Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([OH:26])[C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:38][CH3:39]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([O:26][CH2:38][CH3:39])[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCI
Reactant: COC(=O)C(O)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(C(=O)OC)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-(4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-hydroxyacetate (50 mg, 0.142 mmol) in Tetrahydrofuran (THF) (1 mL) was treated with LiHMDS (0.213 mL, 0.213 mmol) and iodoethane (0.069 mL, 0.854 mmol) at 0° C. The mixture was stirred at room temperature for 1 hour and then quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate, washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The residue was used crude in the next step without further purification (44 mg, 82%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.47-8.55 (m, 1 H) 7.46-7.55 (m, 2 H) 7.06-7.21 (m, 3 H) 6.85-6.96 (m, 1 H) 4.87-4.98 (m, 1 H) 3.65-3.68 (m, 2 H) 3.66 (s, 3 H) 2.86-3.00 (m, 3 H) 2.42 (s, 3 H) 2.02 (s, 3 H) 1.10-1.24 (m, 3 H). LC/MS (m/z) ES+=380 (M+1).
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[CH3:30][CH:31](O)[CH3:32]>S(=O)(=O)(O)O>[F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH:31]([CH3:32])[CH3:30])=[O:7]
Reactant: CC(C)O
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
2-[2,4-Difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (70 mg, 0.17 mmol, 1.0 eq) was dissolved in iPrOH (5 mL). Concentrated sulphuric acid (2 drops) was added and the solution was stirred at room temperature overnight. The reaction was quenched by addition of aqueous NaHCO3 and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give the crude product. The compound was triturated in a mixture of petroleum ether and DCM and dried under vacuum to give the title compound (II(d)) as a gummy solid (52 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.O=[C:28]([CH3:42])[CH2:29][CH2:30][N:31]1C(=O)C2C(=CC=CC=2)C1=O>>[F:1][C:2]1[CH:26]=[CH:25][C:5]2[O:6][C:7]([CH:19]3[CH2:20][CH2:21][N:22]([CH:28]([CH3:42])[CH2:29][CH2:30][NH2:31])[CH2:23][CH2:24]3)([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)OC(c1ccc(C(F)(F)F)cc1)(C1CCNCC1)O2
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Oc3ccc(F)cc3O2)CC1

Procedure:
Using general procedure B with the above amine (59 mg, 0.16 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (70 mg, 0.32 mmol) and then using general procedure D gave 3-{4-[5-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (35 mg, 51% over 2 steps).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([CH2:9][S:10][CH3:11])[C:5]([F:12])=[C:4]([F:13])[CH:3]=1.[CH3:14][N:15](P(N(C)C)(N(C)C)=O)C.[Cu](C#N)C#N.C(N)CN>O>[NH2:8][C:7]1[C:6]([CH2:9][S:10][CH3:11])=[C:5]([F:12])[C:4]([F:13])=[CH:3][C:2]=1[C:14]#[N:15]
Reactant: CSCc1c(N)c(Br)cc(F)c1F
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: N#C[Cu]C#N
Solvent: NCCN
Solvent: O
Product: CSCc1c(N)c(C#N)cc(F)c1F
Temperature: 150 °C
Yield: 35.4 %

Procedure:
A mixture of 6-bromo-3,4-difluoro-2-methylthiomethylaniline (99 g), HMPA (130 g) and copper cyanide (48 g) is heated at 150° C. for 4 hours. After cooling, the reaction mixture is poured into a solution of ethylenediamine (50 ml) in water (500 ml), and the mixture is heated at 60° C. for one hour. After cooling, the mixture is extracted with ethyl acetate, and the extract is dried over magnesium sulfate and concentrated. The resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:n-hexane=1:1), and the product is recrystallized from ethanol to give 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (28 g), as a white crystal, m.p. 109°-110° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].S>O>[CH2:16]([O:15][C:13]([NH:6][CH2:5][CH2:4][CH2:3][C@@H:2]([C:7]([OH:9])=[O:8])[NH2:1])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCC[C@H](N)C(=O)O
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Dissolve ornithine (13.3 g, 0.1 mol) in 1N sodium hydroxide (200 mL, 0.2 mol). Add a solution of CuSO4.5H2O (12.5 g, 0.05 mol) in water (50 mL). Stir the mixture until solution is complete. Treat with benzyl chloroformate (17.1 g, 0.1 mol) and stir at room temperature until reaction is complete. Suction filter, wash the residue with 1:3.5 methanol-water and dry at 60° C. to give the copper complex. Suspend the copper complex in water, treat with excess hydrogen sulfide, heat to boiling, then cool to room temperature. Mix with 1N sodium hydroxide and filter. Stir the filtrate with a slight excess of 1N hydrochloric acid and filter. Wash the residue with water and dry to give N5 -benzyloxycarbonyl-ornithine.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH2:30]([O:32][CH2:33][CH2:34][NH2:35])[CH3:31].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:30]([O:32][CH2:33][CH2:34][NH:35][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:28])([F:29])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14])[CH3:31]
Reactant: CCOCCN
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC
Yield: 51.4 %

