Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:20])([CH3:21])[CH2:18][NH:19][C:34](=[O:36])[CH3:35])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CN)ccc2n1CC1CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC(C)(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-1-amine (Step K, 132 mg, 0.350 mmol) and triethylamine (98 μL, 0.700 mmol) in dichloromethane (4 mL) was added acetyl chloride (0.03 mL, 0.420 mmol) at room temperature. After stirring for 15 min, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (ODS, gradient elution with Acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (113 mg, 77%) as an amorphous.
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1.[CH:20]([NH2:23])([CH3:22])[CH3:21]>CO>[OH:1][CH:2]([CH2:19][NH:23][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][CH2:12][C:13]([NH:15][CH3:16])=[O:14])=[O:10])=[CH:7][CH:6]=1
Reactant: CNC(=O)CCC(=O)c1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CO
Product: CNC(=O)CCC(=O)c1ccc(OCC(O)CNC(C)C)cc1
Yield: 97.9 %

Procedure:
A mixture of 3-[4-(2,3-epoxypropoxy)benzoyl]-N-methylpropionamide (20 g, 0.076 mole), methanol (200 ml) and isopropylamine (36 ml, 0.42 mole) was heated under reflux for one hour. Evaporation under reduced pressure gave 3-[4-(2-hydroxy-3-isopropylaminopropoxy)benzoyl]-N-methylpropionamide (24 g, 97%, m.p. 139°-142° C). Crystallisation from water gave the pure amide, m.p. 140°-142° C.
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[CH2:12]([N:14]1[C:18](=[O:19])[C:17](=[C:20](O)[CH:21]=[C:22]2[N:26]([CH2:27][CH3:28])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[S:23]2)[S:16][C:15]1=[S:34])[CH3:13]>N1C=CC=CC=1.C(#N)C>[CH2:12]([N:14]1[C:18](=[O:19])[C:17](=[C:20]([Cl:10])[CH:21]=[C:22]2[N:26]([CH2:27][CH3:28])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[S:23]2)[S:16][C:15]1=[S:34])[CH3:13]
Reactant: CCN1C(=O)C(=C(O)C=C2Sc3ccccc3N2CC)SC1=S
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCN1C(=O)C(=C(Cl)C=C2Sc3ccccc3N2CC)SC1=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
p-Toluenesulfonyl chloride (1.15 g, 0.006 mol) is added to 3-ethyl-5[(3-ethyl-2-benzothiazolinylidene)-1-hydroxyethylidene]rhodanine (1.82 g, 0.005 mol) in dry pyridine (15 ml). After stirring for 30 min. at room temperature, the solution is diluted with acetonitrile (25 ml), chilled and the dye collected, washed with acetonitrile, then ether. The yield is 0.74 g (39%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].[ClH:11].[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.CO>C(O)(=O)C>[ClH:11].[ClH:11].[N:12]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[C@@H:14]([NH:20][C:21]([C:23]1[S:24][C:25]3[CH:31]=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([CH2:38][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:36][CH:37]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: C1COCCN1
Reactant: O=Cc1ccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccc(CN4CCOCC4)cc3)cc2s1

Procedure:
330 mg (3.75 mmol) of morpholine and 40 mg (0.56 mmol) of sodium cyanoborohydride are successively added to a solution of 80 mg (0.19 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride (Example 23A) in 1.5 ml of a 6:1 mixture of methanol and acetic acid. 2 h at room temperature and 6 h at 80° C. are followed by purification by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 87.7 mg (88% of theory) of the title compound.
Reaction SMILES: CN(C)[C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[Cl:21].[OH-].[Na+].CCCC[OH:30].Cl>C1(C)C=CC=CC=1>[CH3:11][C:9]1[CH:8]=[CH:7][C:6]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=2[Cl:21])=[C:5]([CH2:4][C:3]([OH:22])=[O:30])[CH:10]=1
Reactant: Cc1ccc(Nc2c(C)cc(Cl)cc2Cl)c(CC(=O)N(C)C)c1
Reactant: CCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2c(C)cc(Cl)cc2Cl)c(CC(=O)O)c1
Temperature: 25 °C

