Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[CH2:24]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([N:31]1[CH2:36][CH2:35][C:34]([OH:37])([C:9]2[C:18]3[O:17][CH2:16][CH2:15][O:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1cccc2c1OCCO2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: OC1(c2cccc3c2OCCO3)CCN(Cc2ccccc2)CC1

Procedure:
A toluene solution (10 ml) of 5-bromo-2,3-dihydrobenzo[1,4]dioxin (10 mmol) was stirred under argon at 0° C. and was treated with the dropwise addition of n-butyllithium (10 mmol) over ten minutes. After stirring for a further twenty minutes a solution of 1-benzyl-4-piperidone in toluene (10 mmol in 10 ml) was added dropwise over five minutes. Stirring was continued for two hours, at which point water (100 ml) was added and the product extracted into ethyl acetate (4×50 ml). The combined organics were washed with water (2×50 ml), brine (75 ml) and dried (MgSO4). Filtration and concentration in vacuo gave an oil.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCCN)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CCCN2Cc3ccccc3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(4-methoxy-phenyl)-propylamine (0.110 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(4-methoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.114 g, 81%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.98 (m, 2H), 2.63 (t, 2H), 3.64 (t, 2H), 3.76 (s, 3H), 4.36 (s, 2H), 6.78 (d, 2H), 7.18 (d, 2H), 7.52 (m, 3H), 7.82 (d, 1H). GC-MS: m/z 281 (M)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:13]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)([O:15][CH2:16][CH3:17])=[O:14].O>C1COCC1>[C:13]([N:18]1[CH2:19][CH2:20][C:21]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)([OH:24])[CH2:22][CH2:23]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a flask of THF (200 mL) at −78° C. was added n-butyllithium (24.0 mL, 2.5 M), and the resulting mixture was stirred for 10 min. 3-bromopyridine (5.40 mL, 56.0 mmol) was added to this solution and the resulting mixture was stirred for 30 min. A solution of 1-carbethoxy-4-piperidone (7.24 mL, 48.0 mmol) in THF (20 mL) was cannula to the above anion slowly. The reaction mixture was stirred for 2 hours while warmed to room temperature gradually. Water (100 mL) was added and the mixture was concentrated. Extracted with EtOAc (3×100 mL), the organic extract was dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel with EtOAc and 5% MeOH in EtOAc to give 7.26 g of 1-carbethoxy-4-(3-pyridyl)-4-hydroxyl-piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Reactant: COc1cc2c(cc1OC)C(Cc1cc(OC)c(OC)c(OC)c1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1cc(OC)c(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(3,4,5-Trimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])(O)=[O:14].[Na+]>CC(O)=O.OO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[C:10]([CH3:12])[N+:11]=1[O-:14]
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)[n+]([O-])c(Cl)c1
Reaction time: 3 h
Yield: 63 %

Procedure:
A solution of 6.05 g (32.6 mmol) of methyl 2-chloro-6-methylisonicotinate (Aldrich) in 30 mL of AcOH and 30 mL of H2O2 (30 wt. % in H2O) was stirred at 135° C. for 45 min. and 9 mL of H2O2 (30 wt. % in water) was added. Heating was continued for 3 h, and saturated NaHCO3 solution was added to pH=8. The aqueous layer was extracted with EtOAc (4×), and the combined extracts were washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (80% EtOAc/hexanes) provided 4.1 g of the 2-chloro-4-(methoxycarbonyl)-6-methylpyridine 1-oxide as an off-white solid in 63% yield.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:15]([Cl:22])[C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1)=[O:12]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:15]([Cl:22])[C:16]2[N:17]([C:19]([Br:1])=[CH:20][N:21]=2)[CH:18]=1)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cn2c(Br)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reaction time: 5 h

