Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=C(C#N)[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:16]=12.[OH-:32].[K+].Cl.[CH2:35]([OH:37])[CH3:36]>O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:36]([C:35]([OH:32])=[O:37])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:16]=12
Reactant: [OH-]
Reactant: Cc1c(C)n(Cc2ccc(F)cc2)c2c(N3CCc4ccccc4C3)nc(C#N)cc12
Reactant: CCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc12
Yield: 81 %

Procedure:
7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(4-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile (300 mg, 0.73 mmol) prepared in Example 690 was diluted with a mixture of ethanol (7 ml) and water (1 ml). Potassium hydroxide (410 mg, 7.3 mmol) was added to the solution, which was then refluxed for 72 hours. 1N hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 250 mg of the titled compound as a white solid. (Yield: 81%)
Reaction SMILES: C(O[Si:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.[CH:14]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>COC(C)(C)C>[CH:14]1([Si:4]([O:5][CH2:6][CH3:7])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: Br[Mg]C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: CCO[Si](OCC)(OCC)C1CCCC1
Reaction time: 6 h

Procedure:
60 ml of dry t-butyl methyl ether and 14.0 gram (0.067 mole) of tetraethoxysilane were charged in a 250 ml flask equipped with a reflux condenser and a stirring apparatus in an atmosphere of nitrogen and the solution of cyclopentyl magnesium bromide prepared above under (a) was slowly added while keeping the internal temperature below 10° C. After completion of addition stirring was carried out at room temperature for 6 hours and at reflux temperature for 2 hours. To the resulting reaction mass 10-20 ml of saturated aqueous ammonium chloride solution was added drop wise to dissolve magnesium salt. The organic layer was separated from the aqueous layer, dried and evaporated to give crude cyclopentyltriethoxysilane. The crude was purified by fractional distillation under reduced pressure, yielding 12 gram of pure cyclopentyltriethoxysilane (76% of the theoretical maximum yield based on the amount of tetraethoxysilane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][O:34][N:35]([CH3:45])[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36]([N:35]([O:34][CH3:33])[CH3:45])=[O:44])[CH2:43][CH2:42]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CON(C)C(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with N-methoxy-N-methyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-methoxy-N-methyl-acetamide in an analogous manner as described in example 1. LR-MS: 630.3 [(M+H)+].
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:32][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:31]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(N2CCCCC2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(N2CCCCC2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 6-(piperidin-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 410.42 g/mol.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:4][N:3]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:4][N:3]=1)[CH3:21]
Reactant: CNC
Reactant: Fc1ccccc1Cn1cnc2cnc(Cl)nc21
Product: CN(C)c1ncc2ncn(Cc3ccccc3F)c2n1

Procedure:
In a manner analogous to that described in Example 2 it is also possible, by reacting 2-chloro-9-(2-fluorobenzyl)-9H-purine (Example 7) with N,N-dimethylamine, to obtain the 2-(N,N-dimethylamino)-9-(2-fluorobenzyl)-9H-purine, which has a melting range of from 112° to 113° (methanol/diethyl ether), the reaction mixture being heated for 24 hours at from 80° to 85°.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:22][C:23]([CH3:28])([CH3:27])[C:24]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)=[O:25]
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a] imidazole prepared as in Example 16 in 50 ml methylene chloride at 0° C. was added a solution of 0.3 g (3.7 mmole, 0.26 ml) trimethylacetyl chloride in 10 ml CH2Cl2 over a period of 10 minutes. The reaction was allowed to come to room temperature and was stirred for 30 minutes. The mixture was then diluted with methylene chloride and washed with 3N NaHCO3, saturated NaCl, treated with Na2SO4, stripped, then flash chromatographed on silica with methylene chloride containing 1% to 5% MeOH. The isolated material was recrystallized from ethyl acetate to give 0.43 g of the titled compound. 33.5% yield, mp 216°-217.5° C. C22H23N3OS, Calculated, C: 70.00, H: 6.14, N: 11.13; Found, C: 70.01, H: 6.20, N: 10.99.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Br:10].[CH2:11]1[C:16](=O)[CH2:15][C:13](=[O:14])[CH2:12]1.[NH2:18][C:19]1[N:23]([CH3:24])[NH:22][C:21](=[O:25])[CH:20]=1>>[Br:10][C:3]1[CH:4]=[C:5]([CH:6]2[C:20]3[C:21](=[O:25])[NH:22][N:23]([CH3:24])[C:19]=3[NH:18][C:16]3[CH2:11][CH2:12][C:13](=[O:14])[C:15]2=3)[CH:8]=[CH:9][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)C1
Reactant: Cc1ccc(C=O)cc1Br
Reactant: Cn1[nH]c(=O)cc1N
Product: Cc1ccc(C2C3=C(CCC3=O)Nc3c2c(=O)[nH]n3C)cc1Br
Yield: 60.6 %

