Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][C:33]2[CH:34]=[C:35]([NH2:38])[NH:36][N:37]=2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:30][O:29][C:27]1[CH:26]=[C:25]([CH2:31][CH2:32][C:33]2[CH:34]=[C:35]([NH:38][C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([CH:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]4)=[CH:20][CH:19]=3)[NH:36][N:37]=2)[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=1
Reactant: COCCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COCCN1CCC(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Yield: 34.9 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[1-(2-methoxyethyl)piperidin-4-yl]benzamide was prepared following the procedure as outlined for Example 99, starting from methyl 4-(1-(2-methoxyethyl)piperidin-4-yl)benzoate (0.428 g, 1.25 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.309 g, 1.25 mmol) and 2M trimethylaluminium (1.56 mL, 3.13 mmol) in toluene (10 ml). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanol in DCM. Pure fractions were evaporated to dryness and the product was crystallised from DCM/diethyl ether to afford the title compound (0.215 g, 34.9%) as an off white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.[CH3:40][C:41]([CH3:49])([C:43]1[N:47]=[C:46]([CH3:48])[O:45][N:44]=1)[NH2:42]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:42][C:41]([C:43]3[N:47]=[C:46]([CH3:48])[O:45][N:44]=3)([CH3:49])[CH3:40])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CCOCC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=401.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([O:17][CH3:18])[CH:11]=1)[C:3]([O:5]CC)=O.[O-:19][C:20]#[N:21].[K+]>C(O)CCC>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH:2]2[O:1][C:20](=[O:19])[NH:21][C:3]2=[O:5])=[CH:11][C:12]=1[O:17][CH3:18]
Reactant: N#C[O-]
Reactant: CCOC(=O)C(O)CCc1ccc(O)c(OC)c1
Agent: [K+]
Solvent: CCCCO
Product: COc1cc(CCC2OC(=O)NC2=O)ccc1O
Reaction time: 18 h
Yield: 27.7 %

Procedure:
A mixture of ethyl 2-hydroxy-4-(4-hydroxy-3-methoxyphenyl)butanoate (0.73 g), potassium cyanate (KCNO) (0.7 g) and butanol (25 ml) was stirred for 18 hours under reflux. The reaction mixture was concentrated under reduced pressure. The residue was poured into water and acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent. The resulting oily product was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-chloroform (1:4, v/v), was obtained 5-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2,4-oxazolidinedione (0.2 g, 28%),
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][NH:5]/[C:4]/1=[N:13]\[C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40]([N:10]2[CH2:9][CH2:8][C:7]3([NH:3]/[C:4](=[N:13]/[C:14]([C:16]4[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=4)=[O:15])/[NH:5][CH2:6]3)[CH2:12][CH2:11]2)=[O:41])=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)Cc4ccc(OCc5ccccc5)cc4)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide dihydrochloride (Ex. 38) (300 mg, 0.83 mmol), 4-benzyloxyphenylacetic acid (200 mg, 0.83 mmol), N-methyl morpholine (0.40 ml, 3.64 mmol) and HATU (315 mg, 0.83 mmol) in anhydrous DMF (20 ml) is stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo and subjected to column chromatography (basic alumina, 0-3% MeOH in DCM) to obtain pale yellow solid. The product is dissolved in DCM and MeOH and re-precipitated by adding diethyl ether. The supernatant solvent mixture is decanted and the product is washed again with diethyl ether and dried under vacuum to afford the title compound as a pale yellow solid; [M+H]+ 549.
Reaction SMILES: [CH3:1][NH:2][SH:3](=[O:5])=[O:4].Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([CH3:14])=[CH:9][N:8]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:13][C:11]1[C:10]([CH3:14])=[CH:9][N:8]=[C:7]([N:2]([CH3:1])[S:3]([CH3:15])(=[O:5])=[O:4])[N:12]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CN[SH](=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(N(C)S(C)(=O)=O)nc1Cl
Temperature: 80 °C

Procedure:
A mixture of N-methylsulphonamide (3.35 g), 2,4-dichloro-5-methylpyrimidine (5 g) and potassium carbonate (4.3 g) in DMF (50 ml) was heated at 80° C. for 4 h. The reaction was quenched with water (200 ml) and extracted with ethylacetate. The organics were dried, evaporated under reduced pressure and the residue triturated with ether. The solid was filtered off (4-isomer) and the filtrate evaporated under reduced pressure and subjected to RPHPLC to obtain the 2-isomer, yield 0.37 g.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:18].[K+].O>C(#N)C>[C:13]([NH:14][C@:10]([CH3:17])([C:11]([OH:18])=[O:16])[CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[NH2:12]
Reactant: [OH-]
Reactant: CC1(CSCc2ccccc2)NC(=O)NC1=O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@@](CSCc1ccccc1)(NC(N)=O)C(=O)O
Yield: 66.4 %

