Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>CO.O>[Cl:14][C:15]1[N:20]=[C:19]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Sc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a sodium hydroxide (2.38 g, 59 mmol) solution in methanol (50 mL) and water (5 mL), was added dropwise a solution of methyl 4-mercaptobenzoate (9.00 g, 54 mmol) in methanol (100 mL). The mixture was stirred at room temperature for 1 hour, to this was added methanol solution (100 mL) of 2,4-dichloropyrimidine (8.77 g, 59 mmol) over 5 minutes. The whole was stirred at room temperature for 16 hours. Methanol was removed in vacuo, and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated and dried (Na2SO4). Removal of the solvent in vacuo yielded the product (14.60 g, 97%).
Reaction SMILES: [CH3:1][CH:2]1[C:6]([CH3:7])=[C:5]([CH2:8]O)[C:4](=[S:10](=[O:12])=[O:11])[N:3]1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.O=S(Cl)[Cl:22]>C1(C)C=CC=CC=1>[Cl:22][CH2:8][C:5]1[C:4](=[S:10](=[O:12])=[O:11])[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]([CH3:1])[C:6]=1[CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CC1=C(CO)C(=S(=O)=O)N(c2ccc(C)cc2)C1C
Solvent: Cc1ccccc1
Product: CC1=C(CCl)C(=S(=O)=O)N(c2ccc(C)cc2)C1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of the alcohol from Step 2 (6.8 g, 24.3 mmo 1 ) in dry toluene (70 mL) was added dropwise SOCl2 (9.5 mL) and the mixturewas stirred for 3 hours at room temperature. The excess of SOCl2 and the solvent were removed in vacuo and the residue partitioned between water (10 mL) and diethyl ether (100 mL). The organic phase was separated,dried (NaSO4), and concentrated in vacuo to give the required compoundas a brown solid, m.p. 105°-109° C., which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12
Product: Cc1csc2nc(-n3cncn3)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].O.CN([CH:15]=[O:16])C>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:15](=[O:16])[NH:10][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To the solution of 4,5-dichloro-benzene-1,2-diamine (25 g, 0.14 mol) in dry DMF (200 mL), was added CU (23 g, 0.14 mol) as the solid. The reaction solution was stirred at room temperature for 1 hour, then water (500 mL) was added. The precipitated solid was collected by filtration, washed with water, dried thoroughly to afford the titled compound (26.0 g, 90%). The crude product was used in the following reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
4-(4-Nitrophenyl)-1-Butanol (2.5 g, 12.166 mmol) was dissolved in DCM (50 ml). The solution was cooled in an ice-bath. Triethylamine (2.45 ml, 15.2 mmol) was added and then methanesulfonyl chloride (1.533 g, 13.382 mmol) was dropped in. After 1 hour, the ice-bath was removed. The mixture was stirred for 4 hours more. The reaction mixture was washed with water, sodium hydrogencarbonate aqueous solution (1%) and water (×3) and dried with magnesium sulfate. The solvent was evaporated in vacuum and the desired product (3.25 g) was obtained, yield 98%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([O:16][C:17]([CH3:56])([CH3:55])[CH2:18][O:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]2[C:31](=[O:32])[C:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]#[N:47])=[CH:36][CH:35]=3)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]3[N:51]=[C:52]([CH3:54])[N:53]=[C:27]23)[CH2:22][CH2:21]1)(=[O:15])[CH3:14]>C(OCC)(=O)C>[C:13]([O:16][C:17]([CH3:55])([CH3:56])[CH2:18][O:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]2[C:31](=[O:32])[C:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]4[NH:3][C:4](=[O:7])[O:5][N:47]=4)=[CH:36][CH:35]=3)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]3[N:51]=[C:52]([CH3:54])[N:53]=[C:27]23)[CH2:22][CH2:21]1)(=[O:15])[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)OC(C)=O)CC2)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)OC(C)=O)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogen carbonate (0.28 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-1,1-dimethylethyl acetate (0.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.033 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.028 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.064 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[C:13]2=[C:14]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]3[CH:10]([CH3:15])[CH2:11][O:12]2)=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:13]2=[C:14]3[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]3[CH:10]([CH3:15])[CH2:11][O:12]2)=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2c3c(c(Cl)ncc3c1=O)OCC2C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC1COc2c(Cl)ncc3c(=O)c(C(=O)O)cn1c23
Temperature: 0 °C

