Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([CH2:7][CH3:8])=[CH:5][S:4][CH:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C>C(OCC)C>[CH2:7]([C:6]1[C:2]([CH:17]=[O:18])=[CH:3][S:4][CH:5]=1)[CH3:8]
Reactant: CCc1cscc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCc1cscc1C=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromo-4-ethylthiophene, B9, (3.4 g, 0.018 mol) in 40 mL of diethyl ether was cooled to -78° C., and a solution of n-BuLi (12.0 mL, 1.6M) in hexanes was added dropwise. The solution was allowed to warm to -20° C., and DMF (1.46 g, 0.020 mol) was added. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction was quenched with aqueous ammonium chloride solution and extracted twice with diethyl ether. The organic extracts were combined, washed with twice with water and then brine and dried (MgSO4). The solution was filtered and concentrated to provide 4-ethylthiophene-3-carboxaldehyde, C9, which was used directly in the next step. ##STR65##
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[C:4]([C:15]2[N:20]=[C:19]3[C:21]([C:24](O)=[O:25])=[CH:22][NH:23][C:18]3=[N:17][CH:16]=2)=[N:3]1.[CH3:27][C:28]([NH2:31])([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:28]([NH:31][C:24]([C:21]1[C:19]2=[N:20][C:15]([C:4]3[C:5]4[C:10](=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][CH:6]=4)[N:2]([CH3:1])[N:3]=3)=[CH:16][N:17]=[C:18]2[NH:23][CH:22]=1)=[O:25])([CH3:30])([CH3:29])[CH3:27]
Reactant: CC(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(C(F)(F)F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
A mixture of 2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (190 mg, 0.526 mmol), 2-methylpropan-2-amine (58 mg, 0.789 mmol), EDCI (301 mg, 1.578 mmol), HOBt (213 mg, 1.578 mmol) and DIPEA (204 mg, 1.578 mmol) in dry DMF (5 mL) was stirred for 16 hours at room temperature. Water (5 mL) was added, the formed precipitate was separated by filtration then purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 90% acetonitrile/10% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min.) to afford N-tert-butyl-2-(1-methyl-6-(trifluoromethyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (47 mg, 21%) as a yellow solid. LCMS: (M+H)+=417; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.08 (s, 1H), 8.63 (d, 1H, J=8.4 Hz), 8.38 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.49 (d, 1H, J=8.7 Hz), 4.28 (s, 3H), 1.22 (s, 9H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:24])=[O:23])=[CH:20][CH:19]=1>C(#N)C.C(OCC)C>[ClH:24].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=2)[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH2:16][CH2:15][CH2:14][N:13]=1
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cc(NC(=O)c2ccc(F)cc2)ccc1NC1=NCCC1

