Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].[CH2:26]([Mg]Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(OCC)C>[CH2:21]([C:9]1[N:8]([CH2:7][CH2:6][CH2:5][C:4](=[O:24])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1)[CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)N(C)OC
Reactant: CCCCCC[Mg]Br
Solvent: CCOCC
Product: CCCCCCC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21

Procedure:
The general method described in Step 5 of Example 17 was used to react N-methoxy-N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide (6.10 g, 17.9 mmol) with n-hexylmagnesium bromide (13.5 mL of a 2 M solution in diethyl ether, 27 mmol) to provide 1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one (6.10 g) as a yellow oil that was used directly in the next step without further purification.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH3:20])[C:6]=1[C:7]1[S:19][C:10]2[N:11]=[CH:12][N:13]=[C:14](S(C)(=O)=O)[C:9]=2[CH:8]=1.CC1([N:28]2C(C3SC4N=CN=C(S(C)(=O)=O)C=4C=3)=CN=C2)C=CC=CC1>>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH3:20])[C:6]=1[C:7]1[S:19][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH2:28])[C:9]=2[CH:8]=1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Reactant: Cn1cnc(I)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(I)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-(4-iodo-1-methyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 94) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). Beige solid (143 mg, 85%);
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:24][C@@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>>[CH3:24][C@@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:5]2[N:4]=[C:3]([O:9][CH2:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:2]([Br:1])=[CH:7][N:6]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc(Cl)ncc2Br)CC1
Reactant: C[C@H]1CC[C@@H](N)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)CC1

Procedure:
Using the procedure of Example 1 Step 2 tert-butyl 4-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)piperidine-1-carboxylate was reacted with cis-4-methylcyclohexanamine to provide the title compound in 50% yield. 1H NMR (CDCl3, 400 MHz) 8.05 (s, 1H), 5.10 (sb, 1H), 4.15 (m, 4H), 3.96 (m, 1H), 2.71 (m, 2H), 1.95 (m, 1H), 1.78-1.48 (m, 9H), 1.44 (s, 9H), 1.28-1.16 (m, 3H), 0.91 (d, 3H); MS (ESI) m/z: Calc: 482.2 (M+). Found. 484.2 (M++2).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[CH:11][C:10]=2[F:29])[CH:3]=1.[CH3:30][NH2:31].C1COCC1>CCCCO>[F:29][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:19])[CH:13]=[CH:14][C:9]=1[O:8][C:4]1[CH:3]=[C:2]([NH:31][CH3:30])[N:7]=[CH:6][N:5]=1
Reactant: CN
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1)Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCCCO
Product: CNc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)ncn1
Yield: 34 %

Procedure:
A solution of N1-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (100 mg, 0.42 mmol, Example 4) in n-BuOH (3 mL) was treated with 2 M methylamine/THF (0.2 mL) and heated in a screw cap vial at 80° C. for 12 h. The mixture was concentrated and the residue purified by preparative HPLC using a gradient of MeOH—H2O containing 0.1% TFA. The fraction containing the product was lyophilized to give the title compound as a pale yellow solid (60 mg, 34%). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 10.36 (br s, 2H), 8.19 (br s, 1H), 7.76 (d, 1H, J=12.1 Hz), 7.64-7.62 (m, 2H), 7.36-7.27 (m, 2H), 7.15 (dd, 2H, J=8.8, 8.8 Hz), 5.95 (br s, 1H), 3.49 (s, 2H), 2.80 (s, 3H); MS(ESI+) m/z 414.16 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23](O)=[O:24])[N:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])([CH3:11])[CH2:9][NH:10][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:17]3[N:16]=[C:15]([C:14]([F:30])([F:29])[F:13])[O:19][N:18]=3)[CH:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1cccc(Br)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1cccc(Br)c1
Yield: 83 %

Procedure:
This compound was synthesized from 2-(3-bromophenyl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (90 mg, yield 83%). MS (ESI) m/z: Calculated for C20H17BrF3N3O2: 467.05. found: 468.0 (M+H)+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([O:22][CH3:23])=[O:21])[CH2:14][O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C.[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:20]([O:22][CH3:23])=[O:21])[CH2:14][O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C

