Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9](=[O:33])[NH:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:17][N:18]1[CH2:23][C:22](=[O:24])[NH:21][C@@H:20]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:19]1)C1C=CC=CC=1.C1(OC(=O)[NH:42][C:43]2[S:44][C:45]([C:49](=[O:51])[CH3:50])=[C:46]([CH3:48])[N:47]=2)C=CC=CC=1>C(C#N)(C)=O>[C:49]([C:45]1[S:44][C:43]([NH:42][C:9]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:17][N:18]2[CH2:23][C:22](=[O:24])[NH:21][C@@H:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:19]2)=[O:33])=[N:47][C:46]=1[CH3:48])(=[O:51])[CH3:50]
Reactant: O=C1CN(C[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)C[C@H](Cc2ccc(F)cc2)N1
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Agent: CC(=O)C#N
Product: CC(=O)c1sc(NC(=O)N[C@@H]2CCCC[C@H]2CN2CC(=O)N[C@@H](Cc3ccc(F)cc3)C2)nc1C
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A solution of amine from EXAMPLE 3 (75 mg, 0.23 mmol) and carbamate from EXAMPLE 6 (65 mg, 0.23 mmol) in AcCN (4 ml) was warm to 45° C. for 30 minutes. A solid form and the mixture cooled to room temperature and the solid filtered off to give 50 mg of the desired urea. 1H NMR (300 MHz, CDCl3) δ12.21 (bs, 1H), 8.56 (bs, 1H), 6.99-6.90 (m, 4H), 5.49 (bd, J=8 Hz, 1H), 3.52 (m, 1H), 3.40 (m, 1H), 3.24 (d, J=17 Hz, 1H), 2.96 (d, J=17 Hz, 1H), 2.88 (dd, J=5 Hz, J=14 Hz, 1H), 2.73 (dd, J=9 Hz, J=14 Hz, 1H), 2.54 (m, 2H), 2.47 (s, 6H), 2.20-2.06 (m, 3H), 1.90-1.76 (m, 4H), 1.43-1.00 (m, 4H). ESI MS: (M+H)+=502.2; HRMS: (M+H)+=502.2287.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:1][C:2]2[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]3[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=3[CH:11]=2)=[CH:23][CH:22]=1
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2cc3c(cc2C(C)=O)C(C)(C)CCC3(C)C)cc1
Yield: 129.2 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl)-ethanone (0.315 g, 1.28 mmol) was alkylated with 4-methoxybenzylchloride (0.280 g, 1.79 mmol, 0.24 mL) as described in Example 21. Aqueous workup gave 1-[3-(4-methoxybenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]-ethanone 0.606 g (crude) as an orange oil: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, Ar—H), 7.39 (d of ABq, J=8.6 Hz, 2H), 6.92 (d of ABq, J=8.6 Hz, 2H), 6.91 (s, 1H, Ar—H), 5.06 (s, 2H, OCH2), 3.82 (s, 3H, OCH3), 2.55 (s, 3H, CH3), 1.67 (m, 4H, 2CH2), 1.27 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Cl>>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24]
Reactant: Fc1ccccc1CCl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccccc3F)C2=O)CC1
Yield: 77 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-fluorobenzyl chloride, to give the desired product as a white solid (77%).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1N[CH:6]([OH:8])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[OH2:13]>>[O:12]=[CH:1][C@@H:2]([C@H:3]([C@@H:4]([C@@H:5]([CH2:6][OH:8])[OH:9])[OH:10])[OH:11])[OH:13]
Reactant: O
Reactant: OC[C@H]1NC(O)[C@H](O)[C@@H](O)[C@@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A 300 g amount of nojirimycin was dissolved in 1.5 l of distilled water to which was added 80 g of deoxin-1, i.e., a crude powder of glucose oxidase with 10,000 units per mg which is produced by Penicillium amagasakiensis (produced by Nagase Sangyo Co./Japan). The pH of the reaction mixture was adjusted to 6.0 and then the reaction was conducted at 30°C in a 30 l jar fermenter with agitation at 300 r.p.m. under air-flowing conditions. After 65 hours of reaction, the reaction solution was passed through a column filled with Amberlite IR-120 (H+ type, 1.5 l). The column was then washed with 7 l of water. The treated solution and the washings were combined (22 l), and the combined solution was then neutralized with Amberlite IR-45 (OH- type), followed by decolorization with 50 g of carbon powder. The decolorized solution was then condensed. To the condensed solution (500 ml) was added 100 ml of methanol, which was allowed to stand to cool in order to yield a crystalline product. The crystals were separated from the solution by filtration to give 220 g of D-gluconic-δ-lactam as needle-like white crystals (yield of 77%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@:4]([CH:22]=[CH2:23])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[NH:5]OCC1C=CC=CC=1.[ClH:25]>>[ClH:25].[CH:22]([C@@:4]([C:3]([OH:24])=[O:2])([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[NH2:5])=[CH2:23]
