Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].[N:38]1([CH2:44][C:45]2[CH:46]=[C:47]([CH:53]=[CH:54][CH:55]=2)[O:48][CH2:49][CH2:50][CH2:51][NH2:52])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:26]([NH:52][CH2:51][CH2:50][CH2:49][O:48][C:47]2[CH:53]=[CH:54][CH:55]=[C:45]([CH2:44][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:46]=2)=[O:27])[CH3:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: COc1ccc(CN(CCN(C)CCCCN)c2ccccn2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(CN(CCN(C)CCCCNC(=O)NCCCOc2cccc(CN3CCCCC3)c2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 63, using 0.55 g (1.6 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 3-[3-(piperidinomethyl)phenoxy]propylamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=617 ([M+H]+, 1), 121 (100); IR (KBr): 1603 cm-1 (C=O). For further analysis, a portion of the compound is converted into the picric acid salt and recrystallised from ethanol; m.p.: 68°-72° C. (ethanol).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=O)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].C1(CNC2N=CC(C(C3C4C(=NC=CC=4)NC=3)=O)=CC=2)CC1>>[CH:2]1([CH2:1][NH:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)=[CH:10][N:11]=2)[CH2:4][CH2:3]1
Reactant: CC(C)CNc1ccc(C(=O)c2c[nH]c3ncccc23)cn1
Agent: O=C(c1ccc(NCC2CC2)nc1)c1c[nH]c2ncccc12
Product: c1cnc2[nH]cc(Cc3ccc(NCC4CC4)nc3)c2c1

Procedure:
was prepared following the protocol of Scheme 8, substituting (6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0025 with [6-(Cyclopropylmethyl-amino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0030 (prepared as described in Example 5). MS (ESI) [M+H+]+=279.
Reaction SMILES: C(O[CH:5]([C:22]1[CH:26]=[CH:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH:23]=1)[C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])(=O)C.C([O-])=O.[NH4+].CCOC(C)=O.C(Cl)Cl>[Pd].CCOC(C)=O.CCO>[CH2:13]([C@H:12]1[CH2:11][O:10][C:9]([CH3:21])([CH3:20])[N:8]1[C:6](=[O:7])[CH2:5][C:22]1[CH:26]=[CH:25][N:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cc1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 40 h
Yield: 26.8 %

Procedure:
To a mixture of crude 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)-1H-pyrrol-3-yl]-ethanone (1.82 mmol) and 10% palladium on carbon (120 mg) in EtOAc (4.5 mL) and EtOH (4.5 mL) was added ammonium formate (0.58 g, 9.2 mmol). After 40 hours at ambient temperature, the resultant mixture was filtered and the filtrate concentrated to a residue which was dissolved in EtOAc, washed with 1M pH7 phosphate buffer, dried over Na2SO4, and evaporated under reduced pressure to give a crude product. Flash column chromatography with 0-4% EtOAc/CH2Cl2 gradient eluant yielded 220 mg (43%) of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)-1H-pyrrol-3-yl]-ethanone as a pale yellow amorphous solid. 1H NMR: δ 7.62 (t, 4H, J=9.4 Hz), 7.47 (d, 2H, J=7.4 Hz), 7.42 (d, 2H, J=8.5 Hz), 7.35 (t, 2H, J=6.6 Hz), 7.30-7.21 (m, 4H), 7.08 (t, 1H, J=2.6 Hz), 7.05 (s, 1H), 6.28 (t, 1H, J=2.21 Hz), 4.16-4.10 (m, 1H), 3.82 (m, 2H), 3.62, 3.54 (AB quartet, 2H, J=15.5 Hz), 3.07 (dd, 1H, J=3.9, 13.8 Hz), 2.91 (dd, 1H, J=9.9, 13.6 Hz), 1.78 (s, 3H), 1.59 (s, 3H). Anal. Calculated for C30H30N2O2•0.25 H2O: C, 79.18; H, 6.76; N, 6.16. Found: C, 79.24; H, 6.79; N, 6.12.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][OH:14])[C:8]([O:15][CH3:16])=[CH:7][C:4]=1[CH2:5][NH2:6].CN([CH:20]=[O:21])C.ClC[CH:24](O)[CH2:25][OH:26]>>[Br:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH:13]([OH:14])[CH2:20][OH:21])[C:8]([O:15][CH3:16])=[CH:7][C:4]=1[CH2:5][NH:6][C:25](=[O:26])[CH3:24]
