Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH:4]1CCO[CH:5]1OC.[CH3:13][C:14]([O:16][C:17]([CH3:19])=O)=[O:15].[CH3:20][O:21][C:22](=[O:26])[CH2:23][C:24]#[N:25]>[Cl-].[Cl-].[Zn+2]>[CH3:20][O:21][C:22](=[O:26])[C:23]([C:24]#[N:25])=[CH:5][C:4]([CH2:19][CH2:17][O:16][C:14](=[O:15])[CH3:13])=[CH:3][O:2][CH3:1]
Reactant: COC(=O)CC#N
Reactant: CC(=O)OC(C)=O
Reactant: COC(OC)C1CCOC1OC
Agent: [Cl-]
Agent: [Zn+2]
Product: COC=C(C=C(C#N)C(=O)OC)CCOC(C)=O
Temperature: 110 °C
Reaction time: 16 h

Procedure:
Into a dried 3L three neck-round bottom flask with a stirrer bar, nitrogen-inlet, thermocouple and a addition funnel were charged 150 g (851.26 mmol) 3-(dimethoxymethyl)-2-methoxyoxolane, 355.27 g (3.48 mol) Ac2O and 2.12 g (15.55 mmol) ZnCl2 and the mixture was heated for 1.25-1.5 h at 100-120° C. to reflux. The solution started to become brown and a small portion of solvent was distilled off at atmospheric pressure. To the reaction mixture 76.7 g (774 mmol) methylcyanacetate was slowly added over 1 h while continuing to distill off solvent. After the addition was completed, the reaction mixture was evacuated and the residual solvent was distilled off. The residue was treated with 224 g MeOH and again evacuated and the solvent was distilled off. The residual black oil was charged with 500 ml CH2Cl2 and washed twice with 500 ml water. The solvent was distilled off under reduced pressure and the residue was treated with a mixture of 350 ml MTBE and 285 ml heptane. The reaction mixture was heated to reflux at 55-60° C. for 1½ h, then cooled down to 0° C. and kept at 0° C. for 16 h. The crystals were filtered off and three times washed with cold 250 ml MTBE.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][C:7]=2[O:6]1.C(C1C=CC=CC=1C=C)=C>CCOCC>[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10][Cl:3])=[CH:8][C:7]=2[O:6]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: O=S(Cl)Cl
Agent: C=Cc1ccccc1C=C
Solvent: CCOCC
Product: ClCc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
15.04 ml of thionyl chloride are added dropwise, at 0° C., over the space of 25 min and under argon, to 10.82 g of 3,4-methylenedioxybenzyl alcohol (Fluka, Buchs, Switzerland) and 48 g of diisopropylaminomethylpolystyrene (polyhunig base: polystyrene crosslinked with 2% divinylbenzene, diisopropylaminomethylated; Fluka, Buchs, Switzerland) in 200 ml of abs. ether. After having been stirred at 0° C. for a further 1.5 h, the mixture is filtered with suction and the filtrate is concentrated on a RE and then under HV. The residue is purified by chromatography on silica gel (eluent: C), and the title compound thus obtained. TLC Rf (hexane:ethyl acetate, 4:1)=0.47; 1H-NMR (200 MHz, CDCl3): 6.95-6.7(m, 3H), 5.97(s, 2H), 4.53(s, 2H).
