Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl>O1CCCC1>[CH:9]([C:7]1[CH:6]=[CH:5][C:4]([O:11][CH2:21][O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:8]=1)=[O:10]
Reactant: COCCl
Reactant: COc1cc(C=O)ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(C=O)cc1OC
Yield: 96 %

Procedure:
A mixed solution of 15.2 g of 2-methoxy-4-formylphenol, 26 ml of diisopropyl ethylamine, 9 ml of methoxymethyl chloride and 100 ml of tetrahydrofuran (THF) was stirred at room temperature for 3.5 hours. The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 18.9 g of (4-formyl-2-methoxyphenoxy)methoxymethane (yield: 96%, melting point: 34°-37° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COc1ncc(F)cc1C(=O)O
Product: COc1ncc(F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a round bottom flask, 5-fluoro-2-methoxy-nicotinic acid (150, 250 mg, 1.46 mmol) was combined with thionyl chloride (3.00 mL, 41.1 mmol) and the suspension was stirred at room temperature for 3 hours. The reaction was concentrated to dryness under vacuum to provide the desired compound, used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]2[CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:14][CH2:15][CH2:16][OH:17].CCOC(C)=O.C1COCC1>C1COCC1>[OH:17][CH2:16][CH2:15][NH:14][CH2:13][CH:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[OH:12]
Reactant: Cc1cc(C2CO2)ccc1[N+](=O)[O-]
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)CNCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (RS)-2-(3-methyl-4-nitrophenyl)oxirane (4.63 g) in THF (15 ml) was added 2-aminoethanol (15.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (1:1) and extracted with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-(2-hydroxyethylamino)-1-(3-methyl-4-nitrophenyl)ethanol (6.84 g, quant.) as a brown oil which was used in the next step without further purification. MS (ISP): 241.1 ([M+H]+).
Reaction SMILES: Br.C(O)(=O)C.C[O:7][C:8]1[C:9]([O:27]C)=[CH:10][C:11]2[CH2:12][CH2:13][N:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=4[CH2:16][CH:15]3[C:25]=2[CH:26]=1>O1CCCC1>[CH:26]1[C:25]2[CH:15]3[CH2:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19][CH2:20][N:14]3[CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([OH:27])[C:8]=1[OH:7]
Reactant: COc1cc2c(cc1OC)C1Cc3ccccc3CCN1CC2
Agent: Br
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Oc1cc2c(cc1O)C1Cc3ccccc3CCN1CC2

Procedure:
Hydrobromic acid (48%, 30 ml) was added to a glacial acetic acid (3 ml) solution of 5,6,8,9,14,14a-hexahydro-2,3-dimethoxyisoquino[1,2-b][3]-benzazepine (XIIIc, Ex. 20) (0.928 g, 3 mmole), and the resulting solution was heated under reflux for 2.5 hours, then evaporated on a rotary evaporator to give a resinous residue. The residue was dissolved in tetrahydrofurane (about 80 ml), and the solution was allowed to sit at room temperature over a weekend. The crystalline product that was separated was collected on a filter, and washed with tetrahydrofurane to give the titled product which was recrystallized from ethanol. The product (HBr salt) weighed 0.8 g (73%) and melted at 270°-272°.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[N:16]=O.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:7]2[C:3]([NH2:2])=[C:4]([NH2:16])[CH:5]=[N:6]2)=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: COc1ccc(-n2ncc(N=O)c2N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2ncc(N)c2N)cc1

Procedure:
8.0 g (31 mmol) of 5-amino-1-(4-methoxyphenyl)4-nitrosopyrazole hydrochloride from Step 1.2 in 200 mL of ethanol was hydrogenated for 6 hours on 0.8 g of Pd/C (10%) at 8 bar of hydrogen pressure. The catalyst was filtered off, and the reaction mixture was concentrated to a total volume of about 30 mL. After the addition of 40 mL of 3-molar ethanolic hydrochloric acid and agitation in an ice bath, the product crystallized. Suction filtration and washing with 50 mL of ethyl acetate gave 7.4 g (27 mmol), 86% of the theoretical) of 1-(4-methoxyphenyl)-4,5-diamino-1H-pyrazole dihydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[NH2:26][CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:26][CH2:27][CH2:28][C:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][CH:30]=3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncnc(NCCc3c[nH]c4ccccc34)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and Tryptamine (18 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [Na].[C:2]([N:5]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:9]=2[NH:8][C:7](=[O:23])[CH2:6]1)(=[O:4])[NH2:3].[CH3:24]O>>[CH3:24][N:8]1[C:9]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:10]=2[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]([C:2](=[O:4])[NH2:3])[CH2:6][C:7]1=[O:23]
Reactant: CO
Reactant: NC(=O)N1CC(=O)Nc2ccc(Cl)cc2C1c1ccccc1
Agent: [Na]
Product: CN1C(=O)CN(C(N)=O)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 79.5 %

