Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[N+:19]([O-])=O.[N:22]([O-])=O.[Na+]>ClCCl.C(O)(=O)C.O>[Cl:1][C:2]1[C:3]2[N:19]=[N:22][N:8]([C:9]3[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-n2nnc3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
To a solution of (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine in dichloromethane (8 mL) and 50% aqueous acetic acid (6 mL) was added sodium nitrite (64.6 mg, 0.937 mmol) in water (1 mL) dropwise at room temperature. After the addition was complete, the reaction was stirred for additional 15 minutes at room temperature. The organic layer was then separated, washed with water, and dried over anhydrous magnesium sulfate. Filtration followed by removal of volatiles under high vacuum afforded the desired product as a yellow solid (205 mg, 77.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][N:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]#[C:14][C:16]2[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:24]=[CH:25][N:26]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: C#Cc1cc(OC)c(OC)c(OC)c1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccnc(C#Cc2cc(OC)c(OC)c(OC)c2)c1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
3,4,5-Trimethoxyphenylacetylene (1.80 g), ethyl 2-chloroisonicotinate (2.08 g) and copper iodide (71 mg) were dissolved in a mixed solvent of DMF (4 mL) and triethylamine (8 mL), and to the solution bis-(triphenylphosphine)palladium dichloride (0) (131 mg) was added, and the mixture was stirred at 45° C. for 4 hours under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 to 3:1) to obtain the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.O>CO>[CH3:1][O:2][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCc1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of NaOMe (1.6 g, 29.63 mmol) in dry MeOH (40 mL) under inert atmosphere was added 4-chloromethyl-1-methyl-2-nitro-benzene (5.0 g, 26.94 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and EtOH was removed under reduced pressure. The crude product was extracted with DCM (2 times) and the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgSO4 and concentrated to give intermediate II-l as yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 4.48 (s, 2H), 3.41 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][N:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([CH3:27])=[N:29][CH:30]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cn1

Procedure:
The title compound, yellow solid (66 mg, 59%), MS (ISP) m/z=446.4 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 6-methyl-nicotinic acid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14](=O)[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1C>O>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[N:13]=[C:14]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[CH3:2]
Reactant: CCOCCNc1cnccc1NC(=O)CN1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOCCn1c(CN2CCN(Cc3ccccc3)CC2)nc2ccncc21
Reaction time: 16 h
Yield: 56.1 %

Procedure:
A mixture of 37.8 parts of N-[3-[(2-ethoxyethyl)amino]-4-pyridinyl]-4-(phenylmethyl) -1-piperazineacetamide, 0.1 parts of 4-methylbenzenesulfonic acid and 450 parts of dimethylbenzene was stirred for 16 hours at reflux temperature using a water separator. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (93:7 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 20.2 parts (56.1%) of 3-(2-ethoxyethyl)-2-[[4-(phenylmethyl)-1-piperazinyl]methyl]-3H-imidazo[4,5-c]pyridine as a residue (compound 11).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@:10]([CH3:21])([OH:20])[C@H:9]([OH:22])[C:8]=3[CH:7]=[CH:6][N:5]2[C:23]=1[CH3:24].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].ClCCl.[CH3:38][O:39][CH2:40][CH2:41]O>>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@:10]([CH3:21])([OH:20])[C@@H:9]([O:22][CH2:41][CH2:40][O:39][CH3:38])[C:8]=3[CH:7]=[CH:6][N:5]2[C:23]=1[CH3:24]
Reactant: COCCO
Reactant: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@@](C)(O)[C@@H](c1ccccc1)N3
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@]1(C)O
Temperature: 60 °C
Reaction time: 40 h

Procedure:
A mixture of 0.5 g of (7R,8S,9R)-2,3,8-trimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine and 0.2 ml of conc. sulfuric acid in 10 ml of 2-methoxyethanol is heated at an oil bath temperature of 60° C. for 24 h and then stirred at room temperature for 40 h. The reaction solution is poured into a mixture of 50 ml of saturated aqueous sodium hydrogencarbonate solution and 50 ml of dichloromethane and vigorously stirred. After separating off the organic phase, the aqueous phase is extracted a further three times with 50 ml of dichloromethane each time, the organic phases are combined, the solvent is stripped off in vacuo and the residue obtained is chromatographed on silica gel (eluent: diethyl ether/diethylamine 1/1). 0.3 g of the title compound is obtained as colorless crystals of melting point 1734° C. (diethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1>>[CH3:20][C:18]1[CH:17]=[C:16]([CH3:21])[N:15]=[C:14]([NH:13][C:10](=[O:11])[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:19]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(CC(=O)Nc2cc(C)cc(C)n2)cc1