Reaction SMILES: Br[CH:2]1[CH2:7][O:6][CH2:5][CH2:4][O:3]1.[C:8]([O:11][C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=1)(=[O:10])[CH3:9].C(=O)(O)[O-].[Na+].[CH2:32]1[CH2:36]O[CH2:34][CH2:33]1>O>[C:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[O:3][C:4]3[CH:36]=[CH:32][CH:33]=[CH:34][C:5]=3[O:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: BrC1COCCO1
Reactant: CC(=O)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1ccc(C2=COc3ccccc3O2)cc1
Temperature: 110 °C
Yield: 62 %

Procedure:
To a solution of 1,4-benzodioxane (5 g, 36.72 mmol) in CCl4 (200 mL), NBS (14.38 g, 80.79 mmol) and AIBN (500 mg) were added under N2. The mixture was heated at reflux for 12 h. The reaction mixture was cooled to rt. The solution was evaporated to give the crude product, which was purified by chromatography on neutral Al2O3 using 10% EtOAc in hexane to give the di-bromo compound (9.34 g, 86%). To a stirred solution of 2,3-dibromo-2,3-dihydro-1,4-benzodioxine (9.84 g, 33.45 mmol) in Et2O (150 mL), was added potassium t-butoxide (4.5 g, 40.14 mmol) under N2. The mixture was stirred for 3 h at rt. The solid was filtered off and the solution was concentrated to give the crude product, which purified by chromatography on neutral Al2O3 using 10% EtOAc in hexane to give 2-bromodioxane (6.8 g, 95%). To a mixture of 2-bromodioxane (1.0 g, 4.69 mmol), 4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)phenyl acetate (1.23 g, 4.69 mmol), sodium bicarbonate (1.18 g, 14.07 mmol), THF (50 mL) and water (7 mL) was added tetrakis-triphenyl phosphine palladium (271 mg, 0.23 mmol) under N2. The reaction mixture was heated to 110° C. for 5 h and then cooled to rt. Water was added and the mixture was extracted with EtOAc. The organic layer was separated, washed with water, brine, dried and concentrated to give crude product, which was purified by column chromatography, using 20% EtOAc in hexane to give 775 mg of 4-(benzo[b][1,4]dioxin-2-yl)phenyl acetate (62%). MS (ES) m/z: 269.92 (M+1), 268.91 (M); Mp. 123-125° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH:13]=[O:14])[CH:10]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](O)[CH2:30][OH:31].CC1C=CC(S(O)(=O)=[O:41])=CC=1.O>C1C=CC=CC=1.CCOCC>[CH2:1]([N:8]1[CH2:12][CH:11]([CH:13]2[O:31][CH2:30][CH2:29][O:14]2)[CH:10]([C:15]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:20][CH2:21]2)=[O:41])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Reactant: O=CC1CN(Cc2ccccc2)CC1CN1CCC(c2ccc(F)cc2)CC1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: O=C(C1CN(Cc2ccccc2)CC1C1OCCO1)N1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 0.046 g (0.104 mmol) of 1-benzyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidine, 0.058 mL (1.04 mmol) of ethyleneglycol and 0.047 g (0.25 mmol) of TsOH.H2O in 5 mL of benzene was heated at reflux for 2 h. The reaction mixture was cooled to rt and diluted with ether. The reaction mixture was washed twice with sat'd NaHCO3 solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, MeOH:CH2Cl2, 5:95) to give the title compound.
Reaction SMILES: [Br:1][CH2:2][C@H:3]([CH3:6])[CH2:4][OH:5].[C:7](OC(=O)C)(=[O:9])[CH3:8].O.C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([O:5][CH2:4][C@@H:3]([CH3:6])[CH2:2][Br:1])(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CO)CBr
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC[C@@H](C)CBr
Temperature: 70 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
6 g of (R)-(−)-3-bromo-2-methyl-1-propanol (39.2 mmol) were stirred in 6 ml of pyridine at room temperature. 4.08 g of acetic anhydride (43.1 mmol) were added and the reaction mixture was stirred for 4 h at 70° C. Stirring was continued for 16 h at room temperature. 40 ml of water and 60 ml of ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with a further portion of water, then dried over magnesium sulfate, filtered, and evaporated under vacuum, whereby 6.03 g of the title compound were obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[Mg].[CH:15]([C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=1)([CH3:17])[CH3:16].Cl[P:30](Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[P:37](Cl)Cl>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]([P:30]([C:6]2[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[P:37]([C:6]2[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)[C:20]2[CH:19]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[CH:21]=2)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc([Mg]Br)cc(C(C)C)c1
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1
Reactant: ClP(Cl)c1ccccc1P(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)cc(P(c2cc(C(C)C)cc(C(C)C)c2)c2ccccc2P(c2cc(C(C)C)cc(C(C)C)c2)c2cc(C(C)C)cc(C(C)C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
3,5-Diisopropylbromobenzene (3.04 g, 12.60 mmol) was added dropwise to magnesium (0.48 g, 19.75 mmol) and THF (7 mL) in an argon atmosphere. After the dropwise addition, the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to ambient temperature and filtered, and the thus-obtained THF solution of 3,5-diisopropylphenylmagnesium bromide, and 1,2-bis(dichlorophosphino)benzene (0.45 g, 1.61 mmol) were reacted as in Production Example 1. The reaction was allowed to proceed overnight at 60° C. After purification, the title compound was obtained as a yellow oily substance (1.18 g, yield 74%).
