Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]>[C:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:11][CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cccnc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2Cl)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 2,3-dichloropyridine (10 g, 67.5 mmol, Aldrich), tert-butyl 1-piperazinecarboxylate (12.58 g, 67.5 mmol, Aldrich), copper powder (0.5 g, 7.8 mmol) and K2CO3 (9.33 g, 67.5 mmol) in DMF (100 mL) was stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue was dissolved in EtOAc (200 mL). The organic solution was washed with saturated aqueous solution of NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 15% EtOAc/hexane, to give the title compound as an orange oil. MS (ESI, pos. ion) m/z: 298 (M+1).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](I)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[N:12]1([C:17]2[CH:18]=[C:19]([NH:27][C:28](=[O:37])[C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][N:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:30]=3)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: C#Cc1cnc2cnccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A mixture of 3-Ethynylimidazo[1,2-a]pyrazine (0.075 g, 0.52 mmol), 0.245 g (0.52 mmol) of N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide, 0.030 g (0.026 mmol) of Pd(PPh3)4, 0.007 g (0.039 mmol) of CuI, and 0.14 mL (0.78 mmol) of diisopropylethylamine in 3.0 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 10% EtOAc/hexanes, then 100% EtOAc, then 10% MeOH/EtOAc) to provide 0.090 g of product as a solid: 487 m/z (M+H).
Reaction SMILES: [C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH:10]3[C@@:8]2([CH2:23][OH:24])[CH2:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[C:1]1([C@@H:7]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH2:11][CH:10]3[C@@:8]2([C:23]([OH:27])=[O:24])[CH2:9]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(CO)[C@@H]2c2ccccc2)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CC3C[C@@]3(C(=O)O)[C@@H]2c2ccccc2)cc1
Yield: 64 %

Procedure:
To a stirred solution of racemic Intermediate 16, one enantiomer being [(1S,2S)-2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-methanol I (34.5 g, 101 mmol) in acetone (1330 mL) was added Jones Reagent (104 mL) dropwise with stirring. The orange solution was stirred for another 20 minutes. MeOH (˜10 mL) was added cautiously until the solution turned green. The solvent was removed at reduced pressure and the residue partitioned between water and methylene chloride. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. This material was flash chromatographed on silica using a gradient of 10% to 80% EtOAc/Hexanes to give the title compound (23.0 g, 64% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=O)[O:16]CC)=[C:4]([F:20])[CH:3]=1.[OH:21][CH:22]([C:27]([CH3:29])=[CH2:28])[C:23]([O:25]C)=O.Cl>C(N(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:23](=[O:25])[C:22](=[C:27]([CH3:29])[CH3:28])[O:21][C:15]2=[O:16])=[C:4]([F:20])[CH:3]=1
Reactant: C=C(C)C(O)C(=O)OC
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (3.01 g, 10 mmol), methyl 2-hydroxy-3-methyl-3-butenoate (3.09 g, 30 mmol), ferric chloride (162 mg, 1.0 mmol) and tributylamine (92.7 mg, 0.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 3 hours. After the reaction solution was cooled to room temperature, toluene (30 mL) was added, and then the reaction solution was washed with 1N sodium hydroxide (20 mL×2) and 1N hydrochloric acid (20 mL×2). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, acidic methanol (5.0 mL) was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.25 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, washed with a 20:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (2.36 g, yield 66.8%).
