Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.O>CN(C=O)C>[Br:26][C:18]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=12
Reactant: N#Cc1ccc2cc(-c3ccc(F)cc3)nn2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(Br)c(-c3ccc(F)cc3)nn2c1
Yield: 60.4 %

Procedure:
A solution of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carbonitrile (0.6 g 2.53 mmol) and NBS (0.5 g 2.8 mmol) in DMF (10 ml) was stirred at room temperature for 2 hr. The reaction was poured into water (100 ml) and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with water (30 ml), brine (30 ml), dried and purified by biotage chromatography. Elution with cyclohexane/ethyl acetate (20:1) gave the title compound as a white solid (0.483 g 61%). NMR: (CDCl3): δ 7.21 (2H, t) 7.30 (1H, dd) 7.62 (1H, dd) 8.06 (2H, m) 8.80 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: NS(=O)(=O)c1ccc(F)c(F)c1
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Temperature: 110 °C
Yield: 74.3 %

Procedure:
A mixture of 0.5 g (3 mmol) 3,4-Difluoro-benzenesulfonamide and 1.15 g (13 mmol) piperazine in 2.3 ml water was heated to 110° C. for 3 h and subsequently the precipitate was filtered off and washed with water and toluene. The residue was dried under high vacuum to yield 0.578 g (86%) of the title compound as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.[CH3:18][N:19](C)C=O>>[C:18]([C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: O=C1Cc2ccccc2Sc2cc(Br)ccc21
Product: N#Cc1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 0 °C

Procedure:
36.45 G. 3-bromo-10,11-dihydro-11-oxodibenzo[b,f]thiepin and 32.11 g. cuprous cyanide are refluxed in 450 cc. dimethylformamide for five and one half hours. The reaction mixture is cooled down and poured into 2 l. of ice water with good mechanical stirring. The resulting solid is filtered, washed with water, then extracted into 1.7 l. chloroform. The insoluble copper salts are filtered and the filtrate evaporated to dryness. The residue is triturated in methanol and the insoluble yellow product is filtered and weighs 22.4 g. (74.6%), m.p. 166°-170° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[C:6](\[Cl:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([OH:17])=[O:16].[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20]>C(Cl)(Cl)Cl>[CH3:18][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](\[Cl:14])/[C:7](=[O:13])[O:8][CH:9]([CH3:12])[CH2:10][CH3:11])[C@H:3]1[C:15]([O:17][C@H:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:16]
Reactant: CCC(C)OC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: CCC(C)OC(=O)/C(Cl)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step B of Example 43, (1R,cis,Z) 2,2-dimethyl-3-[2-chloro-3-oxo-3-(1-methyl-propoxy)-1-propenyl]-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to form (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[2-chloro-3-oxo-3-(1-methyl-propoxy)-1-propenyl]-cyclopropanecarboxylate with a specific rotation of [α]D20 =+16.5°±2.° (c=0.65% in chloroform).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1.[CH3:14][Si:15]([CH3:24])([CH3:23])[C@@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:22][C@H:19]2[CH2:18][CH2:17][C@@H:16]([Si:15]([CH3:24])([CH3:23])[CH3:14])[CH2:21][CH2:20]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:13]
Reactant: C[Si](C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CCc1ncnc(Cl)c1C(=O)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCc1ncnc(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)c1C(=O)OC

Procedure:
12.4 g (62.0 mmol) of 4-chloro-6-ethyl-5-methoxycarbonylpyrimidine, 11.1 g (62.0 mmol) of cis-4-trimethylsilylcyclohexylamine and 12.55 g (124 mmol) of triethylamine were heated in 30 ml of toluene at 90° C. for 3 hours. After complete reaction, the mixture was partitioned between dichloromethane and water to give, after further extraction with dichloromethane and column chromatography on silica gel, 17.76 g (85.4% of theory) of the cyclohexylaminopyrimidine as a pale brown oil, nD21 =1.5230.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[C:10]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:9]=1.NC1N=CC=CN=1>O1CCOCC1>[N:7]([C:8]1[N:9]=[C:10]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])[CH:11]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[N:13]=1)=[C:2]=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Agent: Nc1ncccn1
Solvent: C1COCCO1
Product: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 81.5 %

