Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13](O)=[O:14])=[CH:4][C:3]=1[O:16][CH3:17].C(N(CC)CC)C.C1(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]([N:39]=[N+:40]=[N-:41])=[O:14])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(-c2ccsc2C(=O)O)ccc1Br
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(-c2ccsc2C(=O)N=[N+]=[N-])ccc1Br
Reaction time: 20 h

Procedure:
A stirred solution of 3-(4-bromo-3-methoxyphenyl)thiophene-2-carboxylic acid (2.23 g, 7.13 mmol) in benzene (28.5 mL) was treated with triethylamine (1.39 ml, 9.98 mmol) and diphenylphosphoryl azide (1.96 g, 7.13 mmol). The mixture was stirred for 20 h, then the volatiles were removed ant the residue was purified by column chromatography on silica gel (eluent: toluene) to afford the title (1.63 g, 68%). LCMS (ES+) m/z 310, 312 (M+H−N2)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2.Cl.C(=O)([O-])O.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:6]2[C:10]=1[CH2:9][CH2:8][CH2:7]2
Reactant: Fc1ccc(OCC2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCO2)c2c1CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1ccc(OCC2CNCCO2)c2c1CCC2
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To 20 ml of a methanalic solution of 0.54 g of 2-[[(7-fluoro-4-indanyl)oxy]methyl]-4-tritylmorpholine was added a methanolic solution (5 ml) of concentrated hydrochloric acid (1.30 g, 12.8 mmol) at room temperature, followed by stirring for 30 minutes. After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The solvent was evaporated, and a saturated aqueous sodium chloride solution was added to the resulting residue, followed by extraction with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to obtain 2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine (0.236 g) as a colorless oily substance from the chloroform-methanol-concentrated ammonia (10:1:0.1) eluate.
Reaction SMILES: [Cl:1][C:2]1[CH:6]([CH3:7])[CH2:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1>C(#N)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: CC1CN(c2cccnc2)N=C1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: Cc1cn(-c2cccnc2)nc1Cl
Temperature: 40 °C

Procedure:
In another embodiment, 3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2) in acetonitrile is oxidized with manganese(IV) oxide and the mixture is heated at about 40° C. The 3-(3-chloro-4-methyl-1H-pyrazol-1-yl)pyridine (3) can be isolated and purified by standard techniques.
Reaction SMILES: C(N(C1C=CC2C(CC)=CCC(C)(C)C=2C=1)C1C=CC(C(O)=O)=CC=1)C.[CH2:27]([O:29][C:30](=[O:54])[C:31]1[CH:36]=[CH:35][C:34]([N:37](CC)[C:38]2[CH:47]=[CH:46][C:45]3[C:44]([CH2:48][CH3:49])=[CH:43][CH2:42][C:41]([CH3:51])([CH3:50])[C:40]=3[CH:39]=2)=[CH:33][CH:32]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:54])[C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]2[CH:47]=[CH:46][C:45]3[C:44]([CH2:48][CH3:49])=[CH:43][CH2:42][C:41]([CH3:50])([CH3:51])[C:40]=3[CH:39]=2)=[CH:35][CH:36]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(N(CC)c2ccc3c(c2)C(C)(C)CC=C3CC)cc1
Agent: CCC1=CCC(C)(C)c2cc(N(CC)c3ccc(C(=O)O)cc3)ccc21
Product: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CC=C3CC)cc1

Procedure:
PNMR (300 MHz, CDCl3) δ 1.18 (t, 3 H, J=7.3 Hz), 1.23 (s, 6 H), 1.39 (t, 3 H, J=7.1 Hz), 2.17 (d, 2 H, J=4.0 Hz), 2.46 (d, 2 H, J=7.3 Hz), 4.34 (q, 2 H J=7.1 Hz), 5.70 (t, 1 H, J=4.0 Hz), 6.07 (s 1 H, NH), 7.00-7.03 (overlapping d & dd, 3 H), 7.11 (s, 1 H), 7.25 (d, 1 H, J=8.6 Hz), 7.93 (d, 2 H, J=8.6 Hz). 4-[Ethyl-(5-ethyl-8,8-dimethyl-7,8-dihydro-naphthalen-2-yl)-amino]-benzoic acid ethyl ester (Compound 74). Following General Procedure D, 4-(5-Ethyl-8,8-dimethyl-7,8-dihydro-naphthalen-2-ylamino)-benzoic acid ethyl ester (Compound 73), (0.13 g, 0.38 mmol) was reacted to give the title compound as a solid. PNMR (CDCl3): δ 1.19 (t, J=7.4 Hz, 3 H), 1.22 (s, 6 H), 1.26 (t, J=7.1 Hz, 3 H), 1.36 (t, J=7.1 Hz, 3 H), 2.21 (d, J=4.5 Hz, 2 H), 2.42 (q, J=7.3 Hz, 2 H), 2.489 (q, J=7.4 Hz, 2 H), 3 80 (q, J=7.1 Hz, 2 H), 4.316 (q, J=7.1 Hz, 2 H), 5.76 (t, J=4.5 Hz, 1 H), 6.71 (d, J=8.9 Hz, 2 H), 6.99 (dd, J=2.2, 8.2 Hz, 1 H), 7.12 (d, J=2.23 Hz, 1 H), 7.30 (d, J=8.2 Hz, 1 H), 7.84 (d, J=8.9 Hz, 2 H). 