Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH3:16])[NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH3:16])[NH:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](C)Nc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Nc1ncccc1N
Yield: 85 %

Procedure:
A solution of (S)-N-(3-nitro-2-pyridinyl)alanine ethyl ester (5.0 g, 0.0209 mole) in tetrahydrofuran (60 ml) was hydrogenated over 5% palladium on carbon (0.5 g) keeping the temperature of the solution at approximately room temperature to give (S)-N-(3-amino-2-pyridinyl) alanine ethyl ester. The solution of the reduction product was cooled in an ice bath and dried over magnesium sulfate under nitrogen. The solution was filtered and 4-chlorobenzoyl chloride (3.84 g, 0.022 mole) and triethylamine (2.22 g, 0.022 mole) were added simultaneously, dropwise, to the cooled and stirred solution. The reaction mixture was stirred at room temperature overnight under nitrogen and the solvents were removed under reduced pressure. The residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed twice with water, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to an oil weighing 6.2 g (85% yield). A 2.2-g portion of the oil was dissolved in isopropyl alcohol and the solution was acidified wtih ethereal hydrogen chloride. The resulting solid was filtered and dried under high vacuum to give 1.70 g of title compound, mp 172°-177° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]([CH3:11])=[CH:3][C:4]1[S:8][N:7]=[C:6]([CH2:9][Cl:10])[N:5]=1.[CH2:12]([C:16]1[O:20][N:19]=[C:18]([CH2:21][Cl:22])[N:17]=1)[C:13]([CH3:15])=O.[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O)([O-:25])=[O:24]>C(O)(C)C>[CH3:15][C:13]1[NH:1][C:2]([CH3:11])=[C:3]([C:4]2[S:8][N:7]=[C:6]([CH2:9][Cl:10])[N:5]=2)[CH:29]([C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)[C:12]=1[C:16]1[O:20][N:19]=[C:18]([CH2:21][Cl:22])[N:17]=1
Reactant: CC(N)=Cc1nc(CCl)ns1
Reactant: CC(=O)Cc1nc(CCl)no1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Product: CC1=C(c2nc(CCl)no2)C(c2cccc([N+](=O)[O-])c2)C(c2nc(CCl)ns2)=C(C)N1
Yield: 15.5 %

Procedure:
A stirred mixture of 343 mg of 5-(2-amino-1-propenyl)-3-chloromethyl-1,2,4-thiadiazole, 316 mg of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole and 273 mg of 3-nitrobenzaldehyde in 5 ml of isopropyl alcohol was heated under reflux for 10 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel using benzene-ethyl acetate (5:1) as eluent to give 134 mg of 1,4-dihydro-2,6-dimethyl-3-(3-chloromethyl-1,2,4-oxadiazol-5-yl)-5-(3-chloromethyl-1,2,4-thiadiazol-5-yl)-4-(3-nitrophenyl)pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[C:3]=1[NH2:10].[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>O=P(Cl)(Cl)Cl>[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]2[NH:10][C:3]3[C:4]([CH3:9])=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(N)c(N)c1C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2c1C