Procedure:
Oxalyl chloride (42.0 mL, 481 mmol) was dissolved in anhydrous 1,4-dioxane (400 mL) under an N2 atmosphere. The resulting solution was heated to 90° C. To the hot solution was slowly added a solution of 2-amino-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (14.0 g, 48 mmol) in anhydrous 1,4-dioxane (50 mL). After addition of the aminopyrimidine solution was complete, heating was continued for 6 h, the heat removed, and the solution cooled to room temperature. The solution was concentrated and the residue distilled at reduced pressure to afford the product as a clear oil (12.4 g, 82% yield): by 53-54° C. (ca. 0.1 to 0.2 mm Hg): 1H NMR (CDCl3) δ 6.19 (s, 1H), 4.82-4.74 (q, 2H, J=8.2 Hz).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[ClH:20]>C(OCC)C>[ClH:20].[CH2:1]([NH:5][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)CN
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of isobutylamine (0.90 mL, 0.0091 mol), bromoacetic acid, ethyl ester (1.0 mL, 0.0090 mol), and triethylamine (1.28 mL, 0.00918 mol) in diethylether (15 mL) was stirred at room temperature for 24 hours. The resulting suspension was filtered off and washed with diethylether. The filtrate and washings were combined and rotary evaporated to an oil. The oil was chromatographed on silica gel (150 g, 230-400 mesh) eluting with dichloromethane-diethylether (19:1, 8×125 mL; 15:1, 7×125 mL; 10:1, 15×125 mL). Fractions containing product were combined and rotary evaporated to give an oil. The oil was dissolved in diethylether, concentrated hydrochloric acid (0.52 mL, 0.0063 mol HCl) was added, and the volatiles were rotary evaporated to give a white solid. The solid was dried in vacuo; yield 1.0 g (59%).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][Mg]Br.Cl>C(OCC)C>[CH:1]1([CH2:6][CH2:7][C:8](=[O:10])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[Mg]Br
Reactant: O=C(O)CCC1CCCC1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)CCC1CCCC1
Temperature: -20 °C

Procedure:
10 parts of 3-cyclopentyl propionic acid are dissolved in 150 parts by volume of ethyl ether and chilled to -20° C. under argon. 50 parts by volume of 2.8 molar methyl magnesium bromide are added dropwise. After the addition of the methyl magnesium bromide is completed, the mixture is allowed to warm to room temperature. The cloudy reaction mixture is treated with 1N hydrochloric acid and the clearified reaction mixture is extracted with ether followed by ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residual oil is chromatographed on silica gel using 10% ethyl acetate/hexane as the eluent, to provide 4-cyclopentyl-2-butanone.
Reaction SMILES: C(N(CC)CC)C.CN(C=O)C.[NH2:13][CH2:14][C:15]1[N:16]2[CH:23]=[N:22][CH:21]=[C:17]2[S:18][C:19]=1[CH3:20].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25]>O.C(=O)([O-])O.[Na+]>[NH2:25][S:24]([NH:13][CH2:14][C:15]1[N:16]2[CH:23]=[N:22][CH:21]=[C:17]2[S:18][C:19]=1[CH3:20])(=[O:27])=[O:26]
Reactant: NS(=O)(=O)Cl
Reactant: Cc1sc2cncn2c1CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1sc2cncn2c1CNS(N)(=O)=O
Temperature: -25 °C
Reaction time: 3 h
Yield: 22.4 %

Procedure:
Under an argon atmosphere at -40° C., 0.84 ml of triethylamine was added dropwise to 5 ml of a dry DMF solution containing 334 mg of 3-aminomethyl-2-methylimidazo[5,1-b]thiazole, and 347 mg of sulfamoyl chloride was further added, followed by stirring at -40 to -10° C. for 3 hours. After the reaction solution was diluted with water, sodium hydrogencarbonate was used to adjust the pH of the solution to about 7.5, and the thus adjusted solution was directly subjected to Diaion HP-20 Resin to obtain 110 mg of the title compound as a light green powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C([N:14]([CH2:17][CH3:18])CC)C.[C:19](Cl)(=O)[CH2:20][CH2:21]CC.CCOC(C)=O.CCCCCC>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:18]([C:17]1[NH:1][C:2]2[C:3]([C:4](=[O:6])[N:14]=1)=[CH:7][C:8]([CH3:11])=[CH:9][CH:10]=2)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1ccc(N)c(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCc1nc(=O)c2cc(C)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of 3.0 g (20 mmol) of 2-amino-5-methylbenzoic acid in 20 mL of dry DMF at 0° C. was added 200 mg of DMAP followed by 6.07 g (60 mmol) of triethyl amine and 5.02 g (40 mmol) of valeryl chloride. The resulting mixture was stirred at 0° C. for 30 minutes. The mixture was heated to 110° C. and monitored by TLC for the formation of the intermediate quinoxazolone (rf=0.8, 40%EtOAc/hexane). Following complete formation of the intermediate 10 g (100 mmol) of NH4CO3 was added cautiously. Heating was continued to ensure consumption of the quinoxazolone and formation of the polar (rf=0.4, 40%EtOAc/hexane) quinazolin-4(1H)-one. The reaction mixture was concentrated in vacuo and the residue was taken up in 50 mL of ether and 50 mL of water. The mixture was filtered and the filtrate discarded after washing the residue with 20 mL of ether. The residue was recrystallized from MeOH to give 1.07 g (5 mmol) of a white crystaline solid. 25% yield overall. 1H-NMR (CDCl3): 0.94 (t, 3H, J=6.7 Hz), 1.50 (m, 2H), 1.83 (m, 2H), 2.49 (s, 3H), 2.78 (t, 2H), 7.60 (m, 2H), 8.05 (m, 1H). Anal (C13H16N2O), C, H, N.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[CH3:30])=[O:5])[CH3:2].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[CH3:30])=[O:5])[CH3:2]
Reactant: Clc1ncccn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncccn2)C3)cc1C

