Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(COC)OC.[C:9]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])([CH3:12])([CH3:11])[CH3:10].C(OCCOCCO[C:29]([F:33])=[C:30]([F:32])[F:31])C>CCCCC.C1OCCOCCOCCOCCOCCOC1>[C:9]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:29]([F:33])=[C:30]([F:32])[F:31])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OCCOCCO
Reactant: CCOCCOCCOC(F)=C(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCC
Product: CC(C)(C)OCCOCCOC(F)=C(F)F
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 63 %

Procedure:
Bu-TFVE was prepared by mixing 2.66 g of NaH (0.111 mol) and 1 g of 18-crown-6 with 135 mL of glyme under inert atmosphere at 65° C. 15.0 g (0.092 mol) of 2-(2-t-butoxyethoxy)ethanol was slowly added to the flask and stirred at 65° C. 1 h. The alkoxide was transferred to the dry 300 mL Parr reactor, stirred and heated at 65° C. for 1 h after which TFE gas was added. The pressure was maintained at ˜50-60 PSI. A very slight exotherm (˜5° C.) was initially observed. After 45 minutes, stirring was stopped and the reactor was cooled to room temperature. Excess TFE was carefully vented and the reactor contents transferred to a 500 mL Erlenmeyer flask. The mixture was diluted to 300 mL with pentane to effect complete precipitation of sodium salts. The mixture was filtered through a course frit funnel to remove sodium salts. The liquid fraction was rotary evaporated to give a clear yellow crude product. The crude product was vacuum fractionally distilled over potassium carbonate. 14.1 g (63% yield) of the desired product, 1-[2-(2-ethoxyethoxy)ethoxy]-1,2,2-trifluoroethene, was isolated at a boiling point of 26-27° C. (pressure 0.15 mmHg, >99% purity by GC). 19F NMR: δ=−123.5 (dd, 1F J=56, 104 Hz, CF), −130.3 (dd, 1F J=104, 108, CF), −135.1 (dd, 1F J=56, 108 Hz, CF); 1H NMR: δ=4.15 (m, 2H, CFOCF2), 3.75 (t, 2H, OCH2), 3.65-3.45 (m, 4H, OCH2), 1.2(s, 9H, C(CH3)3).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@@H:13]1[C@H:18]([CH3:19])[CH2:17][CH2:16][CH2:15][N:14]1C(OCC1C=CC=CC=1)=O>C(O)(=O)C.[Pd]>[CH3:19][C@@H:18]1[CH2:17][CH2:16][CH2:15][NH:14][C@@H:13]1[CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: C[C@@H]1CCCN(C(=O)OCc2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Yield: 87.9 %

Procedure:
To a solution of (2S,3R)-benzyl 2-((1,3-dioxoisoindolin-2-yl)methyl)-3-methylpiperidine-1-carboxylate (14.2 g, 36.1 mmol) in acetic acid (40 ml) was added 10% Pd/C (1.5 g). The reaction was then stirred under H2 until HPLC indicated complete removal of the Cbz group. The reaction was the filtered through diatomaceous earth and concentrated. The crude residue was then dissolved in EtOAc and washed with saturated NaHCO3, brine, dried (MgSO4), and concentrated to yield the title compound as a yellow solid (8.2 g, 88%). 1H NMR (CDCl3, 400 MHz) δ 7.82-7.81 (m, 2H), 7.71-7.70 (m, 2H), 4.19-4.15 (m, 1H), 3.81-3.78 (m, 2H), 3.44 (m, 2H), 2.96 (m, 1H), 2.31 (m, 1H), 1.79-1.67 (m, 2H), 1.27 (d, J=4.0 Hz, 3H). ESI-MS (m/z): 259.2 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([OH:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(N)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(N)ccc1-c1ccc(C(=O)O)cc1
Yield: 105.6 %

Procedure:
4-Bromo-3-methylaniline (7.40 g, 40 mmol) and 4-carboxybenzeneboronic acid (7.90 g, 48 mmol) were stirred in 1,2-dimethyoxyethane (DME) (150 ml). Anhydrous sodium carbonate (19.0 g, 179 mmol) was dissolved in water (150 ml) and added to the above. The mixture was then purged with a stream of argon for 15 minutes. Tetrakis (triphenylphosphine)palladium (O) (0.25 g, 0.2 mmol) was added, and the mixture was stirred at reflux for 20 h under argon. DME was removed by evaporation under reduced pressure, and the clear residue was acidified with 5M HCl to yield a thick grey suspension. The solid was filtered off, washed with water and dried in vacuo at 60° C., to give the title compound (9.60 g, quantitative).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25 mg (1.00 mmol) 95% Sodium hydride were given to a solution of 219 mg (1.00 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 304 mg (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 352 mg (72%) colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[NH:13][N:14]=[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:21]([O:23]C)=O.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:21](=[O:23])[N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:15]2=[N:14]1
Reactant: C#CCOc1cc(NN=C2CCCCN2C(=O)OC)c(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C#CCOc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Temperature: 100 °C
Yield: 87.6 %

