Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)CC(=O)C.[NH2:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1/[C:25](=[CH:27]/[CH:28]([CH3:30])[CH3:29])/[CH3:26].NC1C=CSC=1/C(=C\C(C)C)/C>>[NH2:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH2:26]
Reactant: C/C(=C\C(C)C)c1sccc1N
Agent: C/C(=C/C(C)C)c1sccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)CC(C)C
Product: C=C(CC(C)C)c1sccc1N
Temperature: 25 °C
Yield: 19 %

Procedure:
Into a solution obtained by dissolving 3-aminothiophene (2.5 g, 25.2 mmol) in toluene (85.0 g), which was obtained by the method in Example 1 using methyl 3-aminothiophene-2-carboxylate as a starting material were added p-toluenesulfonic acid (0.2 g, 1.1 mmol) and 4-methyl-2-pentanone (100.0 g, 998.4 mmol) at room temperature, and the resulting solution was stirred under reflux under nitrogen atmosphere for 2 hours. The reaction solution was cooled to room temperature, and then washed with a 10% aqueous sodium hydroxide solution two times, and the obtained organic layer was concentrated under reduced pressure to give an oily substance. The resulting concentrate was purified by silica gel column chromatography to give 0.9 g of an oily substance as a mixture of three compounds including 3-amino-2-{(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-amino-2-{(Z)-(4-methyl-2-penten-2-yl)}thiophene and 3-amino-2-(4-methyl-1-penten-2-yl)thiophene (yield: 19%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].C(N(CC)CC)C.Cl.[I:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>C(#N)C>[I:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH:27][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: NCc1cccc(I)c1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(NC(=S)NCc2cccc(I)c2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 4-isothiocyanatobenzenesulfonamide (378 mg, 1.76 mmol) in dry acetonitrile (10 mL) and triethylamine (0.3 mL, 4.0 mmol) was added 3-iodobenzylamine hydrochloride salt (476 mg, 1.76 mmol). The reaction mixture became warm and a clear solution resulted. After stirring for 2 h the reaction was concentrated and the crude solid recrystallized from methanol/water to afford a white solid. The solid was filtered and washed with hexanes to afford the desired product MIP-1139 (715 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (br, 1H), 8.48 (br, 1H), 7.74-7.61 (m, 5H), 7.36-7.12 (m, 3H), 4.70 (m, 2H); (M+H)+ (448).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:21][C:22]1[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C)C=O>[C:29]1(/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][S:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=3)[N:23]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)CCc1ccc(S)cc1
Reactant: ClCc1coc(/C=C/c2ccccc2)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)CCc1ccc(SCc2coc(/C=C/c3ccccc3)n2)cc1
Reaction time: 2.5 h
Yield: 83.3 %

