Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH3:18])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2].FC(F)(F)C(O[I:24](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([C:3]1([CH3:18])[C:7](=[O:8])[C:6]([I:24])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)[O:4]1)[CH3:2]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCC1(C)OC(c2ccc(S(C)=O)cc2)=CC1=O
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC1(C)OC(c2ccc(S(C)=O)cc2)=C(I)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 162.1 %

Procedure:
8.2 g of 2-ethyl-2-methyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone in 200 ml carbon tetrachloride and 200 ml chloroform was mixed with 6.8 g of [bis(trifluoroacetoxy)iodo]benzene (BTI) and 4.1 g of iodine. The mixture was stirred at room temperature for 6 hours, followed by quenching the reaction by adding saturated aqueous sodium thiosulfate until the characteristic color of iodine disappeared. The quenched solution was extracted with 300 ml water and dichloromethane (200 ml×3). The organic layer was concentrated in vacuo and the resulting residue was purified by column chromatography (hexane/ethylacetate=1:1) to give 10.0 g of 2-ethyl-4-iodo-2-methyl-5-{4-(methylsulfinyl)phenyl}-3(2H)-furanone. NMR: δ0.89 (t, J=7.5 Hz, 3H), 1.51 (s, 3H), 1.93 (m, 2H), 2.73 (s, 3H), 7.81 (d, J=8.7 Hz, 2H), 8.38 (d, J=8.7 Hz, 2H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:11]=[C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]([C:15]([NH2:17])=[O:16])=[CH:14][C:5]1=2)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][C@H:4]1[CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:11]=[C:12]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]([C:15]([NH2:17])=[O:16])=[CH:14][C:5]1=2
Reactant: [N-]=[N+]=N[C@H]1CCCOc2cc(OCC3CCCCC3)c(C(N)=O)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(=O)c1cc2c(cc1OCC1CCCCC1)OCCC[C@@H]2N
Reaction time: 17 h

Procedure:
To (S)-5-azido-8-cyclohexylmethoxy-2,3,4,5-tetrahydro-benzo[b]oxepine-7-carboxylic acid amide (2.5 g, 5.8 mmol) in EtOAc (20 mL) was added 10% Pd/C (0.25 g). The mixture was hydrogenated at STP for 17 h, filtered though glass, and concentrated to a white solid (1.8 g, 98%). MS [M−H]− 317, m.p. 145-146° C. Optical purity determined by Mosher Amide formation, 55% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([CH:23]=O)=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:25][CH3:26].[Br-].[Cl:28][C:29]1[CH:54]=[C:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:52]=[C:51]([F:60])[C:30]=1[CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>CC#N.O>[Cl:28][C:29]1[CH:54]=[C:53]([CH:52]=[C:51]([F:60])[C:30]=1[CH:31]=[CH:23][C:14]1[N:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:11]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:25][CH3:26])[CH:4]=2)([CH3:10])[CH3:9])=[CH:12][N:13]=1)[C:55]([O:57][CH2:58][CH3:59])=[O:56]
Reactant: COc1cc(C(C)(C)c2cnc(C=O)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CCOC(=O)c1cc(F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: [Br-]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(C=Cc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(Cl)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-carbaldehyde (304 mg, 0.815 mmol) and (2-chloro-4-(ethoxycarbonyl)-6-fluorobenzyl)triphenylphosphonium bromide (454 mg, 0.815 mmol) in MeCN (5 mL) was added dropwise DBU (136 mg, 0.896 mmol). After stirring at 50° C. overnight, the mixture was diluted with H2O and extracted with DCM. The combined extracts were dried (MgSO4), filtered, concentrated and purified by flash chromatography (20-90% EtOAc/hexanes) to yield ethyl 3-chloro-4-(2-(5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)vinyl)-5-fluorobenzoate (0.241 g, 51%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.05-7.87 (m, 3H), 7.85-7.58 (m, 13H), 7.20 (tt, J=15.1, 7.1 Hz, 1H), 5.21 (d, J=15.0 Hz, 2H), 4.34 (dq, J=14.2, 7.1 Hz, 2H), 1.33 (dt, J=14.2, 7.1 Hz, 3H).
Reaction SMILES: [Li][Li].[Cl-:3].[Cl-].[Cl-].[Cl-].[Zr+4:7].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=CC=1>>[Cl-:3].[Cl-:3].[CH-:11]1[CH:12]=[CH:13][CH:8]=[CH:14]1.[CH-:11]1[CH:12]=[CH:13][CH:8]=[CH:14]1.[Zr+2:7]
Reactant: Cc1ccccc1
Reactant: [Zr+4]
Agent: [Cl-]
Agent: [Li][Li]
Product: [Zr+2]
Product: c1cc[cH-]c1
Temperature: -78 °C
Reaction time: 48 h