Procedure:
First, 5.0 g of 5-benzylthiomethyl-5-methylhydantoin was mixed with 3.6 g of potassium hydroxide and 3 g of water, and the mixture was subjected to reaction at 94° C. to 96° C. for 12 hours. The HPLC analysis (column: COSMOSIL 5C18-ARII (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=30/70, flow rate: 1.0 ml/min, detection wavelength: 254 nm, column temperature: 40° C.) of the reaction mixture showed the production of 3.56 g yield 66.4%) of the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[C:24]2[N:32]=[CH:31][CH:30]=[CH:29][C:25]=2[N:26]=[CH:27][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[C:24]4[N:32]=[CH:31][CH:30]=[CH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: Clc1ncnc2cccnc12
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2cccnc12)c1nc2ccc(F)cc2n1-c1ccccc1

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.082 g, 0.25 mmol), 4-chloropyrido[3,2-d]pyrimidine (J. Med Chem, 1833, 1996) (0.035 g, 0.21 mmol) and DIPEA (0.174 mL, 1.0 mmol) in IPA (1 mL) was heated to 70° C. in a sealed tube under argon for 1 h. The reaction mixture was cooled, diluted with EtOAc (20 mL) and washed with water (2 mL). The aqueous was extracted with EtOAc (10 mL). The combined organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-8% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated and freeze dried to give 317 as an off white solid, (15 mg, 18%). LCMS (Method C): RT 3.55 min [M+H]+ 385.05. 1H NMR δ (ppm) (DMSO-d6): 8.83 (1H, dd, J=4.24, 1.57 Hz), 8.63 (1H, d, J=7.55 Hz), 8.40 (1H, s), 8.11 (1H, dd, J=8.46, 1.57 Hz), 7.84 (1H, dd, J=8.47, 4.24 Hz), 7.74 (1H, dd, J=8.81, 4.85 Hz), 7.59 (2H, d, J=7.53 Hz), 7.50-7.50 (3H, m), 7.12 (1H, ddd, J=9.87, 8.81, 2.53 Hz), 6.86 (1H, dd, J=8.92, 2.51 Hz), 5.59 (1H, dq, J=7.09 Hz), 1.59 (3H, d, J=6.81 Hz)
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[Br:7].CN([CH:15]=[O:16])C.O.O.C(O)(=O)C(O)=O>CCOCC.O.CCOC(C)=O>[Br:7][C:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3][C:2]=1[CH:15]=[O:16]
Reactant: CN(C)C=O
Reactant: Brc1oc2ccccc2c1Br
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=Cc1oc2ccccc2c1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
2,3-Dibromobenzofuran (1.37 g, 5.0 mmol) is dissolved in Et2O (20 ml) in a dry flask under nitrogen and cooled to −78° C. t-Butylithium (6.47 ml, 11.0 mmol) is added drop-wise, and the chilled solution is stirred 1 h. DMF (0.45 ml, 5.75 mmol) is dissolved in Et2O (5 ml) and also added dropwise, and the mixture is stirred at −78° C. for another 4 h. The reaction is warmed to rt, whereby oxalic acid dihydrate (1.26 g, 10.0 mmol) and water (5 ml) are added. The reaction continued stirring at rt for 2 days and is then diluted with water (25 ml) and EtOAc (35 ml). The layers are allowed to separate, and the aqueous is extracted with EtOAc (1×35 ml). The organics are combined, dried over Na2SO4, filtered, and concentrated to an orange oil that solidified upon standing. The crude material is chromatographed over 100 g slurry-packed silica, eluting with 20% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 628 mg (56%) of 3-bromo-1-benzofuran-2-carbaldehyde as a yellow crystalline solid. HRMS (FAB) calcd for C9H5BrO2+H: 224.9552, found 224.9555.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>C1COCC1.C1(C)C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C>[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2[CH3:12])=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Reactant: BrCc1ccc(Br)cc1
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Reaction time: 0.17 h

