Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:43][CH2:44][CH2:45][CH2:46][N:47]1C(=O)C2=CC=CC=C2C1=O>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:47][CH2:46][CH2:45][CH2:44][CH2:43][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Oc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCCCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 87.7 %

Procedure:
To a solution of 1-[2-[4-[[2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]methyl]phenoxy]ethyl]pyrrolidine (53 mg, 0.123 mmol) in THF (1 mL) was added a solution of potassium bis(trimethylsilyl)amide (0.271 mL of 0.5 M, 1.36 mmol, 1.1 eq.) in toluene at ambient temperature. After 80 min, N-(4-bromobutyl)phthalimide (75 mg, 0.265 mmol, 2.2 eq) was added and the reaction heated at reflux for 18 h. The reaction was cooled to ambient temperature, diluted with ethyl acetate (50 mL) then washed with 10% aqueous sodium bicarbonate (20 mL). The solvent was removed under reduced pressure then the residue purified by flash chromatography (20:1 CHCl3: MeOH then 5:1 CHCl3: MeOH) to give the protected amine as a tan solid (54 mg, 70%) and recovered starting material (8 mg).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17](C=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[BH3-][C:33]#N.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:24][N:25]([CH3:33])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CNC
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CN(C)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 23 °C

Procedure:
A mixture of 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (155 mg, 0.5 mmol) and ethyl 2-(methylamino)acetate (117 mg, 1.0 mmol, 2.0 equiv) in anhydrous ethanol (20 mL) was refluxed for 2 hr and evaporated in vacuum to dryness. Anhydrous EtOH was added and refluxed for 1 hr, and then the mixture was cooled to 23° C. NaBH3CN (60 mg, 1.0 mmol, 2.0 equiv) was added. The resulted mixture was refluxed for 1 h. The reaction mixture was concentrated in vacuum and the residue was purified by chromatography with silica gel (dichloromethane:methanol 20:1) to give product ethyl 2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino)acetate as a white solid (82 mg, yield: 40%). ESI-MS: 411.3 (M+H)+. HPLC: 98.93%. 1H NMR (400 MHz, CDCl3) δ 7.71-7.67 (m, 3H), 7.00 (d, 1H), 7.14-7.13 (m, 2H), 4.30-4.28 (m, 1H), 4.18 (q, 2H), 3.82 (s, 3H), 3.30 (s, 2H), 2.45 (s, 3H), 2.29-2.27 (m, 2H), 1.91-1.88 (m, 2H), 1.46-1.42 (m, 2H), 1.29-1.22 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]([CH3:24])[C:22]([CH3:25])=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26][O:27][CH2:28][CH:29]([NH2:33])[CH2:30][O:31][CH3:32]>S(Cl)(Cl)=O.C(O)C.CN(C)CC>[CH3:24][N:23]1[C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([S:2](=[O:5])(=[O:3])[NH:33][CH:29]([CH2:30][O:31][CH3:32])[CH2:28][O:27][CH3:26])=[CH:9][CH:8]=3)[N:18]=2)=[CH:20][N:21]=[C:22]1[CH3:25]
Reactant: O=S(=O)(O)Cl
Reactant: COCC(N)COC
Reactant: Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Agent: CCN(C)C
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COCC(COC)NS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Chlorosulphonic acid (230 μl, 3.31 mmol) was added to a solution of the 2-anilino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 34; 300 mg, 1.12 mmol) in thionyl chloride (6 ml) at 5° C. The mixture was stirred at 5° C. for 30 minutes, room temperature for 1 hour and heated at reflux for 1.5 hour. The mixture was allowed to cool to room temperature and a solution of excess 1,3-dimethoxy-2-aminopropane (Method 59) in ethanol (20 ml) and dimethylethylamine (0.5 ml) were added to the residue, and the mixture stirred at room temperature for 18 hours. The volatiles were removed by evaporation. The residue was triturated with water and the solid product collected by filtration and dried under vacuum at 60° C. The residue was purified by flash silica chromatography DCM:MeOH (95:5) to give the title compound. NMR: 2.40 (s, 3H), 3.10 (s, 6H), 3.20(d, 4H), 3.32-3.28 (m, 1H), 3.98 (s, 3H), 7.20 (d, 1H), 7.55 (d, 1H), 7.65 (s, 2H), 7.74 (d, 2H), 7.90 (d, 2H), 8.44 (d, 2H), 9.89 (s, 1H); m/z 447
Reaction SMILES: [CH3:1][C@H:2]([O:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[CH2:20][N:21]2[CH:25]=[CH:24][CH:23]=[C:22]2[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:27])[CH:15]=[CH:16][CH:17]=1)[C:3](N1CCOCC1)=[O:4].[OH-:35].[Li+]>O1CCCC1.CO>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]([C:22]2[N:21]([CH2:20]/[CH:19]=[CH:18]/[C:14]3[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=3)[O:11][C@@H:2]([CH3:1])[C:3]([OH:4])=[O:35])[CH:25]=[CH:24][CH:23]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)N3CCOCC3)c2)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)O)c2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of (4-methylphenyl)(1-allyl-1H-pyrrol-1-yl)methanone (47.31 g, 210 mmol) in dimethylformamide (650 ml) were added 4-[(2S)-2-(3-iodophenoxy)propanoyl]morpholine (72.24 g, 200 mmol), sodium hydrogencarbonate (33.60 g, 400 mmol), benzyltriethylammonium chloride (45.56 g, 200 mmol) and palladium acetate (2.245 g, 10.0 mmol), and the mixture was stirred for 6 hours at 50–55° C. After the mixture was allowed to cool to room temperature, thereto was added water (1 L) and the mixture was extracted with toluene/ethyl acetate (1/2) twice (1 L and 0.5 L). The organic layer was washed with an aqueous 10% potassium hydrogensulfate solution three times and then water and an aqueous saturated sodium chloride solution. The organic layer was dried over magnesium sulfate. After addition of charcoal, the organic layer was filtered with Celite. The solvent was removed under reduced pressure to give {1-[(2E)-3-(3-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}phenyl)prop-2-enyl]-1H-pyrrol-2-yl}(4-methylphenyl)methanone (about 10 g). To a solution of {1-[(2E)-3-(3-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}phenyl)prop-2-enyl]-1H-pyrrol-2-yl}(4-methylphenyl)methanone (about 100 g) in tetrahydrofuran (350 ml) and methanol (350 ml) was added an aqueous 2N lithium hydroxide solution (500 ml) and the mixture was stirred for 5 hours at 70° C. The reaction mixture was concentrated, followed by addition of water. The mixture was acidified (pH 2–3) with 1N hydrochloric acid. The solution was extracted with toluene/ethyl acetate (1/2)(1 L×2) and dried over anhydrous magnesium sulfate. The solvent was removed and the residue was dried to give (2S)-2-(3-{(1E)-3-[2-(4-methylbenzoyl)-1H-pyrrol-1-yl]prop-1-enyl}phenoxy)propionic acid (about 90 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.[N+](C1C=CC=CC=1N=NC1C=C(C)C=CC=1O)([O-])=O>>[OH:28][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1