Procedure:
A suspension of 7.80 g (22.0 mmol) of the dilithium salt (EXAMPLE 4) in 200 ml of toluene is cooled to -78° C., and 5.10 g (22.0 mmol) of zirconium tetrachloride are added in portions. The mixture is allowed to warm to room temperature, and the yellow-orange suspension is stirred for a further 48 hours. Insoluble constituents are filtered off via a frit, and the solvent is removed in an oil-pump vacuum. The red-orange oil is powdered by vigorous stirring with pentane, giving the zirconocene dichioride in a crude yield of 30% (2.72 g).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]([F:50])([F:49])[C:41]1[N:42]=[C:43]([C:46](O)=[O:47])[S:44][CH:45]=1>>[N:22]1[C:21]2[NH:25][CH:26]=[CH:27][C:20]=2[C:19]([C:16]2[CH:17]=[CH:18][N:14]([C:12]3([CH2:36][C:37]#[N:38])[CH2:11][N:10]([CH:7]4[CH2:8][CH2:9][N:4]([C:46]([C:43]5[S:44][CH:45]=[C:41]([C:40]([F:49])([F:39])[F:50])[N:42]=5)=[O:47])[CH2:5][CH2:6]4)[CH2:13]3)[CH:15]=2)=[N:24][CH:23]=1
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: Cl
Product: N#CCC1(n2ccc(-c3ncnc4[nH]ccc34)c2)CN(C2CCN(C(=O)c3nc(C(F)(F)F)cs3)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 4-trifluoromethylthiazol-2-ylcarboxylic acid following the procedure described for Example 261, followed by purification with HPLC (method B) provided the title compound. LC-MS: 541.2 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 11.92 (brs, 1H), 8.75 (s, 1H), 8.57 (s, 1H), 7.78 (s, 1H), 7.43 (d, 2H), 7.02 (s, 1H), 6.90 (s, 1H), 4.45 (m, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.55 (d, 2H), 3.45 (d, 2H), 3.37 (s, 2H), 3.20 (m, 2H), 1.80-1.60 (m, 2H), 1.25 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][C@H:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)CCl>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][C@H:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]([O:20][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Under argon, 10 g (20.11 mmol) of (−)-3-(2-benzyloxy-5-iodophenyl)-2(S)-tert-butoxycarbonylaminopropionic acid (Example (−)-6A) are dissolved in 200 ml of acetonitrile. To this are added 246 mg (2.01 mmol) of 4-dimethylaminopyridine and 4.16 ml (40.22 mmol) of benzyl alcohol. The mixture is cooled to −10° C., and 4.63 g (24.13 mmol) of EDC are added. The mixture is allowed slowly to reach RT and is stirred overnight. After about 16 h, the mixture is concentrated on a rotary evaporator in vacuo, and the residue is purified by column chromatography on silica gel (mobile phase: dichloromethane). Yield: 10.65 g (88% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[ClH:13].[CH2:14]=O>>[Cl:13][CH2:14][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:12]
Reactant: C=O
Reactant: Cl
Reactant: O=C1CCCc2cc(O)ccc21
Product: O=C1CCCc2c1ccc(O)c2CCl