Procedure:
3.27 g of Z-Thr(But)-Ser(But)-OMe in 50 ml of ethyl acetate are hydrogenated in the presence of 0.5 g of palladium on charcoal (10% strength). After the absorption of hydrogen has ceased (1 hour), the catalyst is filtered off and the solution is evaporated. The product, which is obtained as an oil, is a single substance according to thin layer chromatography.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]([N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:14]1=2)=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].B.O1CCCC1>O1CCCC1>[CH3:1][N:2]([CH2:10][CH2:11][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:14]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(CC(=O)N1CCSc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Product: CN(CCN1CCSc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a stirred solution of tert-butyl methyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-oxoethyl)carbamate (691 mg, 1.881 mmol) in tetrahydrofuran (5 mL) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran; 5.64 mL, 5.64 mmol). The resulting mixture was then stirred at room temperature for 2 hours and quenched carefully via the slow, dropwise addition of methanol (5 mL). The quenched mixture was then diluted with ethyl acetate and washed sequentially with a 1:1 mixture of water:saturated sodium carbonate (2×) and then with brine. The organic phase was dried, filtered, and concentrated giving a red oil (659 mg, 99%). 1H NMR (DMSO-d6) δ 7.56-7.39 (m, 1H), 7.39-7.31 (m, 1H), 7.24-7.14 (m, 1H), 3.68-3.61 (m, 2H), 3.60-3.49 (m, 2H), 3.48-3.36 (m, 2H), 3.13-3.05 (m, 2H), 2.83 (s, 3H), 1.30, 1.17 (2s, 9H); ESI-MS (m/z, %): 376 (M+Na, 85), 354 (MH+, 24), 298 (100).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][CH2:12][N:6]2[C:5](=[O:16])[CH2:4][CH2:3]1.O=[C:18]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:19]([OH:21])=[O:20]>>[C:19]([CH:18]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][CH2:12][N:6]2[C:5](=[O:16])[CH2:4][CH2:3]1)[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:21])=[O:20]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N[C@H]1CCC(=O)N2CC[C@@H](C(=O)O)N2C1=O
Product: O=C(O)C(CCc1ccccc1)N[C@H]1CCC(=O)N2CC[C@@H](C(=O)O)N2C1=O
Yield: 18.1 %

Procedure:
In a manner analogous to that described in the first paragraph of Example 1, from 1.13 g of 8(S)-amino-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylic acid and 2.7 g of 2-oxo-4-phenylbutyric acid there were obtained 350 mg of 8(S)-(1-carboxy-3-phenylpropylamino)-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylic acid in the form of a lyophilized mixture.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:17]=[N:16][C:7]2[NH:8][C:9]3[CH:14]=[N:13][CH:12]=[C:11]([OH:15])[C:10]=3[C:6]=2[CH:5]=1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C=O)C>[CH2:22]([O:21][C:19]([N:8]1[C:9]2[CH:14]=[N:13][CH:12]=[C:11]([OH:15])[C:10]=2[C:6]2[CH:5]=[C:4]([Br:3])[CH:17]=[N:16][C:7]1=2)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1cncc2[nH]c3ncc(Br)cc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)n1c2cncc(O)c2c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.7 %

Procedure:
Sodium hydride (167 mg, 4.17 mmol) was added to a cooled (0° C.) mixture of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ol (1.0 g, 3.79 mmol) in DMF (15 mL). On complete addition the mixture was stirred for 15 minutes then allowed to warm to ambient temperature and stirred for 15 minutes. A solution of benzyl chloroformate (610 mg, 3.6 mmol) in DMF (1 mL) was added and stirring continued for 18 hours. The solvent was evaporated and the resultant residue diluted with water and extracted with dichloromethane (5×50 mL) and ethyl acetate (3×30 mL). The combined organic layer was dried over (Na2SO4), filtered and evaporated to afford a residue. The resultant residue was purified by flash chromatography (silica, 12 g cartridge, ISCO, 0-7% methanol in dichloromethane). The appropriate fractions were collected and evaporated to afford the title compound as a light yellow solid (240 mg, 17%). LCMS (Method B): RT=4.54 min, M+H+=398/400. 1H NMR (400 MHz, DMSO-d6): 8.99 (s, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.63 (d, J=2.4 Hz, 1H), 8.23 (s, 1H), 7.63 (d, J=7.5 Hz, 2H), 7.48-7.36 (m, 3H), 5.61 (s, 2H).
Reaction SMILES: [F:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][C:5]2[N:6]([CH2:10][C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C(O)C.[OH-].[K+]>Cl>[NH2:19][C:18]1[C:2]([F:1])=[CH:3][C:4]2[S:8][C:7](=[O:9])[N:6]([CH2:10][C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[C:5]=2[CH:17]=1
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)c([N+](=O)[O-])cc32)no1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(Cn2c(=O)sc3cc(F)c(N)cc32)no1
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
A mixture of 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-5-nitro-2(3H)-benzothiazolone (3.1 g) and ethanol (40 ml) was prepared. To this mixture was dropwise added a solution of stannous chloride (3.3 mol equivalents per mol equivalent of the nitro compound) in concentrated hydrochloric acid (40 ml), at a temperature of 10° to 15° C. The reaction mixture was stirred at a temperature of 60° to 70° C. for 1.5 hours, and distilled under a reduced pressure to remove the ethanol and the hydrochloric acid therefrom. The resultant residue was admixed with ice (20 g). To the solution thus formed was added dropwise a 25% aqueous potassium hydroxide solution at a temperature of 10° to 15° C. to make the mixture alkaline. The mixture was extracted with dichloromethane (100 ml×2). The dichloromethane extract was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the aimed compound, i.e. 5-amino-6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (2.2 g). m.p. 158°-161° C.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH:24]([C:30]2[CH:35]=[C:34]([CH:36]=O)[CH:33]=[C:32]([O:38][CH2:39][CH3:40])[CH:31]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=1)#[N:16].[C:41]1([NH2:48])[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47].O>C(#N)C>[NH:47]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:48]=[C:36]1[C:34]1[CH:35]=[C:30]([CH:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:22][CH:21]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:31]=[C:32]([O:38][CH2:39][CH3:40])[CH:33]=1
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(C=O)cc(OCC)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(-c2nc3ccccc3[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in acetonitrile (1.5 ml) was added dropwise very slowly (2 h.) to a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-formyl-phenyl)-acetate (460 mg, 1.305 mmol) obtained in Example 244.1 and 1,2-phenylenediamine in acetonitrile (2 ml). The reaction mixture was stirred for 4 h. at room temperature. Water/saturated Na2CO3 solution (1:1) was added and the mixture was extracted with CH2Cl2. The organic phase was washed with H2O, dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 3:2). There were obtained 173 mg (30%) of ethyl (RS)-[3-(1H-benzoimidazol-2-yl)-5-ethoxy-phenyl]-(4-cyano-phenylamino)-acetate as a colorless solid; MS: 441 ([M+H]+).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12]CC)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1>[OH-].[Na+]>[O:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)c1cnc2ccoc2c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2ccoc2c1
Temperature: 60 °C
Yield: 95 %