Reactant: COc1cc(CN)c(Br)cc1OCCO
Reactant: OCC(O)CCl
Reactant: CN(C)C=O
Agent: Cl
Product: COc1cc(CNC(C)=O)c(Br)cc1OCC(O)CO
Yield: 91.4 %

Procedure:
To a solution of 2-bromo-4-hydroxy-5-methoxy-N-acetyl benzylamine 3 (0.3 g, 1.1 mmol) in dry DMF (10 ml) dry K2CO3 (2 mol eq) and 3-chloro-1,2-dihydroxypropane (2 mol eq) were added. The mixture was refluxed for 6 hours, then the solvent was evaporated off under reduced pressure. After addition of water the aqueous layer was extracted with EtOAc (3×25 ml) and the organic phases were anhydrified over Na2SO4 and evaporated off under reduced pressure to furnish the title compound as pale yellow solid (0.35 g, 84% yield).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[N:21]1([C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([N:21]2[CH2:22][CH2:23][N:24]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:25][CH2:26]2)=[CH:32][CH:31]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3ccc(C(C)=O)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(4-piperazin-1-yl-phenyl)-ethanone via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H28N2O6 [M+H]+: 441.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]([CH2:22][CH3:23])([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:15][CH3:16])[CH:11]=[CH:12][CH:13]=1.[CH2:24]([C:26]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([CH3:44])[CH:30]=1)[CH2:27][CH3:28])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[CH2:24]([C:26]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:29]1[CH:34]=[CH:33][C:32]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH2:22][CH3:23])([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:15][CH3:16])[CH:9]=2)=[C:31]([CH3:44])[CH:30]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCC(CC)(O[Si](C)(C)C)c1cccc(Br)c1
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(O[Si](C)(C)C)c1cccc(-c2ccc(C(CC)(CC)c3ccc(OC[C@H]4CCC(=O)O4)c(C)c3)cc2C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 49.1 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.49 mg, 0.002 mmol), a 2 M sodium carbonate solution (0.1 mL, 0.2 mmol) and [1-(3-bromo-phenyl)-1-ethyl-propoxy]-trimethyl-silane (Example 17-(1); 26.25 mg, 0.091 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 30 mg, 0.061 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1, developed twice) to give the title compound (18 mg, 49.2%).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:12][C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]=2[C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]1=2.[NH2:30][CH2:31][CH2:32][N:33]([CH3:42])[CH2:34][CH2:35][CH2:36][N:37]([CH2:39][CH2:40][NH2:41])[CH3:38]>ClCCl>[NH2:41][CH2:40][CH2:39][N:37]([CH3:38])[CH2:36][CH2:35][CH2:34][N:33]([CH3:42])[CH2:32][CH2:31][NH:30][C:13]1[C:14]2[C:2](=[O:1])[C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:8]=3[C:9]=2[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3ccccc3c3c2C(=O)c2cnccc2-3)cc1
Reactant: CN(CCN)CCCN(C)CCN
Solvent: ClCCl
Product: CN(CCN)CCCN(C)CCNc1nc2ccccc2c2c1C(=O)c1cnccc1-2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A mixture of toluene-4-sulfonic acid 7-oxo-7H-5,9-diaza-benzo[c]fluoren-6-yl ester (102 mg) (the compound of Reference Example 6c-2) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine (0.8 ml) was stirred at 50° C. for 20 minutes. The reaction mixture was diluted with dichloromethane. The solution was washed with saturated NaHCO3 solution and dried over magnesium sulfate. The organic layer was evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol-ammonia water (25%)=90:10:1. The desired product (37 mg) was obtained as a reddish oil.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[Br:6]Br.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])[CH3:9].Cl>O.ClCCl.BrBr>[Br:6][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[CH:13][CH:14]=1