Reaction SMILES: Cl.[CH:2]([O:5][N:6]=[C:7]([C:31]1[N:32]=[C:33]([NH:36]C=O)[S:34][CH:35]=1)[C:8]([NH:10][CH:11]1[C:29](=[O:30])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:4])[CH3:3]>O1CCCC1.CO>[CH:2]([O:5][N:6]=[C:7]([C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1)[C:8]([NH:10][CH:11]1[C:29](=[O:30])[N:13]2[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:4])[CH3:3]
Reactant: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.1 %

Procedure:
Conc. hydrochloric acid (1 ml) was added to a solution of 7-[2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.5 g) in a mixture of tetrahydrofuran (12 ml) and methanol (12 ml). The mixture was stirred for 3.5 hours at ambient temperature and then concentrated to dryness. Water was added to the residue and to the mixture was added sodium bicarbonate to give a solution. The solution was adjusted to pH 3.0 with conc. hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried to give 7-[2-isopropoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.8 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][CH2:15][C@H:16]([OH:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:24](=O)[CH3:25].Cl.[NH2:28][OH:29].[OH-].[K+].C(O)(C)C>O>[CH3:25][C:24]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[N:9]=[CH:10][N:11]=[C:12]([NH:14][CH2:15][C@@H:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[OH:23])[CH:13]=3)=[CH:7][C:2]=2[O:29][N:28]=1
Reactant: NO
Reactant: CC(=O)c1ccc(-c2cc(NC[C@H](O)c3ccccc3)ncn2)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1noc2cc(-c3cc(NC[C@H](O)c4ccccc4)ncn3)ccc12
Temperature: 90 °C
Yield: 27.7 %

Procedure:
A mixture of 1-[2-fluoro-4-(6-{[(2R)-2-hydroxy-2-phenyl-ethyl]amino}-pyrimidin-4-yl)-phenyl]ethanone (88 mg, 0.25 mmol), hydroxylamine hydrochloride (41 mg, 0.60 mmol), KOH (85% aq., 0.158 mL), isopropanol (0.5 mL) and water (0.5 mL) was heated in a sealed tube at 90° C. for 10 h. An additional amount of KOH (85% aq., 2.38 mmol) was added and the temperature increased to 120° C. for an additional 21 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL×3). The combined extracts were dried (Na2SO4), concentrated, and the crude product purified (FCC) to yield the title compound (24 mg, 28%). MS (ESI): mass calcd. for C20H18N4O2, 346.14; m/z found, 347.2 [M+H]+. 1H NMR (CDCl3): 8.70 (d, J=0.8 Hz, 1H), 8.13 (dd, J=1.3, 0.8 Hz, 1H), 7.93 (dd, J=8.3, 1.3 Hz, 1H), 7.70 (dd, J=8.3, 0.8 Hz, 1H), 7.45-7.37 (m, 4H), 7.34-7.30 (m, 1H), 6.80 (d, J=1.0 Hz, 1H), 5.35-5.30 (m, 1H), 5.03-4.99 (m, 1H), 3.94-3.87 (m, 1H), 3.67-3.60 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:14])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:4]=2[O:3]1.C([N-]C(C)C)(C)C.[Li+].[Li]CCCC.[I:28]I>O1CCCC1>[F:14][C:2]1([F:1])[C:6]([F:7])([F:8])[C:5]2[CH:9]=[CH:10][C:11]([I:28])=[C:12]([F:13])[C:4]=2[O:3]1
Reactant: II
Reactant: Fc1cccc2c1OC(F)(F)C2(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1c(I)ccc2c1OC(F)(F)C2(F)F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 24.8 %

Procedure:
2,2,3,3,7-Pentafluoro-2,3-dihydrobenzofuran (500 mg, 2.4 mmol) was added in portions to a −70° C. solution of lithium diisopropylamide (LDA) prepared in dry tetrahydrofuran (7 mL) from disopropylamine (380 mg, 3.8 mmol) and 2.5 M n-BuLi (1.4 mL, 3.6 mmol). After 40 min at −70° C. a solution of iodine (1.0 g, 4.0 mmol) in tetrahydrofuran (5 mL) was added over 15 min. After 20 min at −70° C., the mixture was warmed to −20° C. and quenched by addition of saturated NH4Cl. The mixture was treated with 10% NaHSO3 (15 mL), stirred for 10 min and extracted twice with diethyl ether (15 mL portions). The combined extracts were dried (Na2SO4) and evaporated. The residue was purified by reverse-phase HPLC eluting with 85% acetonitrile-water to afford the title compound (200 mg, 25%): 1H NMR (400 MHz, CDCl3) δ 7.25 (dd, J=8.1, 4.8 Hz, 1H), 6.63 (dd, J=8.0, 1.1 Hz, 1H), 4.13 (s, 3H); EIMS m/z 336.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([OH:11])=[C:6]([Cl:12])[CH:5]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([Cl:10])[CH:9]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,5-dichloro-4-hydroxy benzoic acid methyl ester (5.525 g, 25 mmol), benzyl bromide (5.13 g, 30 mmol) and potassium carbonate (6.91 g, 50 mmol) in N,N-dimethylformamide (100 mL) was stirred overnight at room temperature. The reaction mixture was poured into crushed ice (ca. 300 g) and the product was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The solid residue was recrystallised from ethyl acetate and hexane. Yield: 7.47 g (96%) fine white needles. 1H-NMR (400 MHz, CDCl3) δ=3.93 (s, 3H, —OCH3), 5.12 (s, 2H, —CH2Ph), 7.35-7.44 (m, 3H), 7.54-7.58 (m, 2H), 8.01 (s, 2H). 13C-NMR (100 MHz, CDCl3) δ=52.66, 75.12, 127.18, 128.41, 128.48, 129.79, 130.13, 135.57, 154.57, 164.39.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=1)[CH:5]([CH3:7])[CH3:6]>O>[CH2:4]([C:8]1[CH:18]=[CH:17][C:11]([C:12]([NH:2][NH2:3])=[O:13])=[CH:10][CH:9]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: NN