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (60.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-ethoxy-ethylamine (30.0 mg), DPPA (85.0 mg), and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 495; and 1H NMR (CD3OD, 400 MHz): δ 7.96 (1H, d), 7.77-7.75 (2H, m), 7.65 (1H, d), 7.43-7.41 (1H, m), 7.26-7.24 (1H, m), 4.27-4.26 (2H, q), 3.66-3.64 (2H, m), 3.59-3.55 (4H, m), 1.43-1.39 (3H, t), 1.23-1.20 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH:8]=[O:9].[CH2:10]=[O:11].[OH-].[Na+]>CO>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][C:2]2([CH2:10][OH:11])[CH2:8][OH:9]
Reactant: O=CC1CC2C=CC1C2
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCC1(CO)CC2C=CC1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 364 g of 5-norbornene-2-carbaldehyde (which had been synthesized by Diels-Alder reaction of acrolein with cyclopentadiene) and 1500 ml of methanol under ice cooling, 560 g of a 37% formaldehyde aqueous solution was added and then 546 g of a 25% sodium hydroxide aqueous solution was added dropwise over 30 minutes. After the completion of dropwise addition, the ice bath was removed, and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated by distilling off methanol under a reduced pressure. The resulting solid was dissolved in tetrahydrofuran and washed with a sodium hydroxide aqueous solution. The organic layer was concentrated in vacuum, obtaining crude 5-norbornene-2,2-dimethanol. This crude product was combined with 500 ml of tetrahydrofuran and 10 g of 5% palladium on activated carbon as a hydrogenation catalyst. Hydrogenation was carried out under a hydrogen pressure of 1.4 MPa in an autoclave which was maintained at 30-40° C. by occasional placement in a water bath. The reaction mixture was filtered of the catalyst, combined with ethyl acetate, and washed with a saturated potassium carbonate aqueous solution. The organic layer was dried over sodium sulfate and concentrated in vacuum, obtaining 435 g (yield 94%) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1I.C([Mg]Cl)(C)C.CN([CH:19]=[O:20])C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[CH:19]=[O:20]
Reactant: Fc1cc(Br)c(I)c(Br)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Product: O=Cc1c(Br)cc(F)cc1Br
Temperature: -19 °C
Reaction time: 1.5 h
Yield: 53.7 %

Procedure:
A solution of 1,3-dibromo-5-fluoro-2-iodobenzene (50 g, 132 mmol) in anhydrous toluene (300 mL) cooled to −35° C. was added the solution of isopropylmagnesium chloride (84 mL, 171 mmol, 2.0 M in diethyl ether) over a period of 30 minutes while maintaining the internal temperature below −25° C. A clear brown solution was obtained. Stirring was continued for 1.5 h. Then anhydrous DMF (34 mL, 436 mmol) was added over a period of 30 minutes. The temperature of the reaction mixture increased to −19° C. The reaction mixture was warmed to 10° C. (room temperature) over 1 h and stirred at this temperature for 1.5 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL), filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography (eluting with petroleum ether/ethyl acetate: from 50:1 to 20:1) to give 102a (20 g, yield 54%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]#[N:15]>>[C:1]1([C:7]2[N:11]([CH2:13][C:14]#[N:15])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: N#CCBr
Product: N#CCn1ccnc1-c1ccccc1

