Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:25])=[O:24])[CH:18]=2)=[C:4]([F:9])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A solution of 4-amino-2-fluorophenol (0.81 g, 6.4 mmol, 1.0 eq) in DMF (6.5 mL) was treated with potassium tert-butoxide (0.79 g, 7.1 mmol, 1.1 eq) at room temperature and the reaction mixture was stirred for 1 h. 4-Chloropicolinamide (1.0 g, 6.4 mmol, 1.0 eq) was added and the reaction mixture was heated to 110° C. for 8 h. The reaction was cooled to room temperature and the reaction mixture quenched with water. The resulting heterogeneous solution was filtered and the solid material was washed with water. The solid was triturated with a small amount of MeOH followed by Et2O. The solid was filtered and dried in vacuo to afford the desired product (1.3 g, 82%) as a solid. 1H NMR (DMSO-d6) δ 8.49-8.50 (m, 1H), 8.12 (br s, 1H), 7.71 (br s, 1H), 7.35-7.36 (m, 1H), 7.14-7.16 (m, 1H), 7.01-7.06 (m, 1H), 6.44-6.47 (m, 2H), 5.53 (s, 2H); MS(ESI+) m/z 248 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][N:4]=1.[N-:10]=[N+:11]=[N-:12].CC1C=CC=C2C=1C(C)=C(C)C(C)=N2>C(Cl)Cl>[N:10]([CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][N:4]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc(Cl)ccn1
Agent: Cc1nc2cccc(C)c2c(C)c1C
Solvent: ClCCl
Product: [N-]=[N+]=NCc1cc(Cl)ccn1

Procedure:
The starting material may be obtained as follows. Reaction of 2-chloromethyl-4-chloropyridine with excess tetramethylquinoline azide in CH2Cl2 at ambient temperature for 24 hours gave 2-azidomethyl-4-chlorpyridine. n.m.r. in CDCl3 :-4.5(s, 2H); 7.3(m, 2H); 8.5(d, 1H). Reduction of this compound in MeOH in the presence of 2 equivalents of acetic anhydride with Raneyl nickel at ambient temperature for 30 minutes gave, after purification by silica gel chromatography, 2-acetylaminomethyl-4-chloropyridine, n.m.r. in CDCl3 :-2.1(s, 3H); 4.56(d, 2H); 7.3(m, 2H); 8.48(d, 2H). Reaction of the compound with excess dimethyl sulphate for 30 minutes at 40° gave 2-acetylaminomethyl-4-chloro-1-methylpyridinium methyl sulphate, n.m.r. in solvent F:-2.0(s, 3H); 3.44(s, 3H9; 4.3(s, 3H); 4.7(s, 2H); 8.2(m, 2H); 9.04(d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](=[O:42])[C:39](O)=[O:40])=[CH:30]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:39](=[O:40])[C:38]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:29][CH:30]=3)=[O:42])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)C(=O)c1c[nH]c2ccccc12
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)C(=O)c2c[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (209 mg, 0.51 mmol) in dry N,N-dimethylformamide (4 ml) was added 3-indole-glyoxylic acid (141 mg, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (152 mg, 0.76 mmol), and 1-hydroxy-benzotriazole (100 mg, 0.74 mmol). The mixture was stirred at room temperature for 16 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml), brine (100 ml), dried (MgSO4), filtered, and concentrated in vacuo. The residue was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (2:5) as eluent, which afforded 143 mg (40%) of 2-amino-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH:10]=[CH:9]3)[CH2:6][CH2:5]1.C1C=CC=CC=1>C(Cl)Cl>[OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH:10]=[CH:9]3)[CH2:6][CH2:5]1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Solvent: c1ccccc1
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 1.7 g. of (20S)-21-hydroxy-20-methylpregna-4,6-dien-3-one in 80 ml. of dry benzene was treated with 1.45 g. of dichlorodicyano and then heated under reflux for 10 hours. The resulting suspension was filtered under suction, the filtrate was washed with 5% sodium hydroxide, then with water and dried over sodium sulfate. The residue obtained by evaporation was taken up in methylene chloride and filtered through a column of 10 g. of aluminum oxide. From the filtrate, 1 g. of crude crystals were obtained, were recrystallized from ether to give (20S)-21-hydroxy-20-methylpregna-1,4,6-trien-3-one, m.p. 156°-157°. This was shown to be identical to the compound obtained in Example 8 according to its thin layer chromatogram mixture, melting point and infrared spectrum.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:18]([Mg]Br)#[CH:19]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:18]#[CH:19])[CH:10]=[CH:11][C:12]=1[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)c1cc(C=O)ccc1N1CCCC1
Product: C#CC(O)c1ccc(N2CCCC2)c(C(C)(C)C)c1

