Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([C:11]([F:10])([F:21])[F:22])=[CH:13][CH:14]=2)=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9]
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 14.4 g. (0.12 mole) of 1-methylpyrrole-2-acetonitrile and 25 g. (0.12 mole) of p-trifluoromethylbenzoyl chloride in 120 ml. methylene chloride is chilled to −25° C. (external bath). Then 14 ml. (0.12 mole) stannic chloride is added dropwise over a half hour. The resultant suspension is permitted to come to room temperature and poured into ice-dilute hydrochloric acid. The aqueous phase is separated and washed successively with N,N-dimethyl-1,3-propane-diamine, 3N hydrochloric acid and a saturated solution of sodium chloride. The solvent is evaporated, and the product is isolated from the residual oil by column chromatography using acid-washed alumina. The solvents hexane, benzene, and ether are used as eluents. The first compound-bearing fraction not giving a positive Enrlich's test (in benzene) is collected. The solvent is evaporated and the resultant solid, 1-methyl-5-(p-trifluoromethylbenzoyl)-pyrrole-2-acetonitrile, in purified by recrystallization from isopropanol, m.p. 95-97.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]([S@:32]([NH2:34])=O)([CH3:31])[CH3:30]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19]/[C:20](=[N:34]/[S:32][C:29]([CH3:31])([CH3:30])[CH3:28])/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N(CC/C(=N/SC(C)(C)C)c1ccccc1)C(=O)OC(C)(C)C
Yield: 55.8 %

Procedure:
A mixture of (S)-tert-butyl 1-(4-bromophenyl)ethyl(3-oxo-3-phenylpropyl)carbamate (30 g, 0.069 mol), (R)-2-methylpropane-2-sulfinamide (8.42 g, 0.069 mol), and Ti(i-OPr)4 (31.4 g, 0.138 mol) in THF (300 mL) was heated to reflux overnight. The mixture was treated with brine, and the precipitate was filtered. The filtrate was concentrated to give (S,Z)-tert-butyl 1-(4-bromophenyl)ethyl(3-(tert-butylthioimino)-3-phenylpropyl)carbamate (20 g, 55%) which was used in the next step without further purification. 1H NMR (CDCl3): δ=1.23 (s, 9H), 1.32 (s, 9H), 1.46 (d, 3H), 1.70-1.86 (m, 2H), 3.24-3.75 (m, 2H), 4.08 (m, 1H), 7.09-7.91 (m, 9H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])#[CH:9].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24](I)=[N:25][CH:26]=2)=[CH:17][CH:16]=1>C(#N)C.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:9]#[C:8][Si:10]([CH3:13])([CH3:12])[CH3:11])=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccc(-c2ccc(I)nc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34.9 mL (250 mmol) triethylamine and 20.8 mL (150.0 mmol) ethynyl-trimethyl-silane are added successively to a solution of 34 g (110 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine in 300 mL acetonitrile and 150 mL THF under an argon atmosphere. Then 803 mg (1.10 mmol) Pd(dppf)Cl2 and 209 mg (1.10 mmol) CuI are added. The reaction solution is stirred overnight at RT. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (PE/EtOAc 8:2).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CO.[CH3:34][N:35]([CH3:61])[CH2:36][CH2:37][CH2:38][C:39]#[C:40][C:41]1[CH:42]=[N:43][C:44]([NH:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)(=[O:50])=[O:49])=[N:45][CH:46]=1>C1COCC1>[CH3:61][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][C:39]#[C:40][C:41]1[CH:42]=[N:43][C:44]([N:47]([CH3:1])[S:48]([C:51]2[CH:52]=[CH:53][C:54]([C:57]([F:60])([F:58])[F:59])=[CH:55][CH:56]=2)(=[O:49])=[O:50])=[N:45][CH:46]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)CCCC#Cc1cnc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCCC#Cc1cnc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Yield: 23.4 %

