Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].Cl.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:9][C:4]1[CH:3]=[C:2]([Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: C[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(O)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution 4-bromo-2-fluoro-phenol (75 g, 0.39 mol) in THF (750 mL) was cooled to −78° C. and treated dropwise with n-butyllithium (471 mL, 2.5M solution) over 1 hour keeping the internal temperature below −60° C. After stirring for a further 30 minutes the mixture was treated with chlorotrimethylsilane (128 g, 1.18 mol) in THF (150 mL) over 30 minutes keeping the internal temperature below −60° C. After the addition the mixture was allowed to warm to 0° C. over 40 minutes. The mixture was poured into 1M hydrochloric acid and the layers separated. The aqueous layer was extracted with diethyl ether (×2) and the combined organic layers were washed with water, brine, dried (MgSO4) and concentrated in vacuo to give a colourless liquid. The liquid was dissolved in THF (750 mL) and treated with tetrabutylammonium fluoride (393 mL, 1M solution in THF). After 5 minutes the solution was poured into water and the layers separated. The aqueous layer was extracted with diethyl ether (×2) and the combined organic layers washed with water, brine, dried (MgSO4) and evaporated to a straw-coloured oil. The oil was dissolved in DCM/cyclohexane (1:1, 500 mL) and stirred with silica (15 g) and filtered. The filtrate was evaporated to give the title compound as an oil which solidified on standing (72 g, 100% yield). 1H NMR (CDCl3) 7.04-6.92 (2H, m), 6.92-6.76 (1H, m), and 0.077 (9H, s).
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]([C:11]1[NH:12][C:13](=[O:18])[N:14]=[C:15]([Cl:17])[CH:16]=1)[CH3:10])[CH3:8])(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:17][C:15]1[CH:16]=[C:11]2[N:9]([CH3:10])[CH:7]([CH3:8])[CH2:6][N:12]2[C:13](=[O:18])[N:14]=1
Reactant: CC(COS(C)(=O)=O)N(C)c1cc(Cl)nc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1Cn2c(cc(Cl)nc2=O)N1C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2-((6-chloro-2-oxo-2,3-dihydropyrimidin-4-yl)(methyl)amino)propyl methanesulfonate (800 mg, 2.71 mmol) and K2CO3 (748 mg, 5.41 mmol) in acetonitrile (6 mL) was stirred at 80° C. for 3 h, cooled to room temperature and concentrated. Purification via Biotage Spla HPFC system (C18, mobile phase: 0.01% NH4HCO3/H2O, 10˜95% CH3CN, 9.5 min, 30 mL/min) afforded the title product as an orange solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].B#B>>[CH3:13][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6]
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: B#B
Product: CN(C)CCC(O)c1ccccc1

Procedure:
In that process 3-dimethylamino propiophenone (formula II) is liberated from its hydrochloride salt and reduced with diborane to yield 3-dimethylamino-1-phenyl-1-propanol (formula III) ##STR2##
Reaction SMILES: [Cl:1][CH:2]([CH2:11][CH2:12][CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N+:14]([O-])([OH:16])=[O:15]>>[Cl:1][CH:2]([CH2:11][CH2:12][CH2:13][N+:14]([O-:16])=[O:15])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CCCC(Cl)C(=O)c1ccccc1
Product: O=C(c1ccccc1)C(Cl)CCC[N+](=O)[O-]
Temperature: 0 °C

Procedure:
133 g of 2-chlorovalerophenone are added dropwise to 715 ml of fuming HNO3 at -15° C. and the mixture is poured onto 4 kg of ice. The aqueous phase is then extracted with chloroform and the organic phase is washed, dried and concentrated. The oily compound is further processed as the crude product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:11][C:12]1[N:16]([CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[N:15]=[C:14]([CH2:27][CH3:28])[C:13]=1[O:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]2[N:16]([CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[N:15]=[C:14]([CH2:27][CH3:28])[C:13]=2[O:29][C:30]2[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CN2CCN(C(C)=O)CC2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 5 h
Yield: 92.5 %