Procedure:
To a mixture of 20 g. of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone and 110 ml. of concentrated hydrochloric acid is added 4.6 g. of paraformaldehyde and the mixture is agitated at room temperature for 20 hours. To the reaction mixture is added 200 ml. of water, and the resulting precipitate is recovered by filtration, rinsed with water and benzene and dried. The described procedure provides 5-chloromethyl-6-hydroxy-3,4-dihydro-1(2H)-naphthalenone. Yield 21 g.; melting point: 172°-174° C (decomp.).
Reaction SMILES: [N:1]([C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Br:12])[CH3:5])=[N+]=[N-].[NH4+].[Cl-].[In]>CCO.O>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C@@H:4]([NH2:1])[CH3:5]
Reactant: C[C@H](N=[N+]=[N-])c1ccccc1Br
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@H](N)c1ccccc1Br
Yield: 87.5 %

Procedure:
To a solution of (S)-1-(1-azidoethyl)-2-bromobenzene (45 mg, 0.2 mmol) in EtOH/H2O (5 mL/5 mL) was added in NH4Cl (108 mg, 2.0 mmol) and indium (91 mg, 0.8 mmol). The mixture was refluxed overnight. The reaction mixture was filtered, washed with EtOH and evaporated. The residue was triturated with AcOEt and filtered. The filtrate was evaporated to give the title compound (35 mg, 88%).
Reaction SMILES: C(OCC(C)OCC1C=CC([C:16]2[C:21]([S:22]([NH:25][C:26]3[C:31]([O:32][CH3:33])=[N:30][C:29]([CH3:34])=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=CC=1)(C)(C)C.[Cl-].[NH4+]>FC(F)(F)C(O)=O>[CH3:33][O:32][C:31]1[C:26]([NH:25][S:22]([C:21]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:23])=[O:24])=[N:27][CH:28]=[C:29]([CH3:34])[N:30]=1
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(COC(C)COC(C)(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
A solution of 2-{4-[(2-tert-butoxy-1-methylethoxy)methyl]phenyl}-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (248 mg) in trifluoroacetic acid (1 ml) was left to stand for 30 minutes. Saturated ammonium chloride solution (20 ml) was added and the mixture was extracted with ethyl acetate (2×20 ml). The extracts were dried (MgSO4) and concentrated and the residue was dissolved in dichloromethane (10 ml). The solution was washed with water (2×10 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/ethyl acetate (1:24 v/v), to give 2-[4-([2-hydroxy-1-methyl)ethoxy]methyl) phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (82 mg), 1H NMR (d6 -DMSO): 1.15 (s, 3H), 2.25 (s, 3H), 3.3-3.7 (s, 3H), 3.8 (s, 3H), 4.6 (s, 2H), 7.3-7.55 (m, 5H), 7.6 (dd, 1H), 8.45 (dd, 1H), 8.8 (dd, 1H), 10.35-10.45, (br s, 1H); mass spectrum (+ve ESP): 445 (M+H)+.
Reaction SMILES: [NH:1]1[C:4]2([CH2:9][CH2:8][CH2:7][N:6]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:5]2)[CH2:3][CH2:2]1.CC1N([C:25]([CH2:27][C:28]#[N:29])=[O:26])N=C(C)C=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:26]=[C:25]([N:1]1[C:4]2([CH2:9][CH2:8][CH2:7][N:6]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH2:5]2)[CH2:3][CH2:2]1)[CH2:27][C:28]#[N:29]
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Reactant: c1nc(N2CCCC3(CCN3)C2)c2cc[nH]c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC(=O)N1CCC12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
An optically-active compound of 4-(1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.55 g) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (1.56 g), N,N-diisopropylethylamine (1.66 ml) and 1,4-dioxane (31 ml), and the mixture was heated to 100° C. to stir for 2 hours. The mixture was cooled to room temperature. Then, thereto was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=20/1 to 9/1) to give the titled compound (1.50 g).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CCOC(C)=O.C1COCC1>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1