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 1 g (4 mmol) of 3-tert-butyl-4-pyrrolidin-1-ylbenzaldehyde with 11 ml (5.5 mmol) of a 0.5M solution of ethynylmagnesium bromide. 640 mg of 1-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)prop-2-yn-1-ol are obtained in the form of a colourless oil (yield=62%).
Reaction SMILES: [CH2:1]([CH:3]([C:9](OCC)=O)[C:4]([O:6]CC)=[O:5])[CH3:2].[Na].[C:15]1([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2CBr)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+]>O>[C:15]1([C:21]2[CH:22]=[CH:25][CH:26]=[CH:27][C:28]=2[CH2:9][CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: BrCc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CCC(Cc1ccccc1-c1ccccc1)C(=O)O
Temperature: 130 °C
Yield: 92.8 %

Procedure:
188 g (1 mol) of diethyl ethylmalonate dissolved in 100 cm3 of H2O-free EtOH are added dropwise at room temperature to 23 g (1 mol) of sodium in 400 cm3 of H2O-free EtOH. 247 g (1 mol) of 2-phenylbenzyl bromide in 300 cm3 of H2O-free EtOH were subsequently added dropwise, and the mixture was refluxed for 3 hours. 170 g (3 mol) of KOH dissolved in 300 cm3 of H2O were added at room temperature, and the mixture was refluxed for a further 4 hours. The solvent was removed in vacuo, H2O was added to the residue until the latter had dissolved completely, and the mixture was subsequently acidified to pH 1 by means of concentrated aqueous HCl. The precipitate which formed was filtered off with suction, dried and heated at 130° C. for 1 hour, giving 236 g (93%) of 13 as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].FC1C=CC2N3CCC4C3=C(C=CC=4)C(N3CCN(C)CC3)=NC=2C=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:7][CH2:6][CH2:5]2
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccc2c(c1)CCCN2
Agent: CN1CCN(C2=Nc3cc(F)ccc3N3CCc4cccc2c43)CC1
Product: Cc1ccc2c(c1)CCCN2c1ccccc1[N+](=O)[O-]

Procedure:
Starting with 6-methyl-1,2,3,4-tetrahydroquinoline and 2-fluoronitrobenzene and following steps 1a to 1f of Example 2, one may obtain, in sequence, 6-methyl-1-(2-nitrophenyl)-1,2,3,4 -tetrahydroquinoline, 1-(2-aminophenyl)-6-methyl-1,2,3,4-tetratetrahydroquinol. 1-(2-aminophenyl)-6-methyl-1,2,3,4-tetrahydroquinoline N-[2-(6-methyl-1-phenyl)-1,2,3,4-tetrahydrohydroquinoline, -1-yl]-4-methyl-1-piperazine carboxamide, and 5-methyl-7-(4-methyl-1-piperazinyl)-2,3-dihydro-1H-quino[18-ab][1,5]-benzodiazepine.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][CH:7]=[C:8]([C:14](=[O:28])[C:15]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)=[CH:17][C:16]=2F)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.O>O1CCOCC1>[F:21][C:19]1[CH:20]=[C:15]2[C:16](=[CH:17][C:18]=1[N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1)[N:6]([CH:3]1[CH2:5][CH2:4]1)[CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]2=[O:28]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(-n2cccc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 80 °C
Yield: 77.3 %

Procedure:
0.07 g (0.00115 mol) of a 60% suspension of sodium hydride in mineral oil is added to a solution of 0.41 g (0.00114 mol) of ethyl 3-cyclopropylamino-2-(2,5-difluoro-4-pyrrol-1-ylbenzoyl)acrylate in 10 ml of anhydrous dioxane. The mixture is heated at 80° C. for 2 hours under a nitrogen atmosphere and left to cool, 30 ml of water are added and the precipitate is filtered off and washed with water to give 0.3 g of a product melting at 216°-9° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:7]([CH2:10][O:11]C(=O)C)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(Cl)Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(COC(C)=O)n1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Yield: 81 %

