Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:24](P(=O)(OCC)OCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(C)=O.CC(C)([O-])C.[K+]>O>[Br:1][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Brc1c2ccccc2c(-c2ccc(C=Cc3ccccc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 85.6 %

Procedure:
Under an atmosphere of argon, 9-bromo-10-(4-formylphenyl)-anthracene (3.9 g, 11 mmole) and diethyl benzylphosphonate (3 g, 13 mmole, 1.2 eq) were suspended into DMSO (25 ml). To the resultant suspension, potassium t-butoxide (1.6 g, 14 mmole, 1.1 eq) was added and the obtained mixture was stirred at the room temperature for 10 hours and left standing for one night. The reaction mixture was diluted with water (50 ml) and subjected to extraction with toluene (300 ml). The organic layer was washed with water (50 ml) and a saturated aqueous solution of sodium chloride (50 ml) and dried with magnesium sulfate. Then, the solvent was removed by distillation and a yellow solid was obtained. The obtained solid was purified by recrystallization from toluene (40 ml) and yellow needle crystals (4.1 g, 86%) were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][C:40]([O:46][CH2:47][CH2:48][N:49]4[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]4)=[CH:41][CH:42]=3)[CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:37]=[C:38]3[C:43]([CH:42]=[CH:41][C:40]([O:46][CH2:47][CH2:48][N:49]4[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]4)=[CH:39]3)=[CH:44][CH:45]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3ccc(OCCN4CCN(C)CC4)cc3c2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3ccc(OCCN4CCN(C)CC4)cc3c2)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A solution of 9.15 g (12.14 mmol) (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-naphthalen-2-ylmethoxy]-piperidine-1-carboxylic acid tert-butylester in 250 ml of methanol was treated at room temperature with 36.41 ml of a 2.0 M solution of hydrogen chloride in methanol and the mixture was stirred at 50° C. for 4 hours. Subsequently, the solution was evaporated under reduced pressure and the residue was partitioned between 200 ml of saturated sodium carbonate solution and 150 ml of methylene chloride. The aqueous phase was again extracted twice with 100 ml of methylene chloride; thereafter the organic phases were combined, dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 90:10 mixture of methylene chloride and methanol as the eluent resulting in 5.25 g (66% of theory) of 1-[2-[7-[(3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]-naphthalen-2-yloxy]-ethyl]-4-methyl-piperazine as an amorphous, colourless solid; MS: 654 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)OCc2ccccc2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C. and benzyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-benzyloxycarbonyloxy-2(1H)-primidinone as the residue.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([NH2:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)OCC1.ClC1N2N=CC=C2N=C(C2CCCC3([O:37][CH2:36][CH2:35][O:34]3)C2)C=1.ClC1N2N=CC=C2N=C(C2CCC3(OCCO3)CC2)C=1>>[O:34]1[C:6]2([CH2:5][CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([NH2:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7]2)[O:37][CH2:36][CH2:35]1
Reactant: Clc1cc(C2CCCC3(C2)OCCO3)nc2ccnn12
Reactant: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: Nc1cc(C2CCCC3(C2)OCCO3)nc2ccnn12

Procedure:
5-(1,4-Dioxaspiro[4.5]decan-7-yl)pyrazolo[1,5-a]pyrimidin-7-amine is synthesized in a manner similar to the synthesis of 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine, but with 7-chloro-5-(1,4-dioxaspiro[4.5]decan-7-yl)pyrazolo[1,5-a]pyrimidine substituted for 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([CH3:18])[CH2:4][CH2:3]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:18][C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][N:6]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: C[C@@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[C@@H]1CCC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Benzyl (2R,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate (6.8 g, 27.3 mmol) was dissolved in DCM (100 mL) containing crushed molecular sieves. N-methylmorpholine N-oxide (4.15 g, 35.5 mmol) and tetrapropylammonium perruthenate (0.48 g, 1.36 mmol) were added, and the reaction was stirred at room temperature for 1.5 hours. The mixture was filtered through a celite pad and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate/hexanes, linear gradient) to afford benzyl (2R)-2-methyl-5-oxopiperidine-1-carboxylate. MS ESI calc'd. for C14H17NO3 [M+H]+ 248. found 248.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:17][CH3:18])=[CH:11][CH:10]=1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:17][CH3:18])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=1
Reactant: CCCN(CCC)CCCCN(CC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCN(CCC)CCCCN(CC)Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
The compound (311 mg) obtained in Example 23-5 was dissolved in anhydrous methanol (1.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (3.0 ml) and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution, subjected to extraction with chloroform, and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (219 mg) as a pale-yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[N+:25]([O-])=O>CO.[C].[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[NH2:25]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c(-c2ccc(O)c([N+](=O)[O-])c2)cc1=O
Agent: [Pd]
Solvent: CO
Product: Nc1cc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)ccc1O
Reaction time: 2 h
Yield: 97.9 %

