Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([C:11]([CH3:21])([CH3:20])[C:12](O)([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:5]([O:6]C)[CH:4]=1.[K].CI.COC1C=C(C(C)(C)C(C)=CCCCC)C=C(OC)C=1>CCOCC.C(=S)=S>[CH3:21][C:11]([C:9]1[CH:10]=[C:3]([OH:2])[CH:4]=[C:5]([CH:8]=1)[OH:6])([CH3:20])[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC(C)(O)C(C)(C)c1cc(OC)cc(OC)c1
Agent: CCCCC=C(C)C(C)(C)c1cc(OC)cc(OC)c1
Agent: [K]
Solvent: S=C=S
Solvent: CCOCC
Solvent: CI
Product: CCCCCC(C)C(C)(C)c1cc(O)cc(O)c1
Reaction time: 0.5 h

Procedure:
To 0.2 mol. of methyl magnesium bromide (2N in tetrahydrofuran-benzene), under nitrogen, is added 55.6 g. of 2-(3,5-dimethoxyphenyl)-2-methyloct-3-one [J. Amer. Chem. Soc. 70:664 (1948); Helv. Chim. Acta 52:116 (1969)] in tetrahydrofuran. After refluxing for 12 hours the mixture is quenched with saturated aqueous ammonium chloride and extracted with ether. The extracts are washed with water, dried (MgSO4) and the solvent is removed to give 5-(2-hydroxy-1,1,2-trimethylheptyl)resorcinol dimethyl ether as an oil. A solution of 5.9 g. of the carbinol in ether is allowed to react over a six hour period with a suspension of 0.8 g. of metallic potassium in 60 ml. of ether. Carbon disulfide (1.5 g.) is added and the mixture is stirred for 30 minutes, then 2.8 g. of methyl iodide is added and the reaction mixture is refluxed for six hours and left at 25° for 12 hours. The mixture is filtered and the filtrate is concentrated and distilled in vacuo. The distillate is dissolved in ethanol, refluxed with Raney nickel and redistilled to give a mixture of 5-(1,1,2-trimethylhept-2-enyl)resorcinol dimethyl ether and 5-(1,1-dimethyl-2-methylenylheptyl)resorcinol dimethyl ether. Removal of the protective groups and hydrogenation is accomplished as described in Example 8 to give 5-(1,1,2-trimethylheptyl)resorcinol.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10]>>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([Cl:3])=[O:10]
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Cl)cc1C
Yield: 94.4 %

Procedure:
78 g of thionyl chloride were added to 50 g of 3,4-dimethylbenzoic acid and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was subsequently concentrated, and the residue was taken up twice in toluene and concentrated again. 53 g of 3,4-dimethylbenzoyl chloride were obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](NN)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[Br:20]Br>CCCCCC>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([Br:20])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: NNS(=O)(=O)c1cccc2cccnc12
Reactant: BrBr
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Br)c1cccc2cccnc12
Yield: 749.2 %

Procedure:
A 500 ml, single-neck flask equipped with a magnetic stirrer is charged with 6.59 g (0.0295 mol) of 8-quinolinesulfonyl hydrazine and 200 ml of chloroform. Crushed ice is added, and the slurry is vigorously stirred. 9.50 g of bromine is added dropwise to the slurry with stirring. After the addition of bromine is complete and all of the bromine color has disappeared, the layers are separated. The chloroform layer is dried over anhydrous magnesium sulfate, and the chloroform is removed in vacuo leaving a pale yellow solid. The solid is slurried with hexane, filtered, and vacuum dried to give 6.00 g (0.221 mol) of 8-quinolinesulfonyl bromide m.p. 142°-144° C.
Reaction SMILES: O[C:2]1([CH2:13][CH2:14][CH2:15][OH:16])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CC([O-])(C)C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C1COCC1>[C:9]([O:8][C:6]([N:4]1[CH2:3][C:2]2([O:16][CH2:15][CH2:14][CH2:13]2)[CH2:5]1)=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(O)(CCCO)C1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(CCCO2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(3-hydroxypropyl)azetidine-1-carboxylate (27 mg, 0.13 mmol) in THF (2 ml) was added in rapid succession, KOtBu (31 mg, 0.27 mmol) and p-toluenesulfonylchloride (25 mg, 0.13 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was used crude in the next step.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1C1C=CC=CC=1.Br[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[N:32]=1.IC1C=CC=CC=1>>[CH3:38][O:37][C:33]1[N:32]=[C:31]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cccc(Br)n1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: COc1cccc(-n2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cc2=O)n1

