Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:28]N1C(=O)CCC1=O>O1CCCC1.CCOCC>[Cl:28][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:11]2[CH:12]=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (100 mg, 0.346 mmol) in 4 ml of tetrahydrofuran at −78° C. under N2 was added 2.5 M n-butyllithium in hexanes (22 μl, 2 eq). The mixture was stirred at −78° C. for 30 min and N-chlorosuccinimide (2.2 eqv) was then added. The mixture was allowed to warm to room temperature after 30 min and was stirred at room temperature for 1 hr. The mixture was diluted with ether and washed with 1N hydrochloric acid solution. The aqueous layer was basified with 1N sodium hydroxide solution and extracted thoroughly with ether. The combined organic layers were dried on anhydrous magnesium sulfate, filtered and evaporated. Purification by chromatography yielded 7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (71%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>N1C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=2)(=[O:28])=[O:29])=[C:3]([CH:13]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Solvent: c1ccncc1
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture containing 24.9 g of 2-amino-5-chloro-2'-fluorobenzophenone and 22.1 g of 4-nitrophenylsulfonyl chloride is refluxed for 10 hours in pyridine. It is evaporated to dryness, water and ethyl acetate are then added and the ethyl acetate phase is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The expected product precipitates on evaporation; it is filtered off and recrystallized from a DCM/isopropyl ether mixture to give 20 g.
Reaction SMILES: [OH:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20]>C1COCC1.FC(F)(F)C(O)=O>[CH2:19]([O:21][CH:22]([O:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH3:23])[CH3:20]
Reactant: C=COCC
Reactant: CC1CC(=O)C2CCCCCCCCCC2(O)C1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C)OC12CCCCCCCCCC1C(=O)CC(C)C2
Yield: 81.9 %

Procedure:
A mixture of 2 g (7.9 mmol) of (16) and 0.84 ml (8.7 mmol) ethyl vinyl ether in 2 ml THF was stirred at room temperature in the presence of 20 μl (0.32 mmol) trifluoroacetic acid for 2 days. After a short column filtration (SiO2) using diethyl ether as eluent and evaporation of the solvent 2.6 g of the crude product (18) was obtained. Flash chromatography, using SiO2 and cyclohexanelEtOAc=95:5 as eluent, afforded 2.10 g (82%) of (18) as a ˜1:1 mixture of diastereomers.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:11]1([CH2:18][C:19]2[S:20][C:21]([C:24]([NH:26][NH2:27])=O)=[CH:22][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.BrC(Cl)(Cl)C(Br)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C(#N)C>[CH2:1]([NH:8][C:9]1[O:10][C:24]([C:21]2[S:20][C:19]([CH2:18][N:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:23][CH:22]=2)=[N:26][N:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Reactant: O=C=NCc1ccccc1
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1ccc(CNc2nnc(-c3ccc(CN4CCCCCC4)s3)o2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 33.1 %

Procedure:
0.13 ml (1.05 mmol) of benzyl isocyanate was added to 25 ml of acetonitrile solution containing 253 mg (1.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, and the mixture was stirred at room temperature for 40 hours, 718 mg (2.2 mmol) of 1,2-dibromo-1,1,2,2-tetrachloroethane, 1.22 ml of triethylamine and 1.16 g of triphenylphosphine were added, and then the mixture was stirred at room temperature for 9 hours. The reaction solution was concentrated, chloroform was added to the resulting residue, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 122 mg of the title compound in its free form. By subjecting 117 mg of this compound to salt formation using 27 mg of oxalic acid, 122 mg of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]2)=[CH:4][CH:3]=1.CN([CH:19]=[O:20])C>C1COCC1.C(OCC)C>[CH3:12][C:9]1([CH3:13])[O:8][CH:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([CH:19]=[O:20])=[CH:3][CH:4]=2)[CH2:11][O:10]1
Reactant: CN(C)C=O
Reactant: CC1(C)OCC(Cc2ccc(Br)cc2)O1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OCC(Cc2ccc(C=O)cc2)O1
Reaction time: 0.5 h