Procedure:
A mixture of 10.0 g of the product from Step B and 0.50 g of glacial acetic acid in 50 mL of toluene is heated at 100° C. for 2 h while removing methanol vapor with a stream of nitrogen. Hexane (50 mL) is added at 70° C. and the product is filtered at 25° C. and washed with hexanes to provide 8.0 g (94%) of the title compound, m.p. 168°-169° C. 1H NMR (CDCl3) δ1.9 (m, 4H), 2.55 (t, 1H, J=2.4Hz), 2.74 (t, 2H, J=6Hz), 3.67 (t, 2H, J=6Hz), 4.74 (d, 2H, J=2.4Hz), 7.13 (s, 1H), 7.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)#[N:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[CH:14][CH:15]=2)=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Yield: 85.2 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluoro-benzaldehyde (2 g, 12.8 mmol) (Beta Pharma) was reacted with 4-cyanophenol (1.67 g, 14 mmol) and K2CO3 in N,N-dimethylacetamide to give 4-(4-chloro-2-formyl-phenoxy)-benzonitrile as a light yellow solid (Yield 2.81 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[H-].[Na+].[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][N:25]=[C:24](Cl)[N:23]=1>CN(C=O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[CH:26][N:25]=[C:24]([NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=3)[CH2:8][CH2:9]2)[N:23]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ncc(C#N)c(N)n3)CC2)ccc1Cl
Temperature: 25 °C
Yield: 35 %

Procedure:
To a solution of 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (40.3 mg, 0.15 mmol, 1.2 equiv; intermediate A2) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h 4-amino-2-chloro-pyrimidine-5-carbonitrile (19.3 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 17.1 mg (35%) of the title compound. MS (ISP): 387.3 [M+H]+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=[O:9])=CC=1.[N+:13]([CH2:16][C@@H:17]1[CH2:21][C@H:20](CC([O-])=O)[CH:19]=[CH:18]1)([O-:15])=[O:14]>CO>[N+:13]([CH2:16][C@H:17]1[CH2:21][C@@H:20]([OH:9])[CH:19]=[CH:18]1)([O-:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])C[C@@H]1C=C[C@H](C[N+](=O)[O-])C1
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C[C@@H]1C=C[C@H](O)C1
Reaction time: 8 h

Procedure:
To a 5 mL round-bottom flask is added at room temperature p-toluenesulphonic acid monohydrate (0.01 g, 0.053 mmol), methanol (8 mL) and (1R-cis)-4-nitromethyl-2-cyclopentene -acetate as prepared in Example 10 (0.20 g, 1.1 mmol) and the resulting solution is stirred overnight. The crude reaction mixture is loaded on a silica column (32 μm-63 μm) and purified by flash chromatography by eluting with 20% ethyl acetate/hexane. The fractions containing the product (Rf=0.3) are combined and are concentrated in vacuo to give (1R-cis)-4-nitromethyl-2-cyclopenten-1-ol as a clear oil which exhibited the following physical data: MS(CI) m/z=126 [C6H8NO2 +, Loss of H2O followed by rapid protonation]; and [α]D20 =+4.8° (c=0.16, CHCl3).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]#[N:16])=[C:12]([CH3:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][OH:19]>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:18][OH:19])[NH2:16])=[C:12]([CH3:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: NO
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C#N
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-methylthiophene-2-carbonitrile (2.5 g, 9.2 mmol) that was obtained in Example 11 (11c) and a 40% aqueous solution of hydroxylamine (20 mL). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (1.4 g) in a yield of 52% as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:7]C1C=CC=C2C(NC(=O)C=12)=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C([NH2:23])CCC.C(OCC)C.[ClH:29]>C(O)C>[ClH:29].[CH2:1]([O:7][NH2:23])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN
Reactant: O=C1NC(=O)c2c(OCc3ccco3)cccc21
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: NOCc1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.28 g of [-furfuryloxyphthalimide [prepared as described in step (i) above] were dissolved in 20 ml of ethanol, and 1.37 g of butylamine were added to the resulting solution. The mixture was then stirred for 1 hour at room temperature, after which diethyl ether was added. The mixture was then acidified by the addition of a 10% by volume methanolic solution of hydrogen chloride, and the resulting crystals were collected by filtration, to afford 2.62 g of the title compound. Nuclear Magnetic Resonance Spectrum (CD3OD, 270 MHz), δ ppm: 5.07 (2H, singlet); 6.54 (1H, doublet of doublets, J=2 & 3 Hz); 6.72 (1H, doublet, J=3 Hz); 7.67 (1H, doublet, J=2 Hz).
Reaction SMILES: CC1[N:3]([C@H:8]2[CH2:12][C@@:11]([C:23]3([OH:27])[CH2:26][CH2:25][CH2:24]3)([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)C(C)=CC=1.Cl.NO.NO.O>CO>[NH2:3][C@H:8]1[CH2:12][C@@:11]([C:23]2([OH:27])[CH2:24][CH2:25][CH2:26]2)([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[CH:10]=[CH:9]1
Reactant: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CO
Product: N[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Yield: 95.6 %