Procedure:
0.16 g. (6.85 mmoles) of metallic sodium are dissolved in 2 ml. of absolute methanol, and a suspension of 0.9 g. (2.86 mmoles) of 4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 50 ml. of absolute methanol is added to the solution at room temperature, with stirring. The suspension is stirred at room temperature for 30 minutes, and then evaporated under reduced pressure. The oily residue is dissolved in 9 ml. of dimethyl formamide, and 0.48 ml. of methyl iodide are added to the stirred solution at room temperature. The mixture is stirred for an additional 2 hours, then diluted with 50 ml. of water and extracted with 3×10 ml. of chloroform. The chloroform extracts are combined, dried over sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure, to obtain 0.85 g. of a residue, which is recrystallized from ethanol. 0.75 g. (79.5%) of 1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4 -benzodiazepine-2-one are obtained; m.p.: 217°-220° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 51.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and 5-fluoro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 11 (29 mg, yield 51.5%) as a yellow solid.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[S:20][CH2:19][CH2:18][CH2:17][S:16]2)=[CH:13][S:12][C:11]=1[N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])=[O:9])C.Cl>O>[Cl:27][C:23]1[CH:22]=[C:21]([C:15]2([C:14]3[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:28]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29]4=[O:38])[S:12][CH:13]=3)[S:20][CH2:19][CH2:18][CH2:17][S:16]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(C2(c3cccc(Cl)c3)SCCCS2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(C2(c3cccc(Cl)c3)SCCCS2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-[2-(3-chlorophenyl)-1,3-dithian-2-yl]-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3carboxylic acid ethyl ester (0.7 mmol, Example 27 & 28, Part D). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=2[C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[CH:6][C:5]=1[F:27].[OH-].[Na+].[CH2:31]1COCC1>>[CH2:16]([C:12]1[C:11]([C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH:26][CH3:31])=[CH:24][CH:25]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[C:5]([F:27])[CH:6]=2)[CH:15]=[CH:14][N:13]=1)[CH3:17]
Reactant: C1CCOC1
Reactant: CCc1nccc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1
Agent: [Na+]
Agent: [OH-]
Product: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(NC)nc1
Temperature: 65 °C
Reaction time: 72 h

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 850 mg (2.18 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid methyl ester (A-45) using 3.3 mL (3.3 mmoL) 1N NaOH in 22 mL THF. The reaction mixture is stirred for 72 h at 65° C. The product is precipitated by addition of water and is collected by filtration. Yield after drying: 747 mg (91%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Li].[CH3:27][N:28]([CH3:32])[C:29](Cl)=[S:30]>C1COCC1>[CH3:27][N:28]([CH3:32])[C:29]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])=[S:30]
Reactant: CN(C)C(=S)Cl
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [Li]C
Solvent: C1CCOC1
Product: CN(C)C(=S)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
To a solution of 5.0 g (0.014 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole in 50 ml of THF was added dropwise 15 ml of 1.6 M methyl lithium solution, followed by a solution of 5.5 g (0.045 mole) of dimethylthiocarbamoyl chloride in 25 ml THF. The reaction mixture was heated at reflux several hours, then concentrated by rotary evaporation. The residue was shaken with ether and 1 N hydrochloric acid. The ether layer was washed with 10% sodium bicarbonate solution, then dried and concentrated. The residue (7.8 g) was purified by chromatography on silica gel, eluting with toluene to give 0.8 g of product, mp 133°-133.5° (recrystallized from methyl cyclohexane).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH2:13]O)[CH2:12][CH2:11]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2([CH3:13])[CH2:12][CH2:11]2)=[CH:6][N:7]=1
Reactant: CC1(CO)CC1
Reactant: Cc1ccc(O)cn1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(OCC2(C)CC2)cn1
Yield: 100.6 %

Procedure:
To a solution of 6-methylpyridin-3-ol (0.5 g, 4.6 mmol) in toluene (6 mL) was added (1-methylcyclopropyl)methanol (0.59 g, 6.9 mmol) and stirred under nitrogen atmosphere. The solution was added cyanomethylenetri-n-butylphosphorane (CMBP, 2.5 ml, 9.53 mmol) and stirred at 100° C. for 3 hours. The reaction mixture was evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 (v/v)) to give 820 mg (quantitative yield) of the title compound as a brown oil:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2C)=[CH:5][N:4]=1.IC1C=CC=C([F:27])C=1>>[F:27][C:15]1[CH:14]=[C:13]([C:12]#[C:11][C:6]2[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C#Cc2ccccc2C)cnc1OC
Reactant: Fc1cccc(I)c1
Product: COc1cc(C#Cc2cccc(F)c2)cnc1OC

