Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.[CH3:29][CH2:30]OCC>C1(C)C=CC=CC=1>[CH:11]([CH:5]1[C:4]2[C:3](=[CH:2][CH:9]=[CH:8][CH:7]=2)[CH:30]=[CH:29]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6]
Reactant: CCOCC
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: FB(F)F
Agent: NCc1ccc(F)c(F)c1
Solvent: Cc1ccccc1
Product: C1=CC(C(c2ccccc2)c2ccccc2)c2ccccc21
Yield: 95 %

Procedure:
To a solution of 3,4-difluorobenzylamine (9.8 g, 69 mmol) and benzophenone (13.0 g, 71.0 mmol) in toluene (200 mL) was added a catalytic amount of BF3.OEt2 and the resulting solution was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oil (21 g, >95%), which was characterized by NMR analysis and subjected to the following reaction without any further purification.
Reaction SMILES: ClC[CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10]Cl.[OH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[CH:4]=[CH2:3]
Reactant: ClCCCCOCCCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCCCCOc1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution comprising 14 g of allyl (4-chlorobutyl ether, 14 g of 4-hydroxybenzoic acid, 14 g of potassium carbonate and 50 ml of dimethylformamide was stirred at 90° C. for 3 hours. Water was added thereto, and the liquid was extracted with toluene. The toluene layer was washed well with water, and toluene was distilled off. Sodium hydroxide 20 g, water 50 ml and ethanol 200 ml were added to the resulting residue, and the solution was refluxed for 2 hours. Ethanol was distilled off, and hydrochloric acid was added to acidify the solution. It was extracted with diethyl ether and dried on anhydrous magnesium sulfate. The solvent was distilled off, and a residue thus obtained was recrystallized from a mixed solvent of ethanol and water to obtain 29 g of 4-(4-allyloxybutyloxy)benzoic acid. Phase transition temperature: C 94 N 107 I
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28]>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][N:17]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:40]([NH:39][C:31]2[C:30]([CH:27]([CH3:28])[CH3:29])=[CH:35][CH:34]=[CH:33][C:32]=2[CH:36]([CH3:38])[CH3:37])=[O:41])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Product: CC(C)c1ccc(N(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (3,5-di-tert-butyl-4-hydroxyphenylmethyl)(4-isopropylphenyl)amine (2.0 g) and 2,6-diisopropylphenyl isocyanate (1.8 mL) as starting materials, N-(3,5-di-tert-butyl-4-hydroxyphenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (0.82 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:18][CH3:19])[CH2:9][C@H:10]([CH2:15][CH:16]=[CH2:17])[C:11](OC)=[O:12])=[CH:4][C:3]=1[CH3:20].C1COCC1.[NH2:26][OH:27].[C-]#N.[K+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:18][CH3:19])[CH2:9][C@H:10]([CH2:15][CH:16]=[CH2:17])[C:11]([NH:26][OH:27])=[O:12])=[CH:4][C:3]=1[CH3:20]
Reactant: C=CC[C@@H](C[C@@H](OC)c1ccc(F)c(C)c1)C(=O)OC
Reactant: NO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CC[C@@H](C[C@@H](OC)c1ccc(F)c(C)c1)C(=O)NO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(S)-Methyl 2-((R)-2-(4-fluoro-3-methylphenyl)-2-methoxyethyl)pent-4-enoate (50 mg) was dissolved into 1 mL of a mixture of THF, methanol, and 50% NH2OH in H2O (2:2:1) and to this solution was added 2 mg KCN. The reaction was stirred for 3 days at room temperature and then quenched by the addition of 1M HCl (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×10 mL) before being concentrated under reduced pressure. The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to obtain the title compound (34 mg) as white solid.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=O)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:21][C:22](=[C:25]([NH2:28])[C:26]#[N:27])[C:23]#[N:24]>C(#N)C>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:21]=[C:22]([C:23]#[N:24])[C:25]([C:26]#[N:27])=[N:28][C:12]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: N#CC(N)=C(N)C#N
Reactant: CC(C)n1nc(C(=O)C(=O)c2ccccc2)ccc1=O
Solvent: CC#N
Product: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Temperature: 72.5 °C
Yield: 89.2 %