Procedure:
A mixture of 1.0 g (3.8 mmole) of product compound of Example 9 and 30.5 mmole of p-fluorobenzoyl chloride in 40 ml of acetonitrile was stirred at reflux for four hours, after which time thin-layer chromatography on silica gel (9:1 ethanol/concentrated aqueous ammonia) indicated no unreacted starting amine. The reaction mixture was then diluted eight-fold with diethyl ether. The resultant solid was collected and washed with three portions of ether, then dried in a high vacuum over 5A molecular sieves, giving the title compound as the hydrochloride salt. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1>O1CCOCC1.ClCCl>[NH:12]1[CH2:13][CH2:14][CH:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[NH2:2])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A solution of 4 M HCl in dioxane (25 mL) was added to tert-butyl 4-[3-(amino)phenyl]-1-piperidinecarboxylate (2.60 g, 9.00 mmol) in dichloromethane (250 mL). The reaction mixture was stirred at room temperature overnight, concentrated in vacuo, and the residue was dissolved in water (50 mL). The mixture was nuetralized using KOH pellets and extracted with methylene chloride (3×50 mL). The combined organic extracts were dried (MgSO4), concentrated and chromatographed to give the desired product (1.03 g). 1H NMR (400 MHz, CDCl3) δ 7.01 (t, 1H, J=7.6 Hz), 6.62-6.54 (m, 3H), 3.16 (br d, 2H, J=10.3 Hz), 2.75 (dt, 2H, J=2.7, 12.3 Hz), 2.56 (tt, 1H, J=3.6, 12.3 Hz), 1.81 (br d, 2H, J=12.3 Hz), 1.65 (dq, 2H, J=4.0, 12.3 Hz); ESMS m/e: 177.2 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1C(OC)=O>C1COCC1>[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:25]=1[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
367 ml of NaHMDS (2M in THF) are added to 250 ml of THF and the mixture is cooled to −70° C. 54 g of (4-methoxyphenyl)acetic acid are then added; the mixture is left stirring for 2 hours and then 49 g of methyl 2,4-dichlorobenzoate are added. The reaction mixture is allowed to return to 10° C. and poured onto 2 liters of ice-cold HCl (2N), and the product is extracted with ether. After drying with a saturated sodium bicarbonate solution and then a saturated NaCl solution, drying the organic phase and evaporating, the product crystallizes from heptane; 32 g of the expected compound are obtained.
Reaction SMILES: CO[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]([C:10]2[C:11](=[O:20])[O:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:9])=[CH:5][CH:4]=1.COC1C=CC(CC(C2C(=O)OC3C(C=2)=C(OC)C=C(OC)C=3)=O)=CC=1.COC1C=CC(CC(C2C(=O)OC3C(C=2)=CC([N+]([O-])=O)=CC=3[N+]([O-])=O)=O)=CC=1.COC1C=CC(CC(C2C(=O)OC3C(C=2)=CC(Br)=CC=3)=O)=CC=1.COC1C=CC(CC(C2C(=O)OC3C(C=2)=CC([Cl:119])=CC=3)=O)=CC=1.COC1C=CC(CC(C2C(=O)OC3C(C=2)=CC=C(OC)C=3)=O)=CC=1.COC1C=CC(CC(C2C(=O)OC3C(C=2)=CC=C(O)C=3)=O)=CC=1>>[Cl:119][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]([C:10]2[C:11](=[O:20])[O:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)c2cc3ccccc3oc2=O)cc1
Reactant: COc1ccc(CC(=O)c2cc3cc(Cl)ccc3oc2=O)cc1
Agent: COc1ccc(CC(=O)c2cc3c(OC)cc(OC)cc3oc2=O)cc1
Agent: COc1ccc(CC(=O)c2cc3cc(Br)ccc3oc2=O)cc1
Agent: COc1ccc(CC(=O)c2cc3cc([N+](=O)[O-])cc([N+](=O)[O-])c3oc2=O)cc1
Product: O=C(Cc1ccc(Cl)cc1)c1cc2ccccc2oc1=O