4-[Ethyl-(5-ethyl-8,8-dimethyl-7,8-dihydro-naphthalen-2-yl)-amino]-benzoic acid (Compound 75). Following General Procedure E, 4-[Ethyl-(5-ethyl-8,8-dimethyl-7,8-dihydro-naphthalen-2-yl)-amino]-benzoic acid ethyl ester (Compound 74), (88 mg, 0.23 mmol) was reacted to give the title compound as a solid. PNMR (δ6 acetone) δ 1.18 (t, J=7.3 Hz, 3 H), 1.24 (s, 6 H), 1.25 (t, J=7.1 Hz, 3 H), 2.22 (d, J=4.5 Hz, 2 H), 2.53 (q, J=7.3 Hz, 2 H), 3.87 (q, J=7.1 Hz, 2 H), 5.80 (t, J=4.5 Hz, 1 H), 6.79 (d, J=9.2 Hz, 2 H), 7.08 (dd, J=2.2, 8.1 Hz, 1 H), 7.23 (d, J=2.2 Hz, 1 H), 6-Bromo-1-isopropyl-4,4-dimethyl- 1,2,3,4-tetrahydro-naphthalen-1-ol (Compound 76)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([N+:14]([O-])=O)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])[CH3:2].[Cl-].[NH4+]>O.CO.[Fe]>[NH2:14][C:7]1[CH:6]=[C:5]([O:17][CH3:18])[C:4]([O:3][CH2:1][CH3:2])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOc1cc(C(=O)OC)c(N)cc1OC
Reaction time: 12 h

Procedure:
Mixture of 17.0 g (66.7 mmol) of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate, 13.1 g (233 mmol) of powdered iron and 17.7 g (334 mmol) of ammonium chloride in 95 mL of water and 245 mL of methanol was refluxed for 4.5 h. An additional 13.1 g of iron was added followed by refluxing for 2.5 h. Then an additional 13.1 g of iron and 17.7 g of ammonium chloride was added and refluxing was continued for 12 h. The reaction was filtered through Celite and methanol was removed from the filtrate. The filtrate was extracted with chloroform and the extracts were treated with Darco, evaporated and dried in vacuo (50° C.).The yield was 11.0 g of methyl 2-amino-5-ethoxy-4-methoxybenzoate as tan crystals: mass spectrum (electrospray, m/e): M+H 225.9.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][N:19]=1>C(COC)OC>[CH2:1]([N:8]([CH2:24][C:21]1[CH:20]=[N:19][C:18]([Cl:17])=[CH:23][CH:22]=1)[C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1C=C(NCc2ccccc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C1C=C(N(Cc2ccccc2)Cc2ccc(Cl)nc2)CO1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
6.3 g of 4-(benzylamino)furan-2(5H)-one (Example 16) are initially charged in 75 ml of dimethoxyethane at room temperature. Subsequently, 1.1 g of sodium hydroxide are added and, at 40° C. 25.5 g of a 20% solution of 2-chloro-5-(chloromethyl)pyridine in dimethoxyethane are metered in. The mixture is stirred at 50° C. for a further 6 h. The solvent is substantially removed under reduced pressure and the residue is admixed with 50 ml of water and 50 ml of methylene chloride. The organic phase is removed, and the aqueous phase is extracted once again with 50 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulphate and the solvent is removed under reduced pressure. 8 g of 4-{benzyl[(6-chloropyridin-3-yl)methyl]amino}furan-2(5H)-one are obtained (this corresponds to 85% yield).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.O.[Cl-].[Na+].O>[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[N:9]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](N=Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of L-alanine t-butyl ester hydrochloride (1.03 g, 5.69 mmol), triethylamine (0.792 ml, 5.69 mmol) and magnesium sulfate (463 mg) in methylene chloride (11 ml) is added benzaldehyde (0.549 ml, 5.40 mmol) at room temperature under nitrogen atmosphere. The reaction mixture is stirred at room temperature for 17 hours, then diluted with water (10 ml), and brine, successively, and dried over magnesium sulfate and concentrated in vacuo to give N-(phenylmethylene)alanine