Reactant: CCOC(=O)c1ccc(CC(C)C)cc1
Solvent: O
Product: CC(C)Cc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
Hydrazine monohydrate (2.43 g, 48.5 mmol) was added slowly to a heterogeneous solution of ethyl 4-isobutylbenzoate (5.0 g, 24.2 mmol) and H2O and stirred at reflux for 12 hours. The reaction mixture was cooled to room temperature and filtered. The yellow solid was washed with cold water (1×20 mL) and dried to provide the title compound (3.33 g, 78% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CN([CH:18]=[O:19])C>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[CH:18]=[O:19]
Reactant: Cc1ccc(Cl)cc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
Into a flame-dried 250 mL round-bottom flask equipped with a magnetic stir bar and under N2 was added 2-bromo-4-chlorotoluene (10.0 mL, 75.0 mmol) in anhydrous THF (150 mL). The clear sol. was cooled to −78° C. and BuLi (36.6 mL, 82.4 mmol, 2.25 M sol. in hexanes) was added dropwise over 20 min. The resulting light orange sol. was stirred at −78° C. for 1 h, and DMF (30 mL, 375 mmol) was added in a single addition. The resulting mixture was allowed to warm to rt over 4 h. The reaction was quenched by addition of aq. 1M HCl (20 mL), and stirred at rt overnight. The reaction mixture was poured into a 500 mL separatory funnel containing aq. 1M HCl (200 mL). The mixture was extracted with Et2O (3×100 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to a yellow oil. Purification by short-path distillation under reduced pressure (≈1 mm Hg) yielded the title compound as a light yellow oil (7.99 g, 69%). bp=70-72° C. at 1 mm Hg.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.[C:17](=O)([O-])O.[Na+]>CO>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:17])=[O:12])=[C:9]([CH3:16])[CH:8]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
Concentrated sulfuric acid (500 μL) was added to a methanol (20.0 mL) solution of 4-bromo-2-methylbenzoic acid (2.00 g, 9.30 mmol), and the mixture was stirred for 5 hours at 80° C. The reaction mixture was cooled to room temperature, subsequently a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was subjected to extraction two times with ethyl acetate. The organic layer thus obtained was washed once with saturated brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and thus, the title compound (2.02 g, yield: 95%) was obtained.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH3:23][N:24]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:35]3[CH2:36][CH2:37][CH:32]([N:24]([CH3:23])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:33][CH2:34]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(Cc1cccnc1)C1CCNCC1
Agent: Cl
Product: CN(Cc1cccnc1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and methyl-piperidin-4-yl-pyridin-3-ylmethyl-amine, hydrochloride, praeparative HPLC (Method C) (31%, orange oil). HPLC-MS m/z=487.1 (M+1), Rt: 2.64 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](Cl)(C)C.[CH2:16]([C:19]1[CH:40]=[C:39]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:37][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1)[CH2:17][CH3:18].[Br:48]N1C(=O)CCC1=O>C1COCC1>[Br:48][CH:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][CH2:22][O:21][C:20]2[CH:37]=[CH:38][C:39]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:40][C:19]=2[CH2:16][CH2:17][CH3:18])=[CH:27][CH:28]=1)[C:33]([O:35][CH3:36])=[O:34]
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(CC(=O)OC)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc(C(Br)C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide (27.36 mL, 27.36 mmol) in dry THF ( 80 mL) was treated with trimethylsilyl chloride (5.94 mL, 46.76 mmol) at −78° C. To this mixture was added dropwise a solution of the product of Step B (10.80 g, 24.87 mmol) in THF (15 mL). The reaction mixture was stirred at −78° C. for 2 h. N-bromosuccinimide (4.65 g, 26.12 mmol) was added, and the mixture was allowed to warn to room temperature overnight. THF was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed once with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to provide methyl α-bromo-4-(3-(2-propyl-4-phenoxy-phenoxy)propoxy)phenylacetate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][C:3]=1[NH2:4].F[C:16]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:25][C:24]1[C:16]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([C:9]#[C:10][Si:11]([CH3:13])([CH3:12])[CH3:14])=[CH:8][C:2]=2[F:1])=[C:17]([CH:21]=[CH:22][C:23]=1[F:26])[C:18]([OH:20])=[O:19]