Procedure:
Additional preferred compounds according to the second embodiment of compounds according to Formula IA include: 3-(4-methoxybenzylcarbonyl)-2H-chromen-2-one; 3-(4-methoxybenzylcarbonyl)-5,7-dimethoxy-2H-chromen-2-one; 3-(4-methoxybenzylcarbonyl)-6,8-dinitro-2H-chromen-2-one; 3-(4-methoxybenzylcarbonyl)-6-bromo-2H-chromen-2-one; 3-(4-methoxybenzylcarbonyl)-6-chloro-2H-chromen-2-one; 3-(4-methoxybenzylcarbonyl)-7-methoxy-2H-chromen-2-one; 3-(4-methoxybenzylcarbon-yl)-7-hydroxy-2H-chromen-2-one; mixtures thereof; and salts thereof.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][CH2:3]1.C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:11])C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.O>[CH3:1][CH:2]1[O:6][C@@H:5]([C:7]([OH:11])=[O:8])[CH2:4][CH2:3]1
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: CC1CC[C@H](CO)O1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: O
Solvent: CC#N
Product: CC1CC[C@H](C(=O)O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
Crude (R)-(5-methyltetrahydrofuran-2-yl)methanol was dissolved in 6 mL of 1:1 ACN/water mixture, and bis-acetoxyiodobenzene [BAIB] (0.71 g, 2.20 mmol) was added to the mixture. It was then cooled to 0 C in an ice bath, and TEMPO (0.031 g, 0.2 mmol) was added under argon flow. The mixture was stirred at room temperature for 3 h, and the reaction was quenched by addition of 20 mL of 1 M NaOH. Basic solution was washed 3×15 mL of EtOAc, and re-acidified with 1 M HCl to ca. pH 2. Aqueous layer was then extracted 6×15 mL of EtOAc, organic layers combined, dried over sodium sulfate and evaporated. Resulting oil (0.05 g, 26%) was used in the next step with no purification. 1H NMR (300 MHz, CDCl3) δ 4.48-4.43 (m, 1H), 4.20-4.17 (m, 1H), 2.33-2.21 (m, 3H), 2.08-2.02 (m, 1H), 1.35 (dd, 3H, J1=6.3 Hz, J2=1.8 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:22]=[CH:21][C:6]([NH:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:9]#N)=[CH:5][CH:4]=1.O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[N:7]([C:6]2[CH:21]=[CH:22][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH:24]=1
Reactant: C=C(C)C=O
Reactant: CSc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1
Product: CSc1ccc(-n2cc(C)cc2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methylthioanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly yellow powder (yield 33%), melting at 194-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=4)[N:30]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: COc1cccc(NC(=N)N)c1
Product: COc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 1-(3-methoxyphenyl)guanidine were converted to I-15 (25%): HRMS Calcd. for C11H15ClN4O2: 367.0961, Found 367.0961.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>CO.O>[CH2:12]([N:11]1[C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[C:8]=2[N:9]=[CH:10]1)[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)c2ncn(CC(C)C)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc3c2ncn3CC(C)C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
3-isobutyl-7-(5-methyl-pyridin-2-yl)-3H-benzoimidazole-5-carboxylic acid methyl ester 207 mg, 0.64 mmol) was suspended in a mixture of methanol (10 mL) and water (2 mL). To this suspension was added LiOH (46 mg, 1.92 mmol). The mixture was stirred overnight at room temperature, then made acidic by addition of 1N aqueous HCl, and concentrated to dryness under reduced pressure. The residue was re-dissolved in methanol, filtered to remove insolubles, and the filtrate was concentrated under reduced pressure to provide 165 mg (84%) of 3-isobutyl-7-(5-methyl-pyridin-2-yl)-3H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:26])[CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[N:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6]1.Br[CH2:28][CH2:29][CH2:30][CH3:31].O>CS(C)=O.C(OCC)(=O)C>[CH2:28]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][CH:5]([N:4]([CH3:26])[CH3:3])[CH2:6]3)=[CH:15][CH:14]=2)=[O:25])=[CH:19][N:20]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCBr
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(O)nc3)cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)cc2)cn1
Reaction time: 0.17 h

Procedure:
A solution of 0.1 g of potassium hydroxide in 1ml of DMSO was stirred at room temperature for 10 minutes and then 0.1 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide was added. The reaction solution was stirred for 10 minutes and then 0.084 g of 1-bromobutane was added. The mixture was stirred at room temperature overnight. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 382.24 (C22H30N4O2); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19]>C1C(O)=CC=CC=1C>[CH3:16][N:17]([CH3:20])[C:18]([NH:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[NH:19]
Reactant: Cc1cccc(-c2ccccc2)c1N
Reactant: CN(C)C#N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1cccc(-c2ccccc2)c1NC(=N)N(C)C

Procedure:
A mixture of 2-amino-3-methylbiphenyl hydrochloride (2.65 g), N,N-dimethylcyanamide (1.3 g) and m-cresol (20 ml) was heated at 90°-95° C. for 18 hours to give N,N-dimethyl-N'-(3-methyl-2-biphenylyl)guanidine as a colourless solid (m.p. 144°-145° C.) which was recrystallised from hexane.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:23][CH2:24][C:25]([O:27]CC)=[O:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:20]([CH:17]1[CH2:18][CH2:19][CH:14]([CH:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:4]=[C:3]4[C:2](=[CH:7][CH:6]=3)[O:26][C:25](=[O:27])[CH2:24][CH2:23]4)[CH2:13][CH2:12]2)[CH2:15][CH2:16]1)[CH2:21][CH3:22]
Reactant: CCCC1CCC(C2CCC(c3ccc(O)c(CCC(=O)OCC)c3)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(c3ccc4c(c3)CCC(=O)O4)CC2)CC1