Procedure:
A solution of crude 2-n-butyl-5-acetoxymethyl-1-(2-chlorophenyl)methyl-1H-imidazole (250 g) in methanol (200 mL) was treated with 10% sodium hydroxide solution (700 mL) and the mixture was heated on a steam bath for 4 hours. After cooling, methylene chloride was added, the organic phase was separated, washed with water, dried and concentrated. The residue was dissolved in ether, cooled, and seeded to give the crude product. Recrystallization from ethyl acetate gave 176 g of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp 86°-88° C. This material was identical in all respects to the product prepared by Method 1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].S(Cl)([Cl:16])=O>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCOc1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Product: C=CCOc1ccc(C(=O)Cl)cc1

Procedure:
The 4-(2-propenyloxy)benzoic acid, 5 g (0.028 mol), was refluxed with thionyl chloride (37 mL, 0.51 mol) and several drops of pyridine for 8 hours. The excess thionyl chloride was removed in vacuo leaving 4-(2-propenyloxy)benzoyl chloride as a yellow liquid at 25° C. This acid chloride was used without further purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([O:6][CH:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[CH3:31])[C:9]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:5].[C:38](=O)([O:48]C1C=CC([N+]([O-])=O)=CC=1)[O:39][CH2:40][CH:41]1[CH:45]([CH3:46])[O:44][C:43](=[O:47])[O:42]1.O>CN(C=O)C>[CH3:1][N:2]([CH2:3][C:4]([O:6][CH:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[CH3:31])[C:9]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:5])[C:38]([O:39][CH2:40][C:41]1[O:42][C:43](=[O:47])[O:44][C:45]=1[CH3:46])=[O:48]
Reactant: CNCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Reactant: CC1OC(=O)OC1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CN(C)C(=O)OCc3oc(=O)oc3C)c3cc(Cl)ccc32)c(C)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl methylaminoacetate (0.34 g, 0.65 mmol), and (5-methyl-1,3-dioxolane-2-one-4-yl)-methyl 4-nitrophenyl carbonate (0.22 g, 0.74 mmol) were dissolved in DMF (5 ml), and the mixture was stirred at room temperature over night. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium chloride solution, and then dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate) to obtain 0.44 g (43%) of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} [methyl-(5-methyl-2-oxo-1,3-dioxol-4-yl-methoxycarbonyl)-amino]acetate as amorphous.
Reaction SMILES: C([O:8][C:9]([Cl:12])(Cl)Cl)(OC(Cl)(Cl)Cl)=O.[Si:13]([O:20][CH:21]1[CH2:24][NH:23][CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)CC)C>ClCCl>[Si:13]([O:20][CH:21]1[CH2:24][N:23]([C:9]([Cl:12])=[O:8])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1CNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)Cl)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of ditrichloromethyl carbonate (2.38 g, 8.02 mmol, 1.50 equiv) in dichloromethane (20 mL) was added a solution of 3-[(tert-butyldimethylsilyl)oxy]azetidine (1 g, 5.34 mmol, 1.00 equiv) in dichloromethane (5 mL) dropwise with stirring at 0° C. over 30 min. Stirring was continued for 30 min whereupon a solution of triethylamine (810 mg, 8.00 mmol, 1.50 equiv) in dichloromethane (5 mL) was added dropwise with stirring at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined, washed with 2×40 mL of sodium chloride (sat.), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). Purification afforded 1.3 g (97%) of 3-[(tert-butyldimethylsilyl)oxy]azetidine-1-carbonyl chloride as a light yellow liquid.
Reaction SMILES: CN(C)C(=O)C.C1(C)C=CC(S([O:16][C:17]2[CH:22]=[C:21]([C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:19][C:18]=2[NH2:48])(=O)=O)=CC=1.[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][C:57]=2[S:65](Cl)(=[O:67])=[O:66])[CH2:52][CH2:51]1.Cl>N1C=CC=CC=1>[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][C:57]=2[S:65]([NH:48][C:18]2[CH:19]=[C:20]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:21]([C:23]([CH3:29])([CH3:30])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][C:17]=2[OH:16])(=[O:66])=[O:67])[CH2:52][CH2:51]1
Reactant: CCCCCCCCCCCCCCCCOc1cc(N)c(OS(=O)(=O)c2ccc(C)cc2)cc1C(C)(C)CC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N2CCOCC2)c(O)cc1C(C)(C)CC(C)(C)C