Reactant: C=C[C@@](Cc1ccc(O)cc1)(NOCc1ccccc1)C(=O)OC
Agent: Cl
Product: C=C[C@](N)(Cc1ccc(O)cc1)C(=O)O
Reaction time: 2 h

Procedure:
A mixture consisting of 0.554 g of benzyloxy-α-vinyltyrosine methyl ester and 40 ml of 6 N aqueous hydrochloric acid was heated at reflux with rapid stirring for 2 hours. The reaction mixture was cooled, extracted three times with 5 ml of methylene chloride and treated with activated charcoal. Filtration and evaporation of solvent gave 0.355 g of α-vinyltyrosine hydrochloride as an amorphous solid. NMR (D2O) showed: 3.35 (2H,AB, JAB =15, δAB =22), 5.55 (1H,d, J=18), 5.70 (1H,d,J=12), 6.43 (1H, d of d, J=18,12), 7.27 (2H,AB, JAB =9, δAB =22). m/e 207 (P-36).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[NH3:17]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH2:17])=[O:15]
Reactant: N
Reactant: COCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Product: COCCCCCCCCCCCC(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the title product from Example 11 (1.1 g, 4.3 mmol) in 70 mL of anhydrous tetrahydrofuran was added 20 mL of freshly distilled liquid ammonia in a Parr shaker which was sealed and shaken at room temperature for 16 hours. After filtering and concentration, the crude residue was dissolved in anhydrous methanol and passed through a basic ion exchange resin and eluted with anhydrous methanol. Concentration afforded the title compound (780 mg) as a white solid, m.p. 83.9°-85.6° C. (DSC). The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: C(O[C:5]1[CH:20]=[C:19]([O:21][C:22](=[O:24])[CH3:23])[C:8]2[C:9]([CH3:18])=[C:10]3[N:15]([C:16](=[O:17])[C:7]=2[CH:6]=1)[CH2:14][CH2:13][CH2:12][CH2:11]3)(=O)C.[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:25]([O:28][C:20]1[CH:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]3[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[C:9](=[CH2:18])[C:8]=2[C:19]=1[O:21][C:22](=[O:24])[CH3:23])(=[O:27])[CH3:26]
Reactant: CC(=O)Oc1cc(OC(C)=O)c2c(C)c3n(c(=O)c2c1)CCCC3
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=C1c2c(ccc(OC(C)=O)c2OC(C)=O)C(=O)N2CCCCC12

Procedure:
Reflux crude 8,10-bis(acetyloxy)-1,2,3,4-tetrahydro-11-methyl-6H-benzo[b]quinolizin-6-one (11.8 g), acetic anhydride (20.2 ml), pyridine (20.2 ml), and chloroform (400 ml) for 20 hrs. Concentrate the cooled solution to dryness, and dilute the residue with ethyl acetate. Separate the resulting crystals by filtration, and concentrate the mother liquor. Chromatograph the residue over silica gel, and elute the column with 10% ethyl acetate in dichloromethane. Combine and concentrate fractions, and crystallize to obtain 9,10-bis(acetyloxy)-1,2,3,4,11,11a-hexahydro-11-methylene-6H-benzo[b]quinolizin-6-one, m.p. 129°-132° C. (from CHCl3 -EtOAc).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]1[CH2:8][CH2:7][CH2:6][N:5]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>CC(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:3][C:4]2[CH2:8][CH2:7][CH2:6][N:5]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NC1=NCCC1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: O=C(NC1=NCCC1)Nc1ccc(Br)cc1

Procedure:
Following a procedure similar to that described in Example 2 but using 4.6 g. sodium in 300 ml. dry acetone, 23.2 g. 2-amino-1-pyrroline hydrochloride and 38.9 g. 4-bromophenyl isocyanate in 200 ml. dry acetone, there was obtained after recrystallization from ethyl alcohol 10.8 g. of the hydrochloride of 1-(4-bromophenyl)-3-(1-pyrrolin-2-yl)urea; m.p. 221°-224° C.
