Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl>[C:1]([N:5]([CH2:6][CH2:7][C:8](=[O:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:23](=[O:24])[O:25][CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)NCCC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N(CCC(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 3-(tert-butylamino)-1-phenylpropan-1-one (5.80 g, 0.028 mol) and K2CO3 (7.73 g, 0.056 mol) in CH2Cl2 (100 mL) was added dropwise methyl chloroformate (7.98 g, 0.085 mol) at 0° C., and the reaction mixture was stirred at rt overnight. The solution was filtered. The filtrate was concentrated to give the crude product, which was purified by chromatography to afford methyl tert-butyl(3-oxo-3-phenylpropyl)carbamate (5.09 g, 69%). 1H NMR (CDCl3): 1.43 (s, 9H), 3.16-3.21 (m, 2H), 3.62 (s, 3H), 3.60-3.72 (m, 2H), 7.2-7.49 (m, 2H), 7.51-7.59 (m, 1H), 7.93-7.98 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41](O)=[O:42])=[O:39]>CN(C)C=O>[F:35][C:36]([F:45])([F:44])[CH2:37][S:38]([CH2:40][C:41]([NH:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([C:9]([CH2:19][PH:20]([OH:22])=[O:21])([S:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:10][CH2:11][CH3:12])[CH2:7][S:8][C@H:3]12)=[O:42])=[O:39]
Reactant: O=C(O)CS(=O)CC(F)(F)F
Reactant: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(C[PH](=O)O)(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 0.25 h

Procedure:
A suspension of 4.36 g (0.01 mol) of 7β-amino-3-(1-ethoxyhydroxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 4 ml of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6 N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is treated with Amberlite IR-120H ionexchange resin and lyophilized to give the title compound.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[C:28]1([CH2:34][S:35](Cl)(=[O:37])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][N:23]([S:35]([CH2:34][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:37])=[O:36])[CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Agent: Cl
Product: COc1cc(Nc2nc3c(s2)CN(S(=O)(=O)Cc2ccccc2)CC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 45 from 90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 39 mg (0.2 mmol) alpha-toluenesulphonylchloride yielding 18 mg (18%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(5-phenylmethanesulfonyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine as a yellow solid. MS ISP (m/e): 496.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.36 (s, 1H), 7.64 (s, 1H), 7.47 (s, 1H), 7.38-7.35 (m, 6H), 7.30 (d, 1H), 7.25 (d, 1H), 7.02 (s, 1H), 4.50 (s, 2H), 4.29 (s, 2H), 3.78 (s, 3H), 3.48 (t, 2H), 2.64 (br t, 2H), 2.14 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([Li])CCC>CCCCCC.O1CCCC1>[CH3:22][CH:23]1[CH2:28][CH2:27][N:26]([C:17]([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:16]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: CC1CCNCC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1CCN(C(=O)c2nc(-c3ccccc3)nc3ccccc23)CC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 4-methylpiperidine (2.95 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 4-methyl-1-[(2-phenylquinazolin-4-yl)-carbonyl]-piperidine (1 g), melting at 138° C., is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([C:6]1[N:10]([CH3:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:8][N:7]=1)[CH3:5].[CH3:29]I>CN(C=O)C.O>[CH3:29][N:19]([C:4]([CH3:3])([C:6]1[N:10]([CH3:11])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:8][N:7]=1)[CH3:5])[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: Cc1ccccc1-c1nnc(C(C)(C)NS(=O)(=O)c2ccccc2)n1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nnc(C(C)(C)N(C)S(=O)(=O)c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Sodium hydride (55% oily, 13 mg) was suspended in DMF (2 ml) and then N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]ethyl}benzensulfonamide (100 mg) and methyl iodide (0.017 ml) were added thereto under ice cooling, followed by stirring at room temperature for 7 hours. The reaction solution was diluted with water (30 ml) and then extracted with chloroform (15 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting solid washed with diethyl ether to obtain 81 mg of N-methyl-N-{1-methyl-1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]ethyl}benzensulfonamide (white solid).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])[OH:26])=[CH:20][CH:19]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=C(O)Cc2ccc(Cl)cc2)C(=O)O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (52.7 g, 366 mmol) in DCM (205 mL) at −10° C. in an ice/methanol bath was added pyridine (72.5 mL, 897 mmol) over 10 minutes. To the resulting solution at −10° C. was added a solution of 2-(4-chlorophenyl)acetyl chloride (69.1 g, 366 mmol) in DCM (144 mL) dropwise over 1 hour. The mixture was stirred at −10° C. for 1 hour, then at room temperature for 1 hour. The mixture was poured into a mixture of 2 M HCl (820 mL) and ice (400 mL) and the aqueous layer was extracted with DCM (2×200 mL). The combined DCM layers were washed with 1 N HCl (100 mL) and brine (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 103 g of title compound. (95% yield). LC/MS (FA) ES− 295. 1H NMR (400 MHz, CDCl3) δ: 15.25 (br s, 1H), 7.34-7.26 (m, 4H), 4.37 (s, 2H), 1.72 (s, 6H).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Br[CH2:20][CH2:21][F:22]>O1CCCC1>[F:22][CH2:21][CH2:20][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: FCCBr
Reactant: NS(=O)(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1SCCF
Temperature: 0 °C
Reaction time: 6 h
Yield: 571.9 %