Procedure:
At −78° C. buthyllithium (3.98 mL, 6.37 mmol, 1.6 M solution in hexanes) is added to a solution of 4-(4-bromo-benzyl)-2,2-dimethyl-[1,3]dioxolane (1.57 g, 5.79 mmol) in THF (50 mL). The reaction mixture is stirred at −78° C. for 2 h before DMF is slowly added (2.12 g, 28.95 mmol). Stirring is continued for 30 min at −78° C., then at rt for 1 h. The mixture is diluted with diethyl ether (200 mL) and washed with sat. aq. NaHCO3 and water. The organic layer is dried over MgSO4 and evaporated to leave 4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-benzaldehyde (1.29 g) as a pale brownish oil; LC-MS: tR=0.87 min; 1H NMR (CDCl3): δ 9.98 (s, 1H), 7.84-7.79 (m, 2H), 7.47-7.37 (m, 2H), 4.35 (p, J=6.4 Hz, 1H), 4.02 (dd, J=5.9, 8.2 Hz, 1H), 3.65 (dd, J=7.0, 8.2 Hz, 1H), 3.04 (dd, J=7.0, 14.1 Hz, 1H), 2.90 (dd, J=5.9, 13.5 Hz, 1H9, 1.44 8s, 3H), 1.36 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[F:16][C:17]([CH3:22])([CH3:21])[C@H:18]([NH2:20])[CH3:19].FC(C)(C)[C@H](NC1C2N(C=CC=2)N=CC=1C(N)=O)C.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:20][C@H:18]([CH3:19])[C:17]([F:16])([CH3:22])[CH3:21])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](N)C(C)(C)F
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: C[C@@H](Nc1c(C(N)=O)cnn2cccc12)C(C)(C)F
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)F
Temperature: 25 °C

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 519 mg, 1.89 mmol), (R)-2-fluoro-1,2-dimethyl-propylamine hydrochloride salt (402 mg, 2.84 mmol, from Intermediate 2, step 3), and diisopropylethylamine (0.99 mL, 5.68 mmol) in NMP (2.0 mL) was heated to 100° C. for 1 hour in the CEM microwave. The mixture was cooled to rt, diluted with water and the resulting precipitate then filtered and allowed to air dry. This afforded 595 mg (92%) of a pale white solid as the title compound. HPLC (condition B): retention time=3.67 min. LCMS (condition B): m/z 343.1, 345.1. 1H NMR (500 MHz, CD3OD) δ ppm 8.16 (1 H, s), 7.67 (1 H, d, J=1.66 Hz), 7.04 (1 H, d, J=1.39 Hz), 4.11-4.60 (1 H, m), 1.45-1.54 (6 H, m), 1.43 (3 H, d, J=6.66 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>C1COCC1.CN(C=O)C>[CH:22]([NH:26][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)N
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCC(C)NC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Sec-butylamine (253 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated. It was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (89 mg, 70%). NMR 1H (ppm, CDCl3): 7.95 (s, 1H), 7.68 (d, J3=7.51 Hz, 2H), 7.59 (d, J3=7.63 Hz, 2H), 7.50-7.33 (m, 4H), 5.97 (br. s., 1H), 4.30 (hept., J3=6.86 Hz, 1H), 1.58 (quint., J3=7.26 Hz, 1H), 1.23 (d, J3=6.56 Hz, 3H), 0.97 (t, J3=7.36 Hz, 3H).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][C:18]([NH:25][C:26](=[O:35])[C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[C:15]([CH3:37])([CH3:36])[C:14]2=[O:38])=O)=CC=1)([O-])=O.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:39]([NH:46][C:11]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[C:15]([CH3:36])([CH3:37])[C:14]1=[O:38])=[O:10])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)C3(C)C)cc1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(C(=O)NCc2ccccc2)C(=O)C3(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-(4-methoxy-benzoylamino)-3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-indole-1-carboxylic acid 4-nitro-phenyl ester (54 mg) in CH2Cl2 (10 ml) is added benzyl amine (44 μl) at RT. The reaction mixture is stirred at RT for 20 h. After an aqueous work-up and concentration in vacuo, the residue is dissolved in acetic acid (3 ml) and iron (60 mg; powder) is added. The mixture is stirred in a microwave apparatus at 150° C. for 900 s. After filtration and evaporation of the solvent the crude material is purified by preparative RP-HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:16]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>O1CCCC1>[Cl:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:13](=[O:16])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Temperature: 25 °C
Yield: 250.3 %