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22](O)=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:48][O:49][C:50]([C@H:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)=[O:51].C(N(CC)CC)C>CN(C)C=O.ClCCl>[CH3:48][O:49][C:50]([C@H:52]1[CH2:56][CH2:55][CH2:54][N:53]1[C:22]([C:15]1[N:16]2[C:17]([CH2:18][O:19][CH2:20][CH2:21]2)=[C:13]([C:11](=[O:12])[NH:10][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH3:9])[CH:14]=1)=[O:23])=[O:51]
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)O)n2c1COCC2)c1ccccc1
Reactant: COC(=O)[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C(=O)OC)n2c1COCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a solution of 8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11a) (200 mg, 0.61 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (91 mg, 0.670 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (128 mg, 0.670 mmol). The mixture was stirred for 45 min at 25° C., then (R)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (111 mg, 0.670 mmol) and triethylamine (123 mg, 1.218 mmol) were added and the mixture was stirred at 25° C. overnight. Excess dichloromethane was added and the mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine. The organic layer was evaporated to dryness. The crude product was purified by flash chromatography (silica gel, elution with heptane/ethyl acetate) to give 55 mg (21%) of (R)-1-[8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidine-2-carboxylic acid methyl ester). LC/MS (method 4): Rt=1.21 min; m/z=440.29 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:7]2[CH:6]=[CH:5][N:4]1[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH3:2]>[Pd].C(OCC)(=O)C>[CH2:1]([CH:3]1[C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:7]2[CH2:6][CH2:5][N:4]1[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH3:2]
Reactant: CCC1c2nccnc2C=CN1C(=O)Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC1c2nccnc2CCN1C(=O)Oc1ccccc1

Procedure:
Catalyst (10% palladium on carbon, 140 mg) was added to a solution of phenyl 5-ethylpyrido[3,4-b]pyrazine-6(5H)-carboxylate (238 mg, 0.85 mmol) in ethyl acetate (6.0 mL), and the resultant mixture was stirred under hydrogen (1 atm) for 7.5 h. Filtration through Celite® and evaporation of the solvent gave the crude product. Purification by flash chromatography (silica gel, 6-15% ethyl acetate/dichloromethane) gave the title compound as a colorless oil. LC/MS 284 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[CH3:39][NH:40][CH3:41]>CN(C=O)C>[CH3:39][N:40]([CH3:41])[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1
Yield: 38.5 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indazole-7-carboxamide (Example 46a) (0.076 mmol) in DMF (4 mL) was reacted with K2CO3 (22 mg, 0.16 mmol), sodium iodide (2 mg) and dimethyl amine (0.2 mL, 0.4 mmol) to afford the title compound (13.9 mg, 38%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([CH:21]=[CH2:22])=[CH:20][C:14]2=[N:13]1)(=O)C.C(=O)([O-])O.[Na+].C1(C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C=1)[N+]([O-])=O>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([CH:21]=[CH2:22])=[CH:20][C:14]2=[N:13]1
Reactant: C=Cc1ccc2nn(-c3cc(C)ccc3OC(C)=O)nc2c1
Agent: O=C([O-])O
