Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:8][CH:7]=2)[CH:3]=[N:2]1.[CH3:32]C1C(B2OC(C)(C)C(C)(C)O2)=CNN=1>>[CH3:32][C:5]1[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:8][CH:7]=2)=[CH:3][NH:2][N:1]=1
Reactant: NC(=O)CN1CCC(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ccnc34)cc2)CC1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1n[nH]cc1-c1cnc(Nc2ccc(C3CCN(CC(N)=O)CC3)cc2)c2nccn12

Procedure:
This compound may be prepared using the methods as described for Compound 224, using 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole in Step 4. LCMS: Rt=0.75 min (100%), m/z (ESI) 431 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH2:56])[CH:53]=[C:52]3[C:48]=2[CH:49]=[CH:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:56][C:54]1[CH:53]=[C:52]2[C:48]([CH:49]=[CH:50][NH:51]2)=[C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:55]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(N)cc3[nH]ccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 61.9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (125 mg, 0.21 mmol) was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-amine (110 mg, 0.43 mmol), sodium carbonate (55 mg, 0.52 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (52 mg, 0.06 mmol) in 1,2-dimethoxyethane (5.0 ml) and water (0.125 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 84 mg (56% yield) of the title compound.
Reaction SMILES: [C:1]1([C:6]([CH2:8][C:9]#[N:10])=O)[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(Cl)Cl.CO>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6]1[CH:8]=[C:9]([NH2:10])[O:13][N:12]=1
Reactant: N#CCC(=O)c1cccs1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(-c2cccs2)no1
Temperature: 40 °C

Procedure:
A mixture of 2-thenoylacetonitrile (1 g, 6.6 mmol), hydroxylamine hydrochloride (1.38 g, 19.8 mmol) and sodium acetate (2.17 g, 26.5 mmol) in DCM (20 ml) and MeOH (20 ml) was heated at 40° C. overnight, cooled to rt and concentrated. The residue was partitioned between EtOAc and water, the organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a brown solid 1-4. 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 2H), 7.08 (m, 1H), 5.40 (s, 1H), 4.49 (bs, 21-1); ESI+ MS [M+H]+ C7H7N2OS=167.1.
Reaction SMILES: [C:1]1(=[O:29])[N:5]([CH2:6][C:7]([N:9]2[C@@H:15]3[CH2:16][CH2:17][CH2:18][C@@H:14]3[C:13](=[O:19])[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.[H-].[Na+].Cl[CH2:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[C:34]1([CH2:33][N:12]2[C:13](=[O:19])[C@H:14]3[CH2:18][CH2:17][CH2:16][C@H:15]3[N:9]([C:7](=[O:8])[CH2:6][N:5]3[C:4](=[O:24])[C:3]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]4[C:1]3=[O:29])[C:10]3[CH:23]=[CH:22][CH:21]=[CH:20][C:11]2=3)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)[C@@H]2CCC[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2cccc3ccccc23)C(=O)[C@H]2CCC[C@H]21
Temperature: 28 °C
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
To a suspension of (3aR*,10aS*)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (391 mg, 1.0 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% liquid paraffin dispersion, 44 mg, 1.1 mmol). The mixture was stirred for 10 minutes at 28° C., to which was added 1-(chloromethyl) naphthalene(213 mg, 1.2 mmol), followed by stirring for 20 minutes at the same temperature. To the reaction mixture was added water (5 mL), and the mixture was subjected to extraction twice with chloroform. The organic layers were combined and washed with water, dried over magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was crystallized from ethanol to give 177 mg (yield 33%) of the titled compound, m.p. 266°-270° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([CH3:40])[CH:31]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:39])([F:38])[F:37]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)cc4)c3)n2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(N)(=O)=O)cc4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.057 g) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as a white solid (0.038 g, 7%). MS (ISN) 526.5 [(M−H)−]; mp 287° C.
Reaction SMILES: O[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C1(C)C=CC(S([Cl:35])(=O)=O)=CC=1.Cl>N1C=CC=CC=1>[Cl:35][CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CO)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCl)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
21-Hydroxy-5α-pregnane-3,11,20-trione (3.0 g.) in anhydrous pyridine (15 ml.) was treated with toluene-4-sulphonyl chloride (3.0 g.) and the pale orange solution was stirred at room temperature for 3 hours. The cold solution was vigorously stirred during the slow addition of ice-cold water (200 ml.) and hydrochloric acid (2N;50 ml.). The yellow crystalline precipitate was filtered off, washed well with water and dried in vacuo at 60°, and the resulting crude product (2.4 g.) was recrystallized from acetone/petrol to give crude title compound (1.13 g.) as an off-white crystalline solid, m.p. 168°-172°, [α]D + 137° (c 1.13).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([NH:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:11][CH:9]1[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH2:7][CH2:8]1)[CH:21]=[CH:20]2)=[O:28])([CH3:25])[CH3:24]
Reactant: Cc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: CC(C)N=C=O
Product: Cc1cccc2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(7-methyl-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=375.4 (M+H+).
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](Cl)=[O:16].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[F:26]>C(Cl)(Cl)Cl>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[O:16])=[CH:21][C:20]=1[F:26]
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1ccc(Br)c(F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)c(F)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
2.9 ml of triethylamine and 1.87 g of picolinic acid chloride hydrochloride were added to a chloroform (30 ml) solution of 1 g of 4-bromo-3-fluoroaniline, and stirred at room temperature for 4 hours. The reaction liquid was diluted with chloroform, washed with aqueous saturated sodium bicarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to obtain 1.44 g of the entitled compound as a pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[H-].[Na+].Cl[CH2:14][C:15]([CH3:17])=[CH2:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:15]([CH3:17])=[CH2:14])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: C=C(C)CCl
Reactant: COc1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Product: C=C(C)COc1ccc(Cl)cc1OC
Yield: 90.7 %