Procedure:
A mixture of 29 g of the 2-mercaptophenylsulfonamide triethylamine salt obtained in accordance with Example H6 and 2 g of 2-bromo-1-fluoroethane in 130 ml of tetrahydrofuran is stirred for 6 hours at a temperature of +40° C. to +45° C. The reaction mixture is then cooled to 0° C. and filtered. The filtrate is evaporated and the resulting residue is crystallized from methylene dichloride to give 21.2 g (90.2% of theory) of 2-(2-fluoroethylthio)-phenylsulfonamide having a melting point of +84° to +85° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.[Cu]I>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Reactant: NC(=O)C1CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(NC(=O)C3CC3)cn2)CC1
Temperature: 110 °C
Yield: 55.1 %

Procedure:
A mixture of 0.20 g (0.56 mmol) of [1-(5-iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester, 22 mg (0.12 mmol) of CuI, 0.035 mL (0.22 mmol) of 1,2-trans-di(methylamino)cychlohexane, 0.090 mg (1.1 mmol) of cyclopropanecarboxamide, and 0.24 mg (1.1 mmol) of K3PO4 in 1 mL of 1,4-dioxane was heated under an N2 atmosphere for overnight at 110° C. The mixture was cooled, diluted with 10 mL of EtOAc, and washed with aq. NH4Cl/NH4OH (pH 8), then with aq. NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was triturated with acetonitrile to provide 98 mg (56%) of {1-[5-(cyclopropanecarbonyl-amino)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester as an off-white powder.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26]C(OC)=O)=[CH:21][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:20])[CH2:17][O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[ClH:31]>CO.[OH-].[Na+].O>[ClH:31].[F:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:20])[CH2:17][O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: COCC(=O)Nc1ccc2c(Nc3cc(OC(=O)OC)c(C)cc3F)ncnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCC(=O)Nc1ccc2c(Nc3cc(O)c(C)cc3F)ncnc2c1
Yield: 36 %

Procedure:
A solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-methoxyacetamidoquinazoline (201 mg, 0.5mmol) in methanol (5 ml) and 2M aqueous sodium hydroxide solution (0.5 ml) was stirred at ambient temperature for 1 hour. The mixture was diluted with water and adjusted to pH6 with 2M hydrochloric acid. The precipitated solid was collected by filtration, washed with water, dried and then dissolved in a mixture of methylene chloride and methanol. A 5M solution of hydrogen chloride in isopropanol (0.3 ml) was added and most of the solvent removed by evaporation. The precipitated solid was collected by filtration, washed with methylene chloride and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxyacetamidoquinazoline hydrochloride (70 mg, 36%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:28][CH2:27][C:26](=[O:29])[NH:25]3)=[O:23])=[N:12]2)=[CH:7][CH:6]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:28][CH2:27][C:26](=[O:29])[N:25]3[CH3:32])=[O:23])=[N:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCC(=O)N3)cc2-c2ccccn2)cn1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(=O)N3CCC(=O)N3C)cc2-c2ccccn2)cn1
Reaction time: 0.25 h
Yield: 16 %

