Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8](=O)[CH2:9][CH2:10][CH3:11].O>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:8](=[N:7][S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: O
Product: CCCC=N[S@@](=O)C(C)(C)C
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
To a solution of (S)-2-methyl-propane-2-sulfinamide (6.7 g, 55 mmol) in dichloromethane (125 mL) is added butyraldehyde (4.0 g, 55 mmol) followed by titanium isopropoxide (32 g, 110 mmol). The reaction is then heated at reflux (bath temperature=60° C.) for 4 hours. The resultant mixture is cooled to room temperature and poured into a stirred mixture of diatomaceous earth (10 g) and water (100 mL). The slurry is stirred for 10 min and then filtered. The organic layer from the filtrate is concentrated in vacuo to afford a crude yellow oil which is purified by flash chromatography on silica gel (eluted with 5 to 30% dioxane/hexanes) to afford (S)-2-methyl-propane-2-sulfinic acid butylideneamide as a colorless oil (7.4 g, 77%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@H:11]([CH2:13][OH:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([CH3:12])[CH2:13][O:14][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 108.7 %

Procedure:
Subsequently, to a solution of [(1S)-1-(hydroxymethyl)ethyl]carbamic acid benzyl ester (4.61 g, 22.0 mmol) in dimethylformamide (140 ml) were added t-butyldiphenylsilyl chloride (6.87 ml, 26.4 mmol) and imidazole (1.80 g, 26.4 mmol) in an ice bath. The resulting mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (8:1→6:1) as the eluant to afford [(1S)-2-(t-butyldiphenylsilyloxy)-1-methylethyl]carbamic acid benzyl ester (10.7 g, yield 100%) as a colorless oil.
Reaction SMILES: Cl.[C:2]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].C(N(CC)CC)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>C(Cl)Cl>[C:5]([O:4][C:2](=[O:3])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N+:24]([O-:26])=[O:25])(=[O:34])=[O:35])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.2 %

Procedure:
To a stirred solution of N-Boc 1, 6-diaminohexane hydrochloride (1.51 g, 6 mmol) and triethyl amine (1.31 g, 13 mmol) in 50 mL methylene chloride was added 2-Nitrobenzenesulfonyl chloride (1.326 g, 6 mmol). The reaction mixture was stirred for 6 h at room temperature, quenched with brine, and extracted with methylene chloride (2×50 mL). The organic layer was washed with brine (a saturated solution of sodium chloride in water, unless otherwise specified), dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the titled compound as yellow oil (2.1 g, 87%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][CH:33]([NH2:35])[CH3:34].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH2:32][CH:33]([NH:35][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:34]
Reactant: CC(N)Cc1cc(F)ccc1F
Reactant: CN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Yield: 61.3 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.44 g, 1.34 mmol), 1-(2,5-difluorophenyl)propan-2-amine (0.27 g, 1.61 mmol), n-butanol (30 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a brown solid product, 0.38 g, 61.3% yield. MS: 461.9 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.40 (s, 1H), 11.31 (s, 1H), 10.92 (d, 1H, J=8.0 Hz), 8.13 (s, 1H), 8.00 (s, 1H), 7.42-7.37 (m, 2H), 7.20-7.18 (m, 1H), 7.09-7.04 (m, 1H), 6.18 (d, 1H, J=8.0 Hz), 4.19-4.14 (m, 1H), 3.06 (s, 3H), 3.04-2.98 (m, 2H), 1.33 (d, 3H, J=6.0 Hz).
Reaction SMILES: [F-].C([N+](CC)(CC)CC)C.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]([C:36]3[C:44]4[C:39](=[CH:40][C:41]([CH2:45][O:46][Si](C(C)C)(C(C)C)C(C)C)=[CH:42][CH:43]=4)[N:38]([CH3:57])[CH:37]=3)[C:21]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=3[CH2:34][CH3:35])(=[O:26])=[O:25])=[O:22])=[CH:19][C:14]=2[O:13][CH2:12]1.Cl>C(#N)C>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]([C:36]3[C:44]4[C:39](=[CH:40][C:41]([CH2:45][OH:46])=[CH:42][CH:43]=4)[N:38]([CH3:57])[CH:37]=3)[C:21]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=3[CH2:34][CH3:35])(=[O:26])=[O:25])=[O:22])=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: CCc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc12
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Agent: [F-]
Solvent: CC#N
Product: CCc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(CO)ccc12
Yield: 84.5 %