Procedure:
A mixture of 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione (1.15 g) and 2,3-diamino-2-butenedinitrile (0.46 g) in acetonitrile (6 ml) was heated at 70-75° C. for 3 hours. A reaction mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile as a solid (1.30 g).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[Cu][C:22]#[N:23].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CN(C)C=O>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([C:22]#[N:23])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: N#C[Cu]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3cc(OC)cc(C#N)c3o2)cc1
Yield: 98 %

Procedure:
A solution of 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (200 mg, 0-60 mmol), in anhydrous N,N dimethylformamide (1.5 mL) was stirred and heated to reflux under dry nitrogen with copper(I) cyanide (80 mg, 0.90 mmol) for 4 h. The mixture was cooled and poured into an excess of aqueous ethylenediaminetetraacetic acid. Isolation of the crude product gave the nitrile (164 mg, 98% yield) as tan needles from (30% EtOAc/petroleum ether); m.p. 180-183° C.; MS m/e 281 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]([NH:17][CH:18]([C:24]([O:26][CH2:27]C)=[O:25])[C:19]([O:21][CH2:22]C)=[O:20])(=[O:16])[CH3:15].C[O-].[Na+]>CCO>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:15][C:14]([NH:17][CH:18]([C:24]([O:26][CH3:27])=[O:25])[C:19]([O:21][CH3:22])=[O:20])=[O:16]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: ClCc1ccc2ccccc2n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C(NC(=O)CCc1ccc2ccccc2n1)C(=O)OC
Yield: 107.4 %

Procedure:
To a solution of 2(chloromethyl)quinoline monohydrochloride (5.0 g, 23.4 mmol) and diethyl acetamidomalonate (10.1 g, 46.7 mmol) in EtOH (60 mL) was added sodium methoxide (3.78 g, 70 mmol). The reaction mixture was heated at reflux for 6 h. The reaction mixture was cooled, filtered, and concentrated. The residue was dissolved in EtOAc (400 mL) and extracted with cold 4NHCl (3×150 mL). The aqueous layer was neutralized with 10N NaOH and extracted with EtOAc (3×200 mL). The combined organic extract was washed with water, dried (anhydrous MgSO4), filtered, and concentrated to give the title compound (8.3 g).
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=3)=[N:7][N:6]=[N:5]2)[CH2:3][CH2:2]1.[H][H]>C(O)C.[C].[Pd]>[CH:1]1([N:4]2[C:8]([C:9]3[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([CH3:18])[CH:10]=3)=[N:7][N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nnnn2C2CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(-c2nnnn2C2CC2)ccc1N
Yield: 71.5 %

Procedure:
0.4 g of 5% palladium carbon was added to a solution of 1.6 g (6.5 mmol) of 4-(1-cyclopropyltetrazol-5-yl)-2-methylnitrobenzene in 70 ml of ethanol and the mixture was stirred under 3 atm hydrogen atmosphere overnight. The reaction mixture was filtered and concentrated under reduced pressure and the residual substance was purified with silica gel column chromatography to obtain 1.0 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]([N+:12]([O-])=O)[CH:6]=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:12][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1cccc([N+](=O)[O-])c1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(N)c1C(=O)O
Yield: 100.2 %

Procedure:
A solution of 6-methoxy-2-nitrobenzoic acid (3.25 g, 16.5 mM) in ethanol (180 mL) containing 10% palladium-on-carbon catalyst (0.30g) was hydrogenated using a Parr apparatus. When hydrogen consumption ceased, the resulting mixture was filtered through diatomaceous earth and the filtrate concentrated to provide the title benzoic acid (2.76 g, 100%) as a tan solid; MS(CI): 168 (M+H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38]C=2N=N1.C1(N)CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:34]1([NH:30][C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Agent: NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)NC4CCCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), cyclopentylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:32]4[CH2:31][CH2:30][N:29]([C:27]5[CH:26]=[CH:25][CH:24]=[C:23]6[C:28]=5[N:19]=[CH:20][CH:21]=[CH:22]6)[CH2:34][CH2:33]4)[CH2:17][CH2:18]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(N2CCNCC2)c2ncccc2c1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a solution of 0.247 g of 6-methoxy-8-piperazino-quinoline (Step 4) in 10 mL of dichloroethane, was added 0.226 g of 1-quinolin-8-yl-piperidin-4-one (Step 6) followed by 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product crystallized and filtered to give 0.200 g of the desired product. Mp.194-197° C.; MS (ES) m/z (relative intensity): 454 (M++−H, 100).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][C@H:68]([C:75]([O-:77])=[O:76])[CH2:69][CH2:70][C:71]([O:73][CH3:74])=[O:72].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:67][CH:68]([CH2:69][CH2:70][C:71]([O:73][CH3:74])=[O:72])[C:75]([OH:77])=[O:76])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: COC(=O)CC[C@H](N)C(=O)[O-]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCC(NC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (60 mg, 0.13 mmol) in 10 ml of anhydrous DMF were added HATU (61 mg, 0.16 mmol) and N,N-diisopropylethylamine (52 mg, 0.40 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 5-methyl L-glutamate (32 mg, 0.20 mmol). The mixture was heated at 60° C. for 1 hour, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added slowly until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 2-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]-5-methoxy-5-oxopentanoic acid as white solid. Yield: 30 mg, 38%.
Reaction SMILES: COC(=O)C1C=C(O)C=C(O)C=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21](=[O:66])[C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=2)[CH:25]=[C:24]([O:47]CCCOC2C=CC(OCC3C=CC=CC=3)=CC=2)[CH:23]=1>CC(C)=O.CN(C=O)C>[CH3:19][O:20][C:21](=[O:66])[C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=2)[CH:25]=[C:24]([OH:47])[CH:23]=1
Reactant: COC(=O)c1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Agent: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1cc(O)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Yield: 30 %