Procedure:
A suspension of ethyl furo[3,2-b]pyridine-6-carboxylate (4.5 g, 23.5 mmol) in 1.25M sodium hydroxide (24 mL) was warmed at 60° C. for one hour to give a clear solution. This solution was cooled, filtered through charcoal and made weakly acidic with conc. hydrogen chloride. The precipitated product was extracted into a large volume of diethyl ether/methanol, dried over anhydrous sodium sulfate, filtered and the solvents removed in vacuo. The residue was triturated with ethanol/diethyl ether and collected to give 3.66 g (95% yield), mp: 238°-239° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:28][C:25]([F:26])([F:27])[C:22]1[N:20]2[N:21]=[C:16]([N:12]3[CH2:11][CH2:10][N:9]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=4[CH3:8])[CH2:14][CH2:13]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Product: Cc1cccc(C)c1N1CCN(c2ccc3nnc(C(F)(F)Cl)n3n2)CC1
Yield: 64 %

Procedure:
A mixture of 1-(2,6-dimethylphenyl)piperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-(2,6-dimethylphenyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 64% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=[N:13][C:14](=O)[CH3:15])SC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N)C[NH2:30]>CCCCCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[NH:30][CH2:15][CH2:14][N:13]=1
Reactant: NCCN
Reactant: CSC(=NC(C)=O)Nc1cc(Cl)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCO
Product: Clc1ccc(Cl)c(NC2=NCCN2)c1

Procedure:
2.8 g (0.01 M) of N-(2,5-dichlorophenyl)-N'-acetyl-S-methylisothiourea and 7.0 g (0.03 M) of ethylenediamine mono-p-toluenesulphonate are boiled with 30 ml of n-amyl alcohol for 5 hours. The reaction solution is washed with 50 ml of a saturated solution of sodium carbonate and 50 ml of water. The amyl alcohol is distilled off under vacuum until a dry residue is obtained which after being recrystallized from ethylacetate gives 1.5 g (65% of the theoretical yield of 2-(2',5'-dichlorophenylamino)-imidazoline (2) with a melting point of 179°-182° C. The hydroiodide salt of the above compound has a melting point of 275°-277° C. According to the U.S. Pat. No. 2,899,426 the melting point of 2-(2',5'-dichlorophenylamino)-imidazoline-(2) hydroiodide is 275.4°-277°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:16][C:17]1[C:24]([CH3:25])=[C:23]([CH3:26])[C:22]([CH3:27])=[C:21]([CH3:28])[C:18]=1[CH2:19]Br>CCO>[CH3:19][C:18]1[C:17]([CH3:16])=[C:24]([CH3:25])[C:23]([CH3:26])=[C:22]([CH3:27])[C:21]=1[CH2:28][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: Cc1c(C)c(C)c(CBr)c(C)c1C
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: Cc1c(C)c(C)c(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)c(C)c1C