Procedure:
Tetraethylammonium fluoride (312 mg, 2.18 mmol) was added to a stirred solution of the compound of step (g) (380 mg, 0.55 mmol) in acetonitrile (6 ml) at room temperature under a nitrogen atmosphere. After 12 H the mixture was poured into 1M hydrochloric acid (50 ml) and extracted into ethyl acetate (2×50 ml). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give a yellow foam. Flash column chromatography (eluting with 98% dichloromethane/2% methanol) gave the product as a white solid (242 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([NH2:25])[CH:23]=3)[NH:18][CH:17]=2)=[CH:12]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][C:22]2[CH:23]=[C:24]3[C:16]([C:13]4[CH:14]=[CH:15][O:11][CH:12]=4)=[CH:17][NH:18][C:19]3=[N:20][CH:21]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cnc2[nH]cc(-c3ccoc3)c2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cnc2[nH]cc(-c3ccoc3)c2c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
4-Fluorobenzoyl chloride (29.7 mg, 0.19 mmol) was added to a solution of amine 48 (25 mg, 0.125 mmol), DMAP (1.53 mg, 12.5 μmol) and Et3N (12.6 mg, 0.125 mmol) in DMF (0.6 mL). The mixture was stirred at r.t. overnight, concentrated and separated by means of LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 49 (2.13 mg, 5%). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 6.45 (dd, J=1.9, 0.9 Hz, 1H), 6.91 (t, J=1.8 Hz, 2H), 7.22 (s, 1H), 7.23 (t, J=1.7 Hz, 1H), 7.56 (m, 1H), 7.73-7.76 (m, 2H), 8.15 (d, J=2.1 Hz, 1H), 8.25 (d, J=2.3 Hz, 1H); MS (ES) m/z 363 (MH++MeCN).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[NH:5][C:4](=[S:15])[N:3]=1.I[CH2:17][CH3:18].C(=O)(O)[O-].[Na+].O>CS(C)=O>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[N:5]=[C:4]([S:15][CH2:17][CH3:18])[N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: CCI
Reactant: Nc1cc(-c2ccc(Br)cc2)[nH]c(=S)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCSc1nc(N)cc(-c2ccc(Br)cc2)n1
Yield: 81.8 %

Procedure:
To a solution of 4-amino-6-(4-bromophenyl)pyrimidine-2(1H)-thione (53.90 g, 191.0 mmol) and iodoethane (16.96 mL, 210.1 mmol) in 200 mL of DMSO was slowly added 200 mL of aqueous saturated sodium bicarbonate at ambient temperature with stirring. The reaction was allowed to stir for 1 hour before iodoethane (8.0 mL, 99.1 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was poured into 500 mL of water and stirred for 20 minutes. The solid was collected by means of vacuum filtration and was dried under high vacuum overnight to afford 6-(4-bromophenyl)-2-(ethylthio)pyrimidin-4-amine (51.0 g, 156.2 mmol, 81.76% yield). MS (apci) m/z=310.0 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20].Cl>O1CCCC1>[CH2:20]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCCC(C(=O)OCC)C(=O)OCC
Reaction time: 0.25 h