Procedure:
When using the procedure of Example 1 an equivalent amount of 2-nitro-2'-hydroxy-3',5'-di-tert-amylazobenzene is substituted for 2-nitro-2'-hydroxy-5'-methylazobenzene, the above noted product is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.O.[NH2:23][NH2:24].C(O)CO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:5][C:6]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:24][N:23]=1
Reactant: NN
Reactant: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Solvent: OCCO
Solvent: O
Product: Nc1n[nH]c2nc(N3CCOCC3)cc(-c3ccccc3)c12
Temperature: 130 °C

Procedure:
A mixture consisting of 15.0 gm (0.05 mol) of 2-chloro-6-morpholino-4-phenyl-3-cyano-pyridine (see Example C), 20 ml of 80% hydrazine hydrate and 100 ml of ethylene glycol was heated for 3 hours at 130° C. Thereafter, the resulting solution was poured into about 1 liter of water, whereupon a virtually colorless precipitate formed which was collected by suction filtration, washed with water and then immediately reprecipitated from 700 ml of 0.1 N hydrochloric acid with concentrated ammonia. The reprecipitated product was collected by suction filtration, washed and dried, yielding 13.7 gm (93% of theory) of practically pure 3-amino-6-morpholino-4-phenyl-1H-pyrazolo[3,4-b]pyridine, m.p. 178°-180° C., of the formula ##STR6## After recrystallization from ethanol it had a melting point of 180°-182° C.
Reaction SMILES: CN1CCOCC1.[O:8]=[C:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]([OH:18])=O.[CH:19]1([Mg]Br)[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1.[Cu](I)I>[CH:19]1([C:16](=[O:18])[CH2:15][CH2:14][N:10]2[CH2:11][CH2:12][CH2:13][C:9]2=[O:8])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)CCN1CCCC1=O
Reactant: Br[Mg]C1CCCC1
Agent: I[Cu]I
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(CCN1CCCC1=O)C1CCCC1
Temperature: 0 °C
Yield: 15 %