Procedure:
The foregoing ethyl 3-(2-hydroxy-5-(4-(4-propylcyclohexyl)cyclohexyl)phenyl)propionate was dissolved in toluene, to which was then added p-toluenesulfonic acid (100 mg). A Dean-Stark apparatus was attached, and the mixture was stirred under reflux by heating for 3 hours. After completion of the reaction, the reaction mixture was washed with water, rinsed with a sodium hydrogencarbonate aqueous solution, and then dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo and then subjected to isolation and purification by silica gel column chromatography, thereby obtaining a titled compound (100 mg). As a result of a variety of instrumental analyses, it was confirmed that this was the titled compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:10]=[C:9]([NH:11][C:12]([NH2:14])=[NH:13])[S:8][N:7]=1.[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[CH3:15][NH:16][C:17](=[S:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:10]=[C:9]([NH:11][C:12]([NH2:14])=[NH:13])[S:8][N:7]=1
Reactant: N=C(N)Nc1nc(CSCCN)ns1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NCCSCc1nsc(NC(=N)N)n1

Procedure:
A solution of 3-[(2-aminoethyl)thiomethyl]-5-guanidino-1,2,4-thiadiazole (0.914 g.) in ethanol (10 ml.) was heated under reflux with methyl isothiocyanate (0.288 g.) for 20 minutes and the resulting solution was chromatographed on nine perparative Merck 60 F-254 silica plates (30 cm.×30 cm.) developed with toluene/ethanol/ethyl acetate/ammonia (s.g. 0.88) 60:40:20:10 v/v/v/v. The bands with an Rf value of 0.6 were scraped off, extracted with ethanol and the extracts evaporated to a gum which crystallised on trituration with ethyl acetate to give 3-[2-(3-methyl-thioureido)ethylthiomethyl]-5-guanidino-1,2,4-thiadiazole. The n.m.r. spectrum in d6 dimethyl sulphoxide using tetramethylsilane as an internal standard (δ=0) had the following resonances (δ):-2.76 (2H, triplet); 2.82 (3H, singlet); 3.35 (2H, multiplet); 3.71 (2H, singlet); 7.12 and 7.5 (6H, multiplets).
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6](C(O)=O)/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]O)=[O:23])[CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>COCCOC.C(Cl)Cl.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[C:22]([O:24][C@@H:6]1[N:3]2[C@H:2]([O:11]/[C:7]/1=[CH:8]\[CH2:9][OH:10])[CH2:1][C:4]2=[O:5])=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(O[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21)c1cccc(Cl)c1
Reaction time: 15 h
Yield: 11.4 %

Procedure:
Clavulanic acid (containing ca 0.5 meq. ethyl acetate; 410 mg., 1.7 mmole) was dissolved in dry 1,2-dimethoxyethane/methylene chloride (1:1, 10 ml.). The solution was stirred and ice-cooled with exclusion of moisture while m-chloroperbenzoic acid (380 mg.) and dicyclohexylcarbodiimide (400 mg.) were added. The mixture was stirred with exclusion of moisture for 3 hours at 0° and then for 15 hours at room temperature. The mixture was diluted with ethyl acetate (50 ml.) and was filtered. The filtrate was washed with saturated sodium bicarbonate solution and then with saturated brine. The solution was dried (magnesium sulphate and the solvent was evaporated under reduced pressure to yield a yellow gum. The gum was chromatographed on silica gel (25 g.) using ethyl acetate/petroleum ether (b.p. 60°-80°) to give the title compound as a colourless gum (60 mg., 11% yield). [α]D21 +88.8° (c=1.0 CHCl3). νmax (CHCl3): 3320 (hydroxyl OH), 1805 (β-lactam C=O), 1730 (ester C=O), 1700 (olefinic C=C)cm-1. δ (CDCl3): 2.28 (br.s, 1H, OH), 3.11 (d, J 16 Hz, 1H, C(6)H), 3.48 (dd, J 16, J' 2 Hz, 1H, C(6)H), 4.26 (d, J 7 Hz, 2H, CH2O), 5.03 (t, J 7 Hz, 1H, olefinic H), 5.77 (d, J 2 Hz, 1H, C(5)H), 6.70 (s, 1H, C(2)H), 7.25-7.60 (m, 2H, Ar-H), 7.80-8.00 (m, 2H, Ar-H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[C:17]=1[F:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:13][CH3:14])([CH2:15][CH3:16])[C:6]=3[C:17]=2[F:18])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)c(F)c21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(Cl)c3)c(F)c21