Procedure:
In 10 ml of methanol was dissolved 0.5 g of 6-(4-hydroxy-3-nitrophenyl)-4-oxo-1-(4-fluorophenyl)-1,4-dihydronicotinic acid, and to this solution was added 0.1 g of 5% by weight palladium carbon. The said acid was hydrogenated under atmospheric pressure for 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 0.45 g of 6-(4-hydroxy-3-aminophenyl)-4-oxo-1-(4-fluorophenyl)-1,4-dihydronicotinic acid having a melting point of 231°-233° C.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[C:12]([Cu])#[N:13]>>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1)#[N:13]
Reactant: Cc1cnc(Br)c([N+](=O)[O-])c1
Reactant: N#C[Cu]
Product: Cc1cnc(C#N)c([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 79.3 %

Procedure:
A round bottom flask was charged with 2-bromo-5-methyl-3-nitropyridine (60.53 g, 278.9 mmol) and CuCN (27.52 g, 307.3 mmol) The flask was evacuated, and back-filled with nitrogen. DMF (150 mL) was added via cannula. The solution was heated to 70° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into EtOAc (500 mL) and water (250 mL). Both phases were filtered through a 1 cm bed of celite. The layers were separated, and the organic phase washed with water (2×100 mL) then with a solution of 1:1 sat. aq. NH4Cl/NH4OH (2×100 mL). The combined aqueous layers were extracted with EtOAc (2×200 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (36.10 g, 79% yield).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31](=[O:39])[NH:32][S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21](OC)=[O:22])=[CH:18][C:17]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH3:42][N:43]([CH3:48])[CH2:44][CH2:45][NH:46][CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.Cl.C(N(CC)CC)C.CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([NH:32][S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[O:39])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:46]([CH2:45][CH2:44][N:43]([CH3:48])[CH3:42])[CH3:47])=[O:22])=[CH:18][C:17]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNCCN(C)C
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N(C)C)cc3n2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)N(C)CCN(C)C)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 80 °C
Yield: 121.6 %