Procedure:
2-Chloro-4-6-dimethoxy-1,3,5-triazine (2.68 g, 15.2 mmol) and N-methylmorpholine (4.2 mL, 38.1 mmol) were added to a solution of 3-(2-Oxo-pyrrolidin-1-yl)-propionic acid (2 g, 12.7 mmol, from Step 1) in THF (35 mL). After 1 h the reaction mixture was filtered through a glass frit to remove a white precipitate. The filtrate was treated with copper iodide (2.4 g, 12.7 mmol), cooled to 0° C. and then cyclopentyl magnesium bromide (6.35 mL, 12.7 mmol, 2M in ether) was added. After 4 h the resulting black mixture was quenched with saturated NH4Cl and extracted with CH2Cl2. The organic layers were washed with 1N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purifed by silica gel chromatography (75% EtOAc in hexanes then 5% MeOH in CH2Cl2) to give the title compound as a yellow oil. (0.4 g, 15% yield). 1H NMR (CDCl3): δ 1.55-1.83 (br m, 8H), 1.99 (m, 3H), 2.35 (t, 2H, J=8.3 Hz), 2.74 (t, 2H, J=6.8 Hz), 3.41 (d, 2H, J=7.2 Hz), 3.53 (t, 2H, J=6.6 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:16][CH2:17][CH2:18]O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH2:9]([O:16][CH2:17][CH2:18][O:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCOCc1ccccc1
Reactant: O=C1CCCCC1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: O=C1CCCCC1OCCOCc1ccccc1
Reaction time: 10 h
Yield: 67.1 %

Procedure:
A mixture of dimeric 2-hydroxycyclohexanone (13.7 g), 2-benzyloxyethanol (20 g) and p-toluensulphonic acid (2 g) were dissolved in xylene (500 ml) in a round bottom flask fitted with a Dean Stark apparatus and reluxed for 10 hrs. The resulting solution was cooled, washed with sodium hydrogen carbonate (3×50 ml) dried and concentrated under reduced pressure. The crude oil was then pruified by flash chromatography using cyclohexane/ethyl acetate 60/40 as eluant yielding 20 g of the title compound (RF=0.5).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10](O)(=O)[CH3:11]>>[CH3:10][C:11]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH3:9]
Reactant: CC(=O)O
Reactant: Cc1ccnc(N)c1N
Product: Cc1nc2nccc(C)c2[nH]1

Procedure:
The title compound was prepared from 2,3-diamino-4-picoline (0.246 g, 2 mmol) and acetic acid (0.15 ml) according to the procedure described in Step 1 of Example 9. The crude product was purified by flash chromatography on silica-gel using EtOAc-MeOH (9:1) to give the pure product (0.25 g, 85%) as a light brown solid. 1H NMR (300 MHz, CDCl3 ): 8.14 (d, 1H, J=5 Hz), 7.01 (d, 1H, J=5 Hz), 2.73 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:12]([F:22])[C:11]2[C:7](=[C:8]([CH3:23])[NH:9][N:10]=2)[CH:6]=1)=[O:4].[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:12]([F:22])[C:11]2[C:7](=[C:8]([CH3:23])[N:9]([CH3:24])[N:10]=2)[CH:6]=1)=[O:4].[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:22])[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[N:10]([CH3:24])[N:9]=[C:8]2[CH3:23])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2c(C)[nH]nc2c(F)c1Nc1ccccc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(C)n(C)nc2c(F)c1Nc1ccccc1F
Product: COC(=O)c1cc2c(C)nn(C)c2c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %
Yield: 53 %

