Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([OH:12])=O.[CH2:34]([N:36](CC)[CH2:37]C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CNC>ClCCl.C(#N)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:32]2)[C:14]1=[O:33])[C:10]([N:36]([CH3:37])[CH3:34])=[O:12]
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1ccc(F)cc1F
Reactant: CCN(CC)CC
Agent: CNC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc(F)cc1F
Reaction time: 16 h

Procedure:
The acid (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoic acid (0.747 g) prepared as described above was dried over P4O10 in vacuo for five hours to give 0.724 g drier material; this was dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6 ml) and treated with triethylamine (0.223 ml) and BOP—Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, dissolved in anhydrous dichloromethane:acetonitrile (1:1 v/v, 6 ml) and treated with triethylamine (0.223 ml) and BOP—Cl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride, 0.450 g) and the mixture was sonicated for ca. 1 min to give a gelatinous mass. After 10 minutes at room temperature a solution of dimethylamine in tetrahydrofuran (10 ml of 2M solution) was added to give a clear solution; this was left for 16 hours at room temperature. The solvents were removed under reduced pressure and the mixture was partitioned between dichloromethane and 0.1M hydrochloric acid. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The crude product was purified by flash column chromatography (12 g Biotage™ silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii) ethyl acetate:methanol 9:1) to give the (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide as a colourless solid 0.285 g.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([O:38]CC2C=CC=CC=2)=[O:37])=[C:32]([F:46])[CH:31]=1)[CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].O1CCCC1>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[C:32]([F:46])[CH:31]=1)[CH3:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(F)c1
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)O)c(F)c1
Yield: 68.5 %

Procedure:
Under a hydrogen atmosphere, a tetrahydrofuran suspension (45 ml) of benzyl 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-fluorobiphenyl-4-carboxylate (2.23 g) and 20% palladium hydroxide carbon (2.23 g) was stirred at room temperature overnight. The reaction solution was filtered through Celite, and washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was dried to afford 2′-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-methylpropyl]oxy}-3-fluorobiphenyl-4-carboxylic acid (1.31 g).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[NH:7][N:6]=[C:5]([SH:8])[N:4]=1.[F:11][C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])I.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:18][C:13]([F:19])([C:12]([F:21])([F:20])[F:11])[C:14]([S:8][C:5]1[N:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[NH:7][N:6]=1)([F:17])[F:16]
Reactant: FC(F)(F)c1nc(S)n[nH]1
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nc(SC(F)(F)C(F)(F)C(F)(F)F)n[nH]1
Temperature: 25 °C
Yield: 17.6 %

Procedure:
5-Trifluoromethyl-1H-(1,2,4)-triazole-3-thiol (11.0 g), heptafluoro-1-iodopropane (3.5 g) and triethylamine (0.90 g) were stirred in DMF (10 ml) at 90° C. for 24 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 3-heptafluoropropylsulfanyl-5-trifluoromethyl-1H-(1,2,4)-triazole (0.70 g).
Reaction SMILES: [CH2:1]([C@@:8]([C:31]([O-:33])=[O:32])([CH2:19][CH:20]([N:24]([CH2:28][CH2:29][Cl:30])[CH2:25][CH2:26][Cl:27])[C:21]([O-:23])=O)[NH:9][C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:36](CC)CC)C.C(OC(Cl)=O)C(C)C.N[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=1>O1CCCC1>[CH2:1]([C@@:8]([C:31]([OH:33])=[O:32])([CH2:19][C:20]([N:24]([CH2:25][CH2:26][Cl:27])[CH2:28][CH2:29][Cl:30])([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=1)[C:21](=[O:23])[NH2:36])[NH:9][C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@](Cc1ccccc1)(CC(C(=O)[O-])N(CCCl)CCCl)C(=O)[O-])Oc1ccccc1
Reactant: CCN(CC)CC
Reactant: Cc1cccc(N)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: Cc1cccc(C(C[C@](Cc2ccccc2)(NC(=O)Oc2ccccc2)C(=O)O)(C(N)=O)N(CCCl)CCCl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
α-Benzyl4-[N,N-bis(2-chloroethyl)amino]phenoxycarbonyl-L-glutamate (300 mg) in dry tetrahydrofuran (5 ml) was treated with 1.1 equivalents of triethylamine. Isobutylchloroformate (0.08 ml, 1.1 equiv) in dry THF (10 ml) was added slowly to the reaction mixture at -25° C. After 15 minutes, 1.1 equivalents (0.08 ml) m-toluidine in dry tetrahydrofuran (5 ml) was added. The mixture was allowed to warm up to 25° C. and was then continuously stirred for 18 hrs. The reaction mixture was then filtered and the filtrate evaporated to give a residue which was purified by flash column chromatography using mixtures of ethyl acetate/hexane as eluent. Evaporation of appropriate fractions yielded α-benzyl 4-[N,N-bis(2-chloroethyl)amino]phenoxycarbonyl-γ-(3-methylphenyl)-L-glutamine as a white crystalline solid. The NMR data from this product is set out in Table 17.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([C:12](OC)=[O:13])[CH:4]=1.Cl.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12][OH:13])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2c(c1)OCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(CO)cc2c1OCO2
Temperature: 25 °C
Yield: 88 %

