Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](B(O)O)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:37][N:36]=2)=[CH:31][C:30]=1[F:51])S(C(F)(F)F)(=O)=O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.O>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:29]3[CH:34]=[CH:33][C:32]([C:35]4[N:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:37][N:36]=4)=[CH:31][C:30]=3[F:51])[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Cc2ccc(B(O)O)cc2C1
Reactant: CCCCCCCCCCc1cnc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCc1cnc(-c2ccc(-c3ccc4c(c3)CC(CCCCCCCC)C4)c(F)c2)nc1
Yield: 86.3 %

Procedure:
0.53 g (1.93 mM of 2-octylindan-5-boronic acid, 0.80 g (1.73 mM) of 2-fluoro-4-(5-decylpyrimidine-2-yl)phenyl triflate, 1.5 ml of ethanol, 2.7 ml of toluene, 2.7 ml of 2M-sodium carbonate aqueous solution and 0.09 g of tetrakis (triphenylphosphine) palladium (0) were mixed and heat-refluxed for 130 minutes under stirring. After the reaction, the reaction mixture, water and toluene were added to followed by filtration under reduced pressure. The toluene layer was washed with a common salt aqueous solution followed by drying with anhydrous sodium sulfate. Then, the sodium sulfate was removed from the mixture and the resultant mixture was evaporated to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.81 g of 2-octyl-5-[2-fluoro-4-(5-decylpyrimidine-2-yl)phenyl]indan (Yield: 86.3%). ##STR314##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OC([NH:22][C:23]([CH3:40])([CH3:39])[CH2:24][CH2:25][N+:26]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])([CH3:28])[CH3:27])=O)C1C=CC=CC=1>[Pd].CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[NH2:22][C:23]([CH3:40])([CH3:39])[CH2:24][CH2:25][N+:26]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])([CH3:27])[CH3:28]
Reactant: COCCOCCOCC[N+](C)(C)CCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: COCCOCCOCC[N+](C)(C)CCC(C)(C)N
Temperature: 25 °C
Reaction time: 18 h
Yield: 113.6 %

Procedure:
Under a nitrogen atmosphere, palladium on carbon (10%, 200 mg) was added to a solution of 3-(((benzyloxy)carbonyl)amino)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N,N,3-trimethylbutan-1-aminium 4-methylbenzenesulfonate (0.93 g, 2.2 mmol) in 15 mL of methanol. The flask was degassed and placed under a hydrogen atmosphere, stirring for 18 hours at room temperature. The suspension was filtered through a pad of Celite® washing with methanol, and the filtrate was concentrated under reduced pressure to give a clear oil (700 mg, 2.5 mmol). 1H NMR (D2O, 400 MHz) δ 1.08 (s, 6H), 1.79-1.83 (m, 2H), 2.29 (s, 3H), 3.04 (s, 6H), 3.27 (s, 3H), 3.36-3.41 (m, 2H), 3.45-3.51 (m, 4H), 3.56-3.60 (m, 6H), 3.84 (br m, 2H), 7.26-7.28 (d, J=8.0 Hz, 2H), 7.57-7.60 (d, J=8.0 Hz, 2H). LRMS (ESI/APCI) m/z 277 [M]+
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH2:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:18]=[CH2:19])[CH:15]=2)[C:10]([C:20]#[N:21])=[CH:9]1)[CH3:7].ClCI.[NH4+].[Cl-].[OH-].[NH4+]>C(OCC)(=O)C.ClCCCl>[CH:18]1([O:17][C:14]2[CH:15]=[C:16]3[C:11]([C:10]([C:20]#[N:21])=[CH:9][N:8]3[CH2:6][CH3:7])=[CH:12][CH:13]=2)[CH2:1][CH2:19]1
Reactant: C=COc1ccc2c(C#N)cn(CC)c2c1
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCn1cc(C#N)c2ccc(OC3CC3)cc21
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
Via a syringe, diethyl zinc is added to a mixture of 1-ethyl-6-vinyloxy-1H-indole-3-carbonitrile (288.1 mg, 1.36 mmol), chloroiodomethane (268.9 mg, 1.53 mmol) and 5 ml of 1,2-dichloroethane over a period of 10 min, maintaining the temperature at −10° C. The mixture is warmed to 20-25° C. for 20 min., and then cooled back to 0° C. Saturated NH4Cl (15 mL), concentrated ammonium hydroxide (15 mL), and ethyl acetate (15 mL) are added in sequence at this temperature, and stirred for 10 min. After the phases are separated, the aqueous phase is back-extracted with ethyl acetate (10 mL). The combined organic phases are washed with saturated NH4Cl (10 mL), dried over MgSO4 and then the solution is concentrated and the product is purified by chromatography, eluting with 15-30% ethyl acetate/hexanes to afford 140.5 mg (45.7% yield) of 6-cyclopropoxy-1-ethyl-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>CCOCC>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: Clc1ccc(Cc2c[nH]c3ccccc23)cc1
Yield: 29.1 %