Procedure:
0.95 g (3.1 mmol) of ethyl 9-chloro-3-methyl-6-oxo-3,6-dihydro-2H-1-oxa-3a,8-diazaphenalene-5-carboxylate are heated at reflux in a mixture of 4 ml of acetic acid, 4 ml of water and 0.4 ml of concentrated sulphuric acid for four hours. The cooled mixture is put into ice-water, the product is isolated and washed with water.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([C:18]3([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>CO>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH:16]([C:18]3([C:22]4[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=4)[CH2:21][CH2:20][CH2:19]3)[OH:17])[CH2:10]2)=[CH:32][CH:33]=1
Reactant: O=C(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(C(F)(F)F)cc2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(C(F)(F)F)cc2)CCC1
Yield: 69.7 %

Procedure:
2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanone (30 mg) was dissolved in 3 mL of dry methanol and solid sodium borohydride (10 equiv.) was added in portions. Water (10 mL) was added and the mixture was extracted with ether and the ether extracts were concentrated in vacuo and purified on silica gel to give the desired 2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-1-[1-(4-trifluoromethyl-phenyl)-cyclobutyl]-ethanol (21 mg, 67%). Data for this mixture of diastereomeric amino alcohols: MS 502 (M+1); 1H NMR (300 MHz, CDCl3): δ 7.5-7.6 (m, 4H), 7.29-7.35 (m, 2H), 6.89-6.96 (overlapping doublets, total 2 H), 3.8-4.0 (m, 4H, 1 of which is exchanged upon exposure to D2O), 1.1-3.19 (various overlapping multiplets totaling 17 H); 13C NMR (75 MHz, CDCl3): δ 207 peak in starting ketone is absent. Most peaks are doubled (adjacent equal intensity peaks) due to diastereoisomerism: δ 161.7, 151.0, 128.6 & 128.5, 128.0 & 127.8, 127.15 & 127.10, 126.45, 124.91 & 124.87, 123.30, 122.86, 114.63, 71.2 & 71.1, 59.7 & 59.5, 58.99 & 58.97, 55.96, 49.31 & 49.28, 36.8 & 36.6, 31.0, 29.5 & 29.4, 27.33 & 27.26, 25.24 & 25.03, 16.42.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(=O)=O.[Li]CCCC.Cl[SiH:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>C1COCC1.CC(C)=O>[CH:20]([SiH:19]([CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([CH3:22])[CH3:21]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: COc1ccc(Br)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc([SiH](C(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 94.1 %