Procedure:
A solution of 127 mg (0.485 mmol) triphenylphosphine in 0.5 ml THF was treated at 0° C. with 0.075 ml (0.485 mmol) DEAD, then with 0.016 ml (0.388 mmol) methanol and finally with 80 mg (0.19 mmol) of N-[5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-4-trifluoromethyl-benzenesulfonamide in 0.3 ml THF. The reaction mixture was stirred over night at RT, evaporated and extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were dried over Na2SO4, evaporated and purified by flash column chromatography on silica gel with CH2Cl2/MeOH (99:1 to 95:5) to yield 19 mg (23%) of N-[5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 427 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[CH:13]=[O:14])[CH3:8]>CN(C=O)C>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH:13]=[O:14])[CH3:8]
Reactant: Cc1c[nH]cn1
Reactant: CCOc1cc(C=O)ccc1F
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1-n1cnc(C)c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
4-methylimidazole (244 mg) was added to a DMF (3 mL) solution of 3-ethoxy-4-fluorobenzaldehyde (250 mg) obtained above, and the reaction solution was agitated at 150° C. for 4 hours. The reaction solution was concentrated as it was after the reaction ended, water and ethyl acetate were added to the obtained reaction residue, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate 1:4), and 60 mg (18%) of 3-ethoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[H-].[Na+].Br[CH2:15][C:16]([CH3:23])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH-].[Na+]>CN(C=O)C.CCOCC>[CH3:15][C:16]([CH2:23][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C=C(C)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C=C(C)COc1ccc(C=O)cc1OC
Reaction time: 0.17 h

Procedure:
Vanillin (3.43 g, 22.5 mmol) in 10 ml of DMF is added portionwise, at 0°, to sodium hydride (21.5 g, 23.6 mmol) in ml of DMF. The mixture is stirred for 10 min. and then ethyl 4-bromo-3-methyl-2-butenoate (4.87 g, 23.5 mmol) in 3 ml of DMF is added. After 3 hours, the reaction mixture is poured into ether and 5% sodium hydroxide solution. The aqueous layer is extracted with ether, and the organic layers are combined and washed with 5% sodium hydroxide, with water and with brine and dried. Solvent is removed in vacuo and the crude product is chromatographed to give ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate. To isopropyltriphenylphosphonium iodide (2.26 g, 5.23 mmol) in 15 ml of tetrahydrofuran (THF) is added n-butyllithium (1.6 M; 3.10 ml, 5.0 mmol) at -5°. The mixture is cooled to -60°, and ethyl 3-methyl-4-(4-formyl-2-methoxyphenoxy)-2-butenoate (0.70 g, 2.51 mmol) in 10 ml of THF is added. After 45 min. the reaction mixture is poured into ether and water, and the aqueous phase is extracted with ether. The combined ether layers are washed with water and with brine and dried. Solvent is removed in vacuo, and the crude product is triturated with hexane and the hexane-soluble fraction is purified by prep. TLC to give ethyl 3-methyl-4-[2-methoxy-4-(2-methyl-1-propenyl)phenoxy]-2-butenoate, MS m/e 304 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11][CH3:12])=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH:17]O>C(O)(=O)C>[CH3:1][C:2]1[C:10]([S:11]([CH3:12])=[O:17])=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: OO
Reactant: CSc1c(C(F)(F)F)ccc(C(=O)O)c1C
Solvent: CC(=O)O
Product: Cc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)=O
Temperature: 55 °C
Yield: 93.9 %

Procedure:
1.00 g (4.00 mmol) of 2-methyl-3-(methylthio)-4-(trifluoromethyl)benzoic acid was introduced into 10 ml of glacial acetic acid. The mixture was heated to 50-60° C. At this temperature, 0.35 ml (35% strength, 4.00 mmol) of an aqueous hydrogen peroxide solution was added cautiously dropwise. The mixture was stirred at 60° C. for a number of hours until HPLC analysis no longer indicated any reactant. The reaction mixture was cooled and was worked up by washing with an aqueous 10% strength sodium hydrogensulfite solution. Following analytical verification of the absence of peroxides, the mixture was concentrated. The residue was taken up in water and then 1M hydrochloric acid was added. Extraction was carried out three times with ethyl acetate, and the combined organic phases were thereafter dried and freed from the solvents. 1.00 g of the clean product was isolated.
Reaction SMILES: C(OC(=O)[NH:6][C@@H:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]CC=C)=[CH:23][CH:22]=1)[CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])C=C.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C@H:7]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:11]([CH3:13])[CH3:12])[CH:14]([CH3:16])[CH3:15])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1
Reactant: C=CCOC(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)Cc1ccc(OCC=C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC(C)[Si](OC[C@@H](N)Cc1ccc(O)cc1)(C(C)C)C(C)C
Temperature: 47 °C
Reaction time: 10 h
Yield: 89.3 %