Procedure:
N-bromosuccinimide (14 mg, 0.080 mmol) was added to a solution of 7-(4-bromo-2-chlorophenylamino)-8chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (30 mg, 0.072 mmol) in chloroform (1.0 mL). After stirring for five hours the reaction was diluted with ethyl acetate, washed with NaHSO3, brine, dried over Na2SO4, and concentrated to a yellow solid (33 mg, 92%). MS APCI (+) m/z 494, 496, 498 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.55 (dd, 1H), 7.22 (dd, 1H), 6.53 (d, 1H), 3.98 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C@@H:4]2[CH2:11][C:10](=[O:12])[N:5]2[C:6]=1[C:7]([O-:9])=[O:8].[Na+].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21](OCC)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:2]1[CH2:3][C@@H:4]2[CH2:11][C:10](=[O:12])[N:5]2[C:6]=1[C:7]([O:9][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:8])(=[O:23])[CH3:22]
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Reactant: NC1=C(C(=O)[O-])N2C(=O)C[C@H]2C1
Agent: [Na+]
Product: CC(=O)NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of crystalline diazo keto ester 4 (45 mg, 0.152 mmol) rhodium octanoate (1.2 mg, 0.00154 mmol) and anhydrous toluene (3.0 ml) was heated in an oil bath at 80° and under a nitrogen atmosphere for 15 minutes. (Note: gas evolution occurred at room temperature before heating). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (3 ml), dried over magnesium sulfate, filtered, evaporated under vacuum and stripped with methylene chloride to afford 5 as a pale green oil (41 mg, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[C:18]([N:26]1[CH2:30][CH2:29][C:28]([CH2:39][CH2:40]CS([O-])(=O)=O)([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:8][N:9]([CH2:40][CH2:39][C:28]2([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)[CH2:29][CH2:30][N:26]([C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:27]2)[CH2:10][CH2:11]1)=[O:5]
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C(c1ccccc1)N1CCC(CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccccc3)C2)CC1
Yield: 31.1 %

Procedure:
4-Phenyl-piperidine-4-carboxylic acid methyl ester hydrochloride (0.4143 g, 1.62 mmol) and 2-[1-benzoyl-3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethylmethanesulfonate (0.7165 g, 1.62 mmol) were dissolved in THF/H2O (20 mL/4 mL) and treated with sodium bicarbonate (0.2592 g, 3.24 mmol) at reflux for 16 hours. The solution was diluted with ethyl acetate and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel with 1% methanol in dichloromethane to give 0.2850 g (31%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]2[C:14](=[C:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.F[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1>O>[N+:37]([C:34]1[CH:35]=[CH:36][C:31]([N:10]2[CH2:11][CH2:12][CH2:13][C:14](=[C:15]([CH3:17])[CH3:16])[CH:9]2[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:19][CH:18]=2)=[CH:32][CH:33]=1)([O-:39])=[O:38]
Reactant: COc1ccc(CC2NCCCC2=C(C)C)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC2C(=C(C)C)CCCN2c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A mixture of 1.0 g. of 2-(p-methoxybenzyl)-3-isopropylidenepiperidine hydrochloride, 1.1 g. of powdered potassium carbonate, 10 ml. of dimethyl sulfoxide, and 0.4 ml. of p-fluoronitrobenzene was stirred and heated on a steam bath for 1 hour. The reaction mixture was then poured into water and the water was decanted from the precipitated gum. The gum was washed with several portions of water and then taken up in diethyl ether, and the ether was washed with several portions of water. The ether was dried and filtered, and the filtrate was evaporated to dryness under reduced pressure to yield 1-(p-nitrophenyl)-2-(p-methoxybenzyl)-3-isopropylidenepiperidine as a residue. Neither the residue nor its hydrochloride could be induced to crystallize, although only one component could be observed on thin layer chromatographic analysis using several developing systems on both silica gel and alumina. The nuclear magnetic resonance spectrum (CDCl3) of the crude residue showed: 439 (A2B2), 410, (A2B2), 295 (t,1,J=7 cps), 222 (a,3), 172 (d,2, J=7 cps), 95, (s,3), 76 (d,3,J=1-2 cps). The ultraviolet spectrum (95% ethanol) showed: 272s (ε4100), 286s (ε3500), 400 m (ε16300); lit, p-methylanisole 277 (ε2100), 284 (ε1800); N,N-dimethyl-p-nitroaniline 395 (ε20000).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([CH3:37])([CH3:36])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:39]1[CH:40]=[CH:41][C:42](=[O:46])[N:43]([CH3:45])[CH:44]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([CH3:36])([CH3:37])[C:34]#[N:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:40]=[CH:41][C:42](=[O:46])[N:43]([CH3:45])[CH:44]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cc(Br)ccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 5-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 3 Step 2. LC-MS Method 1 tR=1.45 min, m/z=488; 1H NMR (CDCl3) 7.68(dd, 1H), 7.52(d, 1H), 7.32(q, 2H), 7.17(d, 2H), 7.06(t, 2H), 6.97(d, 2H), 6.91 (d, 1H), 5.66 (q, 1H), 3.72(s, 3H), 2.99(dt, 1H), 2.48(dd, 2H), 2.27(m, 1H), 2.11(s, 2H), 1.55(d, 3H), 1.44(s, 3H), 1.34(s, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[C:14]([Br:15])=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[Br:15][C:14]1[C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc2cccc(Br)c2s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cccc(Br)c2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-7-bromobenzothiazole (0.1 mole) is added with stirring. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 7-bromobenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.Cl[C:21](Cl)([F:26])[C:22]([O:24][CH3:25])=[O:23]>[Zn].[Cu]Cl.O1CCCC1>[F:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:11][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: O=CC1(c2ccc(F)cc2)CC1
Reactant: COC(=O)C(F)(Cl)Cl
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(F)=CC1(c2ccc(F)cc2)CC1
Yield: 40.8 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.12 g) and molecular sieve 4A (1 g), tetrahydrofuran (18 ml), 1-(4-fluorophenyl)-1-formyl-cyclopropane (0.54 g), acetic anhydride (0.38 ml) and methyl dichlorofluoroacetate (0.69 g) to yield the title compound (0.32 g, 42%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3I)=[O:11])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].O.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>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.CO.C1(C)C=CC=CC=1>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22][CH3:23])=[N:17][N:16]=[C:15]3[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1nnc(I)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
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: CO
Solvent: O
Product: COc1nnc(-c2ccccn2)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Temperature: 65 °C
Yield: 49.7 %