Procedure:
N,N-dimethyl-5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetamide (1.5 g, 4.3 mmol) is hydrolyzed with 6N NaOH (70 ml) as a two phase solution with n-BuOH (40 ml) at reflux temperature for 14 hours. After cooling to room temperature, the mixture is poured over ice (100 ml). Toluene (100 ml) is added and the mixture transferred to a separatory funnel. The aqueous phase is brought to a pH of 1 with 3 N HCl. The organic phase is separated and the aqueous phase re-extracted with toluene (100 ml). The combined organic solution is dried (MgSO4) and concentrated under high vacuum (35-50 mbar), on a rotovap, taking care not to warm above 50°. Upon crystallization from Et2O/hexane, 5-methyl-2-(2′,4′-dichloro-6′-methylanilino)phenylacetic acid is obtained as a tan solid, m.p. 137-141°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[CH2:17][CH3:18].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][N:10]([CH2:17][CH3:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC1(c2cccc(Cl)c2F)CCNC1
Reactant: CCI
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2cccc(Cl)c2F)C1
Yield: 35.8 %

Procedure:
Preparation according to Example 2. (+3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (0.234 g, 1.02 mmol), tetrahydrofuran (20 ml), iodoethane (0.122 ml, 1.15 mmol) and triethylamine (0.285 ml, 2.04 mmol), the solution was stirred for 26 h. Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 65:35) gave the title compound 0.094 g (35.9%). [a]D=−16.1° (methanol). The amine was converted to the fumaric acid salt and recrystallized from 2-propanol/diisopropyl ether: M.p. 131-133° C. MS m/z (rel. intensity, 70 eV) 257 (M+, 4), 242 (38), 227 (20), 157 (31), 71 (bp).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][CH2:35][O:36][CH2:37][CH3:38].O>C(#N)C>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:14][CH:15]([C:18]3[N:22]([CH2:34][CH2:35][O:36][CH2:37][CH3:38])[C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[CH2:16][CH2:17][N:12]2[CH3:13])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN2CCC(c3nc4ccccc4[nH]3)CC2)cc1
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOCCn1c(C2CCN(C)C(c3ccc(C(C)(C)C)cc3)C2)nc2ccccc21

Procedure:
To a solution of 3.47 g of 2-[1-((4-(1,1-dimethylethyl)phenyl) methyl)piperidine-4-yl]-1H-benzimidazole in 80 ml of acetonitrile, 1.38 g of potassium carbonate and 1.08 ml of 2-chloroethyl-ethyl ether are added and the mixture is refluxed for 8 hours; then is left to cool and poured onto 200 ml of water; it is extracted with ether (3×30 ml) and the ethereal layer is washed with water (3×20 ml) and dried over anhydrous sodium sulfate. The oil obtained by elimination of the ether is purified by column chromatography by using chloroform/methanol (98/2) as eluent, thus obtaining 2 g of 2-[1-((4-(1.1-dimethylethyl)phenyl(methyl) piperidine-4-yl]-1-(2-ethoxyethyl)-1H-benzimidazole. Mp: 51°-53° C.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH3:24][C@@H:25]1[CH2:27][O:26]1>C1COCC1>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:24][C@H:25]([OH:26])[CH3:27])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H]1CO1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Temperature: 30 °C
Reaction time: 18 h
Yield: 29.8 %

Procedure:
To a suspension of 4-(4-nitrophenoxy)quinolin-7-ol (10 g, 35.5 mmol) in THF (35 mL)/aq. NaOH (37.8 g, 7.4%) was added (R)-2-methyloxirane (10.3 g, 177.3 mmol). The reaction was stirred at 30° C. for 18 hours then concentrated in vacuo. The mixture was diluted with EtOAc (50 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by a column chromatography on silica gel (EtOAc/PE=1:1) to furnish the title compound as a yellow solid (3.6 g, 29.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: Clc1ccc(C2CCCCC2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)ccc1C1CCCCC1
Reaction time: 1 h

Procedure:
To 1-chloro-4-cyclohexylbenzene (1.7 g) in H2SO4 (10 mL) at 20° C. added HNO3 (2.5 g) in H2SO4 (10 mL) maintaining the temperature below 30° C. The mixture was allowed to stir for 1 h and then partitioned between CH2Cl2 and water. The CH2Cl2 layer was washed well with a saturated NaHCO3 solution, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% EtOAc/hexanes to give 5-chloro-2-cyclohexyl-1-nitrobenzene. This compound was then reduced with iron powder as described above to yield the desired compound.
Reaction SMILES: [CH2:1]([C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3]CC.[C:14](=[O:16])=[O:15]>>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:14]([OH:16])=[O:15])=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH3:3]
Reactant: O=C=O
Reactant: CCCCCc1cccc(F)c1F
Product: CCCc1ccc(C(=O)O)c(F)c1F
Temperature: -20 °C