Procedure:
The title compound is synthesized by coupling of 2-Phenyl-1H-imidazole and bromoacetonitrile analogously to the preparation of Intermediate 269.4 as a colorless oil; ES-MS: M+H=184.1: CtRef=3.48.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10](Cl)=[O:11])(=[O:4])=[O:3].[CH3:13][OH:14].Cl>C(Cl)(Cl)Cl>[CH3:13][O:14][C:10]([C:6]1[S:7][CH:8]=[CH:9][C:5]=1[S:2]([Cl:1])(=[O:4])=[O:3])=[O:11]
Reactant: O=C(Cl)c1sccc1S(=O)(=O)Cl
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sccc1S(=O)(=O)Cl

Procedure:
48 G. (0.196 mol) of the obtained 3-chlorosulfonylthiophene-2-carboxylic acid chloride are dissolved in 500 ml. of absolute chloroform, 9.6 g. (0.3 mol) of absolute methanol are added and the mixture is heated to reflux for 3 hours [until no more hydrogen chloride evolution]. The mixture is evaporated to dryness in vacuo and the residue allowed to crystallize. There is obtained pure 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH+:9]([O-])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:3][CH:2]=1.C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:22]([C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][N:1]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)[NH+]([O-])CCc1ccncc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCCc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.1 %

Procedure:
tert-Butyl 2-(4-pyridyl)ethylcarbamate N-oxide (7.4 g, 31 mmol) was dissolved in nitroethane (100 ml), and trimethylsilyl cyanide (9.2 g, 92 mmol) and N,N-dimethylcarbamoyl chloride (6.7 g, 62 mmol) were added thereto. The mixture was stirred at room temperature for 10 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (6.6 g, 86%)
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@@H:8]([CH2:10][CH3:11])[NH2:9].Cl[C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[N+:20]([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>CC(O)C>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:9][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([OH:19])[C:14]=1[N+:20]([O-:22])=[O:21])[CH2:10][CH3:11]
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Reactant: CC[C@@H](N)Cc1sccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC[C@H](Cc1sccc1Cl)Nc1ccnc(O)c1[N+](=O)[O-]
Reaction time: 7 h

Procedure:
To a 3-neck 1 liter round bottom flask fitted with a mechanical stirrer, thermocouple, nitrogen inlet and a condenser is sequentially charged: 14.5 g of (R)-3-chloro-a-ethyl-2-thiopheneethanamine (Compound III), 10.9 grams of 4-chloro-3-nitropyridin-2(1H)-one (Compound II), 35 grams of 2-propanol (IPA) and 25 mL of N,N-diisopropylethylamine (DIPEA). The mixture is stirred at 70° C.±2° C. for 7 hours before the reaction is allowed to cool overnight to room temperature (22° C±3° C.). The mixture is concentrated to 41. 4 g. of a syrup which is subsequently dissolved in 425 ml of ethyl acetate. This solution is washed with 125 mL of water, 2×50 mL of 5N ammonium chloride solution and 2×50 mL of saturated sodium chloride solution before drying over sodium sulfate. The solution is filtered, concentrated, and the resulting solid collected by filtration to give Compound IV, m.p. 150-152° C. Mass Spec. (EI), m/z 328 (6%), 1HNMR (500 Mhz, DMSO) δ 0.91 (3H, t); 1.8-1.6 (2H, m); 3.1 (1H, m); 3.95 (1H, m); 5.9 (1H, d); 7.0 (1H, d); 7.3 (1H, dd); 7.5 (1H, d); 8.8 (1H, d); 11.1 (1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH:7]([O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxy-N-tert-butoxycarbonyl-proline methyl ester (5.89 g, 24 mmol) and triethylamine (4 mL, 28.8 mmol) in dichloromethane (80 mL) was cooled to 0° C. and treated with methylsulfonyl chloride (2.1 mL). After stirring an additional 2 h, the reaction mixture was acidified with 2% HCl (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed successively with sat. aq NaHCO3, and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (5% ethyl acetate in heptane) gave 4-methylsulfonyloxy-N-tert-butoxycarbonyl-proline methyl ester. 1H NMR (CDCl3), 5.25 (m, 1H), 4.41 (m, 1H), 3.78 (m, 5H), 3.06 (s, 3H), 2.61 (m, 1H), 2.22 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])=[C:4]([N+]([O-])=O)[CH:3]=1.[CH3:21][O-:22].[Na+].CO>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])=[C:4]([O:22][CH3:21])[CH:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 4,4′-dibromo-2,2′-dinitro-biphenyl (6.58 g, 16.5 mmol) in DMF (50 ml) at 0° C. was added a solution of sodium methoxide in Methanol (4.4 M, 4.5 ml, 19.8 mmol). The mixture was stirred at 25° C. for 12 hours and was poured into ice-water (140 ml). The mixture was extracted with EtOAc (2×). The combined organic phase was washed with water and brine and dried with Na2SO4. Concentration under reduced pressure gave pale solid. The re-crystallization from CH3CN/MeOH gave 4,4′-dibromo-2-methoxy-2′-nitro-biphenyl as a white solid (3.76 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[O:11][C@H:10]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[C:32]1[NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:45]([OH:55])[CH:44]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:63][CH2:64][CH2:65][Cl:66]>CN(C)C=O>[Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[C@@H:12]([CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26])[O:11][C@H:10]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[C:32]1[NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[C:45]([O:55][CH2:63][CH2:64][CH2:65][Cl:66])[CH:44]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)c(O)c3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)c(OCCCCl)c3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 42 h