Procedure:
Methyl 13-cyclohexyl-10-(((dimethylamino)sulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (700 mg, 1.27 mmol) was dissolved into MeOH//THF (1:1, 14 mL) and treated with 1M aqueous NaOH (3 mL). The reaction mixture was stirred and heated at 80° C. with microwave irradiation for 15 min and cooled to rt. The clear solution was neutralized with 1M aqueous HCl (3 mL) and concentrated to remove organic solvents. The residue was stirred with H2O (10 mL) for 1 h and the resultant solids were collected by filtration, washed with H2O and dried under vacuum. To a solution of these solids, N1,N1,N2-trimethylethane-1,2-diamine (191 mg, 1.88 mmol) and triethylamine (0.700 mL) in DMF (5 mL) was added HATU (620 mg, 1.63 mmol). The reaction mixture was stirred at rt for 1 h, diluted with H2O (25 mL) and 1M HCl (aq.) (5 mL) and stirred 20 The precipitates were collected by filtration, rinsed with H2O and dried to yield impure 13-cyclohexyl-N6-(2-(dimethylamino)ethyl)-N10-((dimethylamino)sulfonyl)-3-methoxy-N6-methyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide (960 mg) as a yellow powder. A crude sample of 13-cyclohexyl-N6-(2-(dimethylamino)ethyl)-N10-((dimethylamino)sulfonyl)-3-methoxy-N6-methyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide (100 mg) was dissolved into MeOH/DMF (3:1, 4 mL), filtered and purified by preparative HPLC (H2O/CH3CN with 10 mM NH4OAc buffer) to yield 13-cyclohexyl-N6-(2-(dimethylamino)ethyl)-N10-((dimethylamino)sulfonyl)-3-methoxy-N6-methyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide (78 mg, 0.13 mmol, 95%) 1HNMR (300 MHz, CD3OD) δ 1.11-3.07 (m, 24H), 2.99 (s, 6H), 3.50-3.76 (m, 2H), 3.93 (s, 3H), 4.27-4.44 (m, 1H), 5.05-5.25 (m, 1H), 7.05 (s, 1H) 7.08 (d, J=2.6 Hz, 1H), 7.16 (dd, J=8.8, 2.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.64 (dd, J=8.8, 1.5 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 8.16 (br s, 1H). LCMS: m/e 620 (M−H)−, ret time 2.32 min, column A, 4 minute gradient.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C1COCC1>[C:21]([O:24][CH2:25][C:26](=[O:27])[CH2:9][C:4]1[O:3][C:2]([CH3:10])([CH3:1])[O:7][C:6](=[O:8])[CH:5]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)CC1=CC(=O)OC(C)(C)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (20 g, 141 mmol) in dry THF (400 mL) was cooled to −78° C. To this solution was slowly added a LiHMDS (1M-THF, 160 mL, 160 mmol). The resulting solution was maintained at −78° C. with stirring for 30 min. To the reaction mixture was added acetoxy acetylchloride (17 mL, 160 mmol) and the resulting mixture was maintained at −78° C. for at 1 h. The reaction was then allowed to slowly warm to rt and stir for an additional 1 h. The reaction was then quenched with addition of a 1N solution of ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate (5×). The organics were combined, dried, and concentrated in vacuo. The crude product was purified using a medium pressure liquid chromatography biotage system. Elution with hexanes-ethyl acetate (3:1) gave 13.1 g (38%) of a red-brown oil. The product looks clean by NMR. 1H NMR (300 MHz, CDCl3) δ 5.42 (s, 1H), 4.75 (s, 2H), 3.41 (s, 2H), 2.22 (s, 3H), 1.75 (s, 6H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)\[CH:8]([CH3:10])[CH3:9].[OH-].[Na+]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[C:7](/[CH:8]([CH3:10])[CH3:9])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)/C=C/C=C(/c1ccc(OC)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C/C=C/C(=O)O)C(C)C)cc1
Yield: 74 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-6-methyl -2,4-heptadienoic acid methyl ester (4 g) was saponified in a refluxing mixture of methanol (15 mL) and 2N NaOH (15 mL). After 2 hours reaction was worked up in the usual way and the crude acid was crystallized from cyclohexane-hexane to provide 2.8 g of (E,E)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid, mp 140.5°-141.5° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(OC([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)=O)(C)(C)C>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:19]3[CH2:26][CH:25]4[CH:21]([CH2:22][NH:23][CH2:24]4)[CH2:20]3)[S:3][C:4]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Clc1ccc2nc(Cl)sc2c1
Product: Clc1ccc2nc(N3CC4CNCC4C3)sc2c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 23 utilizing 2,6-dichloro-benzothiazole and hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester as starting materials.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:15])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]([OH:14])=O.C[Si](Cl)(C)C.S(Cl)(Cl)=O.[NH2:25][CH2:26][C:27]1[CH2:28][S:29][C@@H:30]2[CH:37]([NH:38][C:39](=[O:55])/[C:40](/[C:49]3[N:50]=[C:51]([NH2:54])[S:52][CH:53]=3)=[N:41]\[O:42][C:43]([C:46]([OH:48])=[O:47])([CH3:45])[CH3:44])[C:36](=[O:56])[N:31]2[C:32]=1[C:33]([OH:35])=[O:34]>C(Cl)(Cl)Cl.CO.O.C(N(CC)CC)C>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:40](=[N:41]/[O:42][C:43]([C:46]([OH:48])=[O:47])([CH3:45])[CH3:44])/[C:39]([NH:38][CH:37]2[C:36](=[O:56])[N:31]3[C:32]([C:33]([OH:35])=[O:34])=[C:27]([CH2:26][NH:25][C:12]([C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:5]=4[N:4]=[C:3]([OH:15])[C:2]([OH:1])=[CH:11]5)=[O:14])[CH2:28][S:29][C@H:30]23)=[O:55])[N:50]=1
Reactant: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1)C(=O)O
Reactant: O=C(O)c1cccc2cc(O)c(=O)[nH]c12
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CNC(=O)c3cccc4cc(O)c(O)nc34)CS[C@H]12)c1csc(N)n1)C(=O)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of 3-hydroxy-8-carboxy-2(1H)-quinolinone (160 mg) in chloroform (15 ml) was added triethylamine (0.62 ml) and speedily trimethylsilyl chloride (0.57 ml). The mixture was heated to 60° C. for 4 hours, cooled to 0° C. and treated with triethylamine (0.114 ml) and thionyl chloride (0.06 ml), whereupon the resultant solution was stirred for 2 hours at 0° C. and at room temperature for 30 minutes. This solution was added to 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (360 mg) in methanol (30 ml) containing triethylamine (0.42 ml) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C., stirred for 30 minutes at room temperature, diluted with water, acidified to pH2, concentrated, and purified by chromatography (HP20SS resin eluting with methanol/water/acetic acid) to give the title compound (85 mg); NMR (DMSO-d6 /CD3COOD/CF3COOD) 1.50(s,6H); 3.55(m,2H); 4.40(m,2H); 5.1(d,1H); 5.75(d,1H); 7.00-7.25(,3H); 7.6(d,1H); 7.80(d,1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]([C:11]#[N:12])[CH2:9][N:10]=2)[CH:7]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: N#CC1CN=C2C=CC(Br)=CN21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1cnc2ccc(Br)cn12
Yield: 85.4 %