Procedure:
3-Propyl-1,2-difluorobenzene (obtainable according to Example 2) is metalated as described in 1c). 20 g of dry ice are added slowly at -70° C. The mixture is subsequently warmed to -20° C. Customary working up gives colourless crystals, m.p. 148° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5](COCCOC)[C:4]=2[N:3]=1.Cl>O1CCOCC1.O>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2COCCOC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Temperature: 100 °C
Yield: 67.8 %

Procedure:
To a solution of 8-chloro-1-methyl-3-({[2-(methyloxy)ethyl]oxy}methyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.9 g, 6.37 mmol) in dioxan (20 ml) and water (20 ml) was added 5M HCl aq. (20 ml). The resulting mixture was heated at 100° C. under nitrogen for 18 hours. The reaction mixture was then concentrated in vacuo, the residue was dissolved in EtOAc (100 ml) and washed with water. The organic extract was dried (MgSO4) filtered and evaporated. Purification by SPE (Si, 20 g) eluting 2:3 EtOAc/cyclohexane afforded the title compound as a white solid (1.04 g, 68%). m/z 241.1[MH+].
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=2[O:20][CH3:21])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:11]=1
Reactant: C1COCCN1
Reactant: COc1cccc(-c2cc3ncccc3c(Cl)n2)c1OC
Product: COc1cccc(-c2cc3ncccc3c(N3CCOCC3)n2)c1OC

Procedure:
A solution of 5-chloro-7-(2,3-dimethoxy-phenyl)-[1,6]naphthyridine 3 (50 mg, 0.17 mmol, 1 eq) in morpholine (1.02 mL, 11.7 mmol, 68 eq) was heated up at 100° C. for 5 h under Ar(g). Once cooled down, the solution was subsequently partitioned and extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:2) to furnish the product, A, as a pale yellow solid (48 mg, 81%).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[C:17](=[O:22])[O:18][CH:19]([OH:21])[CH:20]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[C:29](Cl)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>O1CCCC1>[C:29]([O:21][CH:19]1[O:18][C:17](=[O:22])[C:16]([CH2:15][O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:20]1)(=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCC(=O)OCC1=CC(O)OC1=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCC1=CC(OC(=O)CCCCCCCCCCC)OC1=O
Temperature: 25 °C

Procedure:
To a stirred solution of 3-dodecoyloxymethyl-5-hydroxy-2(5H)-furanone (0.098 g., 0.313 mmol) and pyridine (0.026 g., 0.313 mmol) in 3 ml anhydrous tetrahydrofuran at 0° was added lauroyl chloride (0.082 g., 0.376 mmol). The solution was allowed to warm to room temperature, stirred until starting material was no longer visible by TLC, and partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed twice with 5% sodium bicarbonate solution, twice with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a solid residue. This material was further purified by recrystallization (acetone/methanol) to give the desired ester.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](SC)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[N:16]1)(=O)C1C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[NH2:30].Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[N:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CSc1ncnc2cnn(CCOCCOC(=O)c3ccccc3)c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: OCCOCCn1ncc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 16.5 h
Yield: 30.6 %