Procedure:
To a vigorously stirred solution of 30 mL of 3M MeMgBr in ether was added dropwise a solution of 10 g of indole in 100 mL of ether. After addition was finished, the mixture was heated to reflux for 30 minutes and treated with 22 g of p-chlorobenzyl bromide. The reaction mixture was refluxed for 3 hours, quenched with 50 mL of saturated aqueous solution of NH4Cl, and extracted with 200 mL of ether. The ether layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography eluted with toluene to give 6 g of the title compound as a beige solid.
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][O:6][C:7](=[O:34])[C:8]1[CH:13]=[C:12]([O:14]C)[C:11]([CH3:16])=[C:10]([O:17]C)[C:9]=1[O:19][C:20]1[C:25]([CH:26]=[O:27])=[C:24]([O:28]C)[CH:23]=[C:22]([CH3:30])[C:21]=1[C:31]([OH:33])=[O:32]>ClCCl>[CH3:5][O:6][C:7](=[O:34])[C:8]1[CH:13]=[C:12]([OH:14])[C:11]([CH3:16])=[C:10]([OH:17])[C:9]=1[O:19][C:20]1[C:25]([CH:26]=[O:27])=[C:24]([OH:28])[CH:23]=[C:22]([CH3:30])[C:21]=1[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(OC)c(C)c(OC)c1Oc1c(C=O)c(OC)cc(C)c1C(=O)O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(O)c(C)c(O)c1Oc1c(C=O)c(O)cc(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A solution of boron trichloride (3 mmol) in dichloromethane (0.4 ml) was added dropwise to a stirred solution of 2-(3-methyl-6-formyl-2-carboxy-5-methoxy-phenoxy)-3,5-dimethoxy-4-methyl-benzoic acid methyl ester (1 mmol) in dichloromethane (3 ml) under ice bath. The mixture was stirred under ice bath for 20 min and then at room temperature for 2 h. Upon completion, the mixture was poured into ice water and extracted with dichloromethane, and the residue was purified by column chromatography to afford 2-(3-methyl-6-formyl-2-carboxy-5-hydroxy-phenoxy)-3,5-dihydroxy-4-methyl-benzoic acid methyl ester (87%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[N:9][C:10]([NH:13][NH2:14])=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:15](OCC)(=[O:20])[CH2:16][C:17]([CH3:19])=O.[OH-].[NH4+]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[N:9][C:10]([N:13]3[C:15]([OH:20])=[CH:16][C:17]([CH3:19])=[N:14]3)=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: NNc1ccc(N2CCOCC2)nn1
Reactant: CCOC(=O)CC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(O)n(-c2ccc(N3CCOCC3)nn2)n1
Reaction time: 8 h

Procedure:
A mixture of 0.98 g (5 mmoles) of 3-morpholino-6-pyridazinyl-hydrazine, 0.65 g (5 mmoles) of ethyl acetoacetate and 15 ml of ethanol is stirred at reflux temperature for 3 hours. After cooling the mixture is stirred with 1 ml of concentrated aqueous ammonium hydroxide solution at room temperature for 4 hours and then left to stand overnight. The separated crystals are filtered, washed with water and recrystallized from ethanol. Yield: 0.5 g (39%); m.p.: 189°-192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:23][NH:24][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)COc2ccccc2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(COc3ccccc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 5-methoxy-2-(2-phenoxyacetyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [Br-].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Zn+].FC(F)(F)S(O[C:14]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:16][CH:15]=1)(=O)=O>O1CCCC1>[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:16]1[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C(OS(=O)(=O)C(F)(F)F)C1
Reactant: [Zn+]c1nccs1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC=C(c2nccs2)C1
Temperature: 50 °C
Yield: 52.6 %