Procedure:
To a solution of N,N-dimethylacetamide (200 ml) containing 20 g (0.0314 mol) of 2-amino-4-hexadecyloxy-5-(1,1,3,3-tetramethylbutyl)phenol paratoluene sulfonate and 12.7 ml of pyridine was added 10.6 g (0.0346 mol) of the compound obtained in Step (b) above with stirring while introducing a nitrogen gas and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to 500 ml of aqueous solution containing 15 ml of hydrochloric acid and the precipitate was extracted with ethyl acetate. The ethyl acetate was washed with water and concentrated. To the residue was added 100 ml of methanol and the crystals thus precipitated were collected by filtration. Yield: 22 g (94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH:12]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cccc(CCNC(=O)C2CCCCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of 3-methoxyphenethylamine (1.000 g, 6.61 mmol), cyclohexanecarboxylic acid (0.847 g, 6.61 mmol), 1-hydroxybenzotriazole hydrate (1.340 g, 9.92 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.330 g, 6.94 mmol) in anhydrous CH2Cl2 (20 ml) was stirred at 0° C. under N2 for 1 hr, then warmed to rt and stirred at rt for 18 hr. The reaction mixture was washed sequentially with 1M NaOH (10 ml), 1M HCl (10 ml), and H2O (10 ml), then dried over MgSO4 and concentrated in vacuo to give 1.301 g of off-white solid. Purification by flash chromatography, eluting with hexane:EtOAc (6:4) gave 1.107 g (64% yield) of white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=1[CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:10]([N+:25]([O-:27])=[O:26])=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=1[CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2]
Reactant: CCCc1c(NC(C)=O)ccc(C(C)=O)c1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCc1c(O)c(C(C)=O)cc([N+](=O)[O-])c1NC(C)=O

Procedure:
1-(4-Acetylamino-2-hydroxy-3-propylphenyl)ethanone (58.75 g) was suspended in glacial acetic acid (750 ml), and this suspension was treated with a mixture of glacial acetic acid (250 ml), acetic anhydride (48 ml) and conc. nitric acid (10.2 ml) with vigorous stirring. After 18 hours the insoluble material was collected and dried in vacuo to afford the title compound 29.1 g. The structure was confirmed by NMR and mass spectrometry.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. N,N-dimethylamine (7.7 mL, 15.5 mmol, 2M in tetrahydrofuran) and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) were added, and the reaction was allowed to stir at ambient temperature for 2 hours. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil which deposited needles that were a mixture of the title compound and 4-chloromethyl N,N-dimethylbenzenesulfonamide The resulting needles were collected and dried (2.3 g, 44%). ES-MS m/z 534 (M+H) and 578 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]([OH:17])([C:15]#[CH:16])[CH3:14].CCN(CC)CC>[Cu]I.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.O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:16]#[C:15][C:13]([CH3:14])([OH:17])[CH3:12])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(O)C#Cc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.6 mmol), CuI (141 mg, 0.74 mmol), Pd(PPh3)4, (367 mg, 0.32 mmol) and 2-Methyl-3-butyn-2-ol (1.5 mL, 15.8 mmol) was added 1-methyl-2-pyrorolidone (20 mL) followed by Et3N (6 mL, 22 mmol). After stirring for 4 h 30 min at room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography over silica gel (EtOAc/Hexanes, 2:98, then 5:95) to provide 4-(5-chloro-3-nitro-pyridin-2-yl)-2-methyl-but-3-yn-2-ol. MS m/z: 241.0 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:16][NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(CN)ccc1CN1CCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(CNc2ccccc2[N+](=O)[O-])ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.2 %

Procedure:
2-Fluoronitrobenzene (0.358 mL, 3.4 mmol, 1.0 eq.), 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl amine (750 mg, 3.4 mmol) and anhydrous potassium carbonate (471 mg, 3.4 mmol, 1.0 eq.) were combined in dry THF (35 mL) then allowed to stir 48 h at ambient temperature. The reaction mixture was filtered through a bed of diatomaceous earth then the solvent was removed under reduced pressure. The crude oil was purified by flash chromatography (eluting with 20:1 CHCl3:MeOH, 0.5% TEA) to give the desired product as a right orange oil (676 mg, 58%).