Procedure:
was prepared from 4-methoxyphenylacetyl chloride and 2-amino-4,6-dimethylpyridine following Method B. 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.73 (s, 1H), 7.24 (d, 2H, J=8.34 Hz), 6.91 (d, 2H, J=8.59 Hz), 6.70(s, 1H), 3.81 (s, 3H), 3.66 (s, 2H), 2.35 (s, 3H), 2.29 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 271, found 271.
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[CH3:11][O:12][CH2:13][CH2:14][CH:15]([CH2:18][CH:19]=[CH2:20])[CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:12][CH2:13][CH2:14][CH:15]([CH2:18][CH:19]=[CH2:20])[CH:16]=[O:17]
Reactant: C=CCC(CO)CCOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCC(C=O)CCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
Dry dimethylsulfoxide (18.4 mL, 260 mmol) in dry CH2Cl2 (30 mL) was added dropwise to a stirred solution of 2M (COCl)2 (65 mL, 130 mmol) at −78° C. during 15 min under nitrogen. The alcohol 4 (15 g, 104 mmol), prepared according to Example 3, in dry dichloromethane (50 mL) was then added during 10 min. resulting in a slightly cloudy solution, which was stirred for 30 min at −78° C. A solution of triethyl amine (75 mL, 520 mmol) in dichloromethane (50 mL) was then added dropwise during 15 min. The mixture was then stirred for 1h at room temperature, and the reaction was quenched by adding water (25 mL), with rapid stirring. The resulting slurry was immediately poured into ether (300 mL) and washed with 20% KHSO4 (2×200 mL). The layers were separated, and the aqueous layer was extracted with ether (2×100 mL). The combined organic layers were washed with brine solution (2×100 mL), dried over MgSO4, filtered, and concentrated to afford the crude aldehyde 5 (12.4 g, 84%) as an oil, which was used in the following condensation with ethylene glycol, IR (KBr) υmax 2951, 2921, 2863, 1720, 1638, 1456, 1379, 1255, 1121, 1033, 997, 909 cm−1; 1HNMR (CDCl3) δ1.73-1.77 (m, 1 H), 1.92-1.96 (m, 1 H), 2.23-2.27 (m, 1 H), 2.42-2.46 (m, 1 H), 2.50-2.52 (m, 1 H), 3.29 (s, 3 H), 3.39-3.43 (m, 2 H), 5.05-5.10 (m, 2 H), 5.72-5.77 (m, 1 H), 9.64 (s, 1 H); 13CNMR (CDCl3) δ28.65, 33.04, 48.57, 58.57, 70.00, 117.40, 134.85; mass spectrum (EI), m/z (rel intensity) 167 (23), 157 (17), 149 (100), 143 (16), 142 (4, M+), 141 (12), 129 (28), 127 (64), 112 (22), 111 (26), 109 (14), 100 (16), 97 (23), 95 (31), 93 (22), 87 (24), 85 (36), 84 (53), 83 (45), 82 (21), 81 (49), 79 (27), 71 (70), 70 (26), 69 (51), 67 (55), 59 (49), 57 (80), 55 (87), 53 (31).
Reaction SMILES: Cl.[Cl:2]C1C=CC([C:9]2[CH:13]=[C:12]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[O:28][CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[NH:11][N:10]=2)=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1C1C=C(C(O)=O)NN=1>>[ClH:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:9]1[CH:13]=[C:12]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C@H:23]3[O:28][CH2:27][CH2:26][NH:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:15])[NH:11][N:10]=1
Reactant: O=C(O)c1cc(-c2ccccc2Cl)n[nH]1
Reactant: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2ccc(Cl)cc2)n[nH]1
Agent: Cl
Product: O=C(Nc1ccc([C@@H]2CNCCO2)cc1)c1cc(-c2ccccc2Cl)n[nH]1