Procedure:
A mixture of 4-iodo-1-methoxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.128 g, 0.27 mmol), K2CO3 (0.075 g, 0.54 mmol), water (0.5 mL), toluene (3 mL), methanol (3 mL), 3-pyridineboronic acid (0.04 g, 0.325 mmol), Pd(PPh3)4 (0.094 g, 0.081 mmol) was heated to 65° C. for 2 hour. The reaction was cooled, filtered through celite, rinsed with methanol and concentrated. The residue was taken up in EtOAc, washed with sat. aq. NaHCO3 and dried (Na2SO4). Column chromatography (Hex/EtOAc) afforded 1-methoxy-4-pyridin-2-yl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (57 mg), m/z 425.01
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9][N:8]2[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27]
Reactant: CCOC(=O)CCc1cn(CC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cn(CC(=O)OC(C)(C)C)c2cccc(N)c12
Reaction time: 1 h

Procedure:
A mixture of ethyl 3-[1-(2-tert-butoxy-2-oxoethyl)-4-nitro-1H-indol-3-yl]propanoate from Step B (1.20 g, 3.19 mmol) and 10% Pd/C (150 mg) in EtOH (100 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 1 h, the reaction mixture was filtered through a Celite pad and concentrated in vacuo to give the title compound. MS: m/z=347 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[CH:5][O:4][C:3]=1[C:8]([OH:10])=[O:9].[Li+].CC([N-]C(C)C)C.[P:19](Cl)([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20]>C(OCC)C>[CH2:22]([O:21][P:19]([C:5]1[O:4][C:3]([C:8]([OH:10])=[O:9])=[C:2]([Cl:1])[C:6]=1[Cl:7])([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: O=C(O)c1occ(Cl)c1Cl
Reactant: CCOP(=O)(Cl)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOP(=O)(OCC)c1oc(C(=O)O)c(Cl)c1Cl