Procedure:
N-Acetylpiperazine (42 mg, 0.330 mmol) in N,N-dimethylformamide (1 ml) was added to a stirred solution of the bromide of Example 137 (148 mg, 0.300 mmol) and diisopropylethylamine (57 μL, 0.330 mmol) in N,N-dimethylformamide (2 ml) at room temperature. The reaction was stirred for 5 hours and the mixture was concentrated under reduced pressure. A solution of the residue in dichloromethane (30 ml) was washed with 1M aqueous potassium carbonate solution (10 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to provide the title compound (150 mg) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1>>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[C:18]([F:23])[CH:17]=1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(Cl)cc1F
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-chloro-2-fluoroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[NH2:11][C:10]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(C(=O)O)cnc1Cl
Yield: 60 %

Procedure:
To a solution of 6-chloro-5-nitronicotinic acid in acetic acid (240 ml) was added iron (20 g) and the mixture was heated with stirring on a steam bath. After 11/2 hours, the mixture was filtered hot and washed with hot acetic acid. The filtrate was concentrated to dryness and the residue was treated with 10% NaOH, filtered and the pH adjusted to 2-3. The solid was filtered to yield 8.0 g (60% yield) of 5-amino-6-chloronicotinic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][N:36]1[CH2:37][CH2:38][N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][CH2:35]1)[CH:9]=2
Reactant: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)c1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CO
Product: COc1cc(OC)cc(-c2cc(=O)c3ccc(OCC(O)CN4CCN(c5ccccc5)CC4)cc3o2)c1

Procedure:
3′,5′-Dimethoxy-7-(2,3-epoxy-propoxy)-flavone, 32 (400 mg, 1.13 mmol) and 1-phenyl piperazine (0.17 mL, 1.13 mmol) in dry methanol (100 mL) were reacted in a similar manner to that described under 34 to afford 45. Yield 490 mg (84%); mp 195-196° C.; MS (FAB) 517 (M++1); IR (KBr) 3417, 1633; 1H NMR (200 MHz, DMSO-d6) δ 7.97 (d, J=8.8 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H), 7.24 (d, J=1.9 Hz (d, J=7.9 Hz, 2H), 7.12 (dd, J=8.9 Hz, 1.9 Hz, 1H), 7.04 (s, 1H), 6.93 (d, J=8.2 Hz, 2H), 6.80 (d, J=7.1 Hz, 1H), 6.74 (s, 1H), 4.25-4.09 (m, 3H), 3.87 (s, 6H), 3.13 (t, J=6.5 Hz, 4H), 2.63 (d, J=4.5 Hz, 2H), 2.47-2.43 (m, 4H). Analysis Calcd for C30H32N2O6: C, 69.75; H, 6.24; N, 5.42. Found: C, 69.61; H, 6.53; N, 5.61.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[I:5][C:6]1[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)(O)[O-].[K+].CN(C=O)C>C(Cl)Cl.O>[I:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:2][CH2:3][CH3:4])=[CH:10][N:11]=1
Reactant: Oc1ccc(I)nc1
Reactant: CCCI
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCCOc1ccc(I)nc1
Temperature: 80 °C

Procedure:
Iodopropane (0.18 mL, 1.8 mmol) was added dropwise to a mixture comprising 6-iodopyridin-3-ol (0.32 g, 1.14 mmol), potassium bicarbonate (0.23 g, 1.7 mmol) and DMF (2 mL). The mixture was heated at 80° C. for 1 hour, cooled and diluted with methylene chloride and water. The aqueous layer was separated and extracted with methylene chloride (20 mL). The combined organic layers were washed with water 30 mL, dried (MgSO4) and concentrated under reduced pressure to provide 2-iodo-5-propoxypyridine. MS (ESI); Calculated for C8H10NIO, 266.1, Found (MH+): 222.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1.N1CCCCC1>C(O)C.CCOCC>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])=[CH:21][C:20]=1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(C=O)cc1-c1cccs1
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)cc1-c1cccs1
Reaction time: 8 h
Yield: 14.6 %