Procedure:
2-(4-Nitrophenyl)-4,5-dimethyl benzimidazole was prepared by mixing 1,2-diamino-3,4-dimethylbenzene (1.36 g, 9.8 mmole with 4-nitrobenzoic acid (1.67 g, 9.8 mmole) and dissolved in POCl3 (10 ml) and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice. The resulting solid was filtered, washed with NaHCO3 and used without further purification.
Reaction SMILES: [C:1]1([S:7][C:8]2[C:13]([CH2:14]O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:18]>CC#N>[Cl:18][CH2:14][C:13]1[C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCc1cccnc1Sc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: ClCc1cccnc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-Phenylsulfanyl-pyridin-3-yl)-methanol (20 mg, 0.09 mmol) obtained in Step B was dissolved in CH3CN (20 mL), and SOCl2(13 uL, 0.18 mmol) was added dropwise thereto at 0° C. The mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:9][O:10][C:11]1[CH:36]=[CH:35][C:14]([CH2:15][O:16][CH2:17][C@H:18]([CH3:34])[C@H:19]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C@@H:20]([CH3:25])[CH2:21][CH2:22][CH2:23][OH:24])=[CH:13][CH:12]=1.N1C=CN=C1>C(Cl)Cl>[Si:27]([O:26][C@H:19]([C@@H:20]([CH3:25])[CH2:21][CH2:22][CH2:23][O:24][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[C@@H:18]([CH3:34])[CH2:17][O:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:36][CH:35]=1)([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TBSCl (0.92 g, 6.11 mmol) was added to a solution of above alcohol 61 (2.51 g, 6.11 mmol) and imidazole (0.46 g, 6.76 mmol) in CH2Cl2 (20 mL). The resulting slurry was stirred for 1 h at room temperature. The organic phase was washed with water (100 mL) and brine (2×100 mL). After drying over MgSO4, filtration and evaporation under vacuum, the residue was used directly in next step: IR (CHCl3) 2930, 2856, 1613, 1513, 1471, 1360, 1250, 1098, 1040, 835, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 6.90-6.88 (m, 2H), 4.46 (d, J=11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 3.81 (s, 3H), 3.62 (t, J=6.3 Hz, 2H), 3.58-3.52 (m, 2H), 3.28 (dd, J=8.8, 7.7 Hz, 1H), 2.02-1.94 (m, 1H), 1.66-1.54 (m, 2H), 1.52-1.39 (m, 2H), 1.28-1.18 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.94 (s, 9H), 0.92 (s, 9H), 0.89 (d, J=6.8 Hz, 3H), 0.09 (s, 6H), 0.07 (s, 3H), 0.06 (3H); 13C NMR (75 MHz, CDCl3) δ 159.0, 130.9, 129.0, 113.6, 77.5, 72.8, 72.6, 63.4, 55.1, 38.0, 36.3, 31.1, 30.8, 26.1, 25.9, 18.4, 18.3, 15.2, 14.4, −3.8, −4.1, −5.3; LRMS (ESI) 547.4 [M+Na]+413.3, 212.1; HRMS (ESI) calcd for C29H56O4Si2Na 547.3615 [M+Na]+, found 547.3638; [α]20D−9.9 (c 2.5, CHCl3).
Reaction SMILES: Br[C:2]1[C:3]2[NH:22][N:21]=[C:20]([NH:23][CH2:24][CH3:25])[C:4]=2[CH:5]=[N:6][C:7]=1[NH:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])=[O:10].O1CCOC[CH2:27]1.C[Zn]C>CN1C(=O)CCC1>[CH2:24]([NH:23][C:20]1[C:4]2[CH:5]=[N:6][C:7]([NH:8][C:9]([NH:11][C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])=[O:10])=[C:2]([CH3:27])[C:3]=2[NH:22][N:21]=1)[CH3:25]
Reactant: CCNc1n[nH]c2c(Br)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Reactant: C1COCCO1
Agent: C[Zn]C
Solvent: CN1CCCC1=O
Product: CCNc1n[nH]c2c(C)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 100 °C
Reaction time: 17 h

Procedure:
An oven-dried 5 mL microwave vial was charged with (R)-1-(7-bromo-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (100 mg, 0.198 mmol), PdOAc2 (8.5 mg, 0.038 mmol), and PCy3-BF4H (30 mg, 0.08 mmol). The reaction mixture was sealed under N2, then charged with dioxane (1.0 mL) and NMP (0.25 mL), followed by drop-wise addition of dimethylzinc (1.653 mL, 1.984 mmol, 1.2 M in toluene). The reaction was heated to 100° C. and stirred for 17 h. The reaction was quenched with TFA until gas evolution ceased and then poured into sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-20% MeOH/DCM) followed by purification via mass-triggered reverse-phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)-1-(3-(ethylamino)-7-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C18H22N6O [M+1]+ 339. found 339. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.42-7.19 (m, 5H), 5.01 (q, J=6.9 Hz, 1H), 3.36 (m, 2H), 2.29 (s, 3H), 1.53 (d, J=7.0 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH3:17]
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure A above and using 3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25 % EtOAc/hexanes as the eluant).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.Cl[C:13]1[O:14][CH:15]=[CH:16][N:17]=1.CN1[C:23](=O)[CH2:22][CH2:21][CH2:20]1.O>CCOC(C)=O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[O:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[N:17]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: CN1CCCC1=O
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Clc1ncco1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2[nH]c(C)c(-c3nc4ccccc4o3)c2c1

