Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]#[N:26])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:5][CH:4]=1.C[Si]([N:37]=[N+:38]=[N-:39])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]4[NH:39][N:38]=[N:37][N:26]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCOCCC#N)c23)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCOCCc4nnn[nH]4)c23)cc1

Procedure:
Stir 137 mg (0.32 mmol) 5-(4-methoxyphenyl)-6-phenyl-N-{3-[2-cyanoethoxy]propyl}furo[2,3-d]-pyrimidine-4-amine, 552 mg (4.8 mmol) trimethylsilylazide and 119 mg (0.48 mmol) di-n-butyltin oxide in 10 ml toluene overnight at 80° C. Then cool the mixture and concentrate by evaporation. Dissolve the residue that remains in methylene chloride and wash with water and sodium chloride solution. Dry the organic phase over magnesium sulphate and concentrate in the rotary evaporator at reduced pressure. Purify the residue by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-34 min 5%→98% acetonitrile, 34-38 min 98% acetonitrile). 48.6 mg (32% of theor.) of the title compound is obtained as a colourless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=2)[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: Oc1cncc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: Oc1cncc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 20.5 h

Procedure:
A mixture of 5-chloro-3-hydroxypyridine (0.2 g, 1.6 mmol), morpholine (0.7 mL, 8.0 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl, (X-Phos) (0.12 g, 0.26 mmol), and tris(dibenzylideneacetone)dipalladium (0) (0.06 g, 0.07 mmol) in dry THF (2.0 mL) was degassed by nitrogen. To this mixture was added 1.0M lithium bis(trimethylsilyl)amide in THF (8.8 mL, 8.8 mmol) dropwise, and the resulting reaction was heated to 60° C. After 20.5 h, the reaction was cooled to rt then concd. The residue was purified on silica gel (0-100% of a premixed solution of 89:9:1 DCM:methanol:ammonium hydroxide in DCM) to afford an off white solid as 5-morpholinopyridin-3-ol. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.62 (1H, br. s.), 7.79 (1H, d, J=2.4 Hz), 7.61 (1H, d, J=2.2 Hz), 6.65 (1H, t, J=2.4 Hz), 3.79 (4H, m), 3.16 (4H, m). Mass Spectrum (pos.) m/e: 181.0 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC=CC=1>C(N(CC)CC)C>[CH3:7][N:8]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)CCBr
Reactant: CNc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)CCN(C)c1ccccc1
Yield: 63.4 %

Procedure:
121 g of isoamyl bromide were added dropwise to a mixture of 86 g of N-methyl-aniline, 500 ml of anhydrous benzene and 81 g of anhydrous triethylamine and the mixture was refluxed for 100 hours and was filtered. The filtrate was washed with water, dried and evaporated to dryness. The residue was distilled to obtain 90 g of N-methyl-N-(3-methylbutyl)-aniline boiling at 132° C. at 18 mm Hg.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)=[O:4].[CH2:20]=O.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]([F:18])([F:19])[C:3]([N:5]1[CH2:6][CH2:7][C:8]2[C:13](=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:20]1)=[O:4]
Reactant: C=O
Reactant: O=C(NCCc1ccc(C(F)(F)F)cc1)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc(C(F)(F)F)cc2C1)C(F)(F)F
Reaction time: 0.67 h
Yield: 98.5 %

Procedure:
2,2,2-Trifluoro-N-{2-[4-(trifluoromethyl)phenyl]ethyl}acetamide (4.00 g, 14 mmol) and paraformaldehyde (0.63 g) were combined in a flask and dissolved in acetic acid (11 mL). Sulfuric acid (11 mL) was added slowly. The mixture went from a cloudy solution to clear and an exothermic reaction was observed. After 40 min, the flask was lowered into an ice bath. The reaction was quenched with cold water and the resulting solution was extracted with EtOAc three times. The combined extracts were washed with water, saturated sodium bicarbonate and brine, dried (MgSO4), filtered, and concentrated to afford a yellow oil (4.1 g, 83%). MS calculated for C12H9F6NO: (M+H)+298; found 298.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:21]1[CH2:31][CH2:30][C:24]2[N:25]=[CH:26][N:27]=[C:28](Cl)[C:23]=2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:28]2[C:23]3[CH2:22][N:21]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:31][CH2:30][C:24]=3[N:25]=[CH:26][N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 92.6 %