Procedure:
To a solution of 3-(4-mercaptophenyl)propionic acid (2.0 g) and triethylamine (2.23 g) in N,N-dimethylformamide (50 ml) was added dropwise a solution of 4-chloromethyl-2-[(E)-2-phenyl ethenyl]oxazole (2.20 g) in N,N-dimethylformamide (10 ml) at 0° C. and then stirred for 2.5 hours. To the reaction mixture was added water, and extracted with diethyl ether. The water layer was made acidic with concentrated hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure to give crystals of 3-[4-[2-[(E)-2-phenyl ethenyl]-4-oxazolylmethylthio]phenyl]propionic acid (3.05 g, 84%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 120-121° C.
Reaction SMILES: Br[CH:2]=[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[NH:37][C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1>CN(C=O)C.[Cu]I>[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[N:37](/[CH:2]=[C:3](/[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)\[C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1
Reactant: BrC=C(c1ccccc1)c1ccncc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2/C=C(/c2ccccc2)c2ccncc2)CCN(C)C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-(2-Bromo-1-phenylvinyl)pyridine (310 mg, 1.1 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude product was purified on silica gel (100-200 mesh) using 0-10% MeOH:DCM as eluent. The compound was further purified through reverse phase HPLC. Yield: 28 mg. 1H NMR (CD3OD, free base) δ (ppm): 8.40 (d, 2H), 7.39 (m, 3H), 7.32 (d, 2H), 7.16 (s, 1H), 7.10 (s, 1H), 6.90 (m, 4H), 3.62 (s, 2H), 2.68 (m, 2H), 2.50 (m, 5H), 2.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][N:7]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>O1CCCC1>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:35])[CH:9]=2)=[CH:6][N:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc(-c2cccc(NC(=O)c3ccc(OC)cc3)c2)cnc1N
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 3-amino-6-(3-aminophenyl)-N-methylpyrazine-2-carboxamide (20 mg, 0.07 mmol) and triethylamine (160 mg, 0.16 mmol) in tetrahydrofuran (1 mL) was added p-anisoyl chloride (20 mg, 0.12 mmol) slowly at room temperature. The mixture was allowed to stir overnight. The reaction was quenched with water (10 mL) at 0° C. and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (30 mL), saturated aqueous sodium chloride, and dried over magnesium sulfate. The solution was filtered and concentrated at reduced pressure to afford 3-amino-N-methyl-6-[3-({[4-(methyloxy)phenyl]carbonyl}amino)phenyl]pyrazine-2-carboxamide (13 mg, 48% yield) as yellow solid. 1H NMR (400 MHz, d6-DMSO): 10.10 (s, 1H), 8.85 (s, 2H), 8.30 (s, 1H), 8.02 (d, 2H), 7.90 (m, 2H), 7.40 (m, 1H), 7.02 (d, 2H), 3.80 (s, 3H), 2.82 (br s, 3H); MS (EI) for C20H19N5O3: 378 (MH+).
Reaction SMILES: C(S(N[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[N:11](CCCCN1CC=C(C3C=CC=CC=3)CC1)[C:10]2=[O:34])(=O)=O)C.[S:35](=[O:39])(=[O:38])([OH:37])[OH:36]>CO.C(Cl)(Cl)Cl>[S:35]([OH:39])([OH:38])(=[O:37])=[O:36].[NH:13]1[C:14]2[CH:9]([CH2:8][CH2:7][CH2:16][CH:15]=2)[C:10](=[O:34])[NH:11][C:12]1=[O:17]
Reactant: CCS(=O)(=O)Nc1ccc2[nH]c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)c2c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1NC(=O)C2CCCC=C2N1
Yield: 175 %

Procedure:
To a solution of 6-ethylsulfonylamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (40.9 g) in 10% methanol in chloroform (800 ml) was added a solution of sulfuric acid (10.1 g) in methanol (100 ml) over 15 minutes at 25° C. After evaporation of the solvent, the crystalline residue was recrystallized from 10% water in acetonitrile (600 ml) to give 6-ethylsulfonylamino-3-[4-(4-phenyl-1,2,3,6=tetrahydropyridin-1-yl)butyl]-1,2,3,4=tetrahydroquinazoline-2,4-dione sulfate (39.2 g) as pale brown crystals.
Reaction SMILES: [CH:1]1([C:7]2[CH:13]=[CH:12][C:10]([OH:11])=[CH:9][C:8]=2[OH:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[OH-].[Na+].[Ni]>[O:14]=[C:8]1[CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:12][C:10](=[O:11])[CH2:9]1
Reactant: Oc1ccc(C2CCCCC2)c(O)c1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCC(C2CCCCC2)C(=O)C1
Yield: 63.8 %