Procedure:
To the ethyl ester from Example 7, Step 1 (2.00 g, 8.10 mmol) dissolved in THF (40.0 mL) was added at -78° C. a 0.5M solution of KHMDS (16.0 mL, 8.10 mmol) in toluene and HMPA (200 μL). After a period of 10 min, 4-bromobenzyl bromide was added to the resulting mixture. The reaction mixture was brought to room temperature, quenched by the addition of 25% aqueous NH4OAc solution, extracted with EtOAc, dried over Na2SO4 and evaporated in vacuo. The title product was purified by flash chromotography (15% to 20% EtOAc in hexane) (1.5 g).
Reaction SMILES: FC1C=C[C:5]2C(C3CCN(CCN)CC3)=N[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[ClH:27].[C:28]([Cl:36])(=[O:35])[C:29]1C=CC=N[CH:30]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:29]([O:8][CH:4]([CH3:3])[CH3:5])([CH3:30])[CH3:28].[OH2:35].[ClH:36].[ClH:27]
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C
Product: O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (1.17 g, 4.34 mmol) and triethylamine (1.08 g, 10.8 mmol) in chloroform (30 ml) was added nicotinoyl chloride hydrochloride (0.96 g, 5.4 mmol) in one portion. The mixture was stirred for 1 hour at room temperature. The solution was diluted with methylene chloride (DCM) and washed with brine and dried over anhydrous MgSO4. The solution was concentrated and the crude product was purified by flash chromatography over a silica gel column (SiO2, 25 g; eluted with DCM and 1-3% MeOH in DCM). The free base thus purified weighed 1.7 g. This product was treated with 1 M•HCL in ethanol and recrystallized twice from methanol:isopropyl ether to yield white crystals, 1.19 g, m.p. 243°-245° C. as a dihydrochloride hydrate.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH2:11]Br>>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[CH2:11][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Fc1cc(CBr)cc(F)c1F
Reactant: Nc1nc[nH]n1
Product: Nc1ncn(Cc2cc(F)c(F)c(F)c2)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and 3,4,5-trifluorobenzyl bromide. A pure fraction of the title compound was obtained as a colorless solid (Yield=4%). MS ISP (m/e): 229.2 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([NH2:17])[C:10]([NH2:16])=[CH:11][CH:12]=2)[O:7]1)=[O:5])[CH3:2].[F:18][C:19]([F:24])([F:23])[C:20](O)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[O:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]3[NH:16][C:20]([C:19]([F:24])([F:23])[F:18])=[N:17][C:9]3=2)[CH2:14][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2ccc(N)c(N)c2O1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2ccc3[nH]c(C(F)(F)F)nc3c2O1
Yield: 65 %

Procedure:
A solution of ethyl-7,8-diamino-chroman-2-carboxylate (927 mg, 3 mmol) in trifluoroacetic acid (20 mL) was heated to reflux for 6 hours and then concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 mL) and then washed with saturated NaHCO3 solution (30 mL) and water (2×30 mL), dried over anhydrous Na2SO4. Purification by flash chromatography (30% CH2Cl2-hexanes) afforded 612 mg (65% yield) of the title compound as white solid: mp 134° C.; 1H NMR (400 MHz, CDCl3) :[tautamer a]: δ:1.19 (t, J=7.1, 3H), 2.22 (m, 2H), 2.40 (m, 1H), 2.70 (m, 1H), 4.15 (q, J=7 Hz, 2H), 5.14 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 14.09 (bs, 1H). [tautamer b]: δ1.19 (t, J=7.1, 3H), 2.22 (m, 2H), 2.40 (m, 1H), 2.70 (m, 1H), 4.15 (q, J=7 Hz, 2H), 5.03 (m, 1H), 7.07 (s, 2H), 13.77 (bs, 1H); IR 3450, 3250, 2980, 2600, 1730, 1600, 1500, 1230 cm−1. MS 315 [M+H]+.
Reaction SMILES: O=C1CCCC(CC(O)=O)C1.[F:12][C:13]1[CH:14]=[C:15]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:16][C@H:17]([NH:31][C:32](=[O:44])[CH2:33][CH:34]1[CH2:39][CH2:38][CH:37](CCC)[C:36](=[O:43])[CH2:35]1)[C@H:18]([OH:30])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=1>>[F:12][C:13]1[CH:14]=[C:15]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:16][C@H:17]([NH:31][C:32](=[O:44])[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][C:36](=[O:43])[CH2:35]1)[C@H:18]([OH:30])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=1
Reactant: CCCC1CCC(CC(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)CC1=O
Agent: O=C(O)CC1CCCC(=O)C1
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)CC2CCCC(=O)C2)c1
Yield: 23 %