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 2,3,4,5,6-pentamethylbenzylbromide (0.295 g, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27](Cl)=[O:28]>O>[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:28]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: O=C(Cl)CSCC(F)(F)F
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CSCC(F)(F)F)[C@H]3SC2)s1
Temperature: 25 °C

Procedure:
7-Amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (3.96 g, 14 mmol) was reacted with trifluoroethylmercaptoacetyl chloride in the same manner as described in Example 1. After stirring at room temperature the solution was diluted with water (50 ml), washed with ether (3 × 150 ml), acidified to pH 2 with 3N HCl and extracted with ethyl acetate (3 × 150 ml). The extracts were washed with water dried, and concentrated. The product was collected and converted to its sodium salt by the procedure in Example 1.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22](=[O:27])(=[O:26])[N:23]([CH3:25])[CH3:24])[N:11]([CH2:28][CH2:29][CH2:30][Cl:31])[C:10]=2[CH:9]=1.Cl>C(O)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[S:22](=[O:26])(=[O:27])[N:23]([CH3:24])[CH3:25])[N:11]([CH2:28][CH2:29][CH2:30][Cl:31])[C:10]=2[CH:9]=1
Reactant: C1=COCCC1
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2CCCCl
Agent: Cl
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(OC3CCCCO3)cc1N2CCCCl

Procedure:
15.7 g.) is prepared by reacting dihydropyran (102 g.) with 2-hydroxy-6-dimethylsulphamoyl-10-(3-chloropropyl)-phenothiazine (17.2 g.) in the presence of an 8N solution of hydrogen chloride in ethanol (0.1 cc.).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=4)[CH:19]=3)=[N:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:31](Br)[CH2:32][CH2:33][CH3:34]>C(O)CCC>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH2:31][CH2:32][CH2:33][CH3:34])[CH:24]=4)[CH:19]=3)=[N:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCBr
Reactant: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(O)ccc4c3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCc1ccc(-c2nnc(-c3ccc4cc(OCCCC)ccc4c3)s2)cc1
Yield: 72.8 %

Procedure:
In a 20 ml-round-bottomed flask, 0.30 g (0.77 mM) of 2-(4-hexylphenyl)-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole, 0.08 g (1.21 mM) of potassium hydroxide was 4 ml of n-butanol were placed and dissolved at about 80° C. To the mixture, 0.12 ml (1.12 mM) of n-butyl bromide was added at 80° C. under stirring, followed by refluxing for 4 hours and 10 minutes under stirring. After the reaction, the reaction mixture was cooled on an iced water bath to precipitate a crystal. The crystal was recovered by filtration and washed with methanol. The resultant crystal was dissolved in toluene and washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene-methanol) to obtain 0.25 g of 2-(4-hexylphenyl)-5(6-butoxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 72.8%) ##STR36##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)=[O:4].Cl.[CH2:15]([NH2:17])[CH3:16].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:15]([NH:17][C:8]([C:7]1[CH:11]=[CH:12][N:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1)=[O:10])[CH3:16]
Reactant: COC(=O)c1cc(C(=O)O)ccn1
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccnc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a mixture of 2-(methoxycarbonyl)isonicotinic acid (150 mg, 0.83 mmol), ethylamine hydrochloride salt (203 mg, 2.48 mmol), and diisopropylethylamine (0.72 mL, 4.14 mmol) in DMF is added HBTU (377 mg, 0.99 mmol) at 0° C. After stirring at room temperature for 1 hour, the mixture is poured onto water (30 mL). The aqueous phase is extracted with dichloromethane (30 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (2:1˜1:1) to give 83 mg (48% yield) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[S:21]1[C:29]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]=2[CH:23]=[CH:22]1>CN(C)C=O.C(O)C>[S:21]1[C:29]2[CH2:28][CH2:27][N:26]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[CH:18][CH:19]=5)[O:14][N:13]=4)[CH:7]=3)[CH2:25][C:24]=2[CH:23]=[CH:22]1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Reactant: c1cc2c(s1)CCNC2
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCc2sccc2C1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=408.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])=[O:7].[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(N(CC)CC)C>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]2[S:6]([NH:5][CH2:4][CH2:3][NH:2][S:40]([C:37]1[CH:38]=[CH:39][C:34]([Br:33])=[CH:35][CH:36]=1)(=[O:42])=[O:41])(=[O:8])=[O:7]
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCN)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)NCCNS(=O)(=O)c2ccc(Br)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of the product from Example 89 Step A, was combined with 4-bromobenzenesulfonyl chloride and triethylamine, and stirred at room temperature for 35 minutes. The solvent was removed with a stream of nitrogen to give the titled compound. ESI+ MS: 750 [M+H]+.