Procedure:
20.0 g (0.104 mol) of 4-cyclohexylresorcinol are dissolved in 40 ml of ten percent strength sodium hydroxide solution and are hydrogenated in the presence of 5 g of Raney nickel in an autoclave at 90° under 20 bar for 5 hours. The reaction mixture is rinsed out of the autoclave with alcohol. After removal of the catalyst, 100 ml of 90 percent strength acetic acid are slowly added to the solution. After addition of water, the reaction product crystallises out. It is dried in vacuo over NaOH. 12.9 g of 1,3-dioxo-6-cyclohexyl-cyclohexane of melting point 137°-140° C. are obtained. After recrystallisation from ethyl acetate, the product has a melting point of 142°-144° C. (literature). Yield: 11.1 g (=55%).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:11][C:12]1[C:17]([C:18]([C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=O)=[CH:16][C:15]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)=[CH:14][N:13]=1>C1COCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:15]2[CH:16]=[C:17]3[C:18]([C:20]4[CH:25]=[CH:24][C:23]([NH2:26])=[N:22][CH:21]=4)=[CH:1][NH:11][C:12]3=[N:13][CH:14]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: COc1ccc(-c2cnc(N)c(C(=O)c3ccc(N)nc3)c2)cc1OC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3[nH]cc(-c4ccc(N)nc4)c3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To a suspension of(methoxymethyl)triphenylphosphonium chloride (166 mg, 0.485 mmol) in THF (1 ml) at 0° C. under nitrogen was added potassium bis(trimethylsilyl)amide (97 mg, 0.485 mmol). The mixture was stirred at room temperature for 30 min, then it was added to [2-amino-5-(3,4-dimethoxy-phenyl)-pyridin-3-yl]-(6-amino-pyridin-3-yl)-methanone (34 mg, 0.097 mmol) in one portion. The reaction mixture was stirred for 2 hours, then quenched with wet methanol and concentrated in vacuo. The crude was diluted with 2 ml of 1,4-dioxane and treated with 0.1 ml of aqueous 70% perchloric acid. The mixture was stirred at 80° C. for 19 hours, diluted with THF/methanol (1:1), and treated with 2.0 g of PS-trisamine (Argonaut Technologies, 4 equivalents per equivalent of acid used) for 30 minutes. The resin was filtered off and washed with THF/MeOH (1:1). Purification was accomplished by flash chromotography on silica gel with a gradient of methanol/dichloromethane afforded 5-[5-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyridin-2-ylamine as a yellow solid (9.7 mg, 29% yield). 1H NMR (DMSO-d6): δ 11.8 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 7.77 (dd, J=2.0, 10.0 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.24 (dd, J=2.0, 7.5 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.55 (d, J=8.5 Hz, 1H), 5.90 (broad s, 2H), 3.86 (s, 3H), 3.79 (s, 3H). HPLC/MS m/z: 347.1 [MH]+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:12]([Cl:13])=[C:11]([C:14]2[N:19]=[C:18](S)[N:17]([CH3:21])[C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][N:8]=1>CN(C)C=O>[Cl:3][C:18]1[N:17]([CH3:21])[C:16](=[O:22])[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([Cl:6])[C:12]=2[Cl:13])[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(S)nc(-c2ccnc(Cl)c2Cl)cc1=O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccnc(Cl)c2Cl)cc1=O
Temperature: 60 °C
Yield: 72.2 %

Procedure:
After one hour stirring of a solution of phosphorus oxychloride (2.9 g, 18.9 mmol) in dimethylformamide (30 ml) at room temperature, 6-(2,3-dichloropyridin-4-yl)-2-mercapto-3-methyl-3H-pyrimidin-4-one (3.58 g, 12.4 mmol) was added and heated at 60° C. for 2 hours. The resulting suspension was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was washed by hexane to furnish 2-chloro-6-(2,3-dichloropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (2.6 g, 8.95 mmol, 72%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9](O)[CH2:10][CH3:11])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=1)[CH2:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCC(O)c1ccc(OC)nc1
Solvent: ClCCl
Product: CCC(Cl)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a stirred solution of 1-(6-methoxypyridin-3-yl)propan-1-ol (1.67 g, 9.99 mmol) in dichloromethane (30 mL) at 0° C. was added thionyl chloride (2.46 g, 1.5 mL, 20.68 mmol). The cooling bath was removed, and the mixture was allowed to warm to room temperature. After 1 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution. The phases were separated, and the organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to provide 1.50 g (81%) of 5-(1-chloropropyl)-2-methoxypyridine as a yellow oil.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4]Cl.[CH:6]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH:6]1([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:4][CH:2]3[CH2:1][O:3]3)=[CH:16][CH:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: c1cc(C2CCCCC2)ccc1OCC1CO1