Procedure:
The title compound was prepared in analogy to Example 1 using (R)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (prepared in Example 12) instead of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate and 3-(2-chlorophenyl)-1H-pyrazole-5-carboxylic acid (CAS-890621-13-3) instead of 3-phenyl-1H-pyrazole-5-carboxylic acid. Light brown solid. MS (ISP): 383.1 ([M+H]+).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][N:9]([CH3:24])[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([N:21]([CH3:23])[CH3:22])[C:19]=1[CH3:20])[C:13](OC)=[O:14]>CS(C)=O>[CH3:23][N:21]([CH3:22])[C:18]1[CH:17]=[C:12]([C:13](=[O:14])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:11]=[C:10]([N:9]([CH3:24])[CH3:8])[C:19]=1[CH3:20]
Reactant: COC(=O)c1cc(N(C)C)c(C)c(N(C)C)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(N(C)C)cc(C(=O)CS(C)(=O)=O)cc1N(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 18.8 g. of dimethylsulfone and 3.6 g. of sodium hydride (50% dispersion in oil) in 80 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 2 hours at 50° C. Thereupon, 23.6 g. of methyl 3,5-bis(dimethylamino)-4-methylbenzoate were added and the mixture was stirred at room temperature for 1.5 hours. The solution was diluted with 400 ml. of water and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. After recrystallization of the residue from methanol, there was obtained 3',5' -bis(dimethylamino)-4'-methyl-2-methylsulfonylacetophenone, having a melting point of 161°-163° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10](S(C)(=O)=O)[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[NH:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)N(c1cnccc1C1CC1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cnccc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
A suspension of Example 17E (1.85 g, 6.37 mmol) in tetrahydrofuran (32 mL) was treated with sodium hydroxide solution (1.0 N, 16 mL, 16 mmol) and then stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to remove the tetrahydrofuran and the mixture was diluted with water and cooled to 0° C. The solution was acidified to pH 7 by addition of 1 N aqueous hydrochloric acid solution. The mixture was extracted with dichloromethane (2×) and the combined extracts were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. These procedures afforded the product (1.14 g, 84%) as a light beige solid.
Reaction SMILES: C1(C2CCN(CC[CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])CC2)C=CC=CC=1.O=C1C2C(=CC=CC=2)C(=O)N1CCCCC[N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[C:54]([NH:58][C:59](=[O:63])[CH:60]([CH3:62])[CH3:61])[CH:55]=[CH:56][CH:57]=2)[CH2:48][CH2:47]1>>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][CH2:17][CH2:16][CH2:15][N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[C:54]([NH:58][C:59](=[O:63])[CH:60]([CH3:62])[CH3:61])[CH:55]=[CH:56][CH:57]=2)[CH2:48][CH2:47]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN3C(=O)c4ccccc4C3=O)CC2)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCN1CCC(c2ccccc2)CC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)c1
Yield: 64 %

Procedure:
The synthetic method is the same as described for 2-[6-(4-phenyl-1-piperidinyl)hexyl]-1H-isoindole-1,3(2H)-dione. N-(3-(1-[5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 614 mg (64% yield); 1H NMR (400 MHz, CDCl3) δ 7.87-7.8 (m, 2H), 7.76-7.68 (m, 2H), 7.48 (s, 1H), 7.41 (d, 1H, J=7.6 Hz), 7.21 (t, 1H, J=7.6 Hz), 6.95 (d, 1H, J=7.6 Hz), 3.69 (t, 2H, J=7.2 Hz), 3.39-3.28 (m, 2H), 3.02 (apparent d, 2H, J=11.6 Hz), 2.78 (q, 2H, J=7.2 Hz), 2.64-2.52 (m, 1H), 2.52-2.40 (m, 1H), 2.40-2.31 (m, 2H), 2.01 (dt, 2H, J=3.7, 11.1 Hz), 1.85-1.64 (m, 2H), 1.58 (q, 2H, J=7.6 Hz), 1.45-1.32 (m, 2H), 1.23 (d, 6H, J=6.9 Hz); ESMS m/e: 462.4 (M+H)+; Anal. Calc. for C28H36N3ClO3: C, 67.52; H, 7.29; N, 8.44. Found: C, 67.04; H, 7.06; N, 8.38.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](=[S:21])[NH2:20])=[CH:15]2)(=[O:8])=[O:7].Cl[CH:23]([C:29](=O)[CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(O)C.CN(C)C(=O)C>O>[CH3:30][C:29]1[N:20]=[C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])[S:21][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)nc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.50 g), ethyl 2-chloro-3-oxobutyrate (0.40 mL), ethanol (4 mL) and N,N-dimethylacetamide (4 mL) was stirred at 90° C. overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.47 g, yield 73%) was obtained as pale-yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 226-228° C.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:22])=[O:21]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 0 °C

Procedure:
To 215.2 g (2.72 mole) of pyridine in 1250 ml of dichloromethane is added 238 g (1.44 mole) of ethyl 4-aminobenzoate. After cooling to 0° C., a solution of 177.6 g (1.55 mole) of methanesulfonyl chloride in 250 ml of dichloromethane is added with stirring. Upon completion of the addition, the ice bath is removed and the reaction is stirred for one hour at room temperature.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:35])[C:22]([C:29]4[N:30]=[C:31]([NH2:34])[S:32][CH:33]=4)=[N:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[C:18](=[O:36])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.C([O-])(=O)C.[Na+:41]>CO>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:35])[C:22]([C:29]4[N:30]=[C:31]([NH2:34])[S:32][CH:33]=4)=[N:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[C:18](=[O:36])[N:13]3[C:14]=2[C:15]([O-:17])=[O:16])=[N:5][N:4]=[N:3]1.[Na+:41].[Na+:41].[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:35])[C:22](=[N:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[C:29]4[N:30]=[C:31]([NH2:34])[S:32][CH:33]=4)[C:18](=[O:36])[N:13]3[C:14]=2[C:15]([O-:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1