Procedure:
To the mixture of 2-thiazolylzinc bromide (20 mL, 10 mmol) in dry tetrahydrofuran (30 mL) at 0° C. was added the product from Example 328B (3.3 gm, 10 mmol) and tetrakis(tripehynlphosphine) palladium (0) (10% mole 1.1 g). The mixture was heated at 50° C. for 1 hour, cooled to room temperature, quenched with brine and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 25% ethyl acetate:hexanes) to obtain desired product 1.4 g (60%) as colorless oil. MS (DCI/NH3) m/e 265 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O:17]CC)(=O)[CH2:10][C:11]([O:13]CC)=O>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[O:13])[CH2:10][C:9]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:17]
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)CC(=O)OCC
Product: O=C(CC(=O)Nc1ccccc1F)Nc1ccccc1F
Temperature: 170 °C
Reaction time: 8 h

Procedure:
100 mmol 2-fluoroaniline and 50 mmol diethyl malonate were put together and stirred overnight at 170° C. The formed ethanol was distilled off directly (100 mmol≡6.6 mL) on a stream of nitrogen. N1,N3-di(2-fluoro-phenyl)-malonamide was formed as one solid block. The reaction was cooled and EtOAc was added. The product had to be crushed with a mortar, because it resembled very hard brick. The crushed material was stirred in EtOAc and filtered. EtOAc added was added twice and the mixture was stirred and filtered each time. 9.9 g N1,N3-di(2-fluoro-phenyl)-malonamide was obtained (yield 68.2%, purity 99.3%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[O:25][CH3:26].N1CCCCC1>CC(C)=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:19]=[C:18]([O:25][CH3:26])[CH:17]=[CH:22][C:21]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Reactant: COc1ccc(Br)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)c(OC)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of 36.2 mg (0.18 mmol) N-(1-(4-ethynylphenyl)propan-2-yl)acetamide (I58.3) and 300 μl acetone is added to 50.6 mg (0.15 mmol) 1-bromo-2,4-dimethoxybenzene followed by a suspension of 14.3 (0.02 mmol) bis(triphenylphosphine)dichloropalladium in 300 μl acetone and 600 μl water. After addition of 22.4 mg (0.20 mmol) piperidine the mixture is stirred in a sealed tube for 1.5 h at 60° C. The solvent is removed in vacuo and the residue is purified by HPLC (ACN/H2O/TFA).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25]([OH:27])=O)[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25]([N:49]3[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]3)=[O:27])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:11])[F:12])[CH:8]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1
Agent: O=C1CNCCN1
Product: COc1cc(OC(F)(F)F)cc(-c2cc(C(=O)N3CCNC(=O)C3)nn2-c2cccnc2)c1

Procedure:
50 mg (0.13 mmol) of the compound of Example 56A is reacted analogously to the synthesis of the compound of Example 4 with 14 mg (0.14 mmol) of 2-oxopiperazine. 54 mg (89% of theory) of the title compound is obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:47])(=[O:46])[NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:46])(=[O:47])[NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])=[CH:27][CH:28]=2)[C:7](=[O:21])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:11]=2[Cl:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nn(-c2cc(C(=O)O)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 83.7 %