Procedure:
4-Methyl-3-bromobenzaldehyde (0.3 g, 1.5 mmol), prepared as described in (Pearson et al., J. Org. Chem. (1958) 23, 1412-1416), 1,3-cyclopentadione (0.15 g, 1.5 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.17 g, 1.5 mmol) were processed as described in Example 1 to provide 0.34 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 2.29 (t, 2H), 2.67 (m, 2H), 3.5 (s, 3H), 4.63 (s, 1H), 7.04 (dd, 1H), 7.18 (d, 1H), 7.29 (ds, 1H), 9.51 (bs, 1H), 10.37 (s, 1H); MS (ESI−) m/z 361 (M−H)−; Anal. calcd for C11H16N3BrO2: C, 54.54; H, 4.28; N, 11.23. Found: C, 54.30; H, 4.46; N, 10.94.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[C:10]1[CH:15]=[C:14]([NH:16][CH2:17][CH3:18])[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=1.O>C1COCC1>[CH2:17]([NH:16][C:14]1[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=[C:10]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=1)[CH3:18]
Reactant: CCNc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]

Procedure:
A solution of sodium phenoxide (prepared from phenol and NaH) (6 mmol) in THF (3 mL) was added to a solution of the product from Step 1 (600 mg, 3.0 mmol) in THF (2 mL) and the resulting solution was heated to reflux overnight. The solution was cooled, poured into H2O and extracted with EtOAc. The organic layers were washed with H2O and brine, dried, filtered and concentrated to give a residue which was purified by column chromatography (5-80% EtOAc in hex) to give the title compound which was used directly in the next step. MS (ES+) m/e 260. [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9](O)[CH:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2.C(N(CC)C(F)(F)C([F:25])Cl)C.C(Cl)Cl.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([F:25])[CH:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:14][C:15]([O-:17])=[O:16])[CH:7]=[CH:6]2
Reactant: COC(=O)CC1CCc2cc(OC)ccc2C1O
Reactant: CCN(CC)C(F)(F)C(F)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC1CCc2cc(OC)ccc2C1F
Product: COc1ccc2c(c1)C=CC(CC(=O)[O-])C2
Reaction time: 24 h

Procedure:
A mixture of 25 g. of methyl 6-methoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthylacetate, 38 g. of 1-diethylamino-1,1,2-trifluoro-2-chloroethane and 150 ml. of methylene chloride are allowed to stand for 24 hours. The fluorination reaction mixture is added to 250 ml. of water containing 12 g. of hydrogen chloride; the resulting mixture is separated and the methylene chloride phase is washed with water, dried over sodium sulfate, and evaporated to yield methyl 6-methoxy-1-fluoro-1,2,3,4-tetrahydro-2-naphthylacetate and 6-methoxy-1,2-dihydro-2-naphthylacetate. The mixture is separated on alumina eluting with acetone: diethyl ether (1:4) and the separated fractions are identified by ultraviolet spectroscopy. The fraction containing methyl 6-methoxy-1-fluoro-2-naphthylacetate is evaporated and the residue is refluxed with 23 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 500 ml. of xylene for six hours. The cooled mixture is filtered and chromatographed on alumina eluting with chloroform. The fraction containing the product is evaporated to yield methyl 6-methoxy-1-fluoro- 2-naphthylacetate.
Reaction SMILES: [CH:1](=O)[CH3:2].[ClH:4].Cl.[N:6]1([CH2:12][CH2:13][O:14][NH2:15])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[Na+]>O>[N:6]1([CH2:12][CH2:13][O:14][N:15]=[CH:2][CH2:1][Cl:4])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: Cl
Reactant: NOCCN1CCOCC1
Reactant: CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCC=NOCCN1CCOCC1
Yield: 100 %

