Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:31])([C@H:4](/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[CH2:20][C@@H:21]2[OH:29])=[CH:16][CH:15]=3)[CH2:12][CH2:11]1)[CH3:9])[CH3:5])[CH3:3].[N+]([O-])([O-])=O.[K+]>CCOCC.O1CCCC1>[CH3:9][C@@H:8]([C@@H:10]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][CH2:24]/[C:14](=[CH:15]\[CH:16]=[C:17]3\[CH2:18][C@@H:19]([OH:30])[CH2:20][C@H:21]([OH:29])[C:22]\3=[CH2:23])/[C@@H:13]2[CH2:12][CH2:11]1)/[CH:7]=[CH:6]/[C@@H:4]([C:2]([OH:31])([CH3:1])[CH3:3])[CH3:5]
Reactant: C[C@H](/C=C/[C@H](C)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1/C(=C\C=C2/CCC[C@]3(C)[C@@H]([C@H](C)/C=C/[C@H](C)C(C)(C)O)CC[C@@H]23)C[C@@H](O)C[C@@H]1O
Yield: 22.3 %

Procedure:
(22E)-5,7,22-Ergostatriene-1α,3β,25-triol (Ia) (100 mg, 0.23 mmol) was dissolved in a mixed solution of ether (950 ml) and tetrahydrofuran (50 ml), and the solution was irradiated with high pressure mercury lamp using an 1.5% aqueous potassium nitrate solution as a filter with water cooling in a nitrogen stream for 3 minutes. From the reaction solution was distilled off the solvent and the residue containing previtamin D was dissolved in ethanol (30 ml) and the solution was refluxed for one hour. After distilling off ethanol, the residue was purified by high pressure liquid chromatography (HPLC) (column: LiChrosorb® Si60 (7 μm), φ25×250 mm, Merck Co., Ltd.; column effluent: 4% methanol-methylene chloride; flow rate: 8.0 ml/min; detected at 264 nm) to give 22 mg of the title compound (IIa) which was recrystallized from hexane-ether. m.p. 168°-170° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[S:30]1[C:39]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34][C:33]=2[N:32]=[CH:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[S:30]1[C:39]2[CH2:38][CH2:37][N:36]([C:27]([C:23]3[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]4[CH:17]=[C:18]5[C:13](=[CH:14][CH:15]=4)[CH2:12][C:4]4([C:5]6[C:6](=[N:7][CH:8]=[CH:9][CH:10]=6)[NH:11][C:3]4=[O:2])[CH2:19]5)[CH:22]=3)=[O:29])[CH2:35][CH2:34][C:33]=2[N:32]=[CH:31]1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: c1nc2c(s1)CCNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ncsc2CC1

Procedure:
86 mg (0.21 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 37 mg (0.24 mmol) 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine, 0.13 mL (0.72 mmol) DIPEA and 77 mg (0.24 mmol) TBTU in 1.0 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1([CH2:69][CH:70]2[CH2:75][CH2:74][CH2:73][CH2:72][NH:71]2)[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH2:75][CH:70]1[CH2:69][N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CCN(CC2CCCCN2)CC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN3CCCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(piperidin-1-ylmethyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C(=O)(O)[O-].[Na+].[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>S(=O)(=O)(O)O>[CH3:27][O:26][C:22](=[O:25])[CH2:23][S:24][CH:14]1[C:15]2[C:10](=[N:9][C:8]3[C:3]([C:2]=2[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][CH2:13]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Reactant: COC(=O)CS
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)CSC1CCCc2nc3ccccc3c(N)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (8.82 g) and methyl thioglycolate (40 ml) was added 40 drops of sulfuric acid. The reaction mixture was stirred at ambient temperature for 3 hrs, poured into an iced sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride, and dried over anhydrous magnesium sulfate. The filtrate was concentrated in vacuo and the residue was triturated with ethyl ether to give 2.79 g of product, mp 175°-183° C. (dec.). Recrystallization from methanol/water gave the analytical sample, mp 194°-196° C. (dec.)