Procedure:
4-[3-(6'-Methoxy-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-bromo-6-methoxypyridine for the iodobenzene in Step 3.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([I:15])=[N:6]1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CN(C)C=O>[I:15][C:7]1[C:8]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:14])[N:5]([CH2:4][CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:6]=1
Reactant: C1COCCN1
Reactant: Nc1ncnc2c1c(I)nn2CCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1c(I)nn2CCCN1CCOCC1
Temperature: 70 °C
Reaction time: 66.25 h
Yield: 48 %

Procedure:
A suspension of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.31 mmol) in dimethylformamide (10 mL) was treated with morpholine (0.137 g, 1.572 mmol) and triethylamine (0.133 g, 1.31 mmol). The reaction mixture was stirred at 70° C. for 66.25 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and 1 N hydrochloric acid (20 mL) were added. The layers were partitioned and the aqueous layer was washed with dichloromethane (100 mL). The aqueous layer was neutralized to pH 14 and then extracted with dichloromethane (250 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient of 10% methanol in dichloromethane to 50% methanol in dichloromethane over 58 minutes on a 35 g ISCO column. The column afforded 0.244 g (48%) of pure 3-iodo-1-(3-morpholinopropyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.194 (s, 1H), 4.327-4.293 (t, 2H), 3.485-3.364 (m, 4H), 2.253-2.238 (m, 6H), 1.963-1.895(m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) R, 0.71 min (100%), MH+ 389.0.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:15])[CH3:14])[CH:8]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C1COCC1>[CH:13]([C:9]1[CH:8]=[C:7]([B:20]([OH:21])[OH:19])[CH:12]=[CH:11][CH:10]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1cccc(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
n-BuLi (7.7 mL, 14.0 mmol) was added dropwise to a stirred solution of 1-bromo-3-isopropyl-benzene (2.4 g, 12.1 mmol) in dry THF (40 mL) over 30 min at −70° C. under nitrogen. The reaction mixture was degassed for 15 min, and triisopropylborate (2.63 g, 14.0 mmol) was added at the same temperature. The reaction mixture was gradually warmed to 0° C. during 90 min and stirred for an additional 30 min at 0° C. The reaction mixture was then cooled to −20° C., and an aqueous solution of 2N HCl (20 mL) was added slowly. THF was distilled off and the reaction mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over Na2SO4, and concentrated in vacuo to obtain the crude product (1.85 g, 93.5%), which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:10]([CH3:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:20]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
In a flask equipped with a Dean-stark trap was prepared a solution of 1-(4-Methoxy-phenyl)-propan-2-one (40 g), ethyl cyanoacetate (27.56 g), ammonium acetate (9.40 g), acetic acid (14.64 g) and toluene (150 ml) at room temperature. The solution was heated to reflux overnight. The solution was cooled to room temperature, washed with water and brine, and concentrated. The crude product was purified on a silica gel column, eluting with 10% ethyl acetate/hexane to afford colorless oil (40.76 g). The 1H NMR was consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:4]=[N:3][CH:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:5]4[CH:4]=[N:3][CH:2]=[N:1][CH:6]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1cncnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cncnc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl pyrimidin-5-ylcarbamate (100 mg, 0.369 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (87.4 mg, 0.369 mmol), diisopropylethylamine (0.0643 ml, 0.369 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 2.5 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (26.3 mg, 19.5%) as a solid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=3[CH3:27])[CH:14]=[N:13]2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=3[CH3:27])[CH:14]=[N:13]2)[C:9]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:38])[CH3:36])[N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(Oc2cnn(C(CC3CCCCC3)C(=O)O)c(=O)c2)c(C)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: Cc1ccc(Oc2cnn(C(CC3CCCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)c(=O)c2)c(C)c1
Yield: 75 %