Procedure:
2,5-dimethyl indole (0.3 g), 2-chlorooxazole (0.47 g) and NMP (2 ml) were heated in a microwave at 100 watts for 20 min at 160° C. Water ane EtOAc were added and separated, the aqueous phase was re-extracted with EtOAc (×4). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The precipitate was triturated with EtOAc then recrystallised from methanol to give the title compound (0.19 g).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([OH:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[O:18][CH2:17][C:16](=[O:27])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](O)COc1cc(F)ccc1-3
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)COc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the foregoing alcohol (from Step 3) in DCM (0.06 M) was added DMP (1.5 eq.), and the mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc and washed with a 1:1 (v/v) mixture of sodium thiosulfate and sodium hydrogen carbonate (both saturated aqueous solutions), then with brine. Drying over Na2SO4, filtration and concentration i. vac. gave the crude product, which was used without further purification (92%); MS (ES+) m/z 422 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.C(O)(=O)C.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[OH:7][C:5]1[N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]=[C:3]([C:2]([F:1])([F:11])[F:12])[CH:4]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 10 °C
Yield: 97.7 %

Procedure:
18.4 g (0.1 mole) of ethyl 4,4,4-trifluoroacetoacetate was dissolved in 12.0 g (0.2 mole) of acetic acid. The solution was cooled to 10° C. or lower with stirring. Thereto was dropwise added, in 0.5 hour, 11.8 g (0.11 mole) of phenylhydrazine. After the dropwise addition, the mixture was stirred at room temperature for 1 hour and successively at 80° C. for 5 hours to give rise to a reaction. After the reaction, the mixture was cooled to room temperature. Thereto were added 100 ml of water. The resulting crystals were collected by filtration, washed with 50 ml of water twice, and dried in a hot-air drier, to obtain 22.3 g (yield: 98.0%) of a title compound as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[C:4]2[C:22]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[S:16][C:5]2=[N:6][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15].C(N(CC)CC)C.[O:38]1CC[CH2:40][CH2:39]1.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[C:39]([N:19]1[CH2:20][CH2:21][C:22]2[C:4]3[C:5]([S:16][C:17]=2[CH2:18]1)=[N:6][C:7]([CH2:8][N:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]1=[O:14])=[C:2]([Cl:1])[C:3]=3[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:38])[CH3:40]
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCNC4)cc1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CCN(C(C)=O)C4)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution mixture containing the compound obtained in Example 1 (1 g), triethylamine (343 mg) and tetrahydrofuran (50 ml) was added acetic anhydride (254 mg) while cooling with ice. After stirring for 2 hours at room temperature, the reaction solution was concentrated under reduced pressure. The residue thus obtained was dissolved in ethyl acetate (50 ml), washed with water, dried (MgSO4) and then the solvent was distilled off to obtain the title compound (582 mg, 53%). The product was recrystallized from tetrahydrofuran. A colorless prism crystal. M.p. 266 to 267° C.
Reaction SMILES: [C:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2].Cl[C:14]1[N:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>>[C:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH:5]1[CH2:9][CH2:8][N:7]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]3[CH2:24][CH3:25])=[CH:16][C:15]=2[F:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCCN(C(C)=O)C1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Product: CCCN(C(C)=O)C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CC)C1

Procedure:
3-(N-Acetyl-n-propylamino)pyrrolidine was allowed to react with 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid in the same manner as described above and yield 7-[3-(N-acetyl-n-propylamino)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Subsequent hydrolysis of this compound with hydrochloric acid gave 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-N-propylamino-1-pyrrolidinyl)-1,8-naphthyridine-3-carboxylic acid hydrochloride, m.p. about 270° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:28])[CH:12]([C:14]1[N:19]=[C:18]([O:20]C)[CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:15]=1)[CH3:13].[I-].[K+].C(#N)C.C[Si](C)(C)Cl>C(OCC)(=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:28])[CH:12]([C:14]1[NH:19][C:18](=[O:20])[CH:17]=[C:16]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:15]=1)[CH3:13]
Reactant: COc1cc(N2CCOCC2)nc(C(C)C(=O)N2CCc3c(F)cccc32)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C(=O)N1CCc2c(F)cccc21)c1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 80.5 %

Procedure:
210 mg of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-morpholin-4-yl-pyrimidin-2-yl)propan-1-one, 270 mg of potassium iodide, 7 ml of acetonitrile and 208 ml of trimethylchlorosilane are added to a microwave tube. After microwave irradiation for one hour at a temperature of 100° C., the reaction medium is diluted with 20 ml of ethyl acetate and 20 ml of water. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is stirred in the presence of 5 ml of ethyl acetate and 20 ml of petroleum ether. The solid obtained is filtered off and then dried under reduced pressure. 163 mg of 2-[1-(4-fluoro-2,3-dihydro-1H-indol-1-yl)-1-oxopropan-2-yl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are thus obtained in the form of a pale yellow solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]2[CH2:16][CH2:15]2)[C:11]=1[O:12][CH3:13])[C:6]([Cl:26])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1C1CC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1C1CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-5-cyclopropyl-4-methoxybenzoic acid (200 mg), toluene (2 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.10 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained resiue was azeotroped with toluene and used for the synthesis of (d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:18][O:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:21]#[N:22].[Na+].O.C(OCC)(=O)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:21]#[N:22])[CH2:10][C@H:9]1[CH2:18][O:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Yield: 97.5 %