Procedure:
To a solution of 21 (6.05 g, 13.5 mmol, 1.0 equiv) in THF (135 mL) at room temperature, was added morpholine (11.8 mL, 135.6 mmol, 10 equiv), then tetrakis(triphenylphosphine)palladium(0) (1.56 g, 1.35 mmol, 0.1 equiv) in the dark. The solution was warmed to 47° C. The reaction was stirred at 47° C. for 10 hours, after which time the solution was cooled to room temperature and the THF was removed under reduced pressure. Purification by flash chromatography (30% EtOAc/hexane→100% EtOAc) afforded 22 (3.9 g, 90%) as a brown solid with a minor amount of Ph3PO. Rf=0.2 (EtOAc); FTIR (film, cm−1) 2938, 2866, 1515, 1462, 1251, 1105; 1H NMR (500 MHz, CDCl3) δ7.01 (d, J=8.5 Hz, 2H), 6.71 (d, J=8.5 Hz, 2H), 4.5 (br s, 2H), 3.75 (dd, J=10.0, 3.5 Hz, 1H), 3.61, (dd, J=9.5, 6.5 Hz, 1H), 3.19 (br s, 1H), 2.79 (dd, J=13.3, 6.0 Hz, 1H), 2.64 (dd, J=13.8, 7.5 Hz, 1H), 1.05 (m, 21H); 13C NMR (100 MHz, CDCl3) δ155.1, 130.3, 129.1, 115.8, 115.6, 66.2, 54.9, 37.9, 18.1, 11.9; HRMS (ES+) calculated for C18H33NO2Si (M+H)+: 324.2281, found: 324.2374.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:50][CH2:49][N:48]3[C:41](=[CH:42][C:43]4[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=43)[C:40]2=[O:53])=[N:26][CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:50][CH2:49][N:48]3[C:47]4[CH2:46][C:45]([CH3:52])([CH3:51])[CH2:44][C:43]=4[CH:42]=[C:41]3[C:40]2=[O:53])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CCc1nccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 229b (277 mg, 0.90 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (358 mg, 0.90 mmol), Pd(dppf)Cl2 (74 mg, 0.090 mmol), K3PO4 (381 mg, 1.80 mmol), water (2 mL), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 3 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 229c as white solid (291 mg, 50%). MS-ESI: [M+H]+ 582.4
Reaction SMILES: C([Mg]Cl)(C)(C)C.[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O.[N:20]1[C:29]2[C:24](=[CH:25][C:26](C(OC)=O)=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1.Cl>C(OCC)C.C1COCC1.O>[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[N:20]2)=[O:19]
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Reactant: COC(=O)c1ccc2nccnc2c1
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CC(=O)c2ccc3nccnc3c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2M solution of tert-butylmagnesium chloride (CAS Reg. No. 677-22-5) in diethyl ether (5.9 ml) was added to 2-chloro-4-methoxyphenylacetic acid (1.173 g, CAS Reg. No. 91367-09-8) in THF (10 ml). The mixture was stirred at room temperature for 30 min. A solution of methyl 6-quinoxalinecarboxylate (1 g, CAS Reg. No. 23088-23-5) in THF (3 ml) was added and the resulting mixture was stirred overnight. Aqueous HCl (25%, 1.5 ml) and water (30 ml) were added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:2) to give the title compound (480 mg) as a light brown solid. MS (m/e)=313.2 [M+H+].
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([NH2:9])=[S:8])([CH3:5])[CH3:4].Br[CH2:11][C:12]([C:14]1[CH:15]=[C:16]([C:20]#[N:21])[N:17]([CH3:19])[CH:18]=1)=O>C(O)C>[OH:1][CH2:2][C:3]([NH:6][C:7]1[S:8][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]([C:20]#[N:21])[N:17]([CH3:19])[CH:18]=2)[N:9]=1)([CH3:5])[CH3:4]
Reactant: Cn1cc(C(=O)CBr)cc1C#N
Reactant: CC(C)(CO)NC(N)=S
Solvent: CCO
Product: Cn1cc(-c2csc(NC(C)(C)CO)n2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
N-(2-Hydroxy-1,1-dimethylethyl)thiourea (0.75 g, 5 mmol), prepared in step 2 of Example 52, was added to 4-(2-bromo-acetyl)-1-methyl-1H-pyrrole-2-carbonitrile (1.15 g, 5 mmol), prepared in the previous step, in ethanol (20 mL) and the mixture was heated under reflux. After 2 h, the reaction was cooled to room temperature, the precipitate was collected, washed with ethanol, suspended in water and made basic with a 1 N sodium carbonate solution. The mixture was extracted with ethyl acetate, the organic layer was then washed with a 1 N sodium carbonate solution, water, dried (anhydrous MgSO4) and evaporated to afford 4-[2-(2-hydroxy-1,1-dimethyl-ethylamino)-thiazol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile (0.92 g, 67%), which was used without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][N:8]=[C:9]([C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.CN1C=CN=C1.[OH-].[Na+].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][N:8]=[C:9]([C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=NOCc1ccc(F)cc1)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCc2ccc(F)cc2)C(=O)O)cs1
Yield: 94.9 %