Procedure:
A mixture of 6-pyridin-3-yl-1,3-dihydro-indol-2-one (100 mg, 0.5 mmol), 4-methoxy-3-thiophen-2-yl-benzaldehyde (110 mg, 0.5 mmol) and piperidine (0.23 mL) in ethanol (4 mL) was heated to reflux and stirred overnight. The reaction mixture was then cooled and diluted with ether to afford a precipitate which removed by filtration. Thefiltrate was column chromatographed (eluant—isopropanol/dichloromethane) to give 30 mg (15%) of 3-(4-methoxy-3-thiophen-2-yl-benzylidene)-6-pyridin-3-yl-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([O-:16])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:19])#[N:2].[Li+].Cl.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.C(N(C(C)C)CC)(C)C>>[OH:36][C:32]1[CH:31]=[C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH2:23][NH:22][C:14](=[O:16])[CH2:13][C:12]2[N:8]([CH2:7][C:6]3[CH:17]=[CH:18][C:3]([C:1]#[N:2])=[C:4]([F:19])[CH:5]=3)[CH:9]=[N:10][CH:11]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: NCc1ccccc1-c1cccc(O)c1
Reactant: N#Cc1ccc(Cn2cncc2CC(=O)[O-])cc1F
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: N#Cc1ccc(Cn2cncc2CC(=O)NCc2ccccc2-c2cccc(O)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of lithium 1-(4-cyano-3-fluorobenzyl)imidazol-5-ylacetate from Step D (143 mg, 0.55 mmol), 2-aminomethyl-3′-hydroxybiphenyl hydrochloride from Example 4, Step H (118 mg, 0.50 mmol), 1-hydroxybenzotriazole hydrate (74 mg, 0.55 mmol), EDC (105 mg, 0.55 mmol), and diisopropylethylamine (129 mg, 1.00 mmol) in dry, degassed DMF (2 mL) was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between sat. aq. NaHCO3 (3 mL) and CHCl3 (5 mL). The aqueous layer was extracted further with CHCl3 (2×5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with a gradient of 3-5% MeOH/0.3-0.5% NH4OH in CHCl3 to give the titled product as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10](OS(C1C=CC(C)=CC=1)(=O)=O)[C:9]=2[N+:28]([O-:30])=[O:29])=[O:5])[CH3:2].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClC1C=CC=CC=1Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]=2[N+:28]([O-:30])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(=O)c2ccc(OS(=O)(=O)c3ccc(C)cc3)c([N+](=O)[O-])c2o1
Reactant: NCc1ccccc1
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(=O)c2ccc(NCc3ccccc3)c([N+](=O)[O-])c2o1
Temperature: 170 °C
Yield: 66.8 %

Procedure:
To a solution of 8-nitro-4-oxo-7-(toluene-4-sulfonyloxy)-4H-chromene-2-carboxylic acid ethyl ester (433 mg, 1 mmol) in o-dichlorobenzene was added benzylamine (214 mg, 2 mmol). The reaction mixture was heated at 170° C. for 1 hour, and the solvent was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate and washed sequentially with aqueous HCl (2N 50 ml), NaOH (2N, 50 mL) and water, dried over anhydrous Na2SO4, and filtered. The solvent was evaporated in vacuo to give a solid residue. Recrystallization of the residue from ethyl acetate-hexane (2:1) provided 246 mg (67%) of the title compound: mp 168° C.; 1H NMR (400 MHz, CDCl3): 1.43 (t, J=7 Hz, 3H), 4.45 (q, J=7.0 Hz, 2H), 4.61 (d, J=5.0 Hz, 2H), 6.90 (d, J=9.2 Hz), 7.09 (s, 1H), 7.42-7.32 (m, 5H), 8.04 (t, J=5 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H); IR: 3350, 2980, 1730, 1660, 1600,1420,1250 cm−1; MS 369 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[O:9])[CH3:8])[CH:2]=1.[BrH:10].BrBr>C(O)(=O)C.C(OCC)C>[BrH:10].[Br:10][CH2:8][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: CC(=O)c1cccnc1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(CBr)c1cccnc1
Temperature: 40 °C
Yield: 132.9 %