Procedure:
Treatment of 4-chloro-2-methoxyphenol (15.00 g, 0.10 mol) with sodium hydride (4.4 g, 0.11 mol, 60 wt. %) and 3-chloro-2-methylpropene (12.00 g, 0.12 mol) generally according to the procedure described for Intermediate 13 provided 19.3 g (91%) of 4-chloro-2-methoxy-1-[(2-methylprop-2-enyl)oxy]benzene as a colorless oil. Treatment of the allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 afforded 15.5 g (78%) of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol as a pale yellow oil. Treatment of 4-chloro-2-methoxy-6-(2-methylprop-2-enyl)phenol (10.00 g, 0.047 mol) with 3-chloroperoxybenzoic acid (20.00 g, 0.089 mol, 77%) followed by potassium carbonate (20.00 g, 0.145 mol) generally according to the Procedure described for Intermediate 9 provided 8.00 g (74%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol as a light yellow oil. Treatment of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methanol (10.8 g, 0.047 mol) with p-toluenesulfonyl chloride (13.5 g, 0.071 mol), diisopropylethylamine (12.15 g, 0.094 mol), and 4-(dimethylamino)pyridine (0.35 g, 2.83 mmol) generally according to the procedure described for Intermediate 45 gave 13.8 g (76%) of (±)-(5-chloro-7-methoxy-2-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. mp 113-115° C.; Anal. calcd. for C18H19ClO5S: C, 56.47; H, 5.00. Found: C, 55.82; H, 4.94.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[C:11]3=[O:34])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:36][CH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[N:12]([CH2:27][C:28]([NH:30][CH:31]([CH3:32])[CH3:33])=[O:29])[C:11](=[O:34])[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:1]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:36][CH2:37][OH:38])[CH2:3][CH2:2]4)[CH:9]=3)[N:14]=2)=[CH:19][C:20]=1[O:25][CH3:26]
Reactant: COc1cc(-c2nc3ccc(N4CCCNCC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3ccc(N4CCCN(CCO)CC4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Temperature: 100 °C