Reactant: BrBr
Reactant: CC(=O)Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
4.3 ml of alkaline (lime) bromine (containing 0.242 g bromide and 0.051 g bromate per ml of solution) and 0.52 g sodium bromate in 10 ml water were taken in a round bottom flask with total bromine content of 19.135 mmol. Into this was added 2.5 g (18.517 mmol) of acetanilide in 12.5 ml dichloromethane. 25 ml of 3.6 N hydrochloric acid was added over a period of 13 min under stirring at room temperature. Stirring was continued for another 30 min. The precipitate was filtered, washed with water and dried to give 3.689 g (92.7%) of p-bromoacetanilide (m.p. 164-168° C.) characterized through spectroscopic techniques.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>>[C:24]([N:13]1[CH2:12][C:11]2[CH:23]=[C:7]([CH:8]=[CH:9][CH:10]=2)[NH:6][C:5]2=[N:21][C:20](=[C:2]([Cl:1])[CH:3]=[N:4]2)[NH:19][C:18]2=[CH:22][C:14]1=[CH:15][CH:16]=[CH:17]2)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Reactant: CCCC(=O)Cl
Product: CCCC(=O)N1Cc2cccc(c2)Nc2ncc(Cl)c(n2)Nc2cccc1c2
Yield: 50 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and butyryl chloride as the starting materials in 50% yield. LCMS for C21H21ClN5O (M+H)+: m/z=394.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[C:16]([CH2:18][O:19][C:20]4[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=4)[C:23](OC)=[O:24])[N:15]([CH3:30])[C:14]=3[CH:31]=2)=[N:6][C:7]=1Cl.[CH3:32][O-:33].[Na+].[OH2:35]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[C:16]([CH2:18][O:19][C:20]4[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=4)[C:23]([OH:35])=[O:24])[N:15]([CH3:30])[C:14]=3[CH:31]=2)=[N:6][C:7]=1[O:33][CH3:32]
Reactant: O
Reactant: C[O-]
Reactant: COC(=O)c1cccc(OCc2nc3ccc(Oc4ccc(Br)c(Cl)n4)cc3n2C)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1nc(Oc2ccc3nc(COc4cccc(C(=O)O)c4)n(C)c3c2)ccc1Br

Procedure:
Methyl 3-({6-[(5-bromo-6-chloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoate produced in Example (3a) (0.74 g, 1.47 mmol), sodium methoxide (5.0 M solution in methanol, 2.94 mL, 14.7 mmol), water (10 mL) and 1,4-dioxane (20 mL) were stirred with heating under reflux for three days. After leaving to cool, the reaction mixture was concentrated and water (50 mL) was added. This aqueous solution was neutralized by adding 1 M hydrochloric acid and the precipitated solid was collected by filtration to obtain crude 3-({6-[(5-bromo-6-methoxypyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. Trimethylsilyldiazomethane (2.0 M solution in hexane) was added to a solution of the crude 3-({6-[(5-bromo-6-methoxypyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid in toluene (20 mL) and methanol (10 mL) until the raw material disappeared. The reaction mixture was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (hexane/ethyl acetate, 1:1) to obtain the title compound (0.36 g, 49%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=3[CH3:37])[N:21]=2)[N:17]([CH3:19])[CH:18]=1)=[O:13])[CH3:2].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:69][N:70]([CH3:77])[CH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>CN(C)C=O.O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:20]2[C:25]([CH3:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]3[CH:36]=[CH:35][C:31]([C:32]([N:74]4[CH2:75][CH2:76][CH:71]([N:70]([CH3:77])[CH3:69])[CH2:72][CH2:73]4)=[O:33])=[CH:30][C:29]=3[CH3:37])[N:21]=2)[N:17]([CH3:19])[CH:18]=1)=[O:13])[CH3:2]