Procedure:
A mixture of 2.0 g (11.9 mmol) of 3,5-dihydroxybenzoic acid methyl ester, 3.8 g (11.9 mmol) of 3-[(4-phenylmethoxy)phenoxy]propyl bromide and 1.7 g (12.3 mmol) of potassium carbonate in 40 ml of acetone and 2 ml of DMF was stirred at reflux for 24 hours. The solvents were removed at reduced pressure, the residue was stirred with methylene chloride and filtered. The filtrate was concentrated to a solid which was recrystallized from methylene chloride-methanol to give 1.77 g, mp 134°-136°, of 3,5-bis[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester. The filtrate was concentrated to a solid which was purified by chromatography on 20 g of silica gel (230-400 mesh) using 10% ethyl acetate-hexane to give 1.47 g (30% yield, mp 120°-122°) of 3-hydroxy-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester.
Reaction SMILES: [C:1]1([CH:13]2[CH:18]([CH3:19])[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1.[ClH:27]>O1CCOCC1.CCOCC>[ClH:27].[CH3:19][CH:18]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:1]1[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1c1ncc2cnc3[nH]ccc3n12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1CCNCC1c1ncc2cnc3[nH]ccc3n12
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate (12.2 g, 34.3 mmol) in 1,4-dioxane (100 mL) was added 4N HCl (4N in 1,4-dioxane, 25.7 mL, 103 mmol). The reaction mixture was heated at about 60° C. for about 2 h. The mixture was allowed to cool to ambient temperature and was diluted with Et2O (100 mL). The mixture was triturated and filtered, and the precipitate was washed with Et2O (100 mL) to give 1-(4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (10 g, 98% yield) as a tan solid: LC/MS (Table 2, Method a) Rt=1.05 min; MS m/z: 256 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([O-:16])=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH2:19]([NH:26][C:14](=[O:16])/[C:13](/[O:17][CH3:18])=[CH:12]/[CH:11]=[CH:10]/[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CO/C(=C\C=C\c1cc2ccccc2[nH]1)C(=O)[O-]
Reactant: NCc1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CO/C(=C\C=C\c1cc2ccccc2[nH]1)C(=O)NCc1ccccc1
Yield: 32.4 %

Procedure:
This compound was prepared following the same procedure of Example 9 and starting from (2Z,4E)-5-(2-indolyl)-2-methoxy-2,4 pentadienoate (0.1 g, 0.39 mmol), benzylamine (0.043 ml, 0.39 mmol) and a solution of 2M trimethylaluminium in toluene (0.4 ml, 0.8 mmol). After crystallisation from isopropanol, 42 mg (32.4%) of the title compound were obtained, m.p.=204-205° C. 1H-NMR (acetone-d6): 10.55 (br s, 1H); 7.94 (br t, 1H); 7.51 (d, 1H); 7.38-7.21 (m, 6H); 7.18 (dd, 1H); 7.11 (ddd, 1H); 6.99 (ddd, 1H); 6.91 (d, 1H); 6.85 (d, 1H); 6.61 (s, 1H); 4.50 (d, 2H); 3.79 (s, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH:14](=O)[CH2:15][CH3:16]>[Zn].C(OC(=O)C)(=O)C>[CH3:2][C:3]1[NH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[C:7]=1[CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: CCC=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Product: CCCc1c(C)[nH]c(C(=O)OCC)c1C