Procedure:
To a mixture of R-epichlorohydrin (9.8 g, 106 mmol) and 4-cyclohexylphenol (3.73 g, 21.2 mmol) in acetonitrile (40 ml) was added cesium carbonate (6.9 g, 21.2 mmol). The mixture was heated at reflux for 3 hours. The reaction mixture was cooled, poured into water (100 mL) and extracted twice with EtOAc. The organic phases were combined and washed with water, brine, dried (Na2SO4), concentrated and dried under high vacuum overnight to give the title compound.
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15])([CH3:10])[CH3:9].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br-:1].[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=2)=[O:15])([CH3:9])[CH3:10])=[O:41])=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: C[N+](C)(CCCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Br-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[N+](C)(CCCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A solution of (5-amino-pentyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate O) (1.0 g, 2.35 mmol), 4-benzyloxy phenyl acetic acid (0.57 g, 2.35 mmol), N-methylmorpholine (1.0 mL, 9.09 mmol), DCC (0.49 g, 2.35 mmol) and HOBt (0.32 g, 2.36 mmol) in DMF (20 mL) is stirred at RT for 1 h. The reaction mixture is concentrated in vacuo, and the residue is purified by column chromatography (basic alumina, 0-4% methanol in DCM) to afford a brown solid which is crystallised from methanol and EtOAc to afford the title compound. M+ 568.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([OH:11])=O)=[O:7])=[CH:2]1.[NH2:12][CH:13]1[C:27](=[O:28])[N:15]2[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][N:21]=[N+:22]=[N-:23])[CH2:18][S:19][C@H:14]12>>[S:1]1[CH:5]=[CH:4][C:3]([S:6]([CH2:8][C:9]([NH:12][CH:13]2[C:27](=[O:28])[N:15]3[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][N:21]=[N+:22]=[N-:23])[CH2:18][S:19][C@H:14]23)=[O:11])=[O:7])=[CH:2]1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CS(=O)c1ccsc1
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)c3ccsc3)[C@H]2SC1

Procedure:
380 mg. of 3-thienylsulfinylacetic acid of the R form and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 410 mg. of 7-(3-thienylsulfinylacetamido)-3-azidomethyl-3-cephem-4-carboxylic acid of the R form were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.Cl>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(CSc1cccc(OC)c1)c1ccc(OC)cc1
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(C(CSc2cccc(OC)c2)C(=O)O)cc1
Yield: 91.4 %