Reactant: CN(C)C1CCNCC1
Reactant: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(Nc3ccc(C(=O)O)cc3C)ncc2C)n(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(Nc3ccc(C(=O)N4CCC(N(C)C)CC4)cc3C)ncc2C)n(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.5 %

Procedure:
A suspension of 4-{4-[4-(2,6-Diethyl-phenylcarbamoyl)-1-methyl-1H-pyrrol-2-yl]-5-methyl-pyrimidin-2-ylamino}-3-methyl-benzoic acid (177 mg, 0.356 mmol) in anhydrous dimethylformamide (10 mL) was treated with N-ethyl-N,N-diisopropylamine (0.60 mL, 3.55 mmol) and TBTU (183 mg, 0.569 mmol). The mixture was then treated with dimethyl-piperidin-4-yl-amine (91 mg, 0.711 mmol). The reaction was stirred at room temperature for 24 h. The reaction was diluted with water and the resulting precipitate was collected by filtration. The crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 9/1) to afford 118 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([CH3:41])[CH:31]=1)[CH3:29]>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][C@@H:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([CH3:41])[CH:31]=2)[CH3:29])=[O:13])=[CH:7][C:6]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: Cc1cc([C@@H](C)NC(=O)COc2ccc(C(C)(C)C)c(F)c2)ccc1NS(C)(=O)=O
Yield: 43.5 %

Procedure:
(4-tert-Butyl-3-fluorophenoxy) acetic acid (153 mg, 0.68 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (110 mg, 0.68 mmol), triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (180 mg, 0.68 mmol) were mixed in the same procedure described in Example 2(b) to give 129 mg (44% yield) of the title compound as a white solid.
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[CH2:24]([O:26][C:27]([C:29]1[C:34]([NH2:35])=[CH:33][CH:32]=[C:31](Br)[N:30]=1)=[O:28])[CH3:25].CC1(C)C(C)(C)OB([C:45]2[CH:46]=[N:47][N:48]([CH2:50][CH2:51][CH2:52][CH2:53][OH:54])[CH:49]=2)O1>>[NH2:35][C:34]1[C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])=[N:30][C:31]([C:45]2[CH:46]=[N:47][N:48]([CH2:50][CH2:51][CH2:52][CH2:53][OH:54])[CH:49]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1nc(Br)ccc1N
Reactant: CC1(C)OB(c2cnn(CCCCO)c2)OC1(C)C
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CCOC(=O)c1nc(-c2cnn(CCCCO)c2)ccc1N
Yield: 52.8 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-6-bromopyridine-2-carboxylic acid ethyl ester (Compound 6E, 300 mg, 1.22 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butan-1-ol (Compound 14C, 358 mg, 1.35 mmol) to afford 196 mg of the title compound (55%). 1H NMR (400 MHz, CDCl3) δ 8.12 (br. s., 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 5.94 (br. s., 2H), 4.23 (t, J=6.9 Hz, 2H), 3.70 (q, J=5.9 Hz, 2H), 3.03 (d, J=5.1 Hz, 3H), 2.03 (quin, J=7.3 Hz, 2H), 1.60-1.67 (m, 3H) [OH proton obscured].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1.C([O-])([O-])=[O:28].[Cs+].[Cs+]>CN(C=O)C>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:17]2[S:16][C:15]3[C:14](=[O:28])[C:13]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][NH:11][C:12]=4[C:19]=3[CH:18]=2)=[CH:21][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(N)nc4)cc2-3)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2n[nH]c3c2C(=O)c2sc(-c4ccc(N)nc4)cc2-3)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-2-ylamine (0.18 g, 0.5 mmol) and Cs2CO3 (1.6 g, 5.0 mmol) in DMF (10 mL) was stirred under molecular oxygen at ambient temperature. The reaction mixture was stirred for 12 hr. Afterward, the mixture was poured into ice water, followed by aqueous wash, and evaporation of the solvent, which provided the corresponding 2-(6-Amino-pyridin-3-yl)-6-(4-methoxy-phenyl)-4H-1-thia-4,5-diaza-cyclopenta[a]pentalen-7-one as yellow solid in 92% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