Procedure:
A solution of 71 mg (0.102 mmole) of 5-n-butyl-2-[5-(carbomethoxy)-2-chlorophenyl]-4-[[2'-[N-(2-chlorobenzoyl)-sulfamoyl]-biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 65, Step D) in 0.7 mL (0.7 mmole) of 1N NaOH (methanolic) was stirred at 60° C. overnight and then concentrated to dryness. The residue was dissolved in 1 mL of methanol, acidified to approximately pH 1.5 by addition of 1N HCl (methanolic), and again concentrated. The residue was dissolved in CHCl3, dried over Na2SO4, and filtered through Celite. Evaporation of the solvent yielded 58 mg (84%) of the title compound as a white solid; nearly homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 679 (M+1)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.[CH:11]12[CH2:18][CH:15]([NH:16][CH2:17]1)[CH2:14][C:13](=O)[CH2:12]2.Cl>C(O)(=O)C>[Br:2][C:3]1[C:4]2[NH:9][C:13]3[CH2:12][CH:11]4[CH2:18][CH:15]([C:14]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1)[NH:16][CH2:17]4
Reactant: NNc1ccccc1Br
Reactant: O=C1CC2CNC(C1)C2
Agent: Cl
Solvent: CC(=O)O
Product: Brc1cccc2c3c([nH]c12)CC1CNC3C1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
(2-Bromophenyl)hydrazine hydrochloride (1.8 g 8.0 mmol; Aldrich) and 6-azabicyclo[3.2.1]octan-3-one (1.0 g, 8.0 mmol; GLSyntech) were combined with a solution of HCl in acetic acid (1.0 M, 30 mL; Aldrich) and stirred at 100° C. for 18 hours in a sealed tube. The reaction mixture was concentrated under vacuum and partitioned between sodium carbonate (1.0 M, 500 mL) and chloroform (2×300 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 50×100 mm, flow rate 100 mL/minute, 40-100% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.89-1.94 (m, 1H), 2.05 (ddd, J=10.8, 6.0, 4.3 Hz, 1H), 2.81 (dd, J=16.8, 2.4 Hz, 1H), 3.03 (dd, J=9.6, 1.4 Hz, 1H), 3.09-3.17 (m, 2H), 3.42 (t, J=3.7 Hz, 1H), 3.88 (dt, J=5.7, 2.8 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H), 7.14 (dd, J=7.6, 0.9 Hz, 1H), 7.41 (dd, J=7.9, 0.9 Hz, 1H); MS (ESI+) m/z 277/279 (M+H)+.
Reaction SMILES: [C:1](/[CH:4]=[CH:5]/[C:6]1[C:11]2[CH2:12][C:13]3([O:18][C:10]=2[C:9]([O:19][CH3:20])=[CH:8][CH:7]=1)[CH2:17][CH2:16][CH2:15][CH2:14]3)([OH:3])=O.C(Cl)Cl.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1>O.O1CCOCC1>[CH3:20][O:19][C:9]1[C:10]2[O:18][C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:12][C:11]=2[C:6](/[CH:5]=[CH:4]/[C:1]([NH:39][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[O:3])=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C/C(=O)O)c2c1OC1(CCCC1)C2
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C/C(=O)Nc2ccncc2)c2c1OC1(CCCC1)C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 57.4 %