Procedure:
Methyl 7-methoxybenzo[3,4-d]1,3-dioxolane-5-carboxylate(10 g, 47.57 mmol) prepared in Step 3 was dissolved in tetrahydrofuran(200 ml), borane methylsulfide(BMS, 10M) (9.5 ml, 95.0 mmol) was added thereto, and the mixture was stirred under reflux for 1.5 hour. The reaction vessel was cooled down to room temperature and the reaction mixture was neutralized to pH 6-7 using 1N—HCl at 0-5° C., which was then extracted with ethyl acetate. The extract was washed with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2, v/v) to give (7-methoxybenzo[3,4-d]1,3-dioxolan-5-yl)methan-1-ol(7.63 g, Yield 88%) as a white solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[C:27]1([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CS(C)=O>[C:27]1([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:12]2([CH3:11])[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: O
Solvent: CS(C)=O
Product: CC1(NCCCCc2ccccc2)COc2ccc3c(c2O1)CC(=O)N3
Temperature: 85 °C
Yield: 26.3 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.05 g, 2.80 mmole) and phenylbutylamine (1.99 ml, 12.5 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, 200 ml of water was added and the mixture was extracted twice with 300 ml portions of 50% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 1% methanol/CH2Cl2 as eluant. The free base of the title compound (0.26 g, 30%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.25 g of the (S) enantiomer of the title compound as an tan solid fumarate, one-half hydrate, m.p. 185-186° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10]Cl)=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[C:15]1([S:12]([C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH2:10])(=[O:14])=[O:13])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)C(CCl)Sc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(Sc1ccc(Br)cc1)S(=O)(=O)c1ccccc1

Procedure:
A solution of 10.2 g (26.1 mmoles) of 2-chloro-1-(phenylsulfonyl)ethyl p-bromophenyl sulfide in 50 ml of tetrahydrofuran was diluted with 50 ml of diethyl ether and treated with 3.63 ml (2.65 g, 26.2 mmoles) of triethylamine. After 20 minutes the triethylamine hydrochloride was removed by filtration. The filtrate was freed of solvent by evaporation under reduced pressure to leave a viscous, pale yellow oil of n20 1.6338.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:19])[CH2:11][NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:7]=[CH:8][CH:9]=1.[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21].C1CCN2C(=NCCC2)CC1>>[CH3:17][CH:16]([S:13]([NH:12][CH2:11][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][NH:1][S:23]([CH:20]([CH3:22])[CH3:21])(=[O:25])=[O:24])[CH:5]=1)[CH3:19])(=[O:15])=[O:14])[CH3:18]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1cccc(CCN)c1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1cccc(CCNS(=O)(=O)C(C)C)c1
Yield: 54 %

Procedure:
Scheme Va, step C: {2-[3-(2-Aminoethyl)phenyl]propyl}[(methylethyl)sulfonyl]amine (0.57 g, 2 mmol), isopropylsulfonyl chloride (0.24 mL, 2.1 mmol) and DBU (0.33 mL, 2.2 mmol) were combined and sulfonylation was carried out in a manner analogous to the procedure described in example 2 to provide the final title compound, [(methylethyl)sulfonyl]{2-[3-(2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]propyl}amine, (0.422 g, 54%) as a white crystalline solid. Electron spray M.S. 391 (M*+H). Analysis for C17H30N2O4S2:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:4].[OH2:13].[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH2:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:16][C:15]([O:14][CH2:18][CH3:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4]
Reactant: O
Reactant: CCc1ccc(C=O)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=Cc1ccc(CC)cc1