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH:14]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12]2)(=[O:7])[CH3:6].S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[C:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:13][CH2:12]2)(=[O:7])[CH3:6]
Reactant: COC(=O)CC1CCc2cc(NC(C)=O)ccc2C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC1=Cc2ccc(NC(C)=O)cc2CC1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
Sodium borohydride (72.4 mg, 1.91 mmol) was added to a methanol solution (10 ml) of methyl [6-(acetylamino)-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl]acetate (527 mg, 1.91 mmol) obtained in Reference Example 100 under ice-cooling, which was stirred for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by alumina B column chromatography (development solvent; ethyl acetate). Concentrated sulfuric acid (0.14 ml) was added to an acetic acid solution (7 ml) of the oil (404 mg, 1.46 mmol), which was stirred at 40° C. for 5 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:1), to give the titled compound (251 mg).
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:14]([O:16][C:17](=[O:24])[CH:18]([OH:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH3:15].O>CN(C=O)C.C(OCC)C>[Si:10]([O:23][CH:18]([CH2:19][CH2:20][CH2:21][CH3:22])[C:17]([O:16][CH2:14][CH3:15])=[O:24])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CCCCC(O)C(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Reaction time: 18 h
Yield: 96.7 %

Procedure:
Imidazole (4.10 g, 60.22 mmol) and TBDMSCl (3.60 g, 23.89 mmol) was added to a stirred solution of 2-hydroxy-hexanoic acid ethyl ester (3.20 g, 19.97 mmol) in DMF (25 mL). The reaction mixture was kept at ambient temperature for 18 hrs. Water and diethyl ether were added and the two phases were separated. The aqueous phase was extracted with diethyl ether. The organic extracts were combined and washed sequentially with 0.5 M HCl and water, dried over MgSO4 and concentrated in vacuo to give the title product (5.30 g), 1H NMR (300 MHz, CDCl3) δ 4.18 (m, 3H), 1.69 (m, 2H), 1.35 (m, 4H), 1.28 (t, 3H), 0.91 (m, 12H), 0.07 (d, 6H).
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:32]=[CH:31][C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][C:22]=3[CH2:29][CH3:30])=[N:10][CH2:11][C:12]3[N:13]([C:14]([CH:17](Cl)[CH2:18][CH3:19])=[N:15][N:16]=3)[C:7]=2[CH:6]=1)[CH2:2][CH3:3].[CH3:33][NH:34][CH3:35].[I-].[Na+]>>[CH3:33][N:34]([CH3:35])[CH:17]([C:14]1[N:13]2[C:7]3[CH:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[CH:32]=[CH:31][C:8]=3[C:9]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][C:22]=3[CH2:29][CH3:30])=[N:10][CH2:11][C:12]2=[N:16][N:15]=1)[CH2:18][CH3:19]
Reactant: CNC
Reactant: CCCSc1ccc2c(c1)-n1c(nnc1C(Cl)CC)CN=C2c1ccc(CC)cc1CC
Agent: [I-]
Agent: [Na+]
Product: CCCSc1ccc2c(c1)-n1c(nnc1C(CC)N(C)C)CN=C2c1ccc(CC)cc1CC

Procedure:
In the manner given in Example 1, 9-(propylthio)-1-(α-chloropropyl)-6-(2,4-diethylphenyl)-4H-s-triazolo[4,3-a]-[1,4]-benzodiazepine was reacted with dimethylamine in the presence of sodium iodide to give 1-[α-(dimethylamino)propyl]-9-(propylthio)-6-(2,4-diethylphenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.O.[BrH:16].[Br:17]Br>C([O-])(C)(C)C.N1C=CC=CC=1>[Br:16][C:10]1([Br:17])[C:9]2[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3][C:2]1=[O:1]
Reactant: COC(=O)c1cccc2c1CC(=O)N2
Reactant: Br
Reactant: BrBr
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cccc2c1C(Br)(Br)C(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
2,3-Dihydro-2-oxo-1H-indole-4-carboxylic acid, methyl ester, (C. A. Grob and 0. Weissbach, Hely. Chim. Acta, vol. 44, p. 1736, 1961) (2 g, 11.4 mmol) was dissolved in t-butylhydroxide (120 mL) containing 0.5 mL of water. Pyridine.hydrogen bromide.bromine (14.6 g, 45.7 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction was quenched by the addition of water and the t-butylhydroxide was distilled off. The resulting residue was partitioned between water and ethyl acetate, and the ethyl acetate was dried with magnesium sulfate, filtered and concentrated in vacuo to yield the title compound (3.92 g, 98%).