Procedure:
To a vigorously stirred solution of 1-(3-pyridinyl)-ethanone (7.2 mL, 65.44 mmol) in acetic acid (65 mL) and a 48% aqueous solution of hydrogen bromide (11 mL, 97.88 mmol) at 0° C. is added bromine (3.5 mL, 68.11 mmol) drop wise. The reaction is warmed to 40° C. with vigorous stirring and stirred for 2 hours. The reaction is then warmed to 75° C. and is stirred for 2 hours. The reaction mixture is cooled to room temperature and diluted with diethyl ether. The resulting precipitate is collected, washed with diethyl ether, and dried under vacuum to give the title compound as a white crystalline solid (18.27 g, 99%). 1H NMR (d6-DMSO) δ 14.53-14.47 (m, 1H), 9.35 (d, J=1.5 Hz, 1H), 9.01 (d, J=4.9 Hz, 1H), 8.72 (d, J=7.8 Hz, 1H), 7.97-7.91 (m, 1H), 5.09 (s, 2H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C1COCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
Diethyl malonate (7.41 g, 46.3 mmol) was added to a slurry of NaH (60% oil dispersion, 2.04 g, 50.9 mmol) in THF (200 ml) and stirred for 15 min, before adding a solution of 4-nitrobenzyl bromide (10.0 g, 46.3 mmol) in THF (100 ml) by cannula. The reaction was stirred for 3 h at room temperature then quenched by the addition of water (100 ml). The aqueous layer was separated and extracted with Et2O (200 ml). The combined organic layers were washed with brine (200 ml), dried (MgSO4) and the solvent evaporated in vacuo to give an off-white solid. Trituration with Et2O/hexane (1:5, 100 ml), removal of the solid by filtration and concentration of the filtrate in vacuo gave an oil which was purified by chromatography (SiO2;EtOAc/hexane 1:3) to give the title compound as an oil (9.4 g), containing about 20% diethyl malonate. δH (CDCl3) 8.15 (2H, d, J 8.8 Hz, Ar—H), 7.39 (2H, d, J 8.7 Hz, Ar—H), 4.25-4.11 (4H, m, CH2CH3), 3.67 (1H, t, J 7.8 Hz, CHCH2Ar), 3.32 (2H, d, J 7.8 Hz, CHCH2Ar) and 1.23 (6H, t, J 7.2 Hz, CH2CH3).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>CCCCCC.[Cu]I.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>[C:8]([C:6]1[CH:7]=[C:2]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C#C[Si](C)(C)C)cc(C(C)(C)C)c1O