Procedure:
To a solution of 7-fluoro-6-(2-fluoro-phenylamino)-3-methyl-2H-indazole-5-carboxylic acid methyl ester (146 mg, 0.46 mmol) in DMF (5 ml) were added potassium carbonate (95 mg, 069 mmol) and iodomethane (0.034 mL, 0.55 mmol). The reaction was stirred at room temp overnight, diluted with EtOAc and washed with H2O. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. Silica gel chromatography (EtOAc:Hexanes=75:25) yielded 40 mg (26%) of the title compound and 81 mg (53%) of 7-fluoro-6-(2-fluoro-phenylamino)-1,3-dimethyl-1H-indazole-5-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13](OC)[O:14]C)=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.CCOC(C)=O.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1
Reactant: COCCCc1cc(C(OC)OC)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COCCCc1cc(C=O)c(Cl)cn1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
5-Chloro-4-dimethoxymethyl-2-(3-methoxy-propyl)-pyridine (25.5 g, 98.2 mmol) was dissolved in aq. 1M HCl (500 mL), and the mixture was heated to 80° C. for 2 h. The mixture was allowed to cool to rt, and EtOAc was added. The mixture was cooled to 0° C., and was basified with an aq. 2.5M NaOH until a pH=10 was reached. The layers were separated, and the org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (98.1 mmol, 99%) that was used further without purification. LC-MS: tR=0.62 min; ES+: 246.12.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)(=[O:10])[CH3:9]>CN(C=O)C.CS(C)=O>[CH3:9][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH2:2][O:10]1
Reactant: CC(=O)c1ccncn1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccncn2)CO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
Trimethylsulfonium iodide (3.34 g, 16.3 mmol) was dissolved in DMF (20 mL) and stirred at RT for 5 min. Sodium hydride (600 mg, 25 mmol) was added portionwise at the same temperature and stirred for 15 min. 4-Acetyl pyrimidine (1 g, 8.1 mmol) in 0.5 mL DMSO was added dropwise and the reaction mixture stirred for 1 h. After completion of reaction, the mixture was poured into ice-cold water and extracted with Ether (3×). The combined organic layer was washed with water several times followed by brine, and dried over sodium sulfate, then evaporated to provide 600 mg of 4-(2-Methyl-oxiranyl)-pyrimidine. 1H NMR (CDCl3, freebase) δ (ppm): 9.15 (s, 1H), 8.7 (d, 1H), 7.35 (d, 1H), 2.95 (d, 1H), 2.88 (d, 1H), 1.8 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[C:37]([O:47][CH2:48][CH3:49])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:48]([O:47][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])[CH3:49]
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1OCC
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 3-ethoxy-4-(2-ethoxyethoxy)phenyl borate (0.18 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-[3-ethoxy-4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 126) (0.26 g) as colorless crystals.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1C=O.[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:8]1([CH:21]=[O:22])[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22]
Reactant: O=Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCCO
Product: O=Cc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
A mixture of anthraquinone-2-aldehyde (12.0 g), 1,3-propanediol (10 ml), and p-toluenesulfonic acid (20 mg) in toluene (300 ml) was heated under reflux with a removal of water formed from the condensation of anthraquinone aldehyde and 1,3-propane diol for 4 hours. The mixture was then cooled to room temperature, filtered off with suction, washed with water and diethyl ether, and dried under vacuum to afford anthraquinone-2-propaneacetal (12.5 g, 84%).
Reaction SMILES: I[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].[N-:18]=[N+:19]=[N-:20].[Na+]>CCO.O>[N:18]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(CCOCCOCCI)OCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCOCCOCCN=[N+]=[N-])OCC

Procedure:
To a solution of diethyl 2-(2-(2-iodoethoxy)ethoxy)ethylphosphonate (1 eq) in EtOH (0.2 M) was added sodium azide (5 eq) in water (1.4 M). The reaction mixture was heated at reflux overnight. The mixture was then diluted with water, extracted with EtOAc (3 times). The combined organic layers were washed brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give diethyl 2-(2-(2-azidoethoxy)ethoxy)ethylphosphonate as colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[NH:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1.[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([N:10]1[C:6]([NH2:5])=[N:7][C:8]([S:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:9]1)(=[O:3])[CH3:2]
Reactant: Nc1nc(SCc2ccccc2)n[nH]1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1nc(SCc2ccccc2)nc1N
Reaction time: 0.5 h

Procedure:
Acetyl chloride (12.57 g) in methylene chloride (30 ml) was added to the product of stage (a) (30 g) in triethylamine (25 ml) and methylene chloride (300 ml) at 0° C., and the mixture was stirred for 30 minutes. Then 1N sodium hydroxide was added, and the solution was extracted with methylene chloride. On drying, and recrystallisation from ethyl acetate, 33 g of the desired product, mp 146° C., were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:21][Si](C=[N+]=[N-])(C)C.[BrH:28].CC(O)=O.N#N>C(Cl)Cl>[Br:28][CH2:21][C:7]([C:6]1[CH:10]=[CH:11][C:12]([C:13]([F:16])([F:15])[F:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:9]
Reactant: O=C(O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Br
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=S(Cl)Cl
Product: O=C(CBr)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
3-Nitro-4-(trifluoromethyl)benzoic acid (Matrix Scientific, 2.35 g, 10 mmol) is dissolved in thionyl chloride (22 mL, 300 mmol). The stirred solution is heated at 95° C. for 16 hr, then cooled, concentrated and CH2Cl2 (51 mL) and trimethylsilyldiazomethane (20 mL, 2 M in Hexanes, 40 mmol) are added and the reaction is stirred for 2 hr at room temp. The mixture is cooled to 0° C. and HBr/HOAc (6.33 mL, 33% of HBr in HOAc) is added dropwise (N2 evolution). After addition the mixture is stirred at 0° C. for 5 min, then concentrated and purified by silica gel chromatography (CH2Cl2) to give the title compound (2.59 g, 83% yield). LCMS m/z=313.5 [M+H]+, tR=2.65 min.