Procedure:
Prepared as described for 2,3-dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (Intermediate 33) but using 1-iodo-3-fluorobenzene instead of 1-iodo-2-methylbenzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[Mg].[Br:12][C:13]1[CH:14]=[C:15]([CH:22]=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=1)[C:16](N(OC)C)=[O:17].[Cl-].[NH4+]>O1CCCC1>[Br:12][C:13]1[CH:14]=[C:15]([C:16]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=2)=[O:17])[CH:22]=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=1
Reactant: CCOc1cc(Br)cc(C(=O)N(C)OC)c1
Reactant: COc1ccc(Br)cc1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1cc(Br)cc(C(=O)c2ccc(OC)c(C)c2)c1
Temperature: 15 °C

Procedure:
A solution of 4-bromo-2-methylanisole (0.984 g, 4.9 mmol) in tetrahydrofuran (3 mL) was added dropwise to magnesium powder (0.127 g, 5.2 mmol) in tetrahydrofuran (1 mL) at room temperature. Under external heating the reaction mixture was brought up to reflux. After complete addition, reflux was maintained for 1 hour. Thereafter the mixture was cooled to 15° C., then diluted with tetrahydrofuran (1 mL) before a solution of 3-bromo-5-ethoxy-N-methoxy-N-methyl-benzamide (1.238 g, 4.3 mmol) in tetrahydrofuran (3 mL) was added dropwise. After complete addition, the mixture was heated to reflux for 1.5 hours. For the working-up, it was cooled to 5° C. and hydrolysed with a saturated solution of ammonium chloride (25 mL). The aqueous layer was extracted twice with ethyl acetate (2×50 mL), thereupon, the organic layers combined, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product was chromatographed on silica gel using a gradient of heptane/ethyl acetate=100/0 to 6/1 as the eluent. There were obtained 1.16 g (77% of theory) of the title compound as a colourless oil. Mass (calculated) C17H17BrO3 [348]; (found) [M+H]+=349, 351.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH3:8].[SH:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH3:13]>>[CH3:8][C:7]1[N:6]=[CH:5][NH:4][C:3]=1[CH2:2][S:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH3:13]
Reactant: CCC(N)CS
Reactant: Cc1[nH]cnc1CO
Product: CCC(N)CSCc1[nH]cnc1C