Reaction SMILES: [CH3:1][CH:2]([O:4]/[N:5]=[C:6](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:7]([OH:9])=O)[CH3:3].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:41][CH:42]1[C:67](=[O:68])[N:44]2[C:45]([C:51]([O:53][CH:54]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:52])=[C:46]([CH2:49][Cl:50])[CH2:47][S:48][C@H:43]12>ClCCl.C(OCC)(=O)C>[Cl:50][CH2:49][C:46]1[CH2:47][S:48][C@@H:43]2[CH:42]([NH:41][C:7](=[O:9])/[C:6](=[N:5]\[O:4][CH:2]([CH3:3])[CH3:1])/[C:10]3[N:11]=[C:12]([NH:15][C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[S:13][CH:14]=3)[C:67](=[O:68])[N:44]2[C:45]=1[C:51]([O:53][CH:54]([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CC(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.5 %

Procedure:
A mixture of (Z)-2-(2-propoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IVc) (707 mg, 1.5 mmoles) and phosphorus pentachloride (344 mg, 1.65 mmoles) in dichloromethane (14 mL) was stirred at room temperature for 1 hour and poured into a solution of Compound V (677 mg, 1.5 mmoles) and BSA (1.1 mL, 4.5 mmoles) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 mL), washed with aqueous sodium bicarbonate (100 mL) and water (3×100 mL), dried over sodium sulfate and evaporated to give 1.4 g (100%) of Compound VIc.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.O[CH2:22][C:23]1[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:24]=[C:25]([CH:35]=[CH:36][CH:37]=4)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(CNC(=O)OC(C)(C)C)c3)C2=O)cn1
Yield: 89.2 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (070 mg, 0.254 mmol), tert-butyl 3-(hydroxymethyl)benzylcarbamate (0.254 mmol, 60 mg), diethyl azodicarboxylate (0.50 mmol, 86 mg), and P-tBu3 (125 mL, 0.50 mmol) were stirred in THF (1 mL) for 4 hours. The reaction was diluted with ethyl acetate (1.5 mL) and washed with saturated sodium bicarbonate solution (2×, 1.5 mL). The organic phase was collected and the mixture was concentrated under a stream of nitrogen. The crude product was purified by column chromatography on silica gel using ethyl acetate as the eluent. The pure fractions were combined and the solvents were removed on the rotovap to afford tert-butyl 3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzylcarbamate as a white solid (112 mg, 90%). 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 9H), 2.19 (s, 3H), 2.42 (s, 3H), 3.48 (bs, 1H), 3.84 (s, 2H), 4.31-4.30 (d, J=6 Hz, 1H), 4.60 (s, 2H), 4.87 (bs, 1H), 5.06 (s, 2H), 7.36-7.16 (m, 4H), 7.92 (s, 1 H), 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.90 μM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]([C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])C(=O)OC(C)(C)C)[CH:3]=1.FC(F)(F)C(O)=O.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:16]([CH:18]2[CH2:19][CH2:20]2)=[O:17])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)C1CC1)c1cc(Br)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Br)ccn1)C1CC1
Yield: 99.3 %

Procedure:
Dissolve tert-butyl N-(4-bromo-2-pyridyl)-N-(cyclopropanecarbonyl)carbamate (900 mg, 2.8 mmol) in DCM (8 mL), add slowly trifluoroacetic acid (4 mL). Stir the reaction at room temperature for 3 hrs. Pour the reaction mixture to water (50 mL), adjust to pH=7 with saturated NaHCO3 solution. Extract with EtOAc (15 mL×3), combine the organic layers; wash with brine (100 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product (670 mg) which is used without further purification. MS: (M+1): 243.1.
Reaction SMILES: [C:1](=[O:10])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:2].[C:11]([O-:14])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.[CH3:24][C:25]([CH3:27])=O>>[CH3:11][O:14][N:2]([C:24]1[CH:6]=[CH:5][CH:4]=[CH:9][C:25]=1[CH3:27])[C:1](=[O:10])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)Oc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: CON(C(=O)Oc1ccccc1)c1ccccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2.0 g (8.2 mmol) of the phenyl carbamate from Example 4a, 2 g (15 mmol) of K2CO3 and 1.3 g (10 mmol) of dimethyl sulfate in 20 ml of acetone is stirred for 3 hours at room temperature. The reaction mixture is then filtered and evaporated down, and the residue is purified by column chromatography with mixtures of cyclohexane and ethyl acetate. There is obtained 1.5 g (5.8 mmol =71%) of the title compound as a colorless oil, which slowly crystallizes (mp=60° C.).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[NH:25]C(=O)OC(C)(C)C)[C:11]([C:13]2([CH3:16])[CH2:15][CH2:14]2)=O)[CH:6]=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(#N)C.ClCCl>[CH3:24][O:23][C:20]1[CH:19]=[C:18]2[C:17]([C:10]([CH2:9][C:7]3[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][CH:6]=3)=[C:11]([C:13]3([CH3:16])[CH2:15][CH2:14]3)[NH:25]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(C(Cc2cccc(C#N)n2)C(=O)C2(C)CC2)c(NC(=O)OC(C)(C)C)c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(Cc3cccc(C#N)n3)c(C3(C)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 44.5 h
Yield: 82.8 %