Procedure:
Prepared from 6-amino-4,4-diethyl-5-fluoro-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-chloro-4-fluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.03 (s, 1H), 7.32 (t, J=8.8 Hz, 1H), 7.26 (t, J=9.1 Hz, 1H), 6.92 (m, 2H), 6.83 (m, 1H), 3.29 (s, 3H), 2.12 (m, 2H), 1.92 (m, 2H), 0.84 (t, J=7.2 Hz, 6H); MS (ESI) m/z 381/383 ([M+H]+); MS (ESI) m/z 379/381 ([M−H]−); Anal. calcd for C19H19ClF2N2O2: C, 59.93; H, 5.03; N, 7.36. Found: C, 59.68; H, 4.92; N, 7.14.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[C:8]([CH3:43])=[N:7]1.Br[CH2:48][CH2:49][OH:50].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([N:27]5[CH2:28][CH2:29][N:30]([CH2:48][CH2:49][OH:50])[CH2:31][CH2:32]5)[CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH:13]=2)[C:8]([CH3:43])=[N:7]1
Reactant: OCCBr
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(N5CCNCC5)c4)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(N5CCN(CCO)CC5)c4)cnc32)cc1
Yield: 85 %

Procedure:
Using the same reaction conditions as described in step-ii of example-35, 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(3-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.104 mmol) was alkylated with 2-bromoethanol (13 mg, 0.104 mmol) using potassium carbonate (73 mg, 0.522 mmol), DMF (2 ml) to yield 60 mg (84.5%) of the titled compound. MS: m/z=679.3 (M+1).
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:14][C:15]([SH:18])([CH3:17])[CH3:16].CCN(CC)CC>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C1COCC1>[C:15]([S:18][CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])([CH3:17])([CH3:16])[CH3:14]
Reactant: COC(=O)C(C)(C)CCC(=O)CCl
Reactant: CC(C)(C)S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCC(=O)CSC(C)(C)C

Procedure:
A solution of the α-chloroketone (1 eq) from Step 5, 2-methyl-2-propanethiol (1.2 eq), Et3N (1.5 eq) and n-Bu4NBr (catalytic amount) in THF at room temperature under nitrogen was stirred for 24 hours. The mixture was filtered and the solvent removed in vacuo. Chromatography of the oily residue on silica gel (hexane/EtOAc 10:1) provide the title compound as an oil.
Reaction SMILES: [CH3:1][C@@:2]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3]1.P(OCC)(OCC)[O:24]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[OH:24][CH:6]1[C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3][C@:2]1([CH3:1])[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@](C)(C(=O)OC(C)(C)C)CC1=O
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@](C)(C(=O)OC(C)(C)C)C(O)C1=O
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of tert-butyl(3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (9.90 g, 32.6 mmol) and tri ethyl phosphite (6.71 mL, 39.1 mmol) in anhydrous tetrahydrofuran (165 mL), lithium bistrimethylsilyl amide (45.7 mL, 45.7 mmol, 1.0M solution in tetrahydrofuran) was added at −5° C., and the mixture was stirred at the same temperature for 30 minutes. After bubbling oxygen gas into the reaction mixture for 30 minutes, saturated aqueous solution of ammonium chloride (150 mL) was added in an ice bath, and the mixture was concentrated under reduced pressure. Water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane ethyl acetate, 1:1→1:4) to obtain 7.73 g (74%) of the title compound as a pale yellow oily substance.