Reaction SMILES: CN1CCCCC1.Cl.[C:9]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH:16]([CH3:26])[CH2:17][NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21])=[CH:13][CH:12]=1)#[N:10].Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>C(Cl)Cl>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:26])[CH2:17][NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH:21][C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:31])=[CH:27][CH:28]=1)#[N:10]
Reactant: CC(CNC(=O)[C@@H](N)C(C)C)Oc1ccc(C#N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CC(CNC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C)Oc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
0.16 g of N-methylpiperidine was added to a suspension containing 0.25 g of N1 -[2-(4-cyanophenoxy)propyl]-L-valinamide hydrochloride suspended in 20 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.13 g of phenyl chloroformate was added drop by drop to the mixture, and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 3 hours at room temperature. After the methylene chloride was removed under reduced pressure, the residue was purified by column chromatography on silica gel, thus obtaining 0.2 g of the desired product in the form of a white glutinous substance (yield: 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:27][CH2:28][CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[C:9]2[CH:10]=[CH:11][C:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([CH:18]=2)[C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:27][CH2:28][CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[C:9]2[CH:10]=[CH:11][C:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[C:13]([CH:18]=2)[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(NCCn2ccnc2)c2ccc(F)cc2)ccc1Cc1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(C(NCCn2ccnc2)c2ccc(F)cc2)ccc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of methyl 5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylaminomethyl]-2-(4-fluorobenzyl)benzoate (1.5 g) sodium hydroxide (0.65 g), water (10 ml) and methanol (50 ml) was stirred under an inert atmosphere at ambient temperature for 2 hours. It was then acidified to pH 4-5 with 1M citric acid and evaporated to dryness. The residue was partitioned between ethyl acetate and water, the organic layer separated, treated with saturated brine, dried and evaporated to dryness to give 5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethylaminomethyl]-2-(4-fluorobenzyl)benzoic acid as a white foam (1.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>CN(C=O)C.C1COCC1.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>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:12]=[CH2:13])=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 1324.9 %

Procedure:
2 g of 5-bromo-2-(trifluoromethyl)pyridine was dissolved in DMF:THF (3:1, 12 mL). vinyltributyltin (3 g) and tetrakis(triphenylphosphine)palladium (135 mg) were added to this solution. The reaction mixture was degassed and purged with nitrogen for 5 min and then heated at 100° C. for 2 h. at which point the reaction was found complete (monitored by TLC). The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure (Caution: product may be volatile) and the residue was purified by SiO2 chromatography (100-200 mesh, eluent: hexane-ethyl acetate gradient). The requisite fractions were concentrated below 40° C. under reduced pressure to obtain 20.3 g of 2-(trifluoromethyl)-5-vinylpyridine as oil.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5].[Cl:21][CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O)(=O)C>C(O)C>[Cl:21][CH2:22][CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]2[N:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[C:4](=[O:5])[C:3]3[C:2](=[C:18]([O:19][CH3:20])[CH:17]=[CH:16][CH:15]=3)[NH:1]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(NC(=O)c2cccc(OC)c2N)cc1