Procedure:
A mixture of 5.52 g (15.1 mmol) of benzyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-(1-hydroxycyclobutyl)cyclopent-2-ene-1-carboxylate (Preparation SRT-0229), 8.20 g (120 mmol) of hydroxylamine hydrochloride, and 7.0 mL of 50% aqueous hydroxylamine (100 mmol) in 50 mL of methanol was heated at 68 C for 8 h, then cooled. Sufficient water was added to dissolve the crystals which deposited, and the solution was concentrated under reduced pressure to remove methanol. The resulting mixture was brought to pH ˜10 with aq. NaOH and then extracted with several portions of dichloromethane. The organic phase was dried over Na2SO4 and than concentrated under reduced pressure to afford 4.15 g (96%) of the title amine as a nearly colorless oil, of sufficient purity for the subsequent reaction. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42-1.53 (m, 1H) 1.85 (dd, 1H) 1.88-2.08 (m, 4H) 2.19-2.27 (m, 1H) 2.46 (dd, J=14.5, 8.3 Hz, 1H) 3.97-4.02 (m, 1H) 4.70 (s, 1H) 5.16 (s, 2H) 5.84 (dd, J=5.6, 1.6 Hz, 1H) 5.98 (dd, J=5.6, 2.1 Hz, 1H) 7.31-7.38 (m, 5H). LC-MS ES+ 288.2
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=2)=[CH:4][CH:3]=1.[C:26]1([C:32]2[C:33]3[C:38]([C:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]4[C:45]=2[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41]4)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[C:26]1([C:32]2[C:33]3[C:38]([C:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]4[C:45]=2[CH:44]=[C:43]([C:2]2[CH:3]=[CH:4][C:5]([C:8]5[CH:13]=[C:12]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:11]=[C:10]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[CH:9]=5)=[CH:6][CH:7]=2)[CH:42]=[CH:41]4)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: Brc1ccc(-c2cc(-c3ccccc3)nc(-c3ccccc3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2cc(-c3ccc(-c4ccc5c(-c6ccccc6)c6ccccc6c(-c6ccccc6)c5c4)cc3)cc(-c3ccccc3)n2)cc1
Yield: 82.9 %

Procedure:
4-(4-Bromophenyl)-2,6-diphenylpyridine 4.2 g (11 mmol), 9,10-diphenylanthracene-2-boronic acid 4.9 g (13 mmol) and tetrakis(triphenylphosphine)palladium 0.21 g (0.22 mmol) were dissolved in 60 mL of 1,2-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 30 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the solution was filtered, and a solid matter obtained was washed with water, methanol and toluene to obtain 5.8 g (yield: 83%) of a greenish white solid matter. Mass spectral analysis of the above solid matter resulted in confirming that m/e was 635 versus a molecular weight of 635.26 and that it was the aimed compound 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](/[C:32](/[Cl:36])=[CH:33]/[CH2:34]Cl)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:12]3([CH2:13][CH2:14][N:15]([CH2:34]/[CH:33]=[C:32](/[C:29]4[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=4)\[Cl:36])[CH2:16][CH2:17]3)[CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(c1ccnc(Cl)c1)N1CC2(CCNCC2)c2cc(Cl)ccc21
Reactant: ClC/C=C(\Cl)c1ccc(Cl)cc1
Product: O=C(c1ccnc(Cl)c1)N1CC2(CCN(C/C=C(\Cl)c3ccc(Cl)cc3)CC2)c2cc(Cl)ccc21
Yield: 62.5 %

Procedure:
Alkylation of 1-(2-chloropyridin-4-yl)carbonyl-5-chloro-spiro[indolin-3,4′-piperidine] (0.18 g) with 1-chloro-4-((Z)-1,3-dichloro-propenyl)-benzene obtained in step 3 (0.11 g) was carried out following the procedure described in example 101, step 4 to afford 0.17 g of the title compound (64%) as a foam which was characterized by its mass and NMR spectra. MS (ES+) 548.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:20]([O-])=O)=[C:14]([CH:19]=2)[C:15]([NH:17][CH3:18])=[O:16])[CH2:6][CH2:5]1>CO.CO.C(Cl)Cl>[NH2:20][C:13]1[CH:12]=[CH:11][C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16]
Reactant: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1N