Procedure:
Acetic anhydride (20 ml) was added to stirred and cooled concentrated hydrochloric acid (5 ml), and 2,4-dimethyl-5-carbethoxy-pyrrole (0.668 g) was dissolved in this. Propionaldehyde (0.6 ml) and amalgamated zinc (10 g, 20 mesh) was added, the mixture stirred 15 min, at 20°-25° then decanted into ice water (100 ml). The solid was distilled (80°-95°, 1 × 10-4 mm) and crystallized from aqueous ethanol as colourless irregular prisms (48%), m.p. 99°-99.5° (lit19) 98°). Anal. Calc. for C12H19NO2 : C, 68.86; H, 9.15; N, 6.69. Found: C, 68.75; H, 9.19; N, 6.89.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.CCO.[ClH:18]>>[ClH:18].[ClH:18].[NH2:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@@H:6]1[OH:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](O)C1
Agent: Cl
Solvent: CCO
Product: N[C@H]1CNC[C@@H]1O

Procedure:
(3S,4S)-tert-Butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (0.3 g, 1.439 mmol) in 1.25 M HCl 1.25 M in EtOH (11.51 mL, 14.39 mmol) was stirred for 24 h at RT. The white suspension was evaporated to dryness under reduced pressure and the residue was suspended in MeOH (10 mL) and evaporated again to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[CH2:4][C:5]1[N:6]2[CH2:12][CH:11]([CH3:13])[C:10]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:7]2[S:8][CH:9]=1.C1CCN2C(=NCCC2)CC1>C(Cl)(Cl)Cl.CO>[CH3:1][NH:2][C:3](=[O:20])[CH:4]=[C:5]1[CH2:9][S:8][C:7]2=[C:10]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:11]([CH3:13])[CH2:12][N:6]12
Reactant: CNC(=O)CC1=CSC2=C(C(=O)OC(C)C)C(C)CN12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNC(=O)C=C1CSC2=C(C(=O)OC(C)C)C(C)CN12
Temperature: 20 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
2.0 g of N-methyl-(7-isopropoxycarbonyl-6-methyl-5,6- dihydropyrrolo[2,1-b]thiazol-3-yl)acetamide was dissolved in a solvent mixture of 60 ml of chloroform and 6 ml of methanol. 0.3 g of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto and the mixture was stirred at 20° C. for 15 hours. The reaction mixture was then washed with 20 ml of 5% aqueous acetic acid, a 0.5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The chloroform layer was dried over anhydrous sodium sulfate. After distilling off the chloroform, the obtained crude crystals were recrystallized from ethanol to thereby give 1.5 g of the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])[CH2:2][CH3:3].[C:12]1([CH2:18]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CN(C=O)C>[C:12]1([CH2:18][N:6]2[C:5](=[O:11])[CH:4]([CH2:1][CH2:2][CH3:3])[NH:8][S:7]2(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: CCCC1NS(=O)(=O)NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 35.4 %

Procedure:
A mixture of 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (20.74 g, 0.117 mol), phenylmethyl bromide (22.09 g, 0.129 mol), and tetrabutylammonium bromide (3.77 g, 0.012 mol) in toluene (400 ml) and DMF (50 ml) was refluxed for 40 hours, cooled, and poured over ice/water. The crude product was purified by flash chromatography to afford 11.1 g of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VII: R1 =propyl; R2 =R3 =H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[C:27]([C:30]1[N:37]2[C:33]([S:34][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:36]2)=[C:32]([C:51]([C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:52])[N:31]=1)(=[O:29])[CH3:28]>>[C:27]([C:30]1[N:37]2[C:33]([S:34][C:35]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[CH:36]2)=[C:32]([C:51]([C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:52])[N:31]=1)(=[O:29])[CH3:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(C(C)=O)nc(C(=O)c3cccnc3)c2s1
Product: CC(=O)c1nc(C(=O)c2cccnc2)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Yield: 24.5 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[5-acetyl-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (112 mg) was prepared in the same manner as in step a) of Example 1, except that 269 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 437 mg of 5-acetyl-7(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo-[5,1-b]thiazole were used as the starting compounds.