Procedure:
A mixture of 2-{2-[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]ethoxy}ethyl benzoate (200 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (140 mg), pyridine hydrochloride (96 mg) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 140° C. for 16.5 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (30 mL), and extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→20:80). The object fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). 1N Aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 11.5 hrs. After concentration of the reaction mixture under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (45 mL×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) and recrystallized from ethanol-ethyl acetate to give the title compound (78 mg).
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.00 g) was dissolved in dichloromethane (25 ml). Triethylamine (0.42 ml) was added, and a solution of benzoyl chloride (0.32 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 14 hr, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.35 g of 4-amino-N-(1-(6-benzoylaminohexyl)-piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17]([OH:19])=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[N+:66]([CH:69]([C:71]1([OH:75])[CH2:74][NH:73][CH2:72]1)[CH3:70])([O-:68])=[O:67]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:20]=[CH:21][N:22]=2)[CH:5]=[C:6]([C:17]([N:73]2[CH2:74][C:71]([CH:69]([N+:66]([O-:68])=[O:67])[CH3:70])([OH:75])[CH2:72]2)=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[F:16]
Reactant: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(I)cc1F
Reactant: CC([N+](=O)[O-])C1(O)CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC([N+](=O)[O-])C1(O)CN(C(=O)c2cn3ccnc3c(Cl)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A solution of 8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridine-6-carboxylic acid (150 mg, 0.35 mmol) (prepared using procedures similar to those described in US 2006030610 and US 2005054701), N,N-diisopropylethylamine (300 μL, 1.74 mmol), PyBOP (180 mg, 0.35 mmol) and 3-(1-nitroethyl)azetidin-3-ol hydrochloride (76 mg, 0.42 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 15 hours. The reaction mixture was then partitioned between 5% aqueous lithium chloride, and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate. The combined organic portion was washed with 20% aqueous citric acid, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue which was purified by column chromatography. Eluting with 5% methanol in dichloromethane, the isolated product was concentrated in vacuo to afford 195 mg, 0.35 mmol (100%) of 1-({8-chloro-7-[(2-fluoro-4-iodophenyl)amino]imidazo[1,2-a]pyridin-6-yl}carbonyl)-3-(1-nitroethyl)azetidin-3-ol as a yellow foam. 1H NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 7.23 (br s, 1H), 6.55-6.51 (m, 1H), 6.02 (br s, 1H), 4.79 (q, 1H), 4.45-3.96 (4H), 1.56 (d, 3H). MS (EI) for C20H19ClFIN6O4: 560 (MH+).
Reaction SMILES: CCN(CC)CC.[Cl:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:22]/[O:23][CH3:24])/[C:19](Cl)=[O:20])[N:17]=1)=[O:11].[NH2:25][CH:26]1[C:55](=[O:56])[N:28]2[C:29]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:31]([CH3:33])[S:32][C@H:27]12>C(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:22]/[O:23][CH3:24])/[C:19]([NH:25][CH:26]2[C:55](=[O:56])[N:28]3[C:29]([C:39]([O:41][CH:42]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[O:40])=[C:30]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:31]([CH3:33])[S:32][C@H:27]23)=[O:20])[N:17]=1)=[O:11]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2S[C@H]1C
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)[C@H](C)S[C@H]12)c1csc(NC(=O)CCl)n1
Reaction time: 0.75 h
Yield: 59.6 %

Procedure:
A 0.5 ml portion of Et3N, along with 1.13 g of 2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl chloride, was added to a solution of 1.6 g of diphenylmethyl 7-amino-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate in 50 ml of CH2Cl2 at -40° C., and the mixture was stirred at from -20° C. to -15° C. for 45 minutes. The reaction solution was washed with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl solutions, and dried over MgSO4, followed by distilling off the CH2Cl2 under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (5:1) were collected to distill off the solvent, thus yielding 1.5 g (61%) of diphenylmethyl 7-[2-(2-chloroacetylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)(C)(C)C.C([Li])CCC.CN(C)C=O.Cl>O1CCCC1>[NH:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[CH:14]=[CH:6]1
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1cnc2[nH]ccc2c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 134 %

Procedure:
(3-Methyl-pyridin-2-yl)-carbamic acid tert-butyl ester (5 g, 24 mmol) was dissolved in tetrahydrofuran (96 mL) and cooled in an ice-salt bath to −15° C. Butyl lithium solution (1.6 M in hexanes, 30 mL, 48 mmol) was added drop wise over 30 min. After an additional 1 h, N,N-dimethylformamide (1.9 mL, 34.5 mmol) was added and the reaction mixture warmed to 25° C. over 16 h. The reaction mixture was added very slowly to approximately 150 mL of 6M HCl solution. The resulting mixture was warmed to 55° C. for 2 h, then cooled, the phases separated, and ethyl acetate was added to the aqueous layer. 6M sodium hydroxide solution was slowly added until the pH 6, then the layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined ethyl acetate extracts were washed with sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo to give 1H-pyrrolo[2,3-b]pyridine (3.8 g, 134%) as a brown semisolid. This was used directly in the next step without further purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.86 (br. s., 1H) 8.28 (dd, J=4.9, 1.5 Hz, 1H) 7.98 (dd, J=7.7, 1.7 Hz, 1H) 7.36 (d, J=3.4 Hz, 1H) 7.10 (dd, J=7.9, 4.9 Hz, 1H) 6.51 (d, J=3.4 Hz, 1H); LCMS (EI/CI) m/z: 119 [M+H].