Procedure:
A mixture of acetaldehyde (0.1 mL of a 50 wt % soln. in water), O-[2-((morpholin-4-yl))ethyl]hydroxylamine dihydrochloride (0.14 g), NaOH (2N, 0.64 mL) and water (5 mL) was stirred at room temperature overnight. The solution was made basic with NaOH (1N) and extracted with dichloromethane. The organic layer was dried (Na2SO4), and concentrated in vacuo to afford 2-chloroethanal O-[2-((morpholin-4-yl))ethyl]oxime (0.13 g, ˜100%), which was used as such.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].N12CCCN=[C:32]1[CH2:31][CH2:30][CH2:29]CC2.BrCC1CC1.O>C(O)C.C(OCC)(=O)C>[CH:31]1([CH2:32][O:1][C:2]2[CH:3]=[C:4]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]4[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=4)=[O:18])[N:14]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:29][CH2:30]1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CC1
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OCC1CC1

Procedure:
A 0.3 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 and 0.4 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 5 ml of ethanol, 0.24 g of (bromomethyl)cyclopropane was added thereto, and the mixture was heated and refluxed for 4.5 hours. After standing to cool, water was added to the reaction mixture, and ethyl acetate extraction was performed. The extract was washed twice with water, the organic layer was then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), thereby yielding 0.2 g of white powdery 3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methyl pyridin-2-yl)propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27].[CH:30]1([NH:36][C:37]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[C:3]([N:42]2[CH2:43][CH2:44][CH:39]([C:37]([NH:36][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:38])[CH2:40][CH2:41]2)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cn(C2CC2)c2c(Cl)c(N3CCC(C(=O)NC4CCCCC4)CC3)c(F)cc2c1=O
Yield: 10.5 %

Procedure:
200 mg (0.44 mmol) of the compound of Example 70A and 138 mg (0.66 mmol) of 4-(cyclohexylamino)carbonylpiperidine (for preparation see WO 2003031397) are heated with 91 μl (0.66 mmol) of triethylamine in 4 ml of DMSO at 120° C. for 7 h. After cooling, the entire reaction mixture is separated by preparative HPLC (method 6). 30 mg of the title compound are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:15]1([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([OH:27])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C.O>[CH3:14][C:4]([S:10]([CH3:13])(=[O:12])=[O:11])([CH2:3][CH2:2][N:24]1[CH:25]=[CH:26][C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:22][C:23]1=[O:27])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Oc1cc(-c2ccccc2)ccn1
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(CCn1ccc(-c2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 60 °C
Yield: 61.4 %

Procedure:
Ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (25.02 g, 87.1 mmol) was added to a mixture of 4-phenylpyridin-2-ol (12.40 g, 72.43 mmol) and cesium carbonate (49.70 g, 152.5 mmol) in THF (150 mL). The reaction was stirred and heated at 60° C. overnight. The reaction was diluted with ethyl acetate (200 mL) and water (200 mL); the organics were separated and the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organics were dried (MgSO4), filtered, and concentrated to afford a crude solid. The crude was purified via flash chromatography using an Analogix SF65-400 g column and eluted with ethyl acetate in heptane (30-80%) to afford the title compound as a white solid (16.79 g, 61.4%). LC-MS m/z 378.6 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.12 Hz, 3H) 1.58 (s, 2H) 2.41-2.62 (m, 2H) 3.09 (s, 3H) 3.90-4.01 (m, 1H) 4.20-4.32 (m, 3H) 6.40-6.45 (m, 1H) 6.73 (d, J=1.56 Hz, 1H) 7.31 (d, J=7.03 Hz, 1H) 7.37-7.46 (m, 2H) 7.50-7.55 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl-].[Cl-].[Cl-].[Al+3].[N:15]1([CH2:21][CH2:22][C:23]2[N:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]3=[CH:25][N:24]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>ClCCCl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:25]1[N:24]=[C:23]([CH2:22][CH2:21][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=12)=[O:6]
Reactant: O=C(O)c1ccccc1I
Reactant: c1ccn2c(CCN3CCOCC3)ncc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1I)c1nc(CCN2CCOCC2)n2ccccc12
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
To a solution of 2-iodobenzoic acid (487 mg, 1.83 mmol) in 1,2-dichloroethane (20 mL) was added aluminum trichloride (266 mg, 2.00 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine (201 mg, 0.87 mmol) in 1,2-dichloroethane (5 mL) was added. The mixture was stirred at ambient temperature for 30 min. then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (63 mg, 16%). %). 1H NMR (DMSO-d6) 8.54 (1H), 8.10 (1H), 7.92 (1H), 7.50 (1H), 7.41 (2H), 7.22 (1H), 7.10 (1H), 3.52 (4H), 3.18 (2H), 2.67 (2H), 2.40 (4H); m/z (M+H)=462.1.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S(O[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[CH:23][CH:22]=2)=[C:18]([CH3:35])[N:17]=[C:16]([NH2:36])[N:15]=1)(=O)=O.[CH2:37]([NH2:42])[CH2:38][CH2:39][CH2:40][CH3:41]>C(O)CCC>[CH3:35][C:18]1[N:17]=[C:16]([NH2:36])[N:15]=[C:14]([NH:42][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:19]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[CH:25][CH:26]=1
Reactant: CCCCCN
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(COC3CCCCO3)cc2)c(C)c1
Solvent: CCCCO
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(COC2CCCCO2)cc1