Procedure:
A solution of 5-[4-(2-hydroxyethyl)-1-piperazinyl]-N-methyl-2-nitrobenzamide 3 in 250 mL of MeOH in a 250 mL round botton flask was stirred at room temperature under hydrogen balloon over night. The resulted mixture was filtered to get rid of the Pd catalyst. TLC in 10% MeOH/CH2Cl2 showed no more starting material and a major product. The solvent was rotavaped to dryness, and the residue was used without further purification. MS (ES) m/e 279 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.O1CCOCC1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:18]2[CH2:20][CH2:19]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: NC1CC1
Solvent: C1COCCO1
Solvent: CO
Product: Clc1nc(NC2CC2)c2occc2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.7 %

Procedure:
A vial was charged with 2,4-dichlorofuro[3,2-d]pyrimidine (0.50 g, 2.6 mmol, Ark Pharm), TEA (0.369 mL, 2.65 mmol), 1,4-dioxane (20 mL) and cyclopropylamine (0.186 mL, 2.65 mmol). The mixture was stirred at rt for about 5 h and then passed through a 5.0 g SiCO3 SPE cartridge, (MeOH eluent) and concentrated under reduced pressure. The residue was purified by silica gel chromatography with a gradient of 0 to 50% EtOAc/hexanes to give 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (0.5 g, 90%). 1H NMR (CDCl3): δ 7.77 (s, 1H); 6.80 (s, 1H), 5.51 (s, 1H) 3.07 (m, 1H) 0.96 (q, J=5 Hz, 15 Hz, 2H) 0.70, (q, J=5 Hz, 15 Hz, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:1][S:2]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9][CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.56 g, 4.7 mmol) was added to a stirred solution of tert-butyl trans-4-aminocyclohexylcarbamate (J. Org. Chem. 8811, 61, 1996) (1.0 g, 4.7 mmol) and N-ethyl-N-isopropyl-2-propanamine (0.67 g, 0.52 mmol) in dichloromethane (30 ml). The reaction mixture was stirred for 30 min at room temperature and then partitioned between ethyl acetate (300 ml) and water (100 ml). The organic layer was washed twice with 1 molar aqueous citric acid solution and then with a saturated aqueous solution of sodium hydrogen carbonate, dried with anhydrous sodium sulfate and the solvent removed under reduced pressure to give a residue that was triturated with diethyl ether to give the title compound (0.99 g) as a white solid.
Reaction SMILES: [C:1]([CH:9]=[C:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:22][CH2:23][C:24]([OH:26])=[O:25]>>[C:1]([CH2:9][C:10]([S:22][CH2:23][C:24]([OH:26])=[O:25])([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CS
Reactant: CC(=CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Product: CC(CC(=O)c1ccccc1)(SCC(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
As for Example 76, 1-(3-benzoyl-2-methylacryloyl)-L-proline is reacted with mercaptoacetic acid to give the product of the example as a glass.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:14][C:15]([F:22])([F:21])[C:16]([F:20])=[C:17]([F:19])[F:18]>>[F:20][CH:16]([C:15]([F:22])([F:21])[F:14])[C:17]([F:19])([F:18])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: Oc1ccc(-c2ccccc2)cc1
Product: FC(C(F)(F)F)C(F)(F)Oc1ccc(-c2ccccc2)cc1

Procedure:
Analogously, 250 g of 4-hydroxybiphenyl are reacted with hexafluoropropene to give 4-hexafluoropropoxy-biphenyl.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1)[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)c1ccc(OCCCNc2ccc(Cl)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OCCCN(C(C)=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Methyl 4-[3-[N-(4-chlorophenyl)amino]propoxy]benzoate (1.2 g) was dissolved in pyridine (15 ml), and acetic anhydride (0.71 ml) was added thereto. The mixture was stirred at room temperature for 14 hours and concentrated under reduced pressure. The residue was separated into layers by adding ethyl acetate and diluted hydrochloric acid. The organic layer was washed successively with-water, saturated aqueous sodium bicarbonate solution and water, and concentrated under reduced pressure to give the desired product (1.38 g). mp. 68°-69° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:26]([NH:33][C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:6][N:7]=1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Reaction time: 66 h
Yield: 25.2 %

Procedure:
To a solution of [4-(6-aminopyridin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.035 g, 0.12 mmol) in dichloromethane (3 mL) was added benzylisocyanate (0.4 mL, 0.3 mmol). After stirring for 66 h, dichloromethane was removed in vacuo and the residue was diluted with ethyl acetate (20 mL). The organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by preparative thin layer chromatography afforded the title compound as a pale white solid (14.6 mg, 30% yield). 1H NMR (300 MHz, CDCl3) δ 9.61, 8.78, 7.73, 7.58, 7.25, 6.78, 4.59, 3.95, 3.32, 3.13, 2.94. MS (ES+) m/z 484.0 (M+1).