Procedure:
A solution of 33.6 g of triethylphosphonoacetate in 20 mL of tetrahydrofuran was added dropwise with stirring to a slurry of 6.0 g of 60 percent sodium hydride (in mineral oil) in 100 ml of dry tetrahydrofuran. The mixture was allowed to react for 30 min and then a solution of 20.1 g of 4-ethylbenzaldehyde in 100 mL of tetrahydrofuran was added with stirring and the mixture was heated to reflux. After 2 hours the mixture was cooled and water was added. The resulting mixture was extracted with ethyl acetate and the extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure to obtain ethyl 4-ethylcinnamate as the residue.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:23])=[N:19][CH:20]=1
Reactant: C1CSCCN1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N2CCSCC2)nc1
Yield: 98 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using thiomorpholine instead of isopropylamine, to the title compound (125 mg, 98%), which was obtained as a white solid. MS: m/e=397.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.Cl.[N:16]([O-])=[O:17].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[N:16]=[O:17]
Reactant: O=N[O-]
Reactant: C=C(C)Cn1c(N)cc(=O)n(C)c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=C(C)Cn1c(N)c(N=O)c(=O)n(C)c1=O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Methallylamine (211 g, 2.97 mol) is added to a solution of concentrated hydrochloric acid (250 ml) in water (1.9 l), followed by portionwise addition of potassium cyanate (240 g, 2.97 mol). The reaction is then heated for 2 hours at 80° C., prior to cooling and evaporation to afford (2-methyl-allyl)-urea (2445 g), mp 114-115° C. The urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride, (536 ml) and the reaction is heated at 70° C. for 1 hour, cooled to 0° C. and diluted with ether. The resultant solid is collected by filtration, washed with ether, suspended in water (2.2 l) and heated to 75° C. 2M aqueous sodium hydroxide solution is then added portionwise over 30 min to maintain pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 ml), further cooled to 10° C. and the resultant solid is collected by filtration, washed with cold water and dried to afford 6-amino-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 267-269° C. The uracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20° C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour. After standing overnight, the reaction is cooled to 5° C. and the solid collected by filtration to give 6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4dione, mp 162-163° C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.55 l) and concentrated hydrochloric acid (72 ml). A solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30 minutes and the reaction is stirred at 20° C. for 3 hours. The solid is collected by filtration, washed successively with water, methanol and ether to afford 6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyrimidine-2,4dione, mp 213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water (950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69 mol) is added portionwise. After cooling to room temperature, the solid is collected by filtration to afford 5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine2,4-dione, mp 152-153° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[S:22][CH:21]=[CH:20][C:9]=3[N:10]=[C:11]([C:13]3[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH2:3][CH2:2]1.N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C>[Si:32]([O:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:8]3[S:22][CH:21]=[CH:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1)([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(-c2nc(N3CCOCC3)c3sccc3n2)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2nc(N3CCOCC3)c3sccc3n2)c1
Temperature: 70 °C