Procedure:
To a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (6.21 g, 33.16 mmol) and 6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (9 g, 34.65 mmol) in 2-Me-THF (100 mL) was added under nitrogen tBuOK (8.17 g, 72.95 mmol). The mixture was stirred at rt for 25 min. The mixture was quenched with H2O. The organic layer was washed with brine. The resulting organic solution was concentrated in vacuo to provide (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (12.6 g, 89% yield) as a yellow gum.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
2-Nitroaniline (2.15 g (15.6 mmol)) was dissolved in 10.0 ml of pyridine. To this, p-toluenesulfonyl chloride (3.55 g (18.6 mmol)) was added with stirring at room temperature. After stirring for 15 hours at room temperature, water (100 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered, washed with water, dried and then subjected to silica gel column chromatography with ethyl acetate-hexane (2:3) as eluent to give 2.88 g (53%) of 2′-nitro-p-toluenesulfonanilide as yellow crystals, and 1.17 g (17%) of N,N-bis(p-toluenesulfonyl)-2′-nitroaniline (Compound No. 39) as pale yellow crystals. Physical Constants of 2′-nitro-p-toluenesulfonanilide
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:23]([CH:7]2[C:6](=[O:11])[CH2:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][C:8]2=[O:10])=[O:24])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)C1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CC(C)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-isopropyl-1,3-cyclohexanedione with p-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 2-(N-p-CHLOROBENZENESULFONYLCARBAMOYL)-5-ISOPROPYL-1,3-CYCLOHEXANEDIONE, m.p. 100.5°-101.5° C. (resolidified and melting at 183.5° C. with dec.)(corr.).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](B2OC(C)(C)C(C)(C)O2)=[C:14]([NH:16]C(=O)OC(C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[NH:33]1[C:41]2[C:36](=[CH:37][C:38]([C:42]#[C:43][C:44]3[CH:45]=[C:46](Cl)[C:47]([C:50]#[N:51])=[N:48][CH:49]=3)=[CH:39][CH:40]=2)[CH:35]=[CH:34]1>>[NH:33]1[C:41]2[C:36](=[CH:37][C:38]([CH2:42][CH2:43][C:44]3[CH:49]=[N:48][C:47]4[C:50]([NH2:51])=[N:16][C:14]5[CH:15]=[C:10]([CH2:9][OH:8])[CH:11]=[CH:12][C:13]=5[C:46]=4[CH:45]=3)=[CH:39][CH:40]=2)[CH:35]=[CH:34]1
Reactant: CC(C)(C)OC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ncc(C#Cc2ccc3[nH]ccc3c2)cc1Cl
Product: Nc1nc2cc(CO)ccc2c2cc(CCc3ccc4[nH]ccc4c3)cnc12

Procedure:
(2-(2-(1H-indol-5-yl)ethyl)-5-aminobenzo[f][1,7]naphthyridin-8-yl)methanol was prepared from tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 99/step 1) and 5-((1H-indol-5-yl)ethynyl)-3-chloropicolinonitrile (from Example 44/step 3) following the procedures described for Example 44/Step 4 and Example 99/step 3 (deprotection of TBS). 1H NMR (acetone-d6): δ 10.19 (t, 1H), 8.83 (d, 1H), 8.71 (d, 1H), 8.35 (d, 1H), 7.60 (d, 1H), 7.46 (d, 1H), 7.36-7.27 (m, 3H), 7.04 (dd, 1H), 6.57 (br s, 2H), 6.38 (dt, 1H), 4.77 (d, 2H), 4.36 (t, 1H), 3.29 (t, 2H), 3.19 (t, 2H). LRMS [M+H]=369.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[N:11]=[C:10]([CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)[CH:9]=2)=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[N:11]=[C:10]([CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3[N+](=O)[O-])n2)CC(C)(C)O1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N)n2)CC(C)(C)O1
Temperature: 90 °C
Yield: 97.6 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1-(2-nitrophenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazole (Example 61) (1.10 g, 2.50 mmol) in 20 mL of ethanol and 20 mL of acetic acid was added iron powder (1.12 g, 20.0 mmol) and the mixture heated to 90° C. for 1 hr. The mixture was filtered through Celite and concentrated and the residue purified by silica gel chromatography (40-g cartridge, 10-25% EtOAc/heptane) to give 1.0 g (98%) the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[O:15]([C:22](OC1C=CC=CC=1)=[CH:23][N+:24]([O-:26])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:23][N+:24]([O-:26])=[O:25])=[CH:7][CH:6]=1)[CH3:1]
Reactant: O=[N+]([O-])C=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)o1
Yield: 81 %