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: C=Cc1ccc2nn(-c3cc(C)ccc3O)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a 200 ml flask equipped with a reflux condenser and a mechanical stirrer were placed 2(2-acetoxy-5-methylphenyl)5-vinyl-2H-benzotriazole (7.2 g, 24.5 mmole), a 20% solution of sodium hydrogencarbonate (4.2 g), methanol (110 g) and picric acid (0.01 g). The mixture was heated and kept for 1.5 hours at reflux temperature. The clear, yellow solution was cooled to room temperature, filtered and acidified slowly at 0° to 50° C. with 1N aqueous hydrochloric acid solution. The precipitate was dissolved in chloroform (100 ml), and the organic layer was concentrated. Several precipitations of the chloroform or a dichloromethane solution into methanol were sometimes necessary to remove some insoluble material. The vinyl compound was finally crystallized from methanol/water, dried at 0.05 mm, and gave 3.4 g (55%) yield. Which had the following properties.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[CH:11][N:12]=[CH:13][CH:14]=[C:9]2[C:8](N2CCCCC2)=[CH:7]1)[CH3:2].[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32]Cl>>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32][N:12]1[CH2:13][CH2:14][CH:9]([C:8]2[C:9]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:7]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: CCOCCn1cc(N2CCCCC2)c2ccncc21
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)OC)CC2)c2ccncc21
Yield: 52.1 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 0.46 g (1.7 mmol) of 1-(2-ethoxyethyl)-3-piperidin yl-1H-pyrrolo[2,3-c]pyridine and 0.44 g (2.0 mmol) of 2-(2-chloroethoxy)-benzoic acid methyl ester. After standard work-up and purification, 0.2 g (21% yield) of 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)benzoic acid methyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:14])([F:15])[F:13]
Reactant: COc1ccc(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c(Cl)c1
Agent: BrB(Br)Br
Product: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 183, 5-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 195) was reacted with BBr3 to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=360.0 [M+H+].
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:34])[CH:24]([NH:25][C:26](=[O:33])[CH2:27][C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH:35]=[N:36][O:37][CH3:38])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:38][O:37][N:36]=[CH:35][C:18]1[CH2:19][S:20][C@@H:21]2[CH:24]([NH:25][C:26](=[O:33])[CH2:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:34])[N:22]2[C:17]=1[C:15]([OH:16])=[O:14]
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.42 h
Yield: 78.7 %

Procedure:
To a solution of diphenylmethyl-3-methoxyiminomethyl- 7-(2 -thienylacetamido)-3-cephem-4 -carboxylate (394 mg) in methylene chloride (11 ml) are added anisole (1.1 ml) and trifluoroacetic acid (1.1 ml) at 0° C under argon atmosphere, and the mixture is kept at the same temperature for 25 minutes, and at room temperature for 25 minutes. The reaction mixture is evaporated, and trituration of the residue in ether gives 3-methoxyiminomethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (216 mg). m.p. 186°-189° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[N:15][CH:14]=3)[CH:9]=[C:8]([C:19]([O:21]C)=[O:20])[C:7]=2[C:6]([CH3:23])=[CH:5]1)([CH3:3])[CH3:2].CO.[OH-].[Li+].O>O1CCCC1>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[N:15][CH:14]=3)[CH:9]=[C:8]([C:19]([OH:21])=[O:20])[C:7]=2[C:6]([CH3:23])=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2ccnnc2)cc2c1c(C)cn2C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cn(C(C)C)c2cc(-c3ccnnc3)cc(C(=O)O)c12
Temperature: 55 °C
Yield: 95.4 %

Procedure:
To a 100 ml round bottom flask was added methyl 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylate (74.0 mg, 0.239 mmol), Methanol (1595 μl), Tetrahydrofuran (THF) (3189 μl) and a magnetic stir bar. To the same was added lithium hydroxide, H2O (30.1 mg, 0.718 mmol) and the mixture was stirred at 55° C. Reaction progress was monitored by LCMS. LCMS(weekend) showed 50% conversion. To the reaction mixture was added lithium hydroxide, H2O (20.08 mg, 0.478 mmol) The reaction was continued to stir and heated to 55° C. After complete conversion the reaction solvent was removed and the remaining residue dissolved with water (1.5 ml). The aqueous solution was made acidic drop wise with 1N HCl until precipitation was complete. The solid was collected by vacuum filtration and washed with water (5 ml). The solid was dried under vacuum open to the air overnight. The product, 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylic acid (68 mg, 0.228 mmol, 95% yield), was obtained as a brown solid. 1H NMR (400 MHz, DMSO-δ6) δ 9.71-9.83 (m, 1H), 9.23 (dd, J=1.26, 5.56 Hz, 1H), 8.32 (s, 1H), 8.11 (dd, J=2.65, 5.43 Hz, 1H), 7.86 (s, 1H), 7.58 (s, 1H), 4.90-5.09 (m, 1H), 2.34 (s, 3H), 1.47 (d, J=6.82 Hz, 6H).MS(ES) [M+H]+296.2.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[C:26]([F:33])[CH:25]=1.CC(C)=O>CC(C)=O.O>[CH2:10]([O:9][CH2:8][CH2:7][CH:3]([NH:2][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([Br:23])=[CH:25][C:26]=1[F:33])[C:4]([OH:6])=[O:5])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: NC(CCOCc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(CCOCc1ccccc1)C(=O)O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2-amino-4-benzyloxy-butyric acid hydrochloride salt (1.0 mmol) (See Intermediate 34) and sodium carbonate (3.0 mmol) in 1:1 acetone/water (0.5M) in a 0° C. ice bath, slowly add 4-bromo-2-fluoro-benzoyl chloride (1.2 mmol) diluted in acetone (prepared from 4-bromo-2-fluoro-benzoic acid (1.0 mmol) and oxalyl chloride (1.0 mmol) in dichloromethane using catalytic dimethylformamide). Stir for 30 minutes at 0° C. After this time, wash the reaction with 1N hydrochloric acid while extracting with ethyl acetate. Concentrate the organics in vacuo. Purify on an Isco CombiFlash® chromatography system eluting with 1% acetic acid in ethyl acetate and hexane. MS (m/e) (79Br/81Br): 410.3/412.3 (M+1)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[C:33]([F:36])([F:35])[F:34])[C:27](Cl)=[O:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([C:33]([F:34])([F:35])[F:36])=[C:24]([F:23])[CH:25]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)c(F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(C(F)(F)F)c(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To the stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) and 3-fluoro-4-trifluoromethylbenzoyl chloride (0.6 g, 2.8 mmol) in dry methylene chloride (60 mL), was added diisopropylethylamine (0.7 g, 5.4 mmol). After stirring at room temperature overnight, the reaction mixture was quenched with methanol (1 mL) and washed with water (2×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 3:97) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-fluoro-4-trifluoromethyl-benzamide (0.6 g, 53%) as a white solid: mp 165-167° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=8.20 min. (99%); 1H NMR (DMSO-d6) δ 2.06-2.12 (m, 1H), 2.53-2.65 (m, 2H), 2.87-2.93 (m, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5.3 and 12.5 Hz, 1H), 7.76-7.84 (m, 3H), 7.95-8.01 (m, 3H), 9.45 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.97, 30.92, 38.54, 48.87, 115.88 (116.17), 118.56 (118.72, 119.00, 119.16), 122.30, 123.94 (123.98), 120.52 (124.13), 127.25, 127.74 (127.80), 131.55, 133.24, 134.83, 138.51, 140.42 (140.52), 157.04 (160.38), 164.19, 166.91, 167.48, 169.81, 172.74; Anal. Calcd. for C22H15N3O5F4: C, 55.35; H, 3.17; N, 8.80; F, 15.92. Found: C, 55.00; H, 2.95; N, 8.80; F, 15.92.