Procedure:
0.15 g of animal black were added at room temperature to a solution of 1.35 g of the product of Example 4, 9.7 ml of a molar solution of sodium acetate in methanol and 28 ml of methanol containing 10% water and the mixture was stirred and vacuum filtered. The product was rinsed 3 times with 1 ml of methanol containing 10% water and 3 times with 5 ml of methanol. The filtrate was concentrated under reduced pressure at less than 30° C. to a volume of 10 ml and 50 ml of ethanol were slowly added thereto at 20°-25° C. The suspension was stirred for 15 minutes at room temperature and was vacuum filtered. The product was rinsed 3 times with 5 ml of ethanol and 3 times with 10 ml of ether and was dried under reduced pressure to obtain 1.05 g of the syn isomer of disodium 3-[(1-methyl-tetrazol-5-yl)-thiomethyl]-7-[2-(2-amino-4-thiazolyl)-2-(carboxymethyloxyimino)-acetamido]-ceph-3-eme-4-carboxylate with a specific rotation of [α]D20 =-16.5°±1° (c=1% in water).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:24]([C:20]1[N:21]=[CH:22][N:23]=[C:18]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:19]=1)(=[O:25])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1ccccc1)c1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
0.20 g (0.67 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.15 g (0.33 mmol) (6-chloro-pyrimidin-4-yl)-phenyl-methanone and 0.20 mL (1.1 mmol) DIPEA in 3 mL DMF were heated to 80° C. for 1 h. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([F:19])=[C:17]2[C:12]([C:13]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([F:28])[C:14]=3[C:15](=O)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC(OCC)=C(F)C=1.COCCOC.[BH4-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:18]([F:19])=[C:17]2[C:12]([C:13]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[C:21]([F:28])[C:14]=3[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc2c(c1F)c(=O)oc1c(F)c(OCc3ccccc3)ccc12
Agent: CCOc1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCOc1ccc2c(c1F)COc1c-2ccc(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
2.00 g (5.24 mmol) of 3-benzyloxy-8-ethoxy-4,7-difluoro-6H-benzo[c]chromen-6-one, the compound of Example 841, were dissolved in 12 ml of THF, and 2.37 ml (23.0 mmol) of boron trifluoride/THF complex were added with ice-cooling. 24 ml of ethylene glycol dimethyl ether and then in portions 530 mg of sodium borohydride were subsequently added. The mixture was subsequently stirred at room temperature for 18 hours and then transferred onto ice. The mixture was subjected to conventional purification, giving 1.5 g (78% of theory) of 3-benzyloxy-8-ethoxy-4,7-difluoro-6H-benzo[c]chromene as colourless crystals. These were dissolved in THF, hydrogenated at a pressure of 1 bar in the presence of 0.6 g of Pd/C (5%), filtered and evaporated, giving 1.2 g (99% of theory) of 8-ethoxy-4,7-difluoro-3-hydroxy-6H-benzo[c]chromene as colourless crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:23][N:24]([CH3:32])/[CH:25]=[CH:26]\[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1(C)C=CC=CC=1.O>[CH3:23][N:24]([CH3:32])/[CH:25]=[C:26](/[C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[F:1])\[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)/C=C\N(C)C
Reactant: O=C(O)c1cc(I)ccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Temperature: 25 °C
Yield: 85.1 %

Procedure:
2-Fluoro-5-iodobenzoic acid (5.20 g, 19.55 mmol, Aldrich) was suspended in thionyl chloride (1.427 mL, 19.55 mmol, Aldrich) and heated to reflux for 30 min The reaction mixture was cooled to room temperature and concentrated under reduced pressure to a tan solid. The solid was dissolved in toluene (30 mL) and concentrated under reduced pressure again. To a solution of the resulting solid (5.20 g, 19.55 mmol) in toluene (30 mL) was added triethylamine(2.72 mL, 19.55 mmol, Acros) and (Z)-ethyl 3-(dimethylamino)acrylate (3.64 mL, 25.41 mmol, Acros) and the reaction mixture was heated to 90° C. for 1 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by Isco column (0%-100% ethyl acetate/dichloromethane) afforded the desired compound as a yellow solid (6.51 g).