Procedure:
To acetone solution(300 ml) of ethyl 2-(4-methoxyphenyl)-3-(3-methoxyphenylthio)propionate (3) (30.2 g, 87.3 mmol) obtained above was added aqueous 6N--HCl solution (200 ml) and then heated under refluxing for 60 hours. The reaction solution was extracted with ether, and the organic layer was alkalized with aqueous 20% NaOH solution. Then the aqueous layer was separated, acidified with 20% HCl solution and extracted with ether. The ether layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent to obtain 25.4 g (yield: 91%) of 2-(4-methoxyphenyl)-3-(3-methoxyphenylthio)propionic acid (4).
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:16][CH2:2][CH2:3][CH3:4])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1ccc(Cl)cc1C(=O)OC
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A mixture of 1-bromo-propane (1 ml, 11 mmol), methyl 5-chloro-2-hydroxy-benzoate (1.0 g, 5.4 mmol), potassium carbonate (1.5 g, 10.9 mmol), and acetonitrile (20 ml) was heated under reflux for 4 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium chloride solution (50 ml). The organic layer was concentrated under reduced pressure to provide methyl 5-chloro-2-propoxy-benzoate (1.2 g, 97% yield).
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].CN([CH2:9][C:10]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][CH:11]=1)C.COS(OC)(=O)=O>CCO>[N+:19]([C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][CH:17]=1)[NH:12][CH:11]=[C:10]2[CH2:9][CH:4]([N+:1]([O-:3])=[O:2])[CH3:5])([O-:21])=[O:20]
Reactant: CC[N+](=O)[O-]
Reactant: CN(C)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Solvent: COS(=O)(=O)OC
Solvent: CCO
Product: CC(Cc1c[nH]c2ccc([N+](=O)[O-])cc12)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of 0.3 g (0.013 mole) of Na in 65 ml of abs EtOH was added 2.93 g (0.039 mole) of nitroethane dropwise. To the white suspension was added 2.19 g (0.01 mole) of 5-nitrogramine suspended in 40 ml of abs EtOH, followed by 2.5 g (0.02 mole) of dimethylsulfate in 20 ml of abs EtOH dropwise over 15 minutes. The mixture was stirred for 2 hours, then poured into 350 ml of ice water. The yellow solid was filtered, washed with ice water and air-dried to give 1.63 g (64%) of product: m.p. 130-131.5.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1.N>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)=[CH:14][CH:13]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccc(Cl)cc1
Agent: N
Product: Clc1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-chloro-4-ethynylbenzene (Aldrich, 68 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.62-7.75 (m, 3H), 7.79 (s, 1H), 7.89-8.01 (m, 2H), 8.40 (dt, J=8.1, 1.7 Hz, 1H), 8.78 (dd, J=5.1, 1.4 Hz, 1H), 9.16 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+, 257 (M+H)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([Cl:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[C:22]([Cl:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12](=[O:15])[CH2:13]Br)[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1cc(Cl)ccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40 %

Procedure:
A solution of 4-chloro-2-(bromoacetamido)benzoic acid from Example 40 (6.5 g, 0.02 mol), aniline (5.2 mL, 250 mol %) and anhydrous DMF (50 mL) was heated to 100°-105° C. for 4h, and stirred at rt for 20h. The reaction mixture was poured into ice-water (400 mL) and the precipitated product was solubilized by adding aqueous 5% KOH (60 mL). The resulting milky homogenous solution was extracted with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were set aside and the aqueous layer was acidified with aqueous 5% HBr to pH=3. The resulting oil was extracted into EtOAc (3×100 mL) and the combined extract was washed with brine, dried, filtered and concentrated. Trituration of the resulting solid with diethyl ether afforded 4.5 g (66%) of the crude title compound as light-beige crystals, mp 177.8°-180° C. The crude compound (4.5 g) was stirred with EtOAc (~100 mL) and the resulting insoluble portion was filtered off. The filtrate was concentrated to a light-beige solid which was refluxed with benzene (80 mL) for 40 min. The bnenzene mixture was filtered while hot and the filtered solid was dried for 4 h under high vacuum, yielding 2.75 g (40%) of the title compound as light crystals, mp 229°-230° C. (became "wet" at 227° C.); 1H NMR (DMSO-d6) δ 13.6 (bs, 1H), 12.11 (s, 1H), 8.82 (d, J=1.6, 1H), 7.93 (d, J=8.8, 1H), 720 (dd, J=6.0, J=2.6, 1H), 7.10 (t, J=7.6, 2H) 6.63-6.58 (m, 4H), 3.85 (s, 2H); 13C NMR (DMSO-d6)δ 171.48, 168.31, 148.01, 141.53, 138.58, 132.86, 128.97, 128.30, 122.61, 118.72, 118.67, 117.16, 114.68, 112.45, 48.89.