Procedure:
2-(6-(1,4-Diazepan-1-yl)-2-(4-fluoro-3-methoxyphenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (EXAMPLE 1i) (28 mg, 0.06 mmol), 2-bromoethanol (30 mg, 0.017 mL, 0.24 mmol), potassium carbonate (17 mg, 0.12 mmol,) and potassium iodide (1 mg, 5.99 μmol) were combined in a microwave vial and DMF (1 mL) added. The reaction mixture was heated at 100° C. for 5 min in the microwave. LCMS indicated that the desired product was being formed. Additional 2-bromoethanol (30 mg, 0.017 mL, 0.24 mmol) was added and reaction mixture was heated at 100° C. for a further 5 min in the microwave. Product was purified by preparative LCMS to afford 2-{2-(4-fluoro-3-methoxyphenyl)-6-[4-(2-hydroxyethyl)perhydro-1,4-diazepin-1-yl]-4-oxo-4H-quinazolin-3-yl}-N-isopropylacetamide (EXAMPLE 4q) (4 mg, 7.82 μmol, 13%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1N1CCOCC1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
To a vial containing 5-bromo-2-chloro-3-nitropyridine (0.99 g, 4.16 mmol) in DMSO (4.0 mL) was added morpholine (0.8 mL, 9.19 mmol) dropwise. The reaction was stirred at 23° C. and monitored with TLC and LC-MS. After 20 h, LC-MS showed that the reaction was complete, then the mixture was diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated in vacuo to afford a yellow-orange solid as 4-(5-bromo-3-nitropyridin-2-yl)morpholine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (1H, d, J=2.3 Hz), 8.47 (1H, d, J=2.3 Hz), 3.70 (4H, m), 3.41 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(CC(C)=O)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CC(C)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 59 %

Procedure:
To a solution of 4-methoxyphenylacetone 9 (6.56 g, 4 mmol) in acetic anhydride (16 mmol) was added 90% HNO3 dropwise at −5° C. After adding HNO3, the ice-bath was removed and allowed to warm up to room temperature. The reaction was quenched by adding ice water. The resulting solution was extracted with ethyl acetate three times. The organic phase was dried over Na2SO4. Removal of the solvent under reduced pressure afforded crude product. Purification of the crude product by using silica gel column gave 10 (4.9 g, 59%). 1HNMR(CDCl3): 7.70 (d, J=2.1 Hz, 1H), 7.37 (dd, J=2.2 Hz, 8.5 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 3.95 (s, 3H), 3.74 (s, 2H), 2.21 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH:20][CH2:21][CH2:22][NH2:23])[CH3:19]>>[CH2:18]([N:20]1[C:1]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[C:10]([C:11](=[O:13])[N:23]2[CH2:22][CH2:21]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:19]
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: CCNCCN
Product: CCN1CCN2C(=O)c3ccccc3C12c1ccccc1