t-butyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([C:14]#N)[CH2:13][CH2:12][CH2:11][CH2:10]1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:28])C>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH:14]=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CC1(c2cc(Cl)ccc2Cl)CCCC1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=CC1(c2cc(Cl)ccc2Cl)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To a stirred solution of 1-(2,5-dichloro-phenyl)-cyclopentanecarbonitrile (198) (32 g, 133.891 mmol) in dichloromethane (350 mL), was added Diisobutylaluminiumhydrid (25% in toluene, 191.0 mL, mmol) for 1 h at −70° C. and the reaction mixture was stirred 2 h at the same temperature (silica TLC, 10% ethyl acetate in hexane, Rf=0.7) The reaction mixture was quenched with saturated potassium sodium tartarate solution very slowly and stirred at room temperature for 16 h. It was extracted with dichloromethane, washed with brine and dried, concentrated to get the crude residue which was purified over nor mal silica gel (100-200 mesh) column chromatography using gradient eluent 2-20% ethyl acetate in hexane to get 1-(2,5-dichloro-phenyl)-cyclopentanecarbaldehyde (199) (25 g, 76.8%), as colorless liquid.
Reaction SMILES: C(C1C=C(NC2N=C(NC3C=CC=C(C(O)=O)C=3)C(F)=CN=2)C=CC=1)(O)=O.[OH:28][C:29]1[CH:30]=[C:31]([NH:39][C:40]2[N:45]=[C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]([O:55]C)=[O:54])=[C:49]([OH:57])[CH:48]=3)[C:43]([F:58])=[CH:42][N:41]=2)[CH:32]=[CH:33][C:34]=1[C:35]([O:37]C)=[O:36].[OH-].[Na+]>>[OH:28][C:29]1[CH:30]=[C:31]([NH:39][C:40]2[N:45]=[C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]([OH:55])=[O:54])=[C:49]([OH:57])[CH:48]=3)[C:43]([F:58])=[CH:42][N:41]=2)[CH:32]=[CH:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: COC(=O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)OC)c(O)c3)n2)cc1O
Agent: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Nc2ncc(F)c(Nc3ccc(C(=O)O)c(O)c3)n2)cc1O
Yield: 78.1 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of N2,N4-bis[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine (70 mg, 0.16 mmol) and NaOH (100 mg, 2.5 mmol) gave N2,N4-bis(3-hydroxy-4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (50 mg, 77%) as a white solid. 1H NMR (DMSO-d6): δ 7.21 (dd, J=1.5 and 8.7 Hz, 1H), 7.46-7.52 (m, 3H), 7.63 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 8.28 (d, J=3.3 Hz, 1H), 9.71 (s, 1H, NH), 9.79 (s, 1H, NH), 11.34 (br, 2H); 19F NMR (282 MHz, DMSO-d6): δ −161.10; LCMS: ret. time: 20.76 min.; purity: 84.65%; MS (m/e): 400.95 (MH+).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:33]([N:36]([CH3:54])[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[C@H:39]([CH2:44][S:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH2:38]1)([CH3:35])[CH3:34].[OH-].[Na+]>C1COCC1>[CH:33]([N:36]([CH3:54])[C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@H:39]([CH2:44][S:45]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)(=[O:46])=[O:47])[CH2:38]1)([CH3:35])[CH3:34]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: O=C(O)CCC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CCC(=O)c2cccc(C(F)(F)F)c2)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Commercially available 4-oxo-4-(3-trifluoromethylphenyl)butyric acid (45.5 mg, 0.185 mmol) was dissolved in dry THF (3 mL). To the above solution was added triethyl amine (18.7 mg, 0.185 mmol) and isobutyl chloroformate (25.3 mg, 0.185 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min. before the solution of (1R,3R,4S)—N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)cyclohexane-1,4-diamine (see 30b) (50 mg, 0.154 mmol) in dry THF (3 mL) was added. The resulting mixture was warmed up to room temperature. The reaction was completed by 0.5 h. The mixture was treated with 1 N NaOH (5 mL) and extracted with CH2Cl2 (10 mL×2) The organic extracts were washed with water, brine and evaporated. The residue was chromatographed on silica gel (4% NH4OH/MeOH/CH2Cl2) to give the product (53 mg). MS found:(M+1)+: 553.32