Procedure:
60% Sodium hydride (142.4 mg) was added to the above-obtained 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-oxopyrazolidine (0.542 g) in N,N-dimethylformamide (5 mL) at room temperature, followed by stirring for 15 minutes. Subsequently, methyl iodide (0.828 mL) was added to the resultant mixture, followed by stirring for 10 days. Potassium carbonate (0.614 g) and methyl iodide (0.276 mL) were added to the reaction mixture. The resultant mixture was stirred at 60° C. for 2 hours, and then cooled in air. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate-hexane), to thereby give the title compound as a solid (89.8 mg, 15%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](O)=[O:14])[C:7]([CH3:16])=[CH:6]2)#[N:2].[Br:21][C:22]1[CH:23]=[C:24]([C:28]([NH:30][NH2:31])=O)[CH:25]=[N:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[O:14][C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:18])([F:19])[F:20])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH3:16])=[N:31][N:30]=2)[CH:25]=[N:26][CH:27]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=O)O
Reactant: NNC(=O)c1cncc(Br)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 35C using [5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 5-bromo-3-pyridinecarbohydrazide: 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J=1.7 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.48 (dd, J=2.0 and 1.7 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 6.65 (s, 1H), 5.99 (s, 2H), 2.58 (s, 3H); MS (ES) m/z 462 (M+1, isotope for Br) and 464 (M+1, isotope for Br)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:10]=[C:11]([C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[N:6][C:7]=1[OH:8].[N:29]([C@@H:32]([CH3:37])[CH2:33][CH2:34][O:35][CH3:36])=[C:30]=S.Cl.C(N=C=NCCCN(C)C)C>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:13]1[NH:12][C:11]([C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[N:10][C:9]=1[C:5]1[N:6]=[C:7]2[O:8][C:30]([NH:29][C@@H:32]([CH3:37])[CH2:33][CH2:34][O:35][CH3:36])=[N:1][C:2]2=[CH:3][CH:4]=1
Reactant: COCC[C@H](C)N=C=S
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc(N)c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COCC[C@H](C)Nc1nc2ccc(-c3nc(C(C)(C)C(=O)OC)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 65.5 °C
Reaction time: 21 h
Yield: 73.4 %

Procedure:
Dimethyl sulfoxide (713 mL) is degassed with nitrogen at 25-30° C. for 0.5-1 h under a nitrogen atmosphere. Methyl 2-[4-(5-amino-6-hydroxy-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]-2-methyl-propanoate (35.0 g, 90.0 mmol) and (3S)-3-isothiocyanato-1-methoxy-butane (19.58 g, 0.14 mol) are added and the reaction heated to 63-68° C. The reaction mixture is stirred for 18-24 h at this temperature and then add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.3 g, 100.7 mmol) is added in portions. The reaction mixture is stirred for 2-4 h at 60-65° C. Additional 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.9 g, 9.9 mmol) is added if the reaction does not reach complete conversion. The reaction mixture is cooled to 20-30° C. and is filtered over diatomaceous earth. Ethyl acetate (351 mL) and water (350 mL) are added to the filtrate. The layers are separated and the aqueous phase extracted with ethyl acetate (312 mL). The organic layers are combined and washed with water (2×210 mL), and then heptane (626 mL) is added. The solution is stirred for 0.5-1 h and filtered over silica gel, rinsing with a mixture of ethyl acetate (351 mL) and heptane (348 mL). The solution is concentrated under reduced pressure below 45° C. and ethyl acetate (156 mL) is added. Activated carbon (3.5 g) is added and the mixture heated to 60-70° C. with stirring for 0.5-1 h. The mixture is cooled to 20-30° C., filtered, and the filtrate concentrated under reduced pressure below 45° C. Toluene (242 mL) is charged to the resulting residue and the material concentrated under reduced pressure below 45° C. Toluene (40 mL) is added and the mixture heated to 60-70° C. with stirring for 0.5-1 h. The mixture is cooled to 25-30° C., stirred for 2-4 h, and then cooled to 0-5° C. The mixture is stirred at 0-5° C. for 2-4 h and the solids are collected by filtration. The filtercake is washed with toluene (40 mL) and is dried under reduced pressure below 60° C. to give the title compound as an off-white solid (33.0 g, 71%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14](I)[CH:13]=2)[O:9][N:8]=1.[CH3:23][N:24](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[C:14]([C:23]#[N:24])[CH:13]=2)[O:9][N:8]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(I)cc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 80 °C
Yield: 78 %