Procedure:
Following General Procedure D and using 4-bromo-2,6-di-t-butyl-phenol (1.43 g, 5 mmol), triethyl amine (15 mL), anhydrous tetrahydrofuran (15 mL), copper(I)iodide (0.06 g, 0.3 1 mmol), trimethylsilyl acetylene (4.9 g, 50 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.18 g, 0.26 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as eluent, the title compound was obtained (1.35 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(=O)C)[CH2:14][C@H:13]2[CH2:21][O:22][C:23]([NH:25]C(=O)C(Cl)(Cl)Cl)=[O:24])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:21][O:22][C:23]([NH2:25])=[O:24])=[O:11])=[CH:32][CH:33]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](COC(=O)NC(=O)C(Cl)(Cl)Cl)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)OC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.67 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-trichloroacetylaminocarbonyloxymethyl-4-acetylthiopyrrolidine (121 mg) was dissolved in 5.8 ml of methanol. To the solution was added 0.45 ml of 1N sodium hydroxide solution under ice-cooling in a nitrogen stream, followed by stirring at the same temperature for 40 minutes. After neutralization by 1.45 ml of 1N hydrochloric acid, the mixture was distilled to remove methanol. The residue was diluted with methylene chloride, washed with water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-aminocarbonyloxymethyl-4-mercaptopyrrolidine.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:7](/[C:10](/[CH3:24])=[C:11](\[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:12]([O:14]CC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:7](/[C:10](/[CH3:24])=[C:11](\[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C(C)=C(\Cc2ccccc2)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ncc(/C(C)=C(\Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
A solution of ethyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-butenoate (623 mg, 1.38 mmol) in ethanol (25 mL) under argon was treated with 10% sodium hydroxide solution (20 mL), and then stirred for 1 hour at room temperature. An additional 25 mL of 10% sodium hydroxide were added and the mixture was stirred overnight at ambient temperature. Acidification to pH 4 with dilute hydrochloric acid solution followed by extraction with methylene chloride and washing with water gave after drying and workup, 630 mg of crude product. Trituration with ethyl acetate/ether provided the title compound (302 mg, 52%), mp 206°-207° C., as the white hydrochloride salt.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.Cl.C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26](S(Cl)(=O)=O)=[CH:25][CH:24]=1>C(#N)C>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H](C)Oc1ccc(C)cc1
Temperature: -5 °C

Procedure:
Methyl (R)-(+)-lactate (3.33 g) and acetonitrile (16.7 ml) were charged to a flask and the resulting solution cooled to −5° C. Triethylamine (4.9 ml) was added. Triethylamine hydrochloride (0.31 g) was added. A solution of para-toluenesulfonyl chloride (5.8 g) dissolved in acetonitrile (16.7 ml) was added dropwise to the reaction mixture (over 40 mins), maintaining the temperature below 5° C. After complete addition a precipitate formed which was filtered. The filtrate was diluted further with acetonitrile (55 ml), to give (2R)-2-(4-methylphenoxy)-propanoic acid, methyl ester. The solution was treated with potassium carbonate (5 g) and 5-chloro-2-hydroxy benzaldehyde. The reaction mixture was heated at 50° C. for 32 h, then cooled to 20° C., diluted with water (100 ml) and extracted with tert-butyl methyl ether (250 ml). The organic phase was washed (brine), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (silica, 5-20% EtOAc/hexane as eluent) to give the sub-title compound (5.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[N:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[N:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)O)n(-c3ccccc3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(C(=O)O)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 50 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-carboxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 3 ml of DCM, 0.1 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[CH3:12].N([O-])=O.[Na+].C1(C)C=CC=CC=1.[BrH:24]>O>[Br:24][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[CH3:12]
Reactant: Br
Reactant: Cc1c(N)ccc(C(=O)O)c1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Br)ccc(C(=O)O)c1F
Reaction time: 1 h

Procedure:
In 14 ml of 4.7% hydrobromic acid was suspended 0.55 g of 4-amino-2-fluoro-3-methylbenzoic acid, and 3.7 g of cupric bromide was added thereto. To the resulting suspension was added dropwise a solution of 0.38 g of sodium nitrite in 4 ml of water under ice-cooling over a period of 15 minutes, and the resulting mixture was stirred at the same temperature for 1 hour and then at room temperature for 24 hours. To the reaction mixture was added 20 ml of toluene and the organic layer was separated. The organic layer obtained was washed with 20 ml of 20% hydrobromic acid, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. n-Hexane was added to the resulting residue and the crystals were collected by filtration to obtain 0.68 g of colorless 4-bromo-2-fluoro-3-methylbenzoic acid.