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)C=O.[BH4-].[Na+].C(Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
2.37 G. 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide under nitrogen is treated with 0.38 g. sodium borohydride at 20°-25° C. After one hour 2.4 ml. benzylbromide is added, the mixture left for 2 hours, then diluted with water, filtered, washed with cyclohexane, recrystallized from methanol yielding 1-acetamido-2-nitro-4-benzylthiobenzene.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([CH3:12])[C:9]=1[O:10][CH3:11])=[O:4].[NH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][CH3:25]>C(OCC)(=O)C>[C:13]([C:7]1[S:6][C:5]([C:3]([NH:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[CH2:24][CH3:25])=[O:4])=[C:9]([O:10][CH3:11])[C:8]=1[CH3:12])([O:15][CH3:16])=[O:14]
Reactant: CCN1CCCC1CN
Reactant: COC(=O)c1sc(C(=O)OC)c(OC)c1C
Solvent: CCOC(C)=O
Product: CCN1CCCC1CNC(=O)c1sc(C(=O)OC)c(C)c1OC

Procedure:
The above compound was prepared by heating dimethyl-3-methoxy-4-methyl-2,5-thiophene dicarboxylate and (±)2-(aminomethyl)-1-ethyl-pyrrolidine at 170° under nitrogen atmosphere. After column chromatography, the title compound was obtained, as its fumarate salt, m.p. 155°-156° ex ethyl acetate.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23]([O:25][CH3:26])=[O:24].Cl>C(Cl)Cl>[C:1]([C:21]1[N:17]([CH3:16])[C:18]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:20]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cccn1C
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C(=O)c2ccc(OC)cc2)n1C
Reaction time: 0.42 h

Procedure:
A solution of 17.0 g. (0.1 mole) of p-anisoyl chloride and 13.3 g. (0.1 mole) of aluminum chloride in 200 ml. of methylene chloride is added over 5 minutes to a solution of methyl 1-methylpyrrole-2-acetate in 100 ml. of methylene chloride at ice bath temperature. The mixture is stirred for 25 minutes and poured into ice acidified with dilute hydrochloric acid. The organic layer is separated and the aqueous layer is washed with methylene chloride. The combined organic solutions are washed successively with dimethylaminopropylamine solution, dilute hydrochloric acid and brine and then dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo to give a dark oily residue which is crystallized from 40 ml. of cold methanol. The solid is collected by filtration, washed with cold methanol and recrystallized from methanol to give white crystalline methyl 5-(p-anisoyl)-1-methylpyrrole-2-acetate, m.p. 104-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]1[C:12]([OH:14])=O.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:12]([C@H:7]1[CH2:8][CH2:9][C:10](=[O:11])[N:6]1[CH2:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=1)=[O:14])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc(Cl)c1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc(Cl)c1

Procedure:
Coupling of (R)-1-(3-chloro-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][NH:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][N:14]1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: c1ccc2c(c1)CNC2
Agent: c1ccc2ncncc2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Ic1ccc2ncnc(N3Cc4ccccc4C3)c2c1
Yield: 87.2 %

Procedure:
0.50 g of 4-chloro-6-iodoquinazoline, 0.27 g of 2,3-dihydro-1H-isoindole, 0.42 ml of triethylamine in 4 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted virtually completely (HPLC check, about 3 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is suspended in EA. The undissolved solid is filtered off, rinsed with water and dried, giving 0.56 g of 4-(1,3-dihydroisoindol-2-yl)-6-iodoquinazoline as slightly yellowish solid (yield 93%, content 94%); MS-FAB (M+H+)=373.8; Rf (polar method): 1.73 min. This is employed for the next step without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]([F:53])([F:52])[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:21]=[C:22]([C:41]3[N:45](C4CCCCO4)[N:44]=[CH:43][CH:42]=3)[C:23]([N:26]3[CH2:30][CH2:29][C:28]([CH2:32][NH:33]C(=O)OC(C)(C)C)([OH:31])[CH2:27]3)=[N:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1>C(Cl)Cl>[NH2:33][CH2:32][C:28]1([OH:31])[CH2:29][CH2:30][N:26]([C:23]2[C:22]([C:41]3[NH:45][N:44]=[CH:43][CH:42]=3)=[CH:21][C:20]([C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([O:10][C:9]([Cl:8])([F:52])[F:53])=[CH:16][CH:15]=3)=[O:19])=[CH:25][N:24]=2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccnn2C2CCCCO2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
TFA (0.288 mL, 3.74 mmol) was added to a solution of tert-butyl ((1-(5-((4-(chlorodifluoromethoxy)phenyl)carbamoyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-2-yl)-3-hydroxypyrrolidin-3-yl)methyl)carbamate (Stage 83.1, 74 mg, 0.112 mmol) in DCM (0.6 mL) and the RM was stirred at RT for 4 h. The solvent was evaporated off under reduced pressure and the crude product was purified by preparative HPLC. The fractions containing pure product were combined, the TFA was removed using a PL HCO3-MP cartridge and the solvent was evaporated off under reduced pressure to afford the title compound as a beige solid. UPLC-MS (Condition 8) tR=0.78 min, m/z=479.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.87 (m, 2H) 2.59 (s, 2H) 3.07 (s, 1H) 3.16-3.48 (m, 3H) 4.74 (br. s, 1H) 6.39 (d, J=1.83 Hz, 1H) 7.34 (d, J=8.93 Hz, 2H) 7.67-7.88 (m, 1H) 7.90 (s, 2H) 8.04 (d, J=2.32 Hz, 1H) 8.74 (s, 1H) 10.20 (s, 1H) 12.93 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=3)[C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:16])([F:17])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][CH:25]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:42])[F:43])[CH:36]=3)[C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCNC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)CCNC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
78 mg (0.12 mmol) of the compound of Example 13 were dissolved in 2.3 ml of methanol, and 360 μl of a 1M aqueous lithium hydroxide solution (0.36 mmol) were added. The mixture was stirred at RT for 1 h and then adjusted to pH 2 by addition of 1N hydrochloric acid, diluted with a little DMSO and separated by preparative HPLC [Method 6]. This gave 67 mg (88% of theory) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15](OS(C)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:37].[Na+].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([SH:37])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(COC(=O)C2=C(OS(C)(=O)=O)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: [SH-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)C2=C(S)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
(a-1) To a solution of 16.5 g (31.3 mM) of p-methoxybenzyl 7β-phenylacetamido-3-methanesulfonyloxy-3-cephem-4-carboxylate in 70 ml of N,N-dimethylformamide were added a solution of 2.75 g (34.4 mM) of 70% sodium hydrosulfide in 30 ml of N,N-dimethylformamide and 6.06 g (47.0 mM) of diisopropylethylamine at -20° C., and the mixture was stirred at 0° C. for one hour. After the reaction, 1 l of water was added, the mixture was washed with ethyl acetate (200 ml×3), and the aqueous layer was adjusted to pH 1 with 3% hydrochloric acid and extracted with ethyl acetate (500 ml and 200 ml). The extract was washed with a saturated aqueous sodium chloride solution (300 ml×2) and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was dissolved in 200 ml of dichloromethane, and the solution was added dropwise to 700 ml of diethyl ether with stirring. The precipitate formed was collected by filtration to give 7.24 g of p-methoxybenzyl 7β-phenylacetamido-3-mercapto-3-cephem-4-carboxylate.