Procedure:
To a solution of tert-butyl {2-[1-(6-cyanopyridin-2-ylmethyl)-2-(1-methylcyclopropyl)-2-oxoethyl]-5-methoxyphenyl}carbamate (270 mg) in acetonitrile/dichloromethane (2.1 mL/2.1 mL) was added trifluoroacetic acid (2.1 mL) under ice-cooling, and the mixture was stirred at room temperature for 44.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane), and then purified by aminopropylated silica gel column chromatography to obtain the title compound (163 mg). 1H-NMR (CDCl3) δ ppm: 0.70-0.78 (2H, m), 0.81-0.89 (2H, m), 1.33 (3H, s), 3.82 (3H, s), 4.39 (2H, s), 6.70 (1H, dd, J=2.3, 8.5 Hz), 6.80-6.85 (1H, m), 7.12-7.22 (2H, m), 7.47-7.53 (1H, m), 7.59 (1H, t, J=7.8 Hz), 7.87 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[CH:12][N+:13]([O-:15])=[O:14])[CH2:9][N+:8]([O-:16])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[N:25]([O-])=[O:26].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:13]([O-:15])=[O:14])=[N:25][OH:26])[CH2:9][N+:8]([O-:16])=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: O=N[O-]
Reactant: O=[N+]([O-])C=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=[N+]([O-])C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Chloro-5-(2-fluorophenyl)-1,3-dihydro-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide* 7 g (0.02 mole), was dissolved by heating in 250 ml of glacial acetic acid. The solution was cooled with tap water and when the temperature reached 70° C. the addition of 1.9 g (0.0275 mole) of sodium nitrite was started. The sodium nitrite was added over a period of 10 min while cooling was continued. Following the addition, the mixture was stirred for 11/2 hr at room temperature, diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulfate and evaporated. Crystallization of the residue from ethyl acetate yielded yellow crystals. The analytical sample was recrystallized from methanol/ethyl acetate to give yellow crystals with undefined mp. The compound decomposes without prior melting.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:8])[CH2:5][S:6][CH:7]=1.Cl[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[NH:3][C:4](=[O:8])[CH2:5][S:6][C:7]=1[CH:21]1[CH:22]=[CH:23][N:18]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])[CH:19]=[CH:20]1
Reactant: CC1=CSCC(=O)N1
Reactant: c1ccncc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Product: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To a solution of 5-methyl-2H-1,4-thiazin-3(4H)-one (1.5 g) in dry pyridine (20 ml), 2,2,2-trichloroethyl chloroformate (2.8 g) was added dropwise under ice bath temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was extracted with chloroform. The extract was washed with 2N hydrochloric acid and water, and dried over anhydrous magnesium sulfate and chloroform was removed under reduced pressure. The residual oil was triturated with ether and recrystallized from ethanol using decolorizing chacoal to give 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (1.4 g, yield 31.5%) as light yellow scales.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N+:7]([C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].[OH-].[Na+].O>N1C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][S:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)(=[O:17])=[O:18]
Reactant: Nc1nccs1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nccs2)c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
To a solution of 2-aminothiazole (1 g, 10.5 mmol) in dry pyridine (3 ml) was added, portionwise, 3-nitrobenzenesulphonyl chloride (2.32 g, 10.5 mmol), maintaining the internal temperature below 55° C. After addition was complete, the mixture was heated at 100° C. for 75 min. 4M Sodium hydroxide solution (2.75 ml, 11 mmol) was then added dropwise and heating was continued for a further 5 min. After cooling, water (25 ml) was added and the precipitate was collected by filtration to afford the product (2.48 g, 87%) as a brown solid. mp 195° C. (dec.). 1H NMR (360 MHz, D6 -DMSO) δ 6.91 (1H, d, J=4.6 Hz), 7.31 (1H, d, J=4.5 Hz), 7.86 (1H, dd, J=8.0 and 8.1 Hz), 8.20-8.26 (1H, m), 8.40-8.45 ( 1H, m), 8.46-8.49 (1H, m), 13.00 (1H, brs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([O-])([O-])=O.[K+].[K+].S(OCC)(O[CH2:47][CH3:48])(=O)=O.O>CS(C)=O>[CH2:47]([O:14][C:13](=[O:15])[C:12]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](=[O:36])[NH:32][C:33]([NH2:35])=[O:34])=[CH:25][CH:24]=2)=[CH:20][CH:21]=1)=[CH:11][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=1)[CH3:48]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(CCC(=O)NC(N)=O)cc3)cc2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CCC(=O)NC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6 (0.40 g, 0.81 mmol) in dry DMSO (3 mL) was added K2CO3 (0.14 g, 0.98 mmol). To this, diethyl sulfate (0.115 g, 0.91 mmol) was added and stirred at room temperature for 30 min. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by column chromatography over silica gel and eluted with hexanes-ethyl acetate (3:1). Yield: 0.39 g, 92.2%.