Procedure:
Compound 90b (0.3 g) obtained in Step B was suspended in a mixed solvent of methylene chloride (6 ml) and dioxane (1 ml), and dicyclohexylcarbodiimide (DCC) (0.23 g) and 4-aminopyridine (0.11 g) were added thereto after cooling the suspension to 0° C., followed by stirring at room temperature for 6 hours. Water was added to the mixture followed by extraction with chloroform. The collected organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (chloroform) to give Compound 90 (0.22 g, 64.5%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=[O:12].[CH2:14](O)[CH:15]([CH3:17])[CH3:16].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=1[O:12][CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CO
Reactant: CC(C)CCC1C(=O)CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CCC1=C(OCC(C)C)CCCC1=O
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of ketoenol 7 (68.0 g, 374 mmol), isobutanol (83.0 g, 1120 mmol), and p-toluenesulfonic acid (1.0 g, 1.2 mmol) in anhydrous benzene (730 mL) was refluxed overnight with azeotropic removal of water (Dean-Stark trap). The reaction mixture was cooled to room temperature, washed with saturated sodium bicarbonate solution (3×250 mL), brine (2×250 mL) and concentrated to give 88.0 g (98.9%) of 8 as a thick oil, which solidified upon cooling. MS m/z 239 (M+1); 1H NMR (300 MHz, CDCl3) δ 3.75 (d, 2H), 2.5 (t, 2H), 2.3-2.2 (m, 4H), 2.0-1.9 (m, 3H), 1.6-1.5 (m, 1H), 1.2-1.1 (m, 2H), 1.0 (d, 6H), 0.9 (d, 6H); 13C NMR (CDCl3) δ 198.4, 171.5, 120.1, 73.9, 38.0, 36.5, 28.8, 28.4, 25.5, 22.6, 21.1, 20.1, 19.1.
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C@H:5]([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[OH-].[K+].Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>C(O)CC>[CH3:14][C@@H:5]([NH:4][CH2:3][C@H:2]([OH:1])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)=[CH:9][CH:8]=1
Reactant: C[C@H](Cc1ccc(O)cc1)NCC(O)COc1ccccc1
Reactant: ClCCN1CCN(c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCCO
Product: C[C@H](Cc1ccc(OCCN2CCN(c3ccccc3)CC2)cc1)NC[C@H](O)COc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 0.5 g of p-[(R)-2-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenol, 185 mg of potassium hydroxide, 410 mg of 1-(2-chloroethyl)-4-phenyl-piperazine and 15 ml of n-propanol was heated to 60° for 2.5 hours. The reaction mixture was poured on to ice-water and extracted with ethyl acetate. After evaporation of the solvent and chromatography of the crude product on silica gel with chloroform/n-propanol/saturated ammonia (1000:10:1) there were obtained 340 mg of pure, amorphous (S)-1-[[(R)-α-methyl-p-[2-(4-phenyl-1-piperazinyl)ethoxy]phenethyl]amino]-3-phenoxy-2-propanol, [α]D20 =-19° (c=0.8 in methanol), ε222 =21890.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]([O:30][C:31]([O:33][CH2:34]I)=[O:32])([CH3:29])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:34][O:33][C:31]([O:30][CH:27]([CH3:29])[CH3:28])=[O:32])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)OC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)OC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 47.3 %

Procedure:
In the same manner as in Example 81, 203 mg of the title compound was prepared from 348 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 252 mg of isopropyloxycarbonyloxymethyl iodide.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1C(C)C)([CH3:3])[CH3:2]>C1C=CC=CC=1>[C:4]1([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)c1ccccc1C(C)C
Solvent: c1ccccc1
Product: CC(C)c1ccccc1

Procedure:
The process of claim 1 wherein benzene is transalkylated with diisopropylbenzene under liquid phase conditions to produce cumene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=1[O:13]C)[CH3:2].Cl.N1C=CC=[CH:26][CH:25]=1>>[CH2:25]([O:20][C:18](=[O:19])[CH2:17][CH2:16][C:15](=[O:21])[C:9]1[CH:10]=[CH:11][C:12]([OH:13])=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH:8]=1)[CH3:26]
Reactant: c1ccncc1
Reactant: CCOC(=O)CCc1cc(C(=O)CCC(=O)O)ccc1OC
Agent: Cl
Product: CCOC(=O)CCC(=O)c1ccc(O)c(CCC(=O)OCC)c1
Yield: 42.4 %

Procedure:
Starting with a mixture of 6.48 g (21.0 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-methoxy-γ-oxobenzenebutanoic acid and 24.4 g (0.211 mol) of pyridine hydrochloride, the title compound (2.87 g, 42.4%) was obtained as a light-tan oil, using the procedure of example 140.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:20])=[C:8]([CH:13]=[CH:14][C:15]=1[S:16]([CH3:19])(=[O:18])=[O:17])[C:9]([O:11]C)=[O:10].[OH-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:20])=[C:8]([CH:13]=[CH:14][C:15]=1[S:16]([CH3:19])(=[O:17])=[O:18])[C:9]([OH:11])=[O:10]
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)OC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Methyl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoate (26 g) was dissolved in methanol (200 mL), and a 20% NaOH aqueous solution (50 mL) was added at room temperature. After stirring for one hour, methanol was distilled off under reduced pressure. To the residue, 2N hydrochloric acid (100 mL) was added, followed by extraction with ethyl acetate (500 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. To the residue, a mixed solvent (ethyl acetate:hexane=1:1, 50 mL) was added, and the mixture was left to stand at 5° C. for 12 hours. The obtained crystals were collected by filtration to obtain 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (19.5 g).