Procedure:
A mixture of the product from step (iii) (6.49 g) and n-pentylamine (7.34 ml) in 1-butanol was heated under reflux for 24 h. The solvent was evaporated and the residue partitioned between EtOAc and water. The organics were separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 8% MeOH/DCM to afford the subtitle compound, 3.4 g.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([O-:29])=O)[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na+].CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:91](=[O:92])[N:60]2[C:61]([C:75]([O:77]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:76])=[C:62](/[CH:65]=[C:66]3/[C:67]([O:73][CH3:74])=[C:68]([CH3:72])[C:69](=[O:71])[O:70]/3)[CH2:63][S:64][C@H:59]12>CN(C=O)C.C(OCC)(=O)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[OH:31])/[C:27]([NH:57][C@@H:58]2[C:91](=[O:92])[N:60]3[C:61]([C:75]([OH:77])=[O:76])=[C:62](/[CH:65]=[C:66]4/[C:67]([O:73][CH3:74])=[C:68]([CH3:72])[C:69](=[O:71])[O:70]/4)[CH2:63][S:64][C@H:59]23)=[O:29])[N:25]=1
Reactant: COC1=C(C)C(=O)O/C1=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1=C(C)C(=O)O/C1=C\C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Sodium 2-(2-tritylaminothiazol-4-yl)-2-Z-trityloxyiminoacetate (0.759 g), in dry DMF (5 mls) was cooled to ca -50° C. under argon. This solution was treated with methanesulphonyl chloride (0.085 mls) and allowed to warm to -15° C. A solution of diphenylmethyl 7β-amino-3-(Z-2,5-dihydro-4-methoxy-3-methyl-2-oxofuran-5-ylidenemethyl)ceph-3-em-4-carboxylate, (0.46 g) in dry DMF (5 mls) was added, and the solution allowed to reach room temperature over 1 h. The solution was diluted with ethl acetate and washed with water, brine and then dried. After removal of solvent the residue was flash chromatographed on silica gel eluting with 50% ethyl acetate/hexane to give the title compound as a yellow foam, (0.375 g, 36%), νmax 3380, 1770(br), 1725, 1685, 1630, 1505(br), 1440, 1370 and 1345cm-1 ; δH (CDCl3) 2.07 (3H,s), 3.74 and 3.96 (2H,ABq, J18.3Hz, sharpens on D2O shake), 5.08 (1H, m, sharpens to d, J5.0Hz on D2O shake), 6.12 (1H, br.m, sharpens to d, J5.0Hz on D2O shake), 6.43 (1H, br.s, sharpens on D2O shake), 6.74 (1H, s), 6.78 (1H, br.s, exch.), 6.98 (1H, s) and 7.20 to 7.55 (40H, m, arom-H); [mass spectrum: +ve ion (NOBA, Na+) MNa+, 1180].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=O)=[CH:5][C:4]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20].[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][CH2:8][CH2:9][CH:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])=[CH:5][C:4]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:18][C:19]=1[CH3:20]
Reactant: O=C1COC(=O)N1
Reactant: COc1ccc(C=CC=O)cc1OCc1nc(-c2ccccc2)oc1C
Product: COc1ccc(CCCC2OC(=O)NC2=O)cc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolyl-methoxy)cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic reduction to yield 5-[3-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from chloroform-methanol to give colorless prisms, m.p.185-187° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:36](Cl)=[O:37])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[N:19]=2)=[C:11]([O:39][CH2:40][CH3:41])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:44][S:45]([CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:47])=[O:46]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C@@:18]2([CH3:20])[C@:17]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[N:16]([C:36]([N:54]3[CH2:53][CH2:52][N:51]([CH2:50][CH2:49][CH2:48][S:45]([CH3:44])(=[O:46])=[O:47])[CH2:56][CH2:55]3)=[O:37])[C:15]([C:12]3[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])(=[O:8])=[O:7])=[CH:10][C:11]=3[O:39][CH2:40][CH3:41])=[N:19]2)=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butylsulfamoyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H49N5O6S2Cl2 [(M+H)+] 806.2574, observed 806.2579.