Procedure:
To a stirred warm (50° C.) solution of 2-amino-6-chlorobenzoic acid (2.00 g, 11.7 mM) in tetrahydrofuran (20 mL) was added bis(trichloromethyl)carbonate (1.20 g, 4.10 mM). A vigorous gas evolution ensued along with the formation of a precipitate. The reaction mixture was allowed to cool to room temperature and the precipitate was collected by filtration and washed with ether. Air drying gave the title compound as a tan solid (2.0 g, 87%); MS(CI): 198 (M+H).
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][OH:12].B.C1COCC1.[OH-].[Na+]>C1COCC1.O>[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][OH:12]
Reactant: CON=Cc1cc(-c2ccccc2)ccc1CO
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(-c2ccccc2)ccc1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the oxime from step B (0.51 g, 2.1 mmol) in THF (15 mL) at 0° C. was added BH3.THF (1M in hexane; 8 mL, 8 mmol) and the resulting solution was stirred at room temperature for 16 h then heated to reflux for 24 h. The solution was cooled to 0° C. and 1N NaOH (10 mL) was added slowly. After 1 h, the mixture was diluted with water, extracted with EtOAc (3×), washed with brine, dried and evaporated to give the title compound as an oil. This was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]([C:17]([O:19][CH3:20])=[O:18])[N:4](C)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Cl)[CH:9]=2)=[CH:6][N:7]=1.C(#N)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[NH2:1][C:2]1[C:3]([C:17]([O:19][CH3:20])=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)C1C(N)=NC=C(c2cccc(CCl)c2)N1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2cccc(CNCc3ccccc3)c2)cnc1N
Temperature: 25 °C
Reaction time: 144 h
Yield: 12.8 %

Procedure:
Methyl 3-amino-6-(3-chloromethylphenyl)-N-methylpyrazine-2-carboxylate (30.6 mg, 0.11 mmol.) was taken into acetonitrile (2 mL) and THF (1 mL) followed by addition of benzylamine (12 uL, 0.11 mmol) then diisopropylethylamine (20 uL, 0.11 mmol) and the mixture was allowed to stir at room temperature over six days. The mixture was then concentrated in vacuo and the residue purified by silica gel flash chromatography initially using ethyl acetate as eluent followed by elution with 10% methanol in dichloromethane. The pure fractions were combined and concentrated then dried in vacuo to give methyl 3-amino-6-(3-{[(phenylmethyl)amino]methyl}phenyl)pyrazine-2-carboxylate (4.9 mg, 13% yield) as a yellow amorphous solid: MS (EI) for C20H21N4O2: 349 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:10][C:11]([C:13]2[C:14]3[CH:21]=[N:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C:15]=3[CH:16]=[N:17][CH:18]=2)=[O:12])[CH2:8][CH3:9])[CH2:2]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCN(S(C)(=O)=O)C1
Reaction time: 18 h

Procedure:
The solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid(1-piperidin-3-yl-propyl)-amide (0.10 g, 0.26 mmol) and Et3N (58 μL, 0.42 mmol) in dichloromethane (3 mL) was added methanesulfonyl chloride (31 μL, 0.39 mmol). After 18 hours, the cloudy mixture was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-95% EtOAc in hexanes to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>O1CCCC1.O>[C:17]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
A solution of ethyl 5-hydroxy-1-methyl-1H-indole-2-carboxylate (2.2 g, 10.0 mmol) in 50 mL of tetrahydrofuran is treated dropwise with acetyl chloride (0.80 mL, 0.88 g, 11.3 mmol) followed by triethylamine (1.6 mL, 1.2 g, 11.5 mmol). The mixture is stirred at room temperature for 16 hours, then diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (anhydrous magnesium sulfate), and evaporated. Recrystallization of the residue from ether-pentane gives 2.0 g (77%) of product; mp 87°-89° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(C1C=C(C)C=[C:15]([C:20](C)(C)C)[C:14]=1[OH:24])(C)(C)C.[C:25](Cl)(=[O:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.Cl>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][O:8][C:25](=[O:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:5][CH2:6][CH2:7][O:8][C:14](=[O:24])[CH:15]=[CH2:20])=[O:31])=[CH:28][CH:27]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)OCCO
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCOC(=O)c1ccc(C(=O)OCCOC(=O)C=C)cc1
Temperature: 0 °C