Procedure:
A solution of 2·14 g (10 mmol) of 2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamine and 2·57 g (10 mmol) of 1,1-diphenoxy-2-nitroethene in 20 ml of acetonitrile is boiled for 2 hours. After concentration of the solution by evaporation under vacuum, the oily residue is chromatographically purified as described in Example 1 and yields 3·06 g (81%) of the title compound as a pale yellow oil which according to thin layer chromatography and 1H-NMR spectrum is identical to the compound from Example 1.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:15])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(CCN2CCCS2(=O)=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CCN4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 89.8 %

Procedure:
Using 4-[2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)ethyl]benzoic acid (162 mg) described in Preparation Example 41 and 1-(3,5-dimethylpyridin-2-yl)piperazine (115 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (239 mg) was obtained.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:18]=[CH:19][CH:20]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2]>C(O)C.Cl.[Pt]=O>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[C:8]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH:9]=1
Reactant: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1-c1cccn1C(=O)OC(C)(C)C
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(N)cc1C1CCCN1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To platinum oxide (0.5 g) was added 1D in ethanol and hydrogen chloride (0.45 mL) under nitrogen. The reaction was placed under hydrogen (40 psi). After 1.5 h the reaction was half done, additional platinum oxide (200 mg) was added and reaction was stirred under hydrogen (40 psi) for 2 h. The catalyst was filtered over Celite® and washed with ethanol. The filtrate was neutralized with diethylamine. The solvent was evaporated and the crude residue was redissolved in dichloromethane. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed and the crude product was purified by flash column chromatography to give a white solid 1E (1.6 g, 88%). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.24 (m, 15H) 1.84 (m, 3H) 2.37 (m, 1H) 3.15 (m, 1H) 3.62 (m, 2H) 5.28 (s, 1H) 6.53 (d, J=19.56 Hz, 2H) 7.50 (d, J=8.56 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:26])[N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1cccc(C)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccccc1C(N)=O)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>C(#N)C>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Nitro-1H-pyrazole (565 mg, 5 mmol) was stirred in acetonitrile (15 mL) with potassium carbonate (829 mg, 6 mmol) for 5 minutes and then 4-methoxybenzyl chloride (861 mg, 0.746 mL, 5.5 mmol) was added. The reaction was stirred at ambient temperature for 18 hours, and then partitioned between ethyl acetate and an aqueous 2M hydrochloric acid solution. The organic layer was separated and the aqueous was extracted with a further portion of ethyl acetate. The combined ethyl acetate layers were dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with 20% ethyl acetate/hexane and then 50% ethyl acetate/dichloromethane to afford the desired title compound as an oil, 1.08 g, 93%.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6](=O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>O>[CH:6](=[N:1][NH:2][C:3]([NH2:5])=[S:4])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=CC=Cc1ccccc1
Reactant: NNC(N)=S
Solvent: CCO
Solvent: O
Product: NC(=S)NN=CC=Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 18.2 g (0.20 m) of thiosemicarbazide in 250 ml of hot water was gradually added to a solution of 26.4 g (0.20 m) of cinnamaldehyde in 250 ml of hot 2 B ethanol. Small, colorless crystals began to ppt from the homogeneous mixture after several minutes of heating on a steam bath. Heating was continued for a half an hour, after which the mixture was cooled to room temperature and the product was collected by filtraton, washed with cold ethanol, and air-dried to yield 25.5 g of small, pale yellow crystals. An additional 18.3 g of product was recovered by concentrating the mother liquors. Recrystallization from ethanol gave 29.3 g (0.14 m) of small, pale yellow crystals, m.p. 137°-139° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C(O)(=O)C.[Na]>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1ccc2[nH]ccc2c1
Agent: [Na]
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20.6 %