Reaction SMILES: [Mg].[CH2:2]([CH:4]([CH2:7][CH3:8])[CH2:5]Br)[CH3:3].[C:9](=[O:11])=[O:10]>C1COCC1.C(OCC)(=O)C.C(Cl)Cl>[CH2:2]([CH:4]([CH2:7][CH3:8])[CH2:5][C:9]([OH:11])=[O:10])[CH3:3]
Reactant: O=C=O
Reactant: CCC(CC)CBr
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)CC(=O)O
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
Into a 2 L 3-necked flask equipped with a condenser attached to a nitrogen inlet tube, a mechanical stirrer, and a 500 mL addition funnel, was added magnesium turnings (18.7 g, 0.769 mol), which were crushed in a mortar and pestle. The reaction was placed under argon. Enough THF was added to just cover the magnesium turnings. With the mechanical stirrer turned off, 2-ethyl-1-bromobutane (155.5 g 0.70 mol) was placed in the addition funnel and about 2-3 mL was added to the magnesium turnings. This area of the THF solution was then heated with a heat gun until vigorous boiling occurred. The remaining 2-ethyl-1-bromobutane was diluted with THF (200 mL) and added dropwise to the stirred reaction mixture at a rate that maintained a gentle reflux. The addition was completed in approximately 3-4 h. After 24 h, the gray slurry was diluted with THF (500 mL), and gently heated with a hot water bath until a homogeneous solution was formed. The warm solution was then poured into two 4 L Nalgene beakers each containing crushed solid carbon dioxide (1 L). The slush was stirred well with a Teflon rod and allowed to stand at room temperature. After 18 h, the solutions were diluted with ethyl acetate (500 mL), and washed with 2N hydrochloric acid (500 mL). The aqueous layer was saturated with sodium chloride and extracted once more with ethyl acetate (500 mL). The combined ethyl acetate layers were dried (Na2SO4). Concentration under reduced pressure gave a wet residue, which was taken up in methylene chloride (600 mL), dried (Na2SO4), and concentrated at 56° C. under reduced pressure to give the title compound as an oil (91 g, 99.8%): 1H NMR (DMSO-d6, 500 MHz): δ11.95 (broad s, 1H), 2.11 (d, J=6.9 Hz, 2H), 1.60 (septet, J=6.5 Hz, 1H), 1.28 (m, 4H), 0.81 (t, J=7.5 Hz, 6H); MS(−ESI): [M—H]−, 129 (100%); Anal. Calc. for C7H14O2: C, 64.58; H, 10.84. Found: C, 64.61; H, 11.11.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[NH:11][N:12]=[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[C:8](=[O:21])[N:7]([CH3:22])[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([B:32]4[O:33][C:34]([CH3:40])([CH3:39])[C:35]([CH3:38])([CH3:37])[O:36]4)=[CH:30][CH:31]=3)[C:13]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:9]2[C:8](=[O:21])[N:7]([CH3:22])[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n[nH]c21
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A mixture of 7-isobutyl-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (12.0 mg, 0.0383 mmol), 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0383 mmol) and potassium carbonate (5.3 mg, 0.0383 mmol) in acetone (2.5 mL) is stirred at room temperature overnight. The solvent is evaporated under reduced pressure. The residue is directly purified by chromatography to give 7.0 mg product as white solids (Yield: 38.0%). MS (ESI) m/z 530.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-bromo-benzenesulfonyl chloride (3.914 mmol, 1.0 equiv) and 1-methyl-piperizine (7.83 mmol, 2.0 equiv) were dissolved in 15 mL DCM. Et3N (15.66 mmol, 4.0 equiv) was added via syringe to the reaction and stirred at room temperature for 2 h. The reaction was diluted with DCM, the organic phase was extracted with saturated NaHCO3 and brine and dried (Na2SO4). The organics were removed under reduced pressure to give 1-(3-bromo-benzenesulfonyl)-4-methyl-piperazine, as a white solid (1.1 g. 88% yield). 1H NMR (DMSO-d6): δ 2.14 (s, 3H), 2.35 (m, 4H), 2.92 (m, 4H), 7.62 (t, J=7.9 Hz, 2H0, 7.55 (dd, J=7.9 Hz, J=0.8 Hz, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.95 (dd, J=9.1 Hz, J=0.9 Hz, 1H) MS (ES+) m/z=321 LC retention time 1.74 min.