Procedure:
Ethyl 2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetate (syn isomer, 25.5 g), 1-methylimidazole (1.3 g), 1N sodium hydroxide solution (118.3 ml.), methanol (250 ml.) and tetrahydrofuran (200 ml.) were treated in a similar manner to that of Preparation 14-(3) to give 2-(4-fluorobenzyloxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer, 22.11 g.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH3:29])[CH:6]([NH:21]C(OC(C)(C)C)=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH3:29])[CH:6]([NH2:21])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](C)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](C)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-butyric acid ethyl ester (300 mg, 0.718 mmol) in THF (10 ml) at −78° C. is added LiHMDS/THF (1M) (1.579 ml, 1.579 mmol). The reaction mixture is stirred at −78° C. for 50 min and then to this mixture is added methyl iodine (0.054 ml, 0.861 mmol) and the reaction is slowly warmed up to room temperature and stirred over night. The reaction is quenched by sat. NH4Cl and is extracted with EtOAc. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude. Reverse phase HPLC [20 to 90% ACN—H2O (0.1% TFA) over 10 min by Sunfire C18] give (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester. LCMS (condition B): 432 (M+1); retention time=1.55 min. To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester (240 mg, 0.556 mmol) in DCM (2 ml) at room temperature was added TFA (1.070 ml, 13.89 mmol) and the mixture is stirred at room temperature. 1 hr the reaction is done so the mixture is concentrated to give (R)-3-amino-4-(3′-chloro-biphenyl-4-yl)-2-methyl-butyric acid ethyl ester trifluoroacetate. LCMS (condition B): 332 (M+1); retention time=1.00 min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=O)[CH:10]=[CH:9]2)[CH2:2][CH2:3][CH3:4].[ClH:19].Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:19].[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([N:30]1[CH2:29][CH2:28][N:27]([CH2:26][C:25]3[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:32][CH2:31]1)=[O:18])[CH:10]=[CH:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: CCCCOc1ccc2cc(C(=O)O)ccc2c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOc1ccc2cc(C(=O)N3CCN(Cc4cc(OC)c(OC)c(OC)c4)CC3)ccc2c1
Yield: 64.6 %

Procedure:
Using 6-butoxy-2-naphthoic acid (0.5 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.7 g), triethylamine (0.85 g), N,N-dimethylformamide (20 ml) and diethyl phosphorocyanidate (0.5 ml), an amidation as that described in Example 6 is carried out. The reaction mixture is purified by silica gel column chromatography (hexane:acetone=3:2). The product is converted to the hydrochloride in a mixture of ethyl acetate and ethyl ether to afford 1-(6-butoxy-2-naphthoyl)-4(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.7 g) as colorless prisms, m.p. 185°-190° C. (decomp.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[C@@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[OH:20])[C:15](=[O:28])[N:14]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:14]2[C@H:13]([C:10]3[CH:11]=[CH:12][C:7]([C:48]4[CH:49]=[CH:50][C:45]([OH:44])=[CH:46][CH:47]=4)=[CH:8][CH:9]=3)[C@@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[OH:20])[C:15]2=[O:28])=[CH:34][CH:33]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)N1c1ccc(F)cc1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3ccc(O)cc3)cc2)N1c1ccc(F)cc1
Reaction time: 5 h
Yield: 76.9 %

Procedure:
4-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (162.5 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium(0) (17.3 mg, 0.015 mmol) were dissolved in toluene (2.5 mL). 2.0 M aqueous potassium carbonate (0.3 mL) and a solution of 4-hydroxyphenylboronic acid (57.9 mg, 0.42 mmol) in ethanol (1.0 mL) were added. The reaction was stirred vigorously for 5 h at refluxing temperature under a nitrogen atmosphere and then diluted with water (2.5 mL), extracted with ethyl acetate (3×10 mL), washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-4-yl)azetidin-2-one (112 mg, 77% yield) as a clear film; mp 110° C.; Rf 0.5 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.5 (d, J=9.0 Hz, 2H) 7.4 (d, J=9.0 Hz, 2H) 7.3 (m, 6H), 6.9 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.15 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M+H] 486.5.