Procedure:
To a solution of 2′,3′,5′-tris-O-(tert-butyl-dimethylsilyl)-8-(2-hydroxybiphenyl-4-ylmethylamino)-adenosine (0.85 g) in N,N-dimethylformamide (5.3 mL) was added potassium carbonate (0.44 g). Then 1-bromo-3-chloropropane (0.16 mL) was added, and the resulting mixture was stirred at 40° C. for 42 hours. The reaction mixture was partitioned between diethyl ether (45 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2), and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.91 g).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].I[CH3:27]>CN(C)P(=O)(N(C)C)N(C)C>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH3:27])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 62.3 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt in 28.4 parts of iodomethane is stirred and heated to 100° C. After cooling to 10° C, there are added dropwise 340 parts of hexamethylphosphoric triamide (slightly exothermic reaction). Upon completion, stirring is continued for 24 hours at room temperature. The reaction mixture is poured onto water (800 parts) and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue solidifies on triturating in 2,2'-oxybispropane. The product is filtered off and crystallized from 2,2'-oxybispropane, yielding methyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 94.9° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:28][C:29]1[CH:50]=[CH:49][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:37]([F:48])[CH:36]=2)=[CH:31][CH:30]=1.Cl>CN(C)C=O>[F:48][C:37]1[CH:36]=[C:35]([O:34][CH2:33][C:32]2[CH:49]=[CH:50][C:29]([CH2:28][N:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)[N:14]=3)=[CH:30][CH:31]=2)[CH:40]=[CH:39][C:38]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Reactant: FC(F)(F)c1ccc(-c2csc(NCCc3ccccc3)n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2-phenylethyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (500 mg, 1.43 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (50 mg, in oil, 1.3 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (350 mg, 1.0 mmol) was added, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-3:2 in volume ratio) to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:17][C:18]([F:34])([F:33])[C:19]([C:29](F)(F)[F:30])=[C:20](F)[C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23]>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[C:29]([F:30])=[C:19]([C:18]([F:34])([F:33])[F:17])[C:20]([C:21]([F:26])([F:27])[C:22]([F:23])([F:24])[F:25])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1Cl
Reactant: FC(=C(C(F)(F)F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1.0 g (7.0 mmol) of 3-chloro-2-hydrazinopyridine is suspended in 2.9 ml (21 mmol) of triethylamine and 40.0 ml of acetonitrile and, at −65° C., added to 2.1 g (7 mmol) of (1,1,1,3,4,4,5,5,5-nonafluoro-2-(trifluoromethyl)pent-2-ene. The reaction mixture is slowly heated to room temperature and then stirred at room temperature for 60 hours. The solid is filtered off and afterwashed with diethyl ether. The solvent is removed under reduced pressure on a rotary evaporator. The product is extracted from the residue three times with cyclohexane. The organic phases are combined and the solvent is removed under reduced pressure on a rotary evaporator. This gives 1.95 g of 3-chloro-2-[5-fluoro-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine (73%) as an orange oil.