Procedure:
A 500 ml round-bottom flask was initially charged with 64.1 g of hydroxyethyl acrylate in 100 ml of pyridine/toluene (1:1, v/v) together with 0.1 g of 2,6-di-tert-butyl-4-methylphenol at 0° C. and 56.1 g of terephthaloyl chloride were slowly added dropwise. The mixture was stirred at room temperature until the hydroxyethyl acrylate content had fallen below 0.1%. Thereafter, the mixture was poured onto 0.5 l of ice-water and acidified with 1 N aqueous hydrochloric acid. The aqueous phase was extracted three times with 0.5 l each time of tert-butyl methyl ether. The organic phase was washed with 10% sodium hydrogencarbonate solution, dried over sodium sulfate and filtered. Another 0.1 g of 2,6-di-tert-butyl-4-methylphenol was added and the organic solvent was distilled off. The product was obtained as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:51])/[C:16](/[N:24]2[CH:27]([S:28]S(C3C=CC(C)=CC=3)(=O)=O)[CH:26]([NH:39][C:40](=[O:49])[CH2:41][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:25]2=[O:50])=[C:17](\N2CCCC2)/[CH3:18])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(OCC)(=[O:61])C>C(#N)C>[C:1]1([CH:7]([O:14][C:15]([C@@H:16]2[N:24]3[C:25](=[O:50])[C@@H:26]([NH:39][C:40](=[O:49])[CH2:41][O:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C@H:27]3[S:28][CH2:18][CH:17]2[OH:61])=[O:51])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: C/C(=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1)N1CCCC1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 139.32 g (160 mmol) of a mixture consisting of the 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(1-pyrrolidinyl)-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 1350 ml of dry acetonitrile is heated at 80° for approximately 6 hours under nitrogen until it is no longer possible to detect any starting material by thin layer-chromatography (silica gel; toluene/ethyl acetate 1:1). The heating bath is removed, the reaction mixture containing the 7β-phenoxyacetamido-3-(1-pyrrolidinyl)-3-cephem-4-carboxylic acid diphenylmethyl ester is left to cool for a further 11/2 hours, 550 ml of 0.1 N hydrochloric acid are added and the mixture is further stirred for 81/2 hours at room temperature. The reaction mixture is diluted with ethyl acetate, the water is separated off, the organic phase is washed twice with 2 N hydrochloric acid and three times with water, dried over sodium sulphate, concentrated by evaporation in vacuo and dried under a high vacuum. The residue, containing the 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16](=O)[CH3:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:17])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12]
Reactant: CC(=O)c1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)C(F)F)c(Cl)c1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (5.11 g, white solid) from 1-(5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanone (4.62 g, 16.2 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (2.94 g, 24.3 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:43]1([CH2:49][NH2:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:43]1([CH2:49][NH:50][C:28]([C:25]2[C:24]3[CH:33]=[C:20]([CH2:19][OH:18])[C:21]([N:35]4[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]4)=[C:22]([F:34])[C:23]=3[O:27][N:26]=2)=[O:30])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: NCC1CCCCC1
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)NCC4CCCCC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and cyclohexylmethanamine
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]O.C(N(C(C)C)CC)(C)C.O>ClCCl>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[O:31][CH3:30])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccccc1CO
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1CN1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 63 %

Procedure:
To a solution of the compound (0.20 g) obtained in Example 1, 2-methoxybenzyl alcohol (0.075 g) and diisopropylethylamine (0.24 g) in dichloromethane (2 ml), EPPA (0.20 g) was added, and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound as colorless oil (0.15 g, 62%).