Procedure:
To a solution of tert-butyl [2-[(4-nitrobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate (598 mg, 1.36 mmol) in 1:1 EtOAc/THF was added 10 mol % Pd/C (136 mg, 1.36 mmol). The reaction mixture was evacuated and refilled with hydrogen (2×). The black reaction mixture was stirred in a parr shaker under 50 psi of hydrogen overnight. The mixture was filtered through a pad of celite (with EtOAc then CH2Cl2 washes) and concentrated to provide tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate which was confirmed by MS: cal'd 410.1 (MH+), exp 410.1 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl.[H-].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
4-(Benzyloxy)phenol (2.89 g, 0.01443 mol) in dimethylformamide (15 ml) and 2-(dimethylamino)ethyl chloride hydrochloride (2.32 g, 0.01611 mol) were added simultaneously in small portions to a 55-65% sodium hydride dispersion in mineral oil (0.033 mol) in dimethylformamide (5 ml) at 0° C. Then the mixture was allowed to warm to 90° C., and stirring was continued for 1.5 h. The cooled mixture was poured into water. The resultant mixture was extracted with toluene. The combined extracts were washed with 2.5 M NaOH and water and dried over Na2SO4. Toluene was evaporated and the residual product was used as such in the next step.
Reaction SMILES: CC(N(C)C)=O.BrCCBr.[Si](Cl)(C)(C)C.[C:16]([N:23]1[CH2:26][CH:25](I)[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[Cl:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[C:31]([Cl:36])[N:30]=1>[Zn]>[Cl:28][C:29]1[CH:34]=[C:33]([CH:25]2[CH2:26][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)[CH:32]=[C:31]([Cl:36])[N:30]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(Cl)c2)C1
Reaction time: 0.5 h

Procedure:
To a suspension of zinc (3.56 g, 3.0 equiv., 53.1 mmol) in DMA (8.3 mL, 88.5 mmol) was added 1,2-dibromoethane (0.37 mL, 0.24 equiv., 4.25 mmol), followed by TMS chloride (0.55 mL, 0.24 equiv., 4.25 mmol). After the reaction ceased down, a solution of 1-boc-3-(iodo)azetidine (11.3 g, 2.2 equiv., 39.0 mmol) in DMA (6.6 mL, 70.8 mmol) was added dropwise. After 30 min at 25° C. and then 2 h at 50° C., LCMS showed no m/z 228 peak. The mixture was transferred dropwise into a suspension of 2,6-dichloro-4-iodopyridine (5.00 g, 17.7 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(ii) dichloride dichloromethane adduct (738 mg, 0.050 equiv., 0.885 mmol) and cuprous iodide (337 mg, 0.10 equiv., 1.77 mmol) in DMA (16.5 mL, 177 mmol). DMA (16.5 mL, 177 mmol)) was used to rinse the flask. The whole reaction mixture was kept at 80° C. in oil-bath for 4 h. DMA was removed at 60° C. under vacuum, and the crude was purified via silica gel chromatography (0-50% EtOAc/Heptanes) to yield 1.73 g (54% based on the conversion) of the title compound. 1H NMR (400 MHz, CDCl3) δ (delta) 7.23 (s, 2H), 4.35 (t, J=8.7 Hz, 2H), 3.92 (dd, J=8.7, 5.6 Hz, 2H), 3.73-3.61 (m, 1H), 1.47 (s, 9H). 13C NMR (101 MHz, CDCl3) δ (delta) 157.03, 156.08, 151.09, 121.24, 80.24, 55.31, 32.48, 28.32. LCMS: m/z 303 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: COc1cc(N)ccc1N1CC[C@@H](O)C1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1N1CC[C@@H](O)C1

