Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].O1CCCCC1[O:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:27][CH2:26][CH2:25][C:24]#[C:23][CH2:22][OH:21])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: ClCCCC#CCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCC#CCO)ccc(C(C)=O)c1O
Reaction time: 52 h
Yield: 81 %

Procedure:
A mixture of 9.77 g of 1-(2,4-dihydroxy-3-propylphenyl) ethanone, 10.90 g of 1-(tetrahydro-2-pyranoxy)-6-chloro-2-hexyne [R. B. Moffet, P. H. Seay and W. R. Reid, J. Med. Pharm. Chem., 14, 1075 (1971)]. 10.43 g of anhydrous potassium carbonate and 8.36 g of potassium iodide in 250 ml of anhydrous acetone was stirred at reflux for 18 hours. Anhydrous dimethyl formamide (100 ml) was added and reflux with stirring was continued for 52 hours. The solvent was removed in vacuo, the residue was stirred with hexane and filtered. The filtrate was concentrated in vacuo to an oil which was dissolved in 300 ml of methanol and 200 ml of 3 N hydrochloric acid and heated on the steam bath for 45 minutes. As the solvent was being removed in vacuo, crystallization occurred. Water was added and the solid was filtered to give 11.78 g, 88°-90°, (81% yield) of 1-[2-hydroxy-4-[(6-hydroxy-4-hexynyl)oxy]-3-propylphenyl]ethanone, the titled compound.
Reaction SMILES: C([Li])CCC.[C:6]([NH:10][C:11](=[O:13])[OH:12])([CH3:9])([CH3:8])[CH3:7].Cl[CH2:15][CH2:16][CH2:17][S:18]([NH2:21])(=[O:20])=[O:19]>C1COCC1>[C:6]([NH:10][C:11](=[O:12])[OH:13])([CH3:9])([CH3:8])[CH3:7].[CH:17]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:15][CH2:16]1
Reactant: NS(=O)(=O)CCCCl
Agent: CC(C)(C)NC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NS(=O)(=O)C1CC1
Temperature: -78 °C