Procedure:
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-oxocyclohexyl)acetamide was prepared in 23% yield from (3-Oxo-cyclohexyl)-acetic acid by the method described for the synthesis of N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-oxo-4-propylcyclohexyl)acetamide (EXAMPLE SP-297.)
Reaction SMILES: [F:1][CH:2]([CH3:35])[CH2:3][N:4]([S:26]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)(=[O:28])=[O:27])[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1.[OH-].[Na+:37]>C1COCC1.CO>[F:1][CH:2]([CH3:35])[CH2:3][N:4]([S:26]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)(=[O:28])=[O:27])[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O-:22])=[O:21])=[CH:24][CH:25]=1.[Na+:37]
Reactant: COC(=O)c1ccc(COc2cc3c(cc2N(CC(C)F)S(=O)(=O)c2nc(C)cs2)CCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1csc(S(=O)(=O)N(CC(C)F)c2cc3c(cc2OCc2ccc(C(=O)[O-])cc2)CCC3)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
351 mg of methyl 4-{[(6-{(2-fluoropropyl)[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate was dissolved in 5.00 mL of THF and 5.00 mL of methanol, and 2.03 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at 50° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, to the obtained residue were added a 5% w/v aqueous citric acid solution and chloroform, and the organic layer was separated using a Phase Separate-filter manufactured by Isotute, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was dissolved in 5.00 mL of ethanol, and 0.765 mL of an aqueous sodium hydroxide solution was added thereto, followed by concentration under reduced pressure. The obtained crude product was crystallized by the addition of isopropanol/ethanol, collected by filtration, and dried under reduced pressure to obtain 268 mg of sodium 4-{[(6-{(2-fluoropropyl)[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([Cl:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:19]([O-])([O-])[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([Cl:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:19][O:20][CH2:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(Cl)c(C)c1Cl
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c(C)c1Cl

Procedure:
14.1 g of the compound from (e), 10.7 g of ethyl orthoformate and 12.3 g of acetic anhydride are boiled for 2 hours. The volatile components are then removed by distillation first in a water-pump vacuum and then in a high vacuum at a bath temperature of 130° C. 14 g of the title compound remain (oil).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-])=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C(O)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 85 °C
Yield: 61 %

Procedure:
In a flask equipped with a reflux condenser, the compound obtained in Example 6 1.60 g (3.77 mmol), reduced iron powder 1.05 g (18.85 mmol, 5 eq), glacial acetic acid (2 mL) and methanol (40 mL) were mixed. The mixture was refluxed in an oil bath at a temperature of 85° C. for 2.5 h. Then the iron powder was filtered of, the filtrate was diluted with ethyl acetate, washed sequentially with NaHCO3 solution and water. The organic phase was dried and concentrated to obtain yellow solid, which was identified as the title compound. Yield: 61%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]([N:17]1[C:18]2=[N:19][CH:20]=[N:21][C:22]([NH2:24])=[C:23]2[C:15]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:16]1)([CH3:27])[CH3:26]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(-c2nn(C(C)C)c3ncnc(N)c23)cc1OC
Temperature: 80 °C
Yield: 59.7 %

Procedure:
A solution of 3,4-Dimethoxyphenylboronic acid (24 mg, 0.13 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA23 (13.1 mg, 60% yield). ESI-MS (M+H)+ m/z calcd 314.0, found 314.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:36].[Na+]>CC(C)=O>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][I:36])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(C=CCCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(C=CCI)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Yield: 60.4 %

Procedure:
After 20.0 g of p-methoxybenzyl 7β-[2-phenylacetamido]-3-[3-chloro-1-propenyl]-3-cephem-4-carboxylate (E/Z=25/75) was suspended in 250 ml of acetone, 29 g of sodium iodide was added to the suspension. The mixture was reacted at 25-30° C. for 3 hours, while stirring. After the reaction was completed, the solution was concentrated at a temperature below 25° C. under a reduced pressure of 100 mmHg and 60 ml of acetone was distilled off. The formed crystals were collected by filtration and washed successively with 50 g of 5% sodium thiosulfate aqueous solution, next with 50 g of ion exchange water and finally with 50 g of acetone to give 14.24 g of p-methoxybenzyl 7β-[2-phenylacetamido]-3-[3-iodo-1-propenyl]-3-cephem-4-carboxylate (content, 97.0%; E/Z=99/1). The yield of E-form was 59%.