Procedure:
(R)-1-(4-Amino-2-methoxyphenyl)pyrrolidin-3-ol, preparation described in PCT application WO 2005/042541, was converted to the title compound (48 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (30 mg) following the procedure described in step C of Example 1. MS (ESI) 412 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>O.ClCCl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2([C:40]([N:11]3[CH2:12][CH2:13][CH2:14][C:9]([OH:15])([CH2:8][O:7][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:17][CH:16]=4)[CH2:10]3)=[O:41])[CH2:39][CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: OC1(COc2ccc(C(F)(F)F)cc2)CCCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(N1CCCC(O)(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
Into a round-bottom flask was added 3-(4-trifluoromethyl-phenoxymethyl)-piperidin-3-ol (100 mg, 0.36 mmol), dichloromethane (5 mL), diisopropylethylamine (0.190 mL, 1.08 mmol), 1-(4-chloro-phenyl)-cyclobutanecarboxylic acid (113.4 mg, 0.54 mmole), and PyBroP (0.252 g, 0.54 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and then extracted with ethyl acetate (3×10 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oil. The oil was purified by column chromatography on silica gel using hexane/ethyl acetate (4:1) to give [1-(4-Chloro-phenyl)-cyclobutyl]-[3-hydroxy-3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-methanone (18.7 mg, 11%). MH+ (468).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:44])[CH2:19][C:20]([NH:22][CH2:23][C:24]2[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]3[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]3=[N:28][C:29]=2[CH2:30][CH3:31])=[O:21])=[CH:4][CH:3]=1.[NH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(O)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:44])[CH2:19][C:20]([NH:22][CH2:23][C:24]2[C:25]([NH:37][CH:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[C:26]3[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]3=[N:28][C:29]=2[CH2:30][CH3:31])=[O:21])=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(-c2cccc(C=O)c2)c1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1ccc(Cl)c(-c2cccc(CN3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.3 %

Procedure:
N-[(6-chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (37.0 mg, 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing piperazine (0.18 mmol) and acetic acid (3.6 mg, 0.6 mmol) and fitted with a magnetic stir bar. The resulting solution was stirring at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and purification was completed using reversed phase HPLC (acidic conditions) via a Gilson. The product after HPLC purification was dissolved in 3 mL of MeOH and was passed through a 0.5 g amine column (washed with 8 mL of MeOH) to afford 12.1 mg of the title compound (29.3%). LC-MS m/z 687 (M+H)+, 1.88 min (ret time).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10](C#N)[C:11]([C:24]#[N:25])=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=1.[OH-].[Na+].[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>CN1CCN(C)C1=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:11]([C:24]#[N:25])=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:22])[CH3:23])[N:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2Br)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: COc1ccc(CNc2nc(-c3ccccc3Br)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Temperature: 27.5 °C
Reaction time: 100 h

Procedure:
To a solution of 5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2,3-pyrazinedicarbonitrile (3.00 g) in 1,3-dimethyl-2-imidazolidinone (6 ml), (4-methoxybenzyl)amine (0.96 ml) was added and the mixture was stirred at 25-30° C. for 100 hours. After addition of 0.5N aq. NaOH (15 ml), the mixture was stirred for one hour and a precipitate was collected by filtration to give a solid. The solid was dissolved in EtOAc, washed with water, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give 5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-2-pyrazinecarbonitrile as an amorphous solid (2.58 g) containing 6-(2-bromophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-2-pyrazinecarbonitrile.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 10.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene, 10.0 g of 1-methylpiperazine and 10.4 g of potassium carbonate in 93 ml of DMSO is stirred at ambient temperature overnight. The mixture is diluted with 160 ml of water and extracted three times with 150 ml of ethyl acetate. The organic phases are dried over magnesium sulfate and concentrated under vacuum. The residue is purified on 200 g of silica, elution being carried out with dichloromethane/methanol (98/2 then 95/5), so as to obtain 13.6 g of 1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazine in the form of a yellow oil.