Procedure:
A solution of n-butyllithium (74.7 mL, 119.5 mmol, 1.6M in hexane) was dissolved in dry THF (105 mL) and cooled to −78° C. under a Argon atmosphere. To this solution was added a solution of 3-chloropropylsulfonylamine tert-butylcarbamate (14 g, 54.3 mmol) in dry THF (105 mL) dropwise over 20-30 minutes. The dry ice bath was removed and the reaction mixture was allowed to warm to room temperature over a period of 2 hours. The reaction mixture was quenched with glacial acetic acid (3.4 mL), concentrated in vacuo, and partitioned between dichloromethane (100 mL) and water (100 mL). The organic phase was washed with brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford the cyclopropylsulfonylamine tert-butyl carbamate as a waxy off-white solid (12.08 g, 100%): 1H NMR (CDCl3) δ 1.10 (m, 2H), 1.34 (m, 2H), 1.50 (s, 9H), 2.88 (m, 1H), 7.43 (s, 1H). 13C NMR (CDCl3) δ6.21, 28.00, 31.13, 84.07, 149.82.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[NH:8][CH:12]=[CH:11]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1Br
Solvent: C1CCOC1
Product: Brc1nccc2cc[nH]c12
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of 2-Bromo-3-nitropyridine (1 in Scheme 1, 2.0 g, 98%, 9.7 mmol) in dry THF (80 mL) was cooled to −78° C. Excess vinylmagnesium bromide (1.0 M in THF, 40 mL, 40 mmol) was added. The reaction mixture was stirred at −40˜−50° C. for 1 h before it was quenched with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc (3 times). The combined organic layers were dried over MgSO4, the dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (EtOAc:n-hexane=1:2) to afford 2 (1.1 g, 60%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH2:20])[C:14]1=[O:21].C12BC(CCC1)CCC2.[O:31]1CCCC1>>[OH:31][CH2:20][CH2:19][C:15]1[C:14](=[O:21])[N:13]([C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[CH2:3][O:2][CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2COC)c1=O
Agent: B1C2CCCC1CCC2
Product: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
23 g (80 mmol) of the compound from Example 29A are dissolved in 80 ml of anhydrous tetrahydrofuran and cooled to 5° C. Over a period of 15 min, 21 g (176 mmol) of 9-borabicyclo[3.3.1]nonane (0.5M solution in tetrahydrofuran) are added. Cooling is removed, and the mixture is stirred at room temperature for another 2 h. The mixture is then again cooled to 5° C., and 400 ml of 1N aqueous sodium hydroxide solution are added. After the addition has ended, 81 ml of 30% strength hydrogen peroxide solution are added a little at a time at this temperature. After dilution with 500 ml of ethyl acetate, the mixture is washed with 32 ml of 40% strength sodium bisulphite solution to destroy the peroxides. The organic phase is separated off, and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and, after filtration, concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 20 g (77% of theory) of the desired product.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][C:10]=2[F:19])[S:6][C:5]=1[NH:20][C:21]1[N:26]=[C:25]([CH:27]([OH:37])[C:28]2[N:29]=[N:30][N:31]([CH2:33][C:34]([O-:36])=O)[CH:32]=2)[CH:24]=[CH:23][CH:22]=1)=[O:3].[K+].C1C=CC2N(O)N=[N:45]C=2C=1.C(Cl)CCl.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:45][C:34](=[O:36])[CH2:33][N:31]1[CH:32]=[C:28]([CH:27]([OH:37])[C:25]2[N:26]=[C:21]([NH:20][C:5]3[S:6][C:7]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][C:10]=4[F:19])=[CH:8][C:4]=3[C:2]([NH2:1])=[O:3])[CH:22]=[CH:23][CH:24]=2)[N:29]=[N:30]1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(O)c4cn(CC(=O)[O-])nn4)n3)s2)c(F)c1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(O)c4cn(CC(N)=O)nn4)n3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium{4-[[6-({3-(aminocarbonyl)-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl](hydroxy)methyl]-1H-1,2,3-triazol-1-yl}acetate (96 mg, 0.17 mmol), HOBT (52 mg, 0.34 mmol), EDC (65 mg, 0.34 mmol), and NH4Cl (46 mg, 0.85 mmol) were combined in DMF (3.0 mL), and DIEA (89 μL, 0.51 mmol) was added. The reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by reverse phase HPLC (10-70% MeCN/water w/0.025% TFA). The isolated product was of insufficient purity, so flash chromatography (dry load, 0-10% MeOH/EtOAc) was performed to afford the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O.C(N(CC)CC)C>ClCCl.C1(C)C=CC(S(N[C@@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@H:10]([OH:13])[CH2:11][Cl:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
(3S)-3-tert-Butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (1.49 g, 5.0 mmol), 90% formic acid (0.224 ml, 5.25 mmol), and triethylamine (0.730 ml, 5.25 mmol) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (3.4 mg, 0.005 mmol, s/c=1000) in dichloromethane (10.0 ml), followed by stirring at room temperature for 1 hour. Dichloromethane (20.0 ml) was added to the reaction mixture, and the stirring was continued for 1 hour at room temperature. After completion of the reaction, the reaction mixture was quantitatively analyzed by HPLC to confirm production of a desired compound, (2S, 3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.50 g; yield: 99.9%). The production ratio of the desired (2S,3S)-form to the isomeric (2R,3S)-form, (2S,3S):(2R,3S), was found to be 12.5:1. The resulting dichloromethane solution was evaporated, and the residue was crystallized from a mixed solvent of water, toluene and ethanol (1:1:3) to give a mixture at a (2S,3S) to (2R,3S) ratio of 99.6:0.4 in a yield of 80%.
Reaction SMILES: C[O-].[Na+].CO.[CH2:6]([S:13][C:14]1[N:18]2[C:19](SC)=[N:20][C:21]([F:23])=[CH:22][C:17]2=[N:16][N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(SC1N=C2N(C(SC)=NC(F)=C2)N=1)C1C=CC=CC=1.C(OCC)(=O)/C=C\[C:49](OCC)=[O:50]>C(O)C.C(O)(=O)C>[CH2:6]([S:13][C:14]1[N:18]=[C:17]2[N:16]([C:19]([O:50][CH3:49])=[N:20][C:21]([F:23])=[CH:22]2)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: CSc1nc(F)cc2nnc(SCc3ccccc3)n12
Agent: CSc1nc(F)cc2nc(SCc3ccccc3)nn12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCO
Product: COc1nc(F)cc2nc(SCc3ccccc3)nn12
Yield: 56.7 %