Procedure:
A solution of p-bromoanisole (28.6 mL, 228 mmol, 1 equiv.) in THF (550 mL) was chilled to −78° C. (CO2(s), acetone). n-BuLi (91.2 mL, 228 mmol, 2.5M in hexanes, 1 equiv.) was added via cannula over a 5 min period. After 5 min a white precipitate begins to form. The mixture was stirred for 30 min at −78° C., after which chlorodiisopropylsilane (34.6 g, 228 mmol, 1 equiv.) was slowly added via syringe. After 1 h the ice bath was removed and the solution was allowed to come to 23° C. with stirring overnight. The reaction was quenched with NH4Cl(sat'd) (50 mL) and extracted with ether (3×500 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a light yellow oil. Filtration through SiO2 (gradient: 3-5% EtOAc/hexanes) yielded 47.7 g (94%) of a colorless oil. This material could also be purified by distillation bp=76-85° C. @ 275 mTorr (40 g, 63%). TLC Rf=0.61 (9:1 Hexanes/EtOAc). IR (film) 2393, 1853, 1710, 1691, 1658, 1584, 1482, 1346 cm−1. 1H NMR (500 MHz, CDCl3) δ7.48 (d, 2H, J=8.10, C3-H, C7-H), 6.95 (d, 2H, J=8.10, C4-H, C6-H), 3.97 (s, 1H, Si—H), 3.85 (s, 3H, C1-H), 1.39 (q, 2H, J=3.0, C8-H, C11-H), 1.10 (d, 6H, J=6.5, C9-H, C10-H), 1.03 (d, 6H, J=7.5, C12-H, C13-H). 13C NMR (125 MHz, CDCl3) δ137.13, 113.73, 113.62, 55.18, 18.95, 18.72, 11.08. Anal. Calcd for C13H22OSi: C, 70.21; H, 9.97; Si, 12.63. Found: C, 70.43; H, 9.83; Si, 12.39.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.[CH3:20][CH:21]([C:27](=O)[CH2:28][CH3:29])[CH2:22][C:23]([O:25]C)=[O:24]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:28]([CH3:29])=[C:27]2[CH:21]([CH3:20])[CH2:22][C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1
Reactant: CCC(=O)C(C)CC(=O)OC
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)c(C)c(C(C)CC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)-hydrazine hydrochloride and methyl 3-methyl-4-oxohexanoate as the starting materials and methanol as the solvent, the title compound was prepared.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>O1CCOCC1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(OCCCBr)cc1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(OCCCn2ccnc2)cc1
Temperature: 100 °C
Yield: 35.6 %

Procedure:
A mixture of imidazole (0.8 g, 11.6 mmol) and 4-(3-bromopropoxy)nitrobenzene (1.5 g, 5.8 mmol) in 1,4-dioxane (75 ml) was heated at 100° C. for 12 hours. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate (150 ml). The solution was washed with saturated sodium bicarbonate (3×50 ml), water (3×50 ml) and saturated sodium chloride (50 ml) and then dried. The solvent was removed by evaporation and the residue was purified by column chromatography, eluting with 0-5% methanol in DCM, to give the product as a yellow oil (0.51 g, 22%). MS (MH+): 248.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 100 °C
Yield: 42.7 %

Procedure:
A mixture of (3-hydroxy-benzyl)-carbamic acid tert-butyl ester (250 mg, 1.12 mmol), 2-fluoro-5-nitro-pyridine (150 mg, 1.12 mmol) and K2CO3 (120 mg) in N,N-dimethylformamide (3 mL) was heated under microwave condition at 100° C. for 10 min. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (7:1) to give the title compound (165 mg, 43%). MS (DCI/NH3) m/z 346 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([F:27])[F:26])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]#[N:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([F:27])[F:26])[C:17]([OH:19])=[O:18])[C:10](=[O:28])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
114 mg (260 μmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoate (racemate) in 8 ml of dichloromethane and 400 μl (5.20 mmol) of TFA were reacted according to General Method 6A. Yield: 99 mg (91% of theory)
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[S:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:13]=2[CH:28]=1)=[O:8]>CC(C)=O.O.CC(C)=O>[CH:22]1([C:20]([NH:19][CH2:18][CH2:17][C:14]2[C:13]3[CH:28]=[C:9]([C:7]([OH:2])=[O:8])[CH:10]=[CH:11][C:12]=3[S:16][CH:15]=2)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=Cc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added at room temperature to a solution of 6.88 mmol of the product obtained in Step E in 30 ml of acetone. The solution is stirred for 2 hours at room temperature and then filtered. The filtrate is concentrated under reduced pressure and chromatographed over silica gel to yield the title product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].Cl>>[CH2:23]([N:25]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1)[CH2:26][CH3:27])[CH3:24]
Reactant: CCNCC
Reactant: ClCCCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Agent: Cl
Product: CCN(CC)CCCOc1ccc(/C=C/c2nc3ccccc3s2)cc1
Yield: 24 %