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(F)c1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Temperature: -78 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
A mixture of the product of Step A, 2-fluoro-4-[(trimethylsilyl)ethynyl]aniline (3.85 g, 18.6 mmol) and 2,3,4-trifluorobenzoic acid (3.27 g, 18.6 mmol) was dissolved in dry THF (25 mL). The flask was fitted with a pressure-equalising dropping funnel and the entire apparatus evacuated and flushed with N2. The solution was then cooled to −78° C. (acetone/dry ice) and a solution of 1.06 M LiHMDS (52.64 mL, 55.8 mmol) was added dropwise from the dropping funnel. Following this addition, the reaction mixture was allowed to warm to room temperature and stirred for a further 15 hours. The reaction solvent was removed under reduced pressure and the resulting residue partitioned between 1 M HCl (100 mL) and EtOAc (2×100 mL). The combined EtOAc fractions were then washed with water (100 mL) and saturated NaCl (100 mL), dried (Na2SO4), and the EtOAc removed under reduced pressure to afford a crude product which was purified by chromatography on flash silica (10% EtOAc/hexanes as eluant), giving the desired product as a pale yellow solid (3.99 g, 59%); m.p. (EtOAc/hexanes) 164–167° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.70 (br s, 1 H), 9.31 (br s, 1 H), 7.82 (ddd, J=9.1, 6.1, 2.0 Hz, 1 H), 7.34 (dd, J=12.0, 1.9 Hz, 1 H), 7.18 (ddd, J=8.3, 1.9, 0.8 Hz, 1 H), 7.16 (td, J=9.5, 7.3 Hz, 1 H), 6.93 (ddd, J=8.9, 8.3, 5.4 Hz, 1 H), 0.22 (s, 9 H). Anal. Calcd for C18H16F3NO2Si: C, 59.5; H, 4.4; N, 3.9. Found: C, 59.7; H, 4.7; N, 3.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:15][C:16]([Br:18])=[O:17].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[Br:18][C:16](=[O:17])[CH2:15][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2ccccc2)c1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Br)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
A mixture of 5 g (0.026 mole) of 3-chlorobiphenyl, 50 ml of methylene chloride, 6.95 g (0.034 mole) of bromoacetyl bromide is cooled to 0-5° C. and 4 g (0.030 mole) of aluminium trichloride are added thereto. Stirring is effected for 1 hour at 5° C. and then 4 hours at room temperature. The mixture is poured into a water/ice mixture, extracted with methylene chloride, the organic phase is washed with a 1N HCl solution, drying is effected over sodium sulphate and the residu is evaporated under reduced pressure. 4.5 g of the title compound are obtained. M.p. 63-65° C.
Reaction SMILES: Cl[C:2]1[N:3]([C@H:24]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[S:33]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([CH3:36])(=[O:35])=[O:34]>CS(C)=O>[CH3:36][S:33]([N:37]1[CH2:42][CH2:41][N:40]([C:2]2[N:3]([C@H:24]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:25]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:7]=[C:6]([C:17]2[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)[N:5]=3)[CH2:39][CH2:38]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)N1CC[C@H](n2c(Cl)nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)C1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2[C@H]2CCN(S(C)(=O)=O)C2)CC1
Temperature: 140 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Dimethyl sulfoxide (1 ml) was added to 5-{8-chloro-9-[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (100 mg, 0.21 mmol) and N-mesylpiperazine (171 mg, 1.04 mmol) and the resulting mixture was stirred at 140° C. for 1 hour. The reaction mixture was partitioned with chloroform and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give the title compound (105 mg, 83%) as a light brown solid.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH:11]2[OH:23])=[CH:5][CH:4]=1.[H][H]>[Pd].CO>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[OH:23])=[CH:5][CH:4]=1
Reactant: OC1CN(Cc2ccccc2)CCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: OC1CNCCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 100 %

Procedure:
A mixture of 27.8 parts of 4-[bis(4-fluorophenyl)methylene]-1-(phenylmethyl)-3-piperidinol hydrochloride and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 80 parts of acetonitrile. The product was filtered off and dried, yielding 21.9 parts (100%) of 4-[bis(4-fluorophenyl)methylene]-3-piperidinol hydrochloride; mp.>260° C. (intermediate 24).