A slurry of 10% palladium on carbon (10 g) in a solution of 4-tert-butoxycarbonyl-1-(2-methoxy-5-nitrophenyl)piperazine (D2) (124.5 g) in ethanol (3.5L) and water (50 ml) was stirred with hydrogen at ambient temperature and atmospheric pressure for 18 h. The reaction mixture was filtered and the filtrate concentrated to afford the title compound (D3) as a gum (112 g, 99%). MH+ 308.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=1.[C:30](#[N:33])[CH:31]=[CH2:32].CCN(C(C)C)C(C)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH2:23]([O:22][C:17]1[C:16]2[N:15]([N:14]=[CH:32][C:31]=2[C:30]#[N:33])[CH:20]=[C:19]([Cl:21])[N:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[n+]1cc(Cl)nc(OCc2ccccc2)c1
Reactant: C=CC#N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1cnn2cc(Cl)nc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
1-amino-3-(benzyloxy)-5-chloropyrazin-1-ium 2,4,6-trimethylbenzenesulfonate (5.34) (657 mg, 1.51 mmol) was suspended in 1,4-dioxane (5.75 mL) and acrylonitrile (0.23 mL, 3.5 mmol) was added followed by iPr2NEt (0.32 mL, 1.9 mmol). The resulting mixture was stirred for 1.75 h at r.t. and DDQ (720 mg, 3.2 mmol) was added in one portion. The resulting mixture was stirred an additional 1 h and was then partitioned between EtOAc, water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (0-20% EtOAc in hexanes) to provide 4-(benzyloxy)-6-chloropyrazolo[1,5-a]pyrazine-3-carbonitrile. 1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 8.18 (s, 1H), 7.61-7.55 (m, 2H), 7.45-7.39 (m, 2H), 7.39-7.33 (m, 1H), 5.67 (s, 2H).
Reaction SMILES: Cl.[CH2:2]([O:5][N:6]=[C:7]([C:35]1[N:36]=[C:37]([NH:40]C=O)[S:38][CH:39]=1)[C:8]([NH:10][CH:11]1[C:33](=[O:34])[N:13]2[C:14]([C:30]([OH:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]>CO>[CH2:2]([O:5][N:6]=[C:7]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:8]([NH:10][CH:11]1[C:33](=[O:34])[N:13]2[C:14]([C:30]([OH:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
Conc. hydrochloric acid (572 mg) was added to a solution of 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.28 g) in methanol (16 ml) at ambient temperature and the mixture was stirred for 30 minutes. The reaction mixture was post-treated according to a conventional manner to give 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (410 mg).
Reaction SMILES: [NH2:1][C:2]1([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.O>[C:19]1([CH2:18][O:17][C:15]([NH:1][C:2]2([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]2)=[O:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 46.1 %

Procedure:
Methyl 1-aminocyclopropanecarboxylate (15.83 g, 104.43 mmol) was dissolved in a mixture of CH2Cl2 (150 mL) and water (150 mL). To this mixture was added NaHCO3 (35.09 g, 417.72 mmol) followed by benzyl chloroformate (15.43 mL, 109.64 mmol). The mixture was stirred vigorously for 2 hours, and after separation of the two layers, the aqueous layer was extracted with 100 mL of CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide methyl 1-({[(phenylmethyl)oxy]carbonyl}amino)cyclopropanecarboxylate (12.0 g, 46%). LCMS: (M+H)+: 206.1.