Reactant: O=Cc1ccc(OCCCl)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(N2C(=O)c3cccc(OC)c3NC2c2ccc(OCCCl)cc2)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a solution of 20.05 g (0.0736 mol) of 2-amino-N-(4-methoxy-phenyl)-3-methoxy-benzamide in 400 mL of ethanol was added 13.6 g (0.0736 mol) of p-(2-chloro-ethoxy)-benzaldehyde (Frinton Labs), and 10 mL of acetic acid. The reaction mixture was stirred and heated to a mild reflux overnight. After cooling to room temperature, the solvent was evaporated in a rotary evaporator. The residue was dissolved in 300 mL of ethyl acetate and washed with water (4×100 mL). The organic phase was removed, dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The residual oil was placed under the vacuum pump, which yielded 26.0 g (mp 122-124° C.) of product.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH2:10]([C:12]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[NH:14][N:13]=1)[CH3:11]>>[CH2:10]([C:12]1[C:16]([N+:6]([O-:9])=[O:7])=[C:15]([C:17]([OH:19])=[O:18])[NH:14][N:13]=1)[CH3:11]
Reactant: CCc1cc(C(=O)O)[nH]n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
Fuming sulphuric acid (17.8 ml) was added dropwise to stirred, ice-cooled fuming nitric acid (16.0 ml), the resulting solution heated to 50° C., 3-ethyl-1H-pyrazole-5-carboxylic acid added portionwise over 30 minutes whilst maintaining the reaction temperature below 60° C. The resulting solution was heated for 18 hours at 60° C., allowed to cool, then poured onto ice. The title compound was obtained as a brown solid (64%). δ (DMSOd6): 1.18 (3H,t), 2.84 (2H,m), 13.72 (1H,s).
Reaction SMILES: CC1C=CC(S(N[C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37](=[O:41])[C:38]([OH:40])=[O:39])([O-:29])=[O:28].C(N(CC)CC)C.C(O)=O>C(N(CC)CC)C.CO>[OH:41][C@H:37]([CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N+:27]([O-:29])=[O:28])[C:38]([OH:40])=[O:39]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)[C@H](O)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 133.2 %

Procedure:
Into 120 ml of methanol were dissolved 293 mg (0.5 mmol) of [RuCl2(p-cymene)]2 and 360 mg (1.0 mmol) of (1R,2R)—N-tosyl-diphenylethylenediamine (hereinafter referred to as (R,R)-TsDPEN) to prepare a solution, and 0.27 ml (2.0 mmol) of triethylamine was dropwise added to the solution, followed by stirring for 0.5 hour at room temperature. To the reaction solution was dropwise added a solution prepared by dissolving 20 g (96 mmol) of o-nitrophenyl pyruvic acid into 80 ml of methanol, and 38.7 g (383 mmol) of triethylamine was furthermore dropwise added thereto. The bath was heated up to a temperature of 40° C., and then 13.2 g (278 mmol) of formic acid was dropwise added over 1 hour, followed by stirring for 2 hours at a bath temperature of 40° C. Upon completion of the reaction, the solvent was distilled off under reduced pressure. Thereto was added 40 ml of water, and then 22.6 g of concentrated hydrochloric acid was gradually dropwise added under ice cooling; thus, pH of the solution was adjusted to 2. Extraction was performed twice with 200 ml of ethyl acetate, and then the organic layer was washed with 20 ml of a saturated aqueous solution of sodium chloride, followed by concentration under reduced pressure. As a result, 27.0 g (yield 97%, 97% ee) of (2R)-hydroxy-3-(o-nitrophenyl)propanoic acid was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:2].C(O[CH2:23][N:24]([CH2:32][Si](C)(C)C)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCCC.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C@H:5]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:32][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23]1)=[O:16])[CH3:2]
Reactant: CCCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C=CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 2 g of 4-tert-butoxycarbonylamino-but-2-enoic acid ethyl ester (8.72 mmol) and 5.12 g N-[(pentyloxy)methyl]-N-[(trimethylsilyl)methyl]-benzene-methanamine (17.4 mmol) in 50 ml dichloromethane was added 10 micro-l. trifluoroacetic acid. The reaction was monitored by TLC. The reaction was complete after 10 min. The mixture was diluted with dichloromethane, washed with sat. sodium bicarbonate solution and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by filtration over a short silica column, using a 7/3 hexane/ethyl acetate mixture as eluent.