Procedure:
Step 4—Synthesis of compound vh: (S)-1-ethyl-3-(2-methyl-4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.043 g, 0.10 mmol) and 2-Chloropyrimidine (0.0121 g, 0.106 mmol) were combined, nitrogen purged three times, added N,N-Dimethylformamide (1.50 mL, 19.4 mmol) and N,N-Diisopropylethylamine (0.0730 mL, 0.419 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=4.7, 2H), 8.12-7.99 (m, 3H), 7.72 (s, 1H), 6.67 (dt, J=10.9, 5.0, 2H), 4.90 (d, J=18.7, 1H), 4.73 (d, J=18.7, 1H), 4.14 (dd, J=17.9, 5.1, 2H), 3.93-3.77 (m, 2H), 3.71 (dd, J=11.2, 2.5, 1H), 3.61 (d, J=12.1, 3H), 3.43 (dd, J=18.5, 7.5, 1H), 3.18-3.06 (m, 2H), 2.74 (s, 2H), 2.26 (s, 3H), 1.25 (d, J=6.6, 3H), 1.08 (t, J=7.2, 3H). LC/MS-m/z+489.3 (M+H)+
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1.[OH-].[Na+]>O>[CH3:6][N:7]([CH3:15])[C:8]1[CH:9]=[C:10]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
Methanesulphonyl chloride (838 mg, 7.35 mmol) was added slowly to a cooled solution (5° C.) of N,N-dimethyl-1,3-phenylenediamine (1.00 g, 7.35 mmol) and sodium hydroxide (5M, 1.5 cm3) in water (10 cm3). The reaction was allowed to warm to room temperature overnight. The mixture was extracted with chloroform (3×15 cm3). The combined extracts were dried over sodium sulphate, filtered and the solvent removed under reduced pressure. Column chromatography (1:20 methanol/dichloromethane) gave the target material as a brown oil (1.24 g, 79%).
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH:28][C:9](=[O:11])[CH2:8][S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=C(O)CSc1ccccc1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(CNC(=O)CSc3ccccc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 14.6 %

Procedure:
Phenylsulfanyl-acetic acid (33.6 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (11.3 mg, 0.0293 mmol, 14.6%) ESI-MS m/z calc. 385.2, found 386.0 (M+1)+. Retention time of 3.12 minutes.
Reaction SMILES: [CH3:1][C:2]([O:7]/[N:8]=[C:9](\[C:16]([NH:18][C@@H:19]1[C:22](=[O:23])[N:21]2[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][S:27][C@H:20]12)=[O:17])/[C:10]1[N:14]=[C:13]([NH2:15])[S:12][CH:11]=1)([C:4]([OH:6])=[O:5])[CH3:3].Cl>>[CH3:3][C:2]([O:7]/[N:8]=[C:9](/[C:16]([NH:18][C@@H:19]1[C:22](=[O:23])[N:21]2[C:24]([C:35]([O-:37])=[O:36])=[C:25]([CH2:28][N+:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][S:27][C@H:20]12)=[O:17])\[C:10]1[N:14]=[C:13]([NH2:15])[S:12][CH:11]=1)([C:4]([OH:6])=[O:5])[CH3:1].[OH2:5].[OH2:5].[OH2:5].[OH2:5].[OH2:5]
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1)C(=O)O
Agent: Cl
Product: CC(C)(O/N=C(/C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1)C(=O)O
Product: O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Another 131 ml aliquot of the ceftazidime solution prepared as described above was adjusted to and maintained at 5° C. and the pH adjusted to 3.5 with 15.2 ml of 1.83M hydrochloric acid. The stirred solution was seeded with ceftazidime pentahydrate crystals and crystallization began. After one hour, the pH of the crystal slurry was readjusted from 4.55 to 3.50 with an additional 2.90 ml of 1.83M hydrochloric acid. The slurry was stirred for three more hours and then filtered. The crystals were washed with 150 ml of chilled water and 100 ml of chilled acetone and air dried. There were obtained 19.3 g of ceftazidime pentahydrate which assayed as follows: HPLC potency, 83.2% (as is); polymer (stressed), 0.82%; related substances, 1.04%; Karl Fischer, 13.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[CH2:7][CH:6]=[CH:5]2.[Br:12]C1C=C(F)C=C2C=1CC=C2.[OH2:23]>CS(C)=O>[Br:12][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[CH:7]1[OH:23]
Reactant: Clc1cc2c(cc1Cl)CC=C2
Reactant: Fc1cc(Br)c2c(c1)C=CC2
Reactant: O
Solvent: CS(C)=O
Product: OC1c2cc(Cl)c(Cl)cc2CC1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
According to Scheme 2, step IV: To a solution of 5,6-dichloro-1H-indene (5f) (1.28 g, 6.92 mmol), which was obtained according to Scheme 2 by following a reaction sequence according to synthesis of (5a), in dimethylsulfoxide (6.5 ml) and water (0.16 ml) N-bromosuccinimide (2.44 g, 13.7 mmol) was added at 10° C. and the mixture was stirred at 25° C. for 1 h. The mixture was poured on water, stirred for 30 min and the solid material was filtered off. The crude product was purified by silica gel chromatography (eluting with 0 to 50% ethyl acetate in heptane) to give 1.46 g of 2-bromo-5,6-dichloro-indan-1-ol which was immediately dissolved in tetrahydrofuran (35 ml). Finely powdered NaOH (1.37 g, 34.2 mmol) was added and the mixture was stirred at 25° C. for 2 h. The mixture was filtered through a short pad of celite and washed with a small amount of ethyl acetate. The filtrate was evaporated to dryness to give 1 g of racemic(1aS,6aR)-3,4-Dichloro-6,6a-dihydro-1aH-1-oxa-cyclopropa[a]indene (6f), which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+].CCN[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C[N:29]1C(=O)C[CH2:31][CH2:30]1>O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:29][CH2:30][CH2:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCNc1ccccn1
Reactant: CN1CCCC1=O
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1NCCc1ccccn1
Temperature: 10 °C