Procedure:
Method 1) 3.83 g of 6-bromo-2,3-dihydroimidazo[1,2-a]pyridine-3-carbonitrile synthesized in Production Example 242 was dissolved in 34 mL 1,4-dioxane, and the solution together with 4.3 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was heated at 90° C. for 2 hours. The reaction solution was diluted with ethyl acetate, insolubles were filtered off with Celite, and the filtrate was washed with an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered through NH silica gel. The solvent was removed, whereby 3.24 g of the title compound (brown solid) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Cl[S:21]([OH:24])(=[O:23])=[O:22]>ClCCl>[CH3:16][C:6]1[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([S:21]([OH:24])(=[O:23])=[O:22])[CH:14]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)cc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)O)c1
Reaction time: 16 h

Procedure:
A solution of the title B compound, 3,5-dimethyl-4-(4′-hydroxyphenoxy)nitrobenzene (7.86 g, 30.35 mmol) in 150 mL of dichloromethane (CH2Cl2) is treated with chlorosulfonic acid (2.4 mL, 36.42 mmol) at RT. After 16 h, the reaction mixture is concentrated and the residue is dissolved in small amount of CH2Cl2 (ca. 5 mL). The product is precipitated by addition of brine (100 mL), collected by vacuum filtration, washed with water, hexanes and diethyl ether (Et2O) and dried in vacuo to give 5-(2,6-dimethyl-4-nitrophenoxy)-2-hydroxy-benzenesulfonic acid: NMR (DMSO-d6) 2.18 (s, 6H), 6.67-6.83 (m, 3H), 8.1 (s, 2H), 10.07 (s, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:10])(=O)C.C(=O)(O)[O-].[Na+]>CO>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[CH2:8][CH2:7][C:6](=[O:18])[CH2:5][OH:4])=[CH:16][CH:15]=1
Reactant: CC(=O)OCC(=O)CCC(=O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(CO)CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
To a round bottom flask containing 5-(4-bromophenyl)-2,5-dioxopentyl acetate (1.3 g, 4.15 mmol) and sodium bicarbonate (0.42 g, 4.98 mmol) was added MeOH (26 ml). The mixture was stir at room temperature for 19 hours. Afterward, the reaction mixture was concentrated and the resulting residue was taken up in water to form a slurry. The slurry was filtered, washed with water to afford the title compound as off-white solid after drying (985 mg, 88% yield). MS (ESI) m/z 273.0 (M+1). Retention time 1.10 min. (Condition R).