.32 (d, 2H, J=8 Hz), 8.20 (s, 1H), 7.56 (d, 2H, J=7.6 Hz), 5.90 (s, 1H), 5.35-5.32 (m, 1H), 4.42 (d, 2H, J=4 Hz), 3.64 (bs, 2H), 3.38 (m, 2H), 2.37 (bs, 2H), 2.28 (bs, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 1.55 (d, 6H, J=6.4 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:7]1([CH2:23][O:24][CH3:25])[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1)=[O:5])[CH3:2].[OH-].[NH4+].[H][H]>[Pd].CO>[CH3:25][O:24][CH2:23][C:7]1([N:6]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:4](=[O:5])[O:3][CH2:1][CH3:2])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1
Reactant: [H][H]
Reactant: CCOC(=O)N(c1ccccc1)C1(COC)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N(c1ccccc1)C1(COC)CCNCC1
Yield: 81.4 %

Procedure:
A solution of 14.2 parts of (phenylmethyl) 4-[(ethoxycarbonyl)phenylamino]-4-(methoxymethyl)-1-piperidinecarboxylate and 1.8 parts of ammonium hydroxide in 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 75 parts of trichloromethane. The solution is washed twice with water, dried, filtered and evaporated, yielding 7.9 parts (81.4%) of ethyl [4-(methoxymethyl)-4-piperidinyl]phenylcarbamate as a residue.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I-].[CH:12]1([CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([C:46]([C:48]2[CH:53]=[CH:52][C:51]([S:54][CH3:55])=[CH:50][CH:49]=2)=O)=[N:42][C:43]=1[O:44][CH3:45].O>O1CCCC1>[Cl:37][C:38]1[C:43]([O:44][CH3:45])=[N:42][C:41](/[C:46](/[C:48]2[CH:53]=[CH:52][C:51]([S:54][CH3:55])=[CH:50][CH:49]=2)=[CH:17]/[CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:40][CH:39]=1
Reactant: COc1nc(C(=O)c2ccc(SC)cc2)ccc1Cl
Reactant: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(/C(=C/C2CCCC2)c2ccc(SC)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of lithiumhexamethyldisilazide in tetrahydrofuran (1 M, 5.22 mL) was added to a solution of (cyclopentylmethyl)triphenylphosphonium iodide (described in WO 2001044216) (2.46 g) in tetrahydrofuran (20 mL) in a nitrogen atmosphere under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was ice-cooled again and a solution of (5-chloro-6-methoxypyridin-2-yl)[4-(methylsulfanyl)phenyl]methanone obtained in Reference Example 1-1 (1.0 g) in tetrahydrofuran (10 mL) was added, after which the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:hexane=1:1) to give 3-chloro-6-{(E)-2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethenyl}-2-methoxypyridine (710 mg, 58%) as a colorless oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[C:18]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][C:21]=2[CH3:26])[CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][C:15]2=[O:27].ClCCl.CO>C(O)(=O)C>[NH2:9][C:10]1[C:19]([I:1])=[C:18]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][C:21]=2[CH3:26])[CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][C:15]2=[O:27]
Reactant: Cc1nnn(C)c1-c1cc(N)c2c(c1)C(=O)NCC2
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1nnn(C)c1-c1cc2c(c(N)c1I)CCNC2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.3 %

Procedure:
N-iodosuccinimide (5.27 g, 23.43 mmol) was added in portions to a solution of 5-amino-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293d, 5.5 g, 21.3 mmol) in glacial acetic acid (400 mL) and the resulting mixture stirred at room temperature for three days. A second portion of N-iodosuccinimide (2.6 g, 12.7 mmol) was then added and stirring continued at room temperature overnight. The mixture was concentrated under vacuum to remove acetic acid. The residue was dissolved in methanol (200 mL), concentrated to dryness, and purified by silica gel chromatography (eluting with 1:1 to 1:2 petroleum ether/ethyl acetate and then with 100:1 to 50:1 dichloromethane/methanol), to give 5-amino-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-iodo-3,4-dihydroisoquinolin-1(2H)-one (293e, 5.0 g, 60% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:32])=O>O1CCCC1>[CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17]([Cl:32])=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 1.0 g (2.5 mmol) of (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionic acid and 1.07 ml (12.5 mmol) of oxalyl chloride in 2 ml of tetrahydrofuran was heated at 500 for 18 hours. Thereafter, the reaction solution was evaporated under reduced pressure. The residue was taken up twice in 30 ml of toluene each time and again evaporated under reduced pressure each time. (RS)-2-[[2-[(Benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride was obtained as a yellowish oil in quantitative yield and was used in the following step without purification and characterization.
Reaction SMILES: [CH2:1]([C:5](C)([CH3:9])[C:6]([NH2:8])=[O:7])CCC.[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].[C:16]1([C:22]2[N:23]=[C:24](I)[O:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1.CCCCCC>[CH2:11]([N:8]([C:24]1[O:25][C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:23]=1)[C:6](=[O:7])[CH:5]([CH3:9])[CH3:1])[CH2:12][CH2:13][CH3:14]
Reactant: [Li]CCCC
Reactant: CCCCC(C)(C)C(N)=O
Reactant: Ic1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(C(=O)C(C)C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 0.08 h

Procedure:
n-Butyl-isobutyramide (2.06 g, 0.0144 m) in dry THF (20 ml) was stirred at room temperature during the dropwise addition of a 1.445 M solution of n-butyl lithium in hexane (10.0 ml., 0.01445 m). After the addition, the mixture was stirred for 5 minutes, and then 4,5-diphenyl-2-iodooxazole (Chemical Abstracts 65 7159h) (5.0 g, 0.0144 m) in dry THF (20 ml) was added dropwise. The mixture was stirred for 6 hours at room temperature and then hydrolysed with water. The solvent was removed in vacuo and the residue extracted with diethyl ether.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9](=[O:22])[NH:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCOC[C@@H]3C)nc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 3-(3-methylmorpholino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, crude) in dichloromethane (30 mL) was added pyridine (79 mg, 2.64 mmol). Then Tf2O (372 mg, 1.32 mmol) was added and stirred overnight at room temperature. The reaction was then quenched by the addition of ice-water (100 mL) and extracted with dichloromethane (3×15 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford (S)-methyl 3-(3-methylmorpholino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[NH:12][C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[CH:16][N:17]=[C:13]3[N:12]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=3)[C:11]([CH3:18])=[C:10]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)Nc2ncnn2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2ncnn2C1c1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
(rac)-Ethyl 7-(4-cyanophenyl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (20 mg, 64 μmol), 3-(trifluoromethyl)phenylboronic acid (25 mg, 0.13 mmol, 2 eq.), anhydrous copper(II) acetate (23 mg, 0.13 mmol, 2 eq.) and molecular sieve (100 mg, 4 Å) were initially charged. Under an atmosphere of argon protective gas, abs. dichloromethane (2 ml), pyridine (10 μl, 0.13 mmol, 2 eq.) and triethylamine (18 μl, 0.13 mmol, 2 eq.) were added. After 24 h of stirring, the mixture was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.05% TFA). After lyophilization, the product was obtained as a solid (10.5 mg, 36% of theory).