Procedure:
To a stirred solution of N-(1H-indol-5-yl)isobutyramide (0.42 g, 2.9 mmol) in acetic acid (10 mL), sodium cynoborohydride (0.29 g, 4.6 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 2-3 h. The reaction was quenched with water and neutralized by 50% NaOH solution, extracted with diethyl ether. The organic layer was separated and concentrated in vacuo to give N-(indolin-5-yl)isobutyramide (0.122 g, 28.5%); MS: 205.1 (M+1).
Reaction SMILES: [Si]([C:8]#[C:9][C:10]1[CH:21]=[CH:20][C:13]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[C:9]([C:10]1[CH:21]=[CH:20][C:13]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)#[CH:8]
Reactant: CC(=O)NCCc1ccc(C#C[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccc(CCNC(C)=O)cc1
Temperature: 25 °C

Procedure:
To 2.20 g (7.30 mmol) N-(4-((tert-butyldimethylsilyl)ethynyl)phenethyl)acetamide (I56.1) in 30 mL DCM are added 2.24 g (8.03 mmol) TBAF*H2O and the mixture is stirred at r.t. over night. The mixture is washed with water (2×). The organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH 10/0→20/1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([N:18]2[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:20][C@H:19]2[C:29]([NH:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)=[O:30])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:50]([O:52][CH3:53])=[O:51]>ClCCl>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:29]([C@H:19]2[N:18]([C:16]([C@H:13]3[CH2:14][CH2:15][C@@H:10]([CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:11][CH2:12]3)=[O:17])[CH2:22][C@@H:21]([N:23]3[CH2:28][CH2:27][N:26]([C:50]([O:52][CH3:53])=[O:51])[CH2:25][CH2:24]3)[CH2:20]2)=[O:30])=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)Cl
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCNCC3)CN2C(=O)[C@H]2CC[C@@H](CNC(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(C(=O)OC)CC3)CN2C(=O)[C@H]2CC[C@@H](CNC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the compound prepared in Example 50 (150 mg) in dichloromethane (3 mL) was added triethylamine (0.3 mL) and methyl chloroformate (22 μL). The mixture was stirred at room temperature overnight. Further methyl chloroformate (11 μL) was added and the reaction stirred at room temperature for an additional 4 days. The reaction mixture was partitioned between dichloromethane (20 mL) and brine (20 mL), the organic layer separated, dried and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound (119 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]([OH:16])=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:19]([O:23][C:24]([NH:26][NH:27][CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][N:27]([C:14]([C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=3[C:6]=2[N:7]=1)=[O:16])[CH:28]([CH3:30])[CH3:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)NNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)OC(C)(C)C)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.4 %

Procedure:
To a mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (5.20 g, 16.0 mmol) and N′-isopropyl-hydrazinecarboxylic acid tert-butyl ester (3.33 g, 19.1 mmol) in DMF (100 mL) at 0° C. was added DIPEA (6.93 mL, 39.9 mmol) followed by HATU (9.09 g, 23.9 mmol). The reaction mixture was stirred at RT for 72 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM (×3) before the combined organic extracts were washed with 10% citric acid, then saturated sodium bicarbonate solution followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a brown oil. The oil was extracted with diethyl ether (×5) and the diethyl ether extracts concentrated in vacuo before being triturated with pentane to give the title compound as a light brown solid (6.14 g, 12.7 mmol, 80%). LCMS: RT=5.02 min, [M+H]+=482/484.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1Cl>CN1C(=O)CCC1>[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)c(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Sodium hydride (2.7 g, 67.5 mmol) was suspended in NMP (75 ml) and benzyl alcohol (7.3 g, 67.6 mmol) was added over 10 minutes. When the addition was complete the solution was stirred at 50° C. for 30 minutes. 4-Amino-3-chlorobenzonitrile (10.3 g, 67.5 mmol), (Synthesis 1985, 669), was added and the mixture was heated at 120-130° C. for 4 hours. After cooling to ambient temperature the mixture was partitioned between water and ether. The ether extracts were washed with brine, dried (MgSO4), the insoluble materials were removed by filtration and the volatiles were removed by evaporation. The crude product was purified by flash chromatography eluting with ether/isohexanes (1/1 increasing to 1/0). The purified product was recrystallized from ethyl acetate/isohexanes to give 4-amino-3-benzyloxybenzonitrile (4.7 g, 31%).