Procedure:
A solution of 3,4-dichloro-2-furoic acid (1 mmol) in diethyl ether was treated with LDA (3 mmol) at −78° C. for 30 min and then treated with diethyl chlorophosphate (3.5 mmol) at −78° C. for 1 h. The reaction was quenched and extracted to give 5-diethylphosphono-3,4-dichloro-2-furoic acid as a yellow foam.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2].S(=O)(=O)(O)O.[CH3:35]O>>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:18]3[C:22]([CH2:23][O:24][CH3:35])=[C:21]([Cl:25])[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: CO
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1
Agent: O=S(=O)(O)O
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1

Procedure:
A solution of 5.00 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole and 1.0 mL of conc. sulfuric acid in 200 mL of methanol was refluxed for 20 hours. After cooling, the solvent was remove in vacuo, and the residue was poured into saturated sodium bicarbonate solution. The resulting mixture was extracted with methylene chloride, and the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography on silica gel (elution: 0-20% ethyl acetate/benzene) furnished 5.35 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-methoxymethylimidazole; NMR (200 MHz, CDCl3): δ 8.26 (t, 1H); 8.03 (d of t, 1H); 7.76 (d of t, 1H); 7.51 (t, 1H); 7.33 (A2M2, 4H); 5.20 (s, 2H); 4.31 (s, 1H); 3.94 (s, 3H); 3.27 (s, 3H); 2.59 (t, 2H); 1.68 (quint., 2H); 1.34 (sext., 2H); 0.87 (t, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH2:22][CH2:23][C:19]=2[CH:18]=1.C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:49][CH:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=N2)C=1)(C)(C)C>O1CCCC1.[Cl-].[NH4+]>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:25]=[CH:24][C:20]2[S:21][CH2:22][CH2:23][C:19]=2[CH:18]=1)[CH2:49][CH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Reactant: COC(=O)Cc1ccc2c(c1)CCS2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCC1)c1ccc2c(c1)CCS2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.2 %

Procedure:
A round bottom flask with a stir bar and argon inlet was charged with tetrahydrofuran (10 mL) and cooled to −78° C. Diisopropyl amine (155 μL, 1.10 mmol) was then added followed by the dropwise addition of a solution of n-butyl lithium (2.5M solution in hexanes, 422 μL, 1.06 mmol) and it was stirred at −78° C. for 15 min. After this time, a solution of (2,3-dihydro-benzo[b]thiophen-5-yl)-acetic acid methyl ester (200 mg, 0.96 mmol) in tetrahydrofuran (3 mL) and 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added dropwise. It was then stirred for 1 h at −78° C. It was then treated with a solution of iodomethylcyclopentane (prepared in PCT WO2004/052869 A1 Example 1, 302 mg, 1.44 mmol) in 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) dropwise. The reaction was then stirred at −78° C. and gradually allowed to warm to 25° C. and stirred at 25° C. for 16 h. The reaction was then diluted with a saturated aqueous ammonium chloride solution (30 mL). The aqueous layer was and extracted with ethyl acetate (3×20 mL). The organics were then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 2% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid methyl ester (193 mg, 69).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[I:39]I>O1CCCC1.C(O)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:36])([F:37])[F:38])=[C:33]([I:39])[CH:34]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)nn2)CC1
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(I)c(C(F)(F)F)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a mixture of butyllithium (2.5 M in hexanes) (6.31 ml, 15.79 mmol) in tetrahydrofuran (125 ml) at 0° C., was added 2,2,6,6-tetramethylpiperidine (3.808 ml, 22.56 mmol). The reaction mixture was then stirred at room temperature for 1 h. The mixture was cooled to −78° C. and then a solution of 4-(6-trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (D9) (2.5 g, 7.52 mmol) in tetrahydrofuran (20 ml) was added. The mixture was stirred for 1 h. at −78° C. before adding a solution of iodine (2.29 g, 9.024 mmol) in tetrahydrofuran (10 ml). The mixture was stirred at −78° C. for 1 h. and then diluted with a 10% solution of acetic acid in tetrahydrofuran. The mixture was then allowed to reach room temperature and then the solvent was evaporated in vacuo. The residue was diluted with dichloromethane and extracted with water. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was precipitated from diethyl ether to yield D10 (2.81 g, 82%) as a light yellow solid. C14H18F31N4O2 requires 458; Found 459 (MH+).