Procedure:
In a similar fashion, a solution of 3-(2-pyridyl)-5-(3-iodo-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (50 mg, 0.122 mmol) in N,N-dimethylformamide (2 mL) was treated with zinc cyanide (22.5 mg, 0.191 mmol), and Pd(PPh3)4 (14 mg, 0.012 mmol). The reaction mixture was heated at 80° C. under an argon atmosphere for 2 hours. The mixture was then diluted with ethyl acetate (25 mL) and washed with water (3×5 mL) and brine (3×5 mL). The organic solution was then dried over anhydrous MgSO4, filtered and concentrated in vacuo. Silica gel chromatography using 30% ethyl acetate in hexane afforded 29.2 mg (78%) of 3-(2-pyridyl)-5-(3-cyano-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): 9.19 (s, 1H), 8.89 (d, 1H), 8.80 (s, 1H), 8.59 (s, 1H), 8.25 (d, 1H), 7.95 (t, 1H), 7.50 (m, 1H), 4.09 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([O:24][CH3:25])[N:18]=1)=[O:15])(=[O:12])=[O:11].O1CCOCC1.[F:33][C:34]([F:38])([F:37])[CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>O>[F:26][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:16][C:17]1[N:18]=[C:19]([O:24][CH3:25])[N:20]=[C:21]([O:36][CH2:35][C:34]([F:38])([F:37])[F:33])[N:22]=1)=[O:15])(=[O:12])=[O:11]
Reactant: OCC(F)(F)F
Reactant: COc1nc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(OCC(F)(F)F)n1
Reaction time: 12 h

Procedure:
A mixture of 8.2 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-chloro-6-methoxy-1,3,5-triazin-2-yl)-urea, 60 ml of dioxane, 20 ml of 2,2,2-trifluoroethanol and 5.5 g of potassium carbonate is stirred at 55°-60° for 12 hours and then taken up in 300 ml of water and filtered over active charcoal. After the mixture has been acidified with 2N hydrochloric acid, the product precipitates and is separated off by filtration. Yield: 7.7 g of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-[4-methoxy-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl]-urea of melting point 155°-157°.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:43]1([NH2:49])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([NH:49][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCC2CN1C(=O)N2OCc1ccccc1
Reactant: NN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCOCC1)C1CCC2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (142 mg, 0.513 mmol) in methylene chloride (3.5 mL) were added triethylamine (226 μl), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (125 mg), 1-hydroxybenzotriazole.monohydrate (100 mg), and morpholin-4-amine (62.7 μl), followed by agitating at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to afford 149 mg of the title compound (yield 80%).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][C:12]1[CH:25]=[CH:24][C:15]2[N:16]3[C:21]([CH:22]=[O:23])=[CH:20][N:19]=[C:17]3[S:18][C:14]=2[CH:13]=1>C1COCC1>[CH3:11][C:12]1[CH:25]=[CH:24][C:15]2[N:16]3[C:21]([CH:22]([CH2:3][CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[OH:23])=[CH:20][N:19]=[C:17]3[S:18][C:14]=2[CH:13]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccc2c(c1)sc1ncc(C=O)n12
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)sc1ncc(C(O)CCc3ccccc3)n12

Procedure:
Magnesium (0.29 g, 12 g atom) in THF (60 mL) was treated with (2-bromoethyl)-benzene (1.64 mL) and reacted for 18 hours. The suspension was treated with solid 7-Methyl-imidazo [2,1-b]benzothiazole-3-carboxaldehyde (Formula K-3) (0.65 g) and reacted for 2 hours. The reaction mixture was decanted into cold 5% ammonium chloride solution and precipitated 7-Methyl-α-(2-phenylethyl)imidazo[2,1-b]benzothiazole-3-methanol (Formula K-4) (0.96 g) was filtered. An aliquot was crystallized from methylene chloride/ethanol solution to yield pure 7-Methyl-α-(2-phenylethyl) imidazo[2,1-b]benzothiazole-3-methanol (Formula K-4), m.p. 209-210°.
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[O-:15][C:16]#[N:17].[K+]>O1CCCC1>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[N:17]=[C:16]=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1N=C=O
Reaction time: 15 h
Yield: 83 %

Procedure:
In an argon atmosphere, 8.33 g (35.8 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 30 mL of tetrahydrofuran and after adding 3.19 g (purity: 96%, 37.8 mmol) of potassium cyanate, the mixture was stirred for 15 hours under heating and refluxing. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 85° C./3.3×102 Pa) to obtain 1,3-di-tert-butyl-2-isocyanato-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NCO) as a colorless liquid (yielded amount: 7.07 g, yield: 83%). The thus-obtained Si(tBuNCHCHNtBu)(H)NCO was measured for the 1H and 13C NMR spectra, as a result, these spectra agreed with spectra of that obtained in Example-29.