Procedure:
To 120 ml of dry tetrahydrofuran (THF) was added 4.9 g of 60% sodium hydride, and 29.5 g of diethyl malonate was added dropwise with stirring under ice-cooling. After addition, stirring was continued for 15 minutes, and then g of 6-bromo-1-hexen was added to the mixture and heated to reflux for 21 hours. The reaction solution was cooled, poured into ice-cold water, neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=20:1) to provide 14.5 g of the objective compound as yellowish oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]([F:24])([F:23])[F:22])=[CH:10][C:9]=1[NH:25][C:26](OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.COC(=N)[C:44]([Cl:47])([Cl:46])[Cl:45]>C(Cl)Cl>[Cl:45][C:44]([Cl:47])([Cl:46])[C:26]1[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][C:21]([F:23])([F:24])[F:22])=[CH:10][C:9]=2[N:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)cc1NC(=O)OC(C)(C)C
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
(3-tert-Butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-yl)-carbamic acid tert-butyl ester (573 mg, 1.22 mmol, as prepared in the previous step) was placed in a mL vial equipped with a magnetic stir bar. DCM (10 mL) and TFA (5 mL) were added, and the mixture stirred at rt for 12 h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM and washed with 2M aq NaOH. The organic extract was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (5 mL) and placed in an 8 mL vial equipped with a magnetic stir bar. The mixture was cooled to 0° C., treated with methyl-2,2,2-trichloroacetimidate (0.167 mL, 1.35 mmol) via syringe, and stirred at rt for 3 days. The solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 12-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 2:5, v/v over 30 min, yielding 409 mg (85%) of the desired compound. 1H-NMR (400 MHz, d4-MeOH) δ: 7.71-7.77 (m, 2H), 7.52-7.57 (m, 1H), 7.39-7.51 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:16](COCC[Si](C)(C)C)[C:15]2[C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[S:12][C:11]3[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=3[C:9]=2[N:8]=1.C(=O)([O-])O.[Na+]>CO.Cl.O>[CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[NH:16][C:15]2[C:14]3[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=3[S:12][C:11]3[CH:29]=[CH:30][CH:31]=[CH:32][C:10]=3[C:9]=2[N:8]=1
Reactant: CN(C)CCOCc1nc2c(n1COCC[Si](C)(C)C)-c1ccccc1Sc1ccccc1-2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)CCOCc1nc2c([nH]1)-c1ccccc1Sc1ccccc1-2
Temperature: 25 °C

Procedure:
To a solution of dimethyl-{2-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-ethyl}-amine (0.32 mmole) in methanol (7.0 ml), 0.5 M hydrochloric acid in methanol (3.2 ml) was slowly added. The reaction mixture was heated under reflux for 3 hours, then it was cooled to room temperature, neutralized with a saturated aqueous solution of sodium hydrogencarbonate, diluted with water and extracted with dichloromethane. The organic extract was washed with an aqueous sodium chloride solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure. After purification by chromatography on a silica gel column, dimethyl-[2-(1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy)-ethyl]-amine in the form of an oily product was isolated;
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=4)[C:27]=3[CH3:28])=[O:22])=[CH:16][C:15]=2[CH3:39])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:28][C:27]1[N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][N:30]=2)[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:15]([CH3:39])[CH:16]=1)=[O:22]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To N-[6-(1-tert-butyloxycarbonylpiperidin-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (7.0 g) were added dichloromethane (128 ml) and trifluoroacetic acid (26 ml), stirred at room temperature for 2 hours, and then to the reaction solution was added 4 N aqueous solution of sodium hydroxide under ice-cooling. The precipitated solid was washed with n-hexane and water, the obtained solid was dissolved in chloroform, water was added thereto, extracted with chloroform and ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The precipitated solid was washed with ethyl acetate to give the titled compound (5.39 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:21])=[C:9]([CH3:20])[C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:4].C(O)(=O)C>C(O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:10]3[C:9]([CH3:20])=[C:8]([CH3:21])[S:7][C:6]=3[NH:5][C:3](=[O:4])[C:2]([CH3:23])([CH3:22])[N:1]=2)=[CH:13][CH:14]=1
Reactant: Cc1sc(NC(=O)C(C)(C)N)c(C(=O)c2ccc(Cl)cc2)c1C
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(C)(C)C(=O)N2