Procedure:
A 25 percent solution of sodium methoxide in methanol (1.9 ml, 0.0085 mol) was added to a solution of 19.9 g (0.065 mol) of 3-benzylthio-7-fluoro-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine containing a small amount of 2-benzylthio-7-fluoro-5-methylthio-1,2,4-triazolo[1,5-c]pyrimidine and 11.2 g (0.065 mol) of diethyl maleate in 250 ml of ethanol at ambient temperature with stirring and allowed to react for about 1 hour. Acetic acid (4 ml) was then added and the volatiles were removed by evaporation under reduced pressure. The residue was dissolved in methylene chloride and the resulting solution was extracted with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was triturated with hexane, filtered, and dried to obtain 10.7 g of the title compound as a white powder melting at 121°-122° C. The nmr and uv spectra were consistent with the assigned structure.
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:25][C:26]([C:28]2([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:33][CH2:32][N:31]([C:34]3[C:35]4[CH:42]=[CH:41][NH:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:7][CH:6]=1>C(O)C>[NH2:14][CH2:13][CH2:12][CH:11]([NH:25][C:26]([C:28]1([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:29][CH2:30][N:31]([C:34]2[C:35]3[CH:42]=[CH:41][NH:40][C:36]=3[N:37]=[CH:38][N:39]=2)[CH2:32][CH2:33]1)=[O:27])[C:8]1[CH:7]=[CH:6][C:5]([Cl:4])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CCN2C(=O)c3ccccc3C2=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CCN)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.5 %

Procedure:
Hydrazine monohydrate (10.32 μL) was added to a stirred suspension of tert-butyl 4-(1-(4-chlorophenyl)-3-(1,3-dioxoisoindolin-2-yl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 37) (14 mg) in ethanol (1.0 mL) under argon. The resulting suspension was stirred at room temperature for 3 days. The mixture was filtered and was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. Pure fractions were evaporated to dryness to afford tert-butyl 4-(3-amino-1-(4-chlorophenyl)propylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate as a white powder (5.00 mg, 44.5%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[F:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([CH3:28])([CH3:27])[CH:25]=[O:26])[CH2:22][CH2:23]2)=[CH:16][CH:17]=1
Reactant: CC(C)(CO)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 97.8 %

Procedure:
To a stirred solution of oxalyl chloride (0.7 mL, 8 mmol) in dichloromethane (30 mL) at −60° C. was added dropwise dimethylsulphoxide (1.1 mL, 15.5 mmol). The mixture was stirred for 2 min, and a solution of 2-(4-(4-fluorophenyl)piperazin-1-yl)-2-methylpropan-1-ol (1.5 g, 4.9 mmol) in dichloromethane (10 mL) was then added. The reaction mixture was stirred for 15 min, triethylamine (5 mL, 25.5 mmol) was added. The reaction mixture was stirred for 5 min and then allowed to warm to room temperature. Water (100 mL) was then added and the aqueous layer was extracted with additional dichloromethane (100 mL). The organic layers were combined, washed sequentially with brine (200 mL), dried over sodium sulphate and evaporated till dryness. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 10% ethylacetate in hexane to obtain the title compound (1.2 g, 83.0%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH3:15][C:16]1[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]([Cl:24])=O)=[CH:18][CH:17]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:24].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:22]1/[CH:21]=[CH:20]/[C:19]1[CH:25]=[CH:26][C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: Cc1ccc(/C=C/C(=O)Cl)cc1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-4-methylcinnamoyl chloride (Aitken, R. A.; Boeters, C.; Morrison, J. J. J. Chem. Soc. Perkin Trans.I; 1994, 17, 2473) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[PH:23](=[O:26])([OH:25])[OH:24].[CH2:27]([C:29]([CH2:57][CH3:58])([CH:31](Br)[C:32]1[N:36]=[CH:35][N:34]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:33]=1)[CH3:30])[CH3:28]>CN(C)C=O.O>[PH:23](=[O:24])([OH:26])[OH:25].[CH2:27]([C:29]([CH2:57][CH3:58])([CH:31]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:32]1[N:36]=[CH:35][N:34]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:33]=1)[CH3:30])[CH3:28]
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: c1nc[nH]n1
Agent: C1COCCOCCOCCOCCO1
Agent: O=[PH](O)O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(CC)C(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)n1cncn1
Reaction time: 3 h
Yield: 39.8 %