Procedure:
Condense o-benzoylbenzoic acid (10 g.) and N-ethylethylene-diamine (15 ml.) by the procedure of Example 1 to obtain 1-ethyl-9b-phenyl-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one, m.p. 122°-4° C. (elemental analysis confirms the empirical formula C18H18N2O).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C@@H:4]2[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].[N:26]([CH2:29][C:30](Cl)=[O:31])=[N+:27]=[N-:28]>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[N:26]([CH2:29][C:30]([NH:1][C:2]1[CH2:3][C@@H:4]2[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:8])=[O:31])=[N+:27]=[N-:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N)C[C@H]12
Reactant: [N-]=[N+]=NCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(NC(=O)CN=[N+]=[N-])C[C@H]12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (35 mg, 0.1 mmol) in anhydrous tetrahydrofuran (2 ml) is cooled to -25° C. and treated with 4-dimethylaminopyridine (15.9 mg, 0.13 mmol) and, dropwise over 5 minutes, with a solution of 2-azidoacetyl chloride (14.3 mg, 0.12 mmol) in tetrahydrofuran (0.5 ml). The resulting mixture is stirred under a nitrogen atmosphere at 0° C. for 4 hours. The mixture is diluted with ethyl acetate, washed with pH 3 phosphate buffer, water, 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and evaporated under vacuum. The residue is chromatographed on a silica gel thin layer preparative plate to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][CH2:20]3)=[C:15]([CH2:30][CH3:31])[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:23]([O:22][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[CH:10][CH:9]=3)=[CH:14][C:15]=2[CH2:30][CH3:31])[CH2:20][CH2:21]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of methyl{4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate (Compound 92, 130.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:19])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](Cl)=[O:32]>ClCCl>[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31]([NH:19][C:11]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=2)=[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1)=[O:32]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a solution of the product from Example 1C (0.318 g, 1.081 mmol) in dichloromethane (8 mL) was added pyridine (0.256 g, 3.24 mmol). 3,3-Dimethylbutanoyl chloride (0.160 g, 1.189 mmol) was slowly added and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A) to yield the title compound (0.38 g, 88%). 1H NMR (400 MHz, CD3Cl) δ ppm 1.11 (s, 6H) 2.33 (s, 2H) 6.86 (dd, J=6.94, 4.12 Hz, 1H) 7.30-7.42 (m, 3H) 7.63-7.79 (m, 2H) 8.51 (dd, J=4.12, 1.73 Hz, 1H) 8.68 (dd, J=6.94, 1.63 Hz, 1H). MS ESI(+) m/z 393.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH2:16][CH3:17])/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.O[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[C:10](\[CH2:16][CH3:17])/[CH:11]=[CH:12]/[C:13]([N:26]2[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]2)=[O:15])=[CH:7][CH:8]=1
Reactant: OC1CCNCC1
Reactant: CCC(/C=C/C(=O)O)=C\c1ccc(OC)cc1
Solvent: O=S(Cl)Cl
Product: CCC(/C=C/C(=O)N1CCCCC1)=C\c1ccc(OC)cc1

Procedure:
The title compound was prepared from 4-methoxybenzaldehyde (5.2 g, 38 mmol) by subjecting it to Grignard's reaction with 1-n-bromopropane by the method described in example 1(i) to give 1-(4-methoxyphenyl)-n-butanol of formula 3 (6.7 g, yield 98%). The secondary alcohol (5.55 g, 30 mmol) was subjected to Vilsmeier reaction with dimethyl formamide-phosphorous oxychloride as described in example 1 (ii) to furnish 2-formyl-1-(4-methoxyphenyl)-1-butene of formula 4 (4.0 g, 70%). The resulting aldehyde (3.8 g, 20 mmol) was subjected to Wittig reaction as described in example 1 (iii) followed by saponification to produce 5-(4-methoxyphenyl)-4-ethyl-2E,4E-pentadienoic acid of formula 6(3.0 g, 65%). The pentadienoic acid (1.0 g, 4.3 mmol) after acid chloride formation with thionyl chloride, and reaction with 4-hydroxypiperidine was purified by column chromatography on silica gel to give 5-(4-methoxyphenyl)-4-ethyl-2E,4E-pentadienoic acid piperidide of formula 1a (0.84 g, 60%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(=O)C(C)(C)C)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(Cl)Cl>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13](=[O:15])[NH:28][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: CC(C)OC(=O)C(C(=O)OC(=O)C(C)(C)C)=C1SC=CS1
Reactant: NC1CCCCC1
Solvent: ClCCl
Product: CC(C)OC(=O)C(C(=O)NC1CCCCC1)=C1SC=CS1

Procedure:
A solution of isoproyl 2-(1,3-dithiol-2-ylidene)-2-(pivaloyloxycarbonyl)acetate (13.2 g) and cyclohexylamine (3.97 g) in methylene chloride (100ml) was stirred at room temperature for 2 hrs. The reaction mixture was washed with aqueous sodium hydroxide solution and water and then evaporated to dryness. The resultant residue was recrystallized from ethyl acetate to afford the pure product. (12.0 g, 91.6%)