Procedure:
5.62 g (0.03 mol) of 2-chloro-5-nitroanisole, 4 g (0.038 mol) of sodium carbonate, 4.5 g (0.037 mol) of 2-(2-ethylamino)pyridine, and 25 ml of NMP were introduced into a three-necked flask under nitrogen. The mixture was heated to 10° C. After reaction for 6 days, the reaction mixture was cooled and 75 ml of distilled water were then added slowly with vigorous stirring. The nitro derivative appeared in the form of a brown semi-solid, and was extracted with dichloromethane and then purified on a column of silica, eluting with 2/3 ethyl acetate/heptane. 2.1 g of expected nitro derivative (9) were obtained in the form of an orange solid. The proton NMR and 13C spectra and microanalyses were in accordance with the expected structure of the product.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21]>CC(N(C)C)=O>[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][O:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C1CCc2cc(OCC(F)(F)C(F)(F)F)ccc21
Temperature: 97.5 °C
Reaction time: 10 h

Procedure:
6.5 g of 5-fluoro-1-indanone are dissolved in 50 ml of dry dimethylacetamide and, after addition of 36.5 g of anhydrous ground potassium carbonate and 12.9 g of 2,2,3,3,3-pentafluoropropanol, stirred at 95-100° C. for 10 h. The solvent is then removed by distillation in vacuo; 300 ml of water are added to the residue, and the aqueous phase is extracted with ethyl acetate several times. The organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo. Purification on silica gel affords 5-(2,2,3,3,3-pentafluoropropoxy)-1-indanone as a brown oil which crystallizes after some time; melting point 52-54° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[N:4][CH:3]=1.[CH2:13]([Li])CCC.IC.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Clc1cncc(NCC2CC2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(CC1CC1)c1cncc(Cl)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 6-chloro-N-(cyclopropylmethyl)pyrazin-2-amine (0.60 g) in tetrahydrofuran (5 mL) was added dropwise n-butyllithium (3.06 mL, 1.6 M hexane solution) at −78° C. The mixture was stirred at −78° C. for 5 min, and iodomethane (1.02 mL) was added dropwise thereto. The mixture was stirred at −78° C. for 30 min, and further stirred at 0° C. for 1 hr. Saturated aqueous sodium thiosulfate solution (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5-*15% ethyl acetate/hexane) to give the title compound (0.46 g, 70%) as a pale-yellow oil.
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:42]=[CH:41][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([NH:30][C:28]([C:27]2[CH:41]=[CH:42][C:24]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:25][CH:26]=2)=[O:29])[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1OC
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: COc1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc1OC

Procedure:
4-{4-[5-(3,4-Dimethoxy-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(3,4-dimethoxy-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C25H26N4O5 [M+H]+: 463.1976. Found: 463.1976.