Procedure:
A stirred solution of 1,2,4-triazole (0.15 g) in dry N,N-dimethyl-formamide (10 ml) was treated, under nitrogen, with sodium hydride (0.075 g, 60% in oil) and 15-Crown-5 (0.02 g). After ten minutes, the stirred mixture was treated with diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 29). After a further three hours, it was poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure, finally at 0.01 mm. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3(1,2,4-triazol-1-yl)-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.39 g) as a colourless oil. NMR (CDCl3): δ 1.2(6H,dt), 1.7-1.8(2H,m), 2.6-2.8(2H,m), 4.05(4H,m), 5.7(1H,t), 7.1(6H,m), 7.3(9H,m), 7.95(2H,2 xs), 8.25(1H,s). M/S: M+ 556.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([CH:19]=[O:20])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:24]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([N:8]1[C:12]2=[CH:13][N:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:11]2[C:10]([C:19]([OH:24])=[O:20])=[C:9]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2cn1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc2c(C(=O)O)c(C(C)C)n(Cc3ccccc3)c2cn1
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (Compound 7, 20 mg, 0.065 mmol) in t-BuOH (1.5 ml) and 2-methyl-2-butene (1 ml) was added a solution of NaH2PO4 (94 mg, 0.78 mmol) and NaClO2 (80%, 73 mg, 0.65 mmol) in H2O (1.5 ml). The mixture was stirred at room temperature and additional 2-methyl-2-butene and a solution of NaH2PO4 and NaClO2 in H2O were added at the above ratio every 6-16 h until the progress of the reaction was satisfactory. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) on silica gel (50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:43]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]([S:48]([C:44]2[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=2)(=[O:50])=[O:49])[CH:12]=[C:11]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH:10]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CN(Cc1c[nH]c(-c2cc(F)ccc2F)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Product: CN(Cc1cc(-c2cc(F)ccc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 146 and using tert-butyl {[5-(2,5-difluorophenyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (135 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.25 mL) and pyridin-3-ylsulfonyl chloride hydrochloride (135 mg), the title compound was obtained as a colorless oil (yield 105 mg, 54%).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[CH2:18][C@H:17]([NH:16][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:15][CH:14]=2)[CH2:26][CH2:25]3)[CH2:28][CH2:29]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C4CCCCC4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Cyclohexylbenzoic acid (0.50 g, 2.4 mmol) was dissolved in thionyl chloride (20 mL) and heated at reflux for 30 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (96 mg, 0.43 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (62 μL, 0.45 mmol) in methylene chloride (20 mL) . After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. Yield: 150 mg (85%) of the title compound as white crystals: mp 224-226° C.; [α]21D −43° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 431 (2, M+).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:6]([N:16]([CH3:27])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](O)=[O:4].S(Cl)([Cl:31])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:28])([CH:6]([N:16]([CH3:27])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([Cl:31])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CC(N(C)S(=O)(=O)c2ccc(C)cc2)C(C)(C)C(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(CC(N(C)S(=O)(=O)c2ccc(C)cc2)C(C)(C)C(=O)Cl)cc1
Reaction time: 3 h

Procedure:
A mixture of 283 g of 2,2-dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulfonamido)butyric acid, 1500 ml of dry benzene and 430 ml of thionyl chloride is boiled for 3 hours. After removal of volatile material by evaporation in vacuo, the residue is taken up in toluene and the solvent is evaporated in vacuo. This procedure is repeated twice whereafter crystallization of the initially oily product is accomplished by treatment with ether, melting point 110°-111° C.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([NH:19][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[N:15][NH:16]2)=[CH:12][CH:11]=1.C(OCC)(=O)C.O>C(#N)C>[Br:9][C:10]1[C:18]([N+:7]([O-:8])=[O:6])=[C:17]2[C:13]([C:14]([NH:19][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[N:15][NH:16]2)=[CH:12][CH:11]=1
Reactant: O=[N+]=O
Reactant: CCCC(=O)Nc1n[nH]c2cc(Br)ccc12
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCC(=O)Nc1n[nH]c2c([N+](=O)[O-])c(Br)ccc12
Temperature: 3 °C
Reaction time: 14 h

Procedure:
235 mg of nitronium tetrafluoroborate are added in a single portion to 500 mg of N-[6-bromo-1H-indazol-3-yl]butanamide, described previously in Example 24, in 25 cm3 of acetonitrile, cooled to about 3° C. The mixture is maintained at about 3° C. for 1 hour and the resulting mixture is then allowed to return to about 19° C. over 14 hours. 15 cm3 of ethyl acetate and 15 cm3 of distilled water are added to the reaction medium. The medium is then evaporated under reduced pressure (2 kPa; 40° C.) and the residue is taken up in 20 cm3 of dichloromethane. The insoluble material is filtered off and washed with 20 cm3 of diisopropyl ether. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with ethyl acetate/cyclohexane (30/70 by volume) and collecting 35 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 30 mg of N-[6-bromo-7-nitro-1H-indazol-3-yl]butanamide are thus obtained in the form of a white product melting at 248° C.