Procedure:
Reaction of 4-hydroxymethyl-5-methylimidazole and 1-mercapto-2-aminobutane in the procedure of Example 1(i) yields 4-methyl-5-[(2-aminobutyl)thiomethyl]imidazole and, when this is reacted with S-methyl-N'-[2-((4-methyl 5-imidazolyl)methylthio)ethyl]thiouronium sulphate in the procedure of Example 1(iii), the title compound is produced.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-nitrophenol (1 g, 7.12 mmol, 1.00 equip, 99%), tert-butyl 2-bromoacetate (1.68 g, 8.53 mmol, 1.00 equip), potassium carbonate (1.49 g, 10.60 mmol, 1.50 equip, 99%), and tetrahydrofuran (50 mL). The resulting solution was stirred for 4 h at 70° C. in an oil bath. The resulting solution was diluted with water (150 mL). The resulting solution was extracted with ethyl acetate (3×100 mL) and the organic layers combined. The resulting mixture was washed with water (1×100 mL) and brine (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20) to yield tert-butyl 2-(4-nitrophenoxy)acetate as a yellow solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([CH3:21])[CH2:12][N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)[CH:7]=[CH:8][CH:9]=1.I[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.O>CN(C)C=O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([O:3][C:4]2[CH:5]=[C:6]([CH2:10][CH:11]([CH3:21])[CH2:12][N:13]3[CH2:14][CH:15]([CH3:20])[O:16][CH:17]([CH3:19])[CH2:18]3)[CH:7]=[CH:8][CH:9]=2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: CC(Cc1cccc(O)c1)CN1CC(C)OC(C)C1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1)CN1CC(C)OC(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
Dimethylformamide (5 ml) was added to 60% sodium hydride (0.12 g) under nitrogen stream, and a solution of 4-[3-(3-hydroxyphenyl)-2-methylpropyl]-2,6-dimethylmorpholine (0.48 g) in dimethylformamide (5 ml) was added thereto in 30 minutes, followed by stirring at room temperature for 2 hours. To the reaction mixture, p-iodonitrobenzene (0.97 g) and cuprous chloride (0.1 g) were added, and the resultant mixture was heated under reflux for 10 hours. Then, water (100 ml) was added to the reaction mixture, which was filtered through celite. The celite was washed with toluene (200 ml). The toluene layer and the toluene washing were combined together and shaken with 15% aqueous sodium hydroxide solution (30 ml). The toluene layer was separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-[3-(3-(4-nitrophenoxy)phenyl)-2-methylpropyl]-2,6-dimethylmorpholine (cis-isomer, 0.27 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15](SC)[N:14]=[C:13]([NH:19][C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C([C:37](OO)=[O:38])C=1>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([O:38][CH3:37])[N:14]=[C:13]([NH:19][C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Nc2ccc3c(c2)OCCO3)cc(-c2ccc(C(C)(C)C)cc2)n1
Solvent: ClCCl
Product: COc1nc(Nc2ccc3c(c2)OCCO3)cc(-c2ccc(C(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 50-mL, round-bottomed flask containing a solution of 6-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylthio)pyrimidin-4-amine from step (b) above (0.41 g, 1.0 mmol) in CH2Cl2 (10 mL) was added m-CPBA (0.38 g, 2.2 mmol, Aldrich). The reaction mixture was stirred at room temperature for 0.5 h, and the solvent was removed in vacuo. The residue was dried in vacuo to provide the title product. MS (ESI, pos. ion) m/z: 439 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12](Cl)(Cl)=[O:13]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][C:12](=[O:13])[NH:9][C:7]2=[O:8]
Reactant: O=C(Cl)Cl
Reactant: NC(=O)c1cc(Cl)ccc1N
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-chloroanthranilamide (3.4 g)in tetrahydrofuran (50 mL) was added phosgene (16 mL, 1.93M solution in toluene) via an addition funnel. The reaction mixture was stirred at room temperature for 4 hours and then heated to reflux for another two hours. The reaction mixture was concentrated to a total volume about 10 mL. After cooling, the title compound (3.72 g) having the following physical data, was collected by filtration and dried in vacuum.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22][C@@H:23]2[O:40][C@H:39]([CH2:41][O:42]C(=O)C)[C@H:34]([O:35]C(=O)C)[C@H:29]([O:30]C(=O)C)[C@H:24]2[O:25]C(=O)C)[C@@H:15]([CH2:46][O:47]C(=O)C)[O:14][C@H:6]1[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])(=O)C>C[O-].[Na+]>[C@@H:23]1([O:22][C@@H:16]2[C@@H:15]([CH2:46][OH:47])[O:14][C@@H:6]([O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[C@H:5]([OH:4])[C@H:17]2[OH:18])[O:40][C@H:39]([CH2:41][OH:42])[C@H:34]([OH:35])[C@H:29]([OH:30])[C@H:24]1[OH:25]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCC[Si](C)(C)C)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Product: C[Si](C)(C)CCO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Yield: 82.5 %

Procedure:
2-Trimethylsilylethyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-β-D-glucopyranoside (1) (Jansson et al., 1988) (29.4 g, 40 mmol) was stirred in methanolic sodium methoxide (5.8 mM, 515 mL) for 15 h. Neutralization with acetic acid, evaporation and crystallization from ethanol gave (2) (14.6 g, 82%).
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.S(=O)(=O)(O)O.[CH3:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>CCCCCCC>[C:5]12([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][C:22]=3[O:21][CH3:20])[C:26]([O:28][CH3:29])=[O:27])[CH2:12][CH:11]3[CH2:10][CH:9]([CH2:8][CH:7]([CH2:13]3)[CH2:6]1)[CH2:14]2
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Product: COC(=O)c1ccc(OC)c(C23CC4CC(CC(C4)C2)C3)c1
Reaction time: 48 h

Procedure:
In a 100 ml three-necked flask, under a nitrogen environment, are placed 2 g of 1-acetoxyadamantane and 20 ml of n-heptane. After total dissolution, 0.5 g of concentrated sulfuric acid is added drop by drop. At a temperature of approximately 20.C, 1.71 g of methyl 4-methoxybenzoate is added slowly and agitated for 48 hours. The solid obtained is filtered with sintered glass and washed with water until neutrality is reached. After drying in a vacuum oven for 24 hours at 25 C, one recovered 2 g of expected raw product (Melting point: 136°-137° C.).