Procedure:
The title compound was prepared as described in Example 28 starting with (F) of Example 28 (3.0 g, 9.8 mmol) and using diethylamine in place of dibutylamine to produce 0.81 g (24% yield) of the title compound as the HCl salt, mp 187°-188° C. IR(KBr): 3400, 1600 cm-1. MS: 367(MH+). 1H NMR (CD3OD): δ 8.22-6.99 (m, 10H), 4.21 (t, J=5.1 Hz, 2H), 3.34 (m, 6H), 2.33 (m, 2H), 1.42 (m, 6H).
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:40])[CH:22]([O:37]C=O)[C:23]4[N:24]=[C:25]([NH:28][C:29]([O:31][C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:30])[S:26][CH:27]=4)[C:18](=[O:41])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1>C(=O)(O)[O-].[Na+]>[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:40])[CH:22]([OH:37])[C:23]4[N:24]=[C:25]([NH:28][C:29]([O:31][C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:30])[S:26][CH:27]=4)[C:18](=[O:41])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: CCC(C)(C)OC(=O)Nc1nc(C(OC=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Agent: CCC(C)(C)OC(=O)N=c1[nH]c(C(OC=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(C)(C)OC(=O)Nc1nc(C(O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)cs1
Reaction time: 6 h

Procedure:
A mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid, (1.49 g.) and 5% sodium bicarbonate aqueous solution (100 ml.) was allowed to stand for 6 hours. After the reaction, the reaction mixture was washed with ethyl acetate. To the reaction mixture was added ethyl acetate, and the mixture was adjusted to pH 7 with dilute hydrochloric acid and then the aqueous layer was separated. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 1 to 2 with dilute hydrochloric acid, and the ethyl acetate layer was separated. The remaining aqueous layer was subjected to salting-out and then extracted with ethyl acetate. The ethyl acetate layer and the ethyl acetate extract were combined together, washed with water, dried over magnesium sulfate, and then the solvent was distilled off. To the residue (2.0 g.) was added diethyl ether, and the mixture was stirred for overnight, collected by filtration and then dried to give pale brown powder of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-acetamido]-3-cephem-4-carboxylic acid, (0.90 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C([Li])(C)(C)C.CN([CH:24]=[O:25])C>CCOCC>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:24]=[O:25])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Temperature: -75 °C
Reaction time: 0.83 h

Procedure:
To a solution of [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Reference Example 2) (15 g, 56.1 mmol) in ether (450 mL), at −75° C. a solution of tert-butyl lithium (99 ml of 1.7 N solution in hexanes, 168 mmol) is added. The mixture is stirred for 50 minutes at −75° C., and then for 30 minutes at −30° C. To the obtained beige suspension, DMF (22.5 ml) is added during 15 minutes, and then the mixture is allowed to warm to ambient temperature. The mixture is poured on water and extracted with diethyl ether (500 mL). After washing the organic layer with brine (3 times 500 mL), and drying (sodium sulfate), removal of the solvent leaves the crude aldehyde, which is recrystallized, from toluene/hexane. Yield of the title compound: 9.9 g (81.8%) yellowish plates, mp=103° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[CH3:14])([O-:3])=[O:2].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>C(O)C.O>[NH2:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[CH3:14]
Reactant: Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Cc1c(N)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2,6-dinitro-4-fluorotoluene (8.1 g) in ethanol (130 mL) is treated dropwise with a solution of sodium sulfide nonahydrate (16.39 g) in water (90 mL). The mixture is allowed to stir at room temperature for 2.5 hours, then diluted with water (500 mL) and extracted with ethyl acetate (4×500 mL). The combined extracts are dried over sodium sulfate and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 15% ethyl acetate/hexane to afford 2-amino-4-fluoro-6-nitrotoluene as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:71]1([CH:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH2:75][CH2:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:16]1[CH2:17][CH2:18][N:13]([C:11]2[N:12]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([N:79]5[CH2:80][CH2:81][CH:76]([N:71]6[CH2:75][CH2:74][CH2:73][CH2:72]6)[CH2:77][CH2:78]5)=[O:33])=[CH:35][CH:36]=4)=[O:37])=[CH:21][CH:20]=3)[N:10]=2)[CH2:14][CH2:15]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2CCC(N3CCCC3)CC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 58.2 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with 4-[1-pyrrolidinyl]piperidine (61 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product as a white solid (37 mg, 58% yield); MS (ESI) m/z=642.7