Procedure:
A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-methanesulfonyloxy-2-methoxymethylpyrrolidine (3.3 g) and sodium cyanide (1.75 g) in dimethyl sulfoxide (35 ml) was heated for three hours and forty minutes at 92° C. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl (1:1, V/V) to give (2S,4S)-1-(tert-butoxycarbonyl)-4-cyano-2-methoxymethylpyrrolidine (2.5 g).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[NH2:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]1[O:27][CH3:28].[Cl:29][C:30]1[N:31]=[C:32]([C:37](OCC)=[O:38])[NH:33][C:34]=1[CH2:35][CH3:36].Cl>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[Cl:29][C:30]1[N:31]=[C:32]([C:37]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][C@H:15]2[O:27][CH3:28])=[O:38])[NH:33][C:34]=1[CH2:35][CH3:36]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCOC(=O)c1nc(Cl)c(CC)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
WSC hydrochloride (580 mg, 3.02 mmol) and DMAP (125 mg, 1.02 mmol) were added to a solution of tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained in Example (1e) (230 mg, 0.99 mmol) and ethyl 4-chloro-5-ethyl-1H-imidazole-2-carboxylate obtained in Example (1d) (85 mg, 0.49 mmol) in DMA (5 mL), and the mixture was stirred at room temperature for three hours. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1, ethyl acetate) to obtain 117 mg of the title compound as a pale yellow solid (62%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)=[O:9])=[CH:4][CH:3]=1.[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH3:25])[CH2:22][S:23][C@H:18]12>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]4[NH:28][N:29]=[N:30][N:31]=4)[CH3:25])[CH2:22][S:23][C@H:18]23)=[O:13])=[O:9])=[CH:6][CH:7]=1
Reactant: CCC(C(=O)O)S(=O)c1ccc(O)cc1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CCC(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)S(=O)c1ccc(O)cc1

Procedure:
456 mg. of 2-(p-hydroxyphenylsulfinyl)butyric acid and 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 237 mg. of 7-[2-(p-hydroxyphenylsulfinyl)butyramido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:26][CH:27]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: ClCCl
Product: CN(C)c1nc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)nc2ccccc12
Temperature: 130 °C
Yield: 87.2 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (0.5 g, 2.6 mmol) and (4-amino-phenyl)-carbamic acid tert-butyl ester (0.5 g, 2.6 mmol) in CH2Cl2 (2 mL) was heated by Smith Synthesizer at 130° C. for 20 min. The mixture was concentrated to give [4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester as a pale yellow solid (0.86 g, 87%). The reaction was repeated six times, and the total product combined was 8.5 g. To a solution of above product (8.5 g, 22.4 mmol) in MeOH (250 mL) was added 4 M HCl in dioxane (8.4 ml, 33.6 mmol) dropwise, and the mixture was stirred at ambient temperature for overnight. The mixture was concentrated to give N2-(4-amino-phenyl)-N4,N4-dimethyl-quinazoline-2,4-diamine hydrochloride as a pale pink solid (6.2 g, 87.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22](COCC[Si](C)(C)C)[S:21]3(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH:13]=1.I[CH:57]([CH3:59])[CH3:58]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][N:52]([CH:57]([CH3:59])[CH3:58])[C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[NH:22][S:21]3(=[O:34])=[O:35])=[CH:16][CH:15]=2)[CH:13]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O
Reactant: CC(C)I
Product: CC(C)N1CCN(c2ccc(-c3ccc(Cc4nc(-c5ccc(Cl)cc5Cl)cn4-c4ccc(N5CC(=O)NS5(=O)=O)cc4)cc3)cc2)CC1=O

Procedure:
4-[4′-(4-(2,4-Dichloro-phenyl)-1-{4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxy methyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one (17 mg, 0.02 mmol) was treated as described in general procedure L (using 2-iodopropane) and general procedure W stepwise to give 4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-1-isopropyl-piperazin-2-one.