Procedure:
A round bottomed flask was charged with 2-amino-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-2-methylpropanamide (1 g, 2.85 mmol) and a stir bar. Ethanol (25 mL, 0.1 M) was added, followed by acetic acid (4.08 ml, 71.3 mmol, 25 equiv), and the solution was stirred at reflux 4 h before being concentrated and purified by column chromatography (eluting with hexanes/ethyl acetate) to yield 5-(4-chlorophenyl)-3,3,6,7-tetramethyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one as a yellow amorphous solid (m/z=333) that was used in the subsequent reaction.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].[CH2:11]([N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24](Cl)[C:18]=2[S:17]1(=[O:27])=[O:26])[CH2:12][CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH2:11]([N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([S:10][CH2:7][CH2:8][CH3:9])[C:18]=2[S:17]1(=[O:27])=[O:26])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCS
Reactant: CCCCCN1Cc2cccc(Cl)c2S1(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN1Cc2cccc(SCCC)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.0 g of potassium-t-butoxide in 40 ml of dry dimethylformamide was added 4.0 ml of propyl mercaptan at -5° C. to 0° C. under an inert atmosphere followed by 11.0 g of 2-pentyl-7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide. The mixture was stirred at room temperature for 16 hours, poured into water and extracted with n-butyl chloride. The extract was washed with water and brine, dried over MgSO4 and concentrated to give 10.3 g of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1 g of methyl 2-chloro-6-methylpyrimidine-4-carboxylate, 20 mL of methanol and 2 mL of 30% sodium methoxide in methanol was stirred under nitrogen at room temperature for 3 hrs, quenched with 3 mL of acetic acid and concentrated under reduced pressure. The residue was partitioned between 25 mL of saturated sodium bicarbonate and 3×20 mL of ethyl acetate and the extracts dried over MgSO4. Concentration under reduced pressure gave a white crystalline solid: MS (m+1)=183.1; 1H NMR (400 MHz, CDCl3) 7.5 (s, 1H), 4.1 (s, 3H), 4.0 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([Cl:23])[CH:14]=1)=O>C(O)C>[Cl:23][C:15]1[CH:14]=[C:13]([C:11]2[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:10]=2)[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: COc1cc(C(=O)CBr)cc(Cl)c1OC
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1nc(-c2cc(Cl)c(OC)c(OC)c2)cs1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of ethyl aminothioxoacetate (16.2 g) in ethanol (80 ml), stirred under nitrogen at reflux, was added dropwise over 10 min, a hot solution of 2-bromo-1-(3-chloro-4,5-dimethoxyphenyl)-ethanone (31.9 g) in ethanol (180 ml). The mixture was heated at reflux for 4 h, then cooled to room temperature. The precipitated solid was collected by filtration and dried under vacuum at 60° C. Recrystallisation from ethanol gave ethyl 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carboxylate as a white solid (21.9 g), m.p. 92°-94° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)=[O:10]
Reactant: O=C(Nc1ccc(O)cc1)c1ccccn1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(NC(=O)c2ccccn2)cc1)c1ccccc1

Procedure:
The title product was prepared from pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (41%,). HPLC-MS: m/z=348.1 (M+1); Rt: 4.00 min.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[C:8]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:23]=2)[C:9]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:20][CH3:21])=[C:17]([F:19])[CH:18]=2)=[N:10][CH:11]=1)[CH3:5])=[N+]=[N-]>C1COCC1.[Pd]>[NH2:1][CH:4]([C:6]1[CH:7]=[C:8]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[N:23]=2)[C:9]([NH:12][C:13]2[CH:14]=[N:15][C:16]([O:20][CH3:21])=[C:17]([F:19])[CH:18]=2)=[N:10][CH:11]=1)[CH3:5]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N=[N+]=[N-])cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(5-(1-azidoethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1 g, 1.571 mmol) in THF (10 mL). Under nitrogen protection, 10% Pd—C (0.5 g) was mixed, the suspension was stirred under a hydrogen balloon for 16 h. The mixture was filtered through a Celite® (diatomaceous earth) pad, washed the pad with EtOAc, the filtrate was concentrated in vacuum to provide 4-(5-(1-aminoethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.8 g, 83% yield) as a black solid. m/z (ESI positive ion) m/z: 611(M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][S:15][C:16]([S:18][C@H:19]2[NH:22][C:21](=[O:23])[C@@H:20]2[O:24][CH3:25])=[S:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:28]([C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38](OCC)[OH:39])=[CH:33][CH:32]=1)([O-:30])=[O:29]>C1(C)C=CC=CC=1.CN(C)C=O>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38]([N:22]2[C@H:19]([S:18][C:16]([S:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:27][CH:26]=3)=[O:11])=[S:17])[C@@H:20]([O:24][CH3:25])[C:21]2=[O:23])[OH:39])=[CH:44][CH:45]=1)([O-:30])=[O:29]
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 23, 646 mg (1.5 mmole) of (3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidine in 22 ml of absolute toluene and 5.5 ml of absolute dimethylformamide are reacted with 848 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in the presence of freshly dried molecular sieves. After working up and chromatography over silica gel the title compound is obtained.