Procedure:
3-(4-morpholinothieno[3,2-d]pyrimidin-2-yl)phenol [synthesized according to Hayakawa et al., Bioorganic & Med. Chem. 14:6847-6858 (2006)] (540 mg, 1.72 mmol, 1.0 eq.) was dissolved in DMF (5 ml). To this imidazole (936 mg, 13.8 mmol, 8.0 eq.) and TBDMSCl (909 mg, 6.02 mmol, 3.5 eq.) were added and the mixture was heated at 70° C. for 3 h. DMF was evaporated under reduced pressure and purification by flash chromatography (hexane:ethyl acetate, gradient from 100%-50% hexane in EtOAc) yielded the title compound as a white solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[N+:4]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br)([O-:6])=[O:5].Cl>CO>[CH3:1][O:2][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[N+:4]([O-:6])=[O:5]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
125 g of 30% strength sodium methylate solution (0.69 mol) in methanol are added dropwise to 130 g (0.6 mol) of o-nitrobenzyl bromide in 200 ml of methanol. During this procedure, the reaction mixture heats up to about 50° C. Stirring is continued for a further 3 hours, the reaction mixture being cooled to room temperature, after which ice water is added to the reaction vessel and the reaction mixture is neutralized by adding dilute hydrochloric acid. The aqueous phase is extracted with three times with ether, and the organic phase is dried over MgSO4 and evaporated down. 101 g (0.6 mol, quantitative yield) of the title compound are obtained as a residue in the form of a brownish oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:24](=O)OC(C)(C)C)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][S:5][N:6]=1.[H-].[Na+].I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:24]([NH:23][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:3]2[C:2]([CH3:1])=[N:6][S:5][N:4]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:22]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: Cc1nsnc1C(=NOCc1cccc(NC(=O)OC(C)(C)C)n1)c1ccccc1
Reactant: CCCCCCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCNc1cccc(CON=C(c2ccccc2)c2nsnc2C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a stirred solution of tert-butyl {6-[({[(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]-amino}oxy)methyl]pyridin-2-yl}carbamate (104 mg, 0.24 mmol) in dry DMF (5 mL) was added sodium hydride (60 wt.-% in mineral oil, 11 mg, 0.27 mmol). After stirring at room temperature for 15 min, 1-iodohexane (62 mg, 0.29 mmol) was added, and the mixture stirred at room temperature for 16 h. After dropwise addition of trifluoroacetic anhydride (1 mL, 13 mmol), the mixture was stirred at 50° C. for 8 h. The cooled reaction mixture was poured into sat. aq. NaHCO3 (40 mL), extracted with ethyl acetate (2×30 mL), the organic layer was washed with water, dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded N-hexyl-6-[({[(4-methyl-1,2,5-thiadiazol-3-yl)(phenyl)methylene]amino}-oxy)methyl]pyridin-2-amine as an orange oil [79 mg, yield 75%; HPLC/MS: m/z=410 (M+H); log P(HCOOH)=3.11].
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[C:25]([NH:27][NH2:28])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH:35]([NH2:38])([CH3:37])[CH3:36]>O1CCOCC1.C(O)(=O)C>[NH2:1][C:2]1[N:38]([CH:35]([CH3:37])[CH3:36])[C:25]([C:19]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=2[NH:17][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[N:27][N:28]=1
Reactant: CC(C)N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)n1c(N)nnc1-c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Cyanogen bromide (111 mg, 1.05 mmol) was added to a solution of 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (200 mg, 0.524 mmol) and potassium carbonate (145 mg, 1.05 mmol) in dioxane (2 mL) and the reaction was stirred for 18 h at room temperature. Isopropyl amine (0.18 mL, 2.09 mmol) and acetic acid (0.15 mL) were added and the reaction was heated at 135° C. for an additional 18 h. The resultant solution was partitioned between ethyl acetate/water and the organic phase was washed with 1N HCl, saturated sodium bicarbonate, and brine; dried over magnesium sulfate, and concentrated in vacuo. The crude product was finally purified by flash column chromatography (10-100% ethyl acetate and hexane) then preparative HPLC (10-90% gradient of MeCN-water) to afford the title compound as a white solid: MS (ES) M+H expected 448.2, found 448.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[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>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([NH:1][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCC(=O)c2ccccc2)cc1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of 2-aminoacetophenone (7.0 g, 0.05 mol) in 30 mL of pyridine was added p-toluenesulfonyl chloride (11.8 g, 120 mol %). The reaction mixture was refluxed with stirring for 2 h, cooled to 40°-50° C. and poured in the cold water (150 mL). The mixture was stirred at rt for 1 h, filtered, washed with warm (~40° C.) water and then dried. Recrystallization from EtOH afforded 7.6 g (51%) of the title compound, mp 148.2°-149.3° C. [lit 147°-148° C. (Kemter, G.; Noack, H.; Russ, G. Z. Chem. 1963, 3, 352)]; 1H NMR (CDCl3) δ 11.48 (s, 1H, NH), 7.79 (dd, 1H, J=1.2, J=6.8), 7.72 (d, 1H, J=8.4), 7.67 (d, 1H, J=8.4), 7.44 (t, 1H, J=8), 7.21 (d, 1H, J=8), 7.02 (t, 1H, J=6), 2.55 (s, 3H), 2.36 (s, 3H); 13C NMR (CDCl3) δ 202.37, 143.83, 139.94, 136.47, 134.82, 131.87, 129.57, 127.16, 122.55, 122.18, 118.92, 28.04, 21.42; MS (EI, m/z) 289 (M+).