Procedure:
Using the method described in Example 49, 3-cyclohexyl-2-[4-(2,4-dimethyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 89) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclohexyl-2-[4-(2,4-dimethyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a light yellow solid (202 mg, 75%); ES+-HRMS m/e calcd for C28H37N5O4 [M+H+] 508.2919 found 508.2920. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85-1.29 (m, 6H), 1.04 (s, 3H), 1.06 (s, 3H), 1.52-1.73 (m, 5H), 1.73-1.90 (m, 1H), 2.11 (s, 3H), 2.11-2.22 (m, 1H), 2.31 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47-5.58 (m, 2H), 6.39 (d, J=2.1 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.10-7.15 (m, 1H), 7.21 (s, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.7 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([O:31][C:32]2[CH:33]=[N:34][CH:35]=[N:36][CH:37]=2)[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].[CH3:38][N:39](C=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:38]([C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([O:31][C:32]2[CH:33]=[N:34][CH:35]=[N:36][CH:37]=2)[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])#[N:39]
Reactant: COC(=O)c1cc(Br)cc(Oc2cncnc2)c1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: COC(=O)c1cc(C#N)cc(Oc2cncnc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A mixture of polymer-bound triphenylphosphine (18 mg, 0.047 mmol, 0.15 eq) and palladium(II) acetate (5.0 mg, 0.022 mmol, 0.07 eq) in DMF (1.0 mL) stirred under argon at rt for 2 h. The supernatant DMF was removed, and fresh DMF (1.0 mL) was added. Methyl 3-bromo-5-(pyrimidin-5-yloxy)benzoate (96 mg, 0.31 mmol, 1.0 eq) and zinc cyanide (37 mg, 0.31 mmol, 1.0 eq) were added, and the vial was subjected to microwave irradiation at 150° C. for 25 minutes. The resin was washed with ether, and the collected filtrate was washed (3×) with water and (1×) with brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 25 mg (32%) of the title compound as a clear oil: 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.76 (s, 2H), 8.16 (s, 1H), 8.07 (dd, J=2.3, 1.3 Hz, 1H), 7.91 (dd, J=2.3, 1.4 Hz, 1H), 3.88 (s, 3H); ES-MS [M+1]+:256.1.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[C:19]([F:22])([F:21])[F:20]>C1CCCCC1>[C:1]([NH:4][C:10]1[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]([C:19]([F:20])([F:21])[F:22])=[C:6]([Cl:5])[C:11]=1[N+:12]([O-:14])=[O:13])#[C:2][CH3:3]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: C1CCCCC1
Product: CC#CNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The compound was prepared by reacting propargylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in cyclohexane to give the product melting at 86°-87° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:13][CH2:14][C@@H:15]1[CH2:20][O:19][CH2:18][CH2:17][N:16]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31]>CO.ClCCl.[Cl-].[NH4+].[Zn]>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:13][CH2:14][C@@H:15]2[CH2:20][O:19][CH2:18][CH2:17][N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])[C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: COc1ccc(CN2CCOC[C@H]2COc2cc(C#N)cc([N+](=O)[O-])c2Cl)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2CCOC[C@H]2COc2cc(C#N)cc(N)c2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
Zinc (107 mg, 1.630 mmol) was added to a mixture of (S)-4-chloro-3-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)-5-nitrobenzonitrile (isomer B, 73 mg, 0.163 mmol) and ammonium chloride (174 mg, 3.26 mmol) in methanol (5 mL) and the reaction mixture was stirred at room temperature for 2 hours. More zinc (107 mg, 1.630 mmol) was added and stirring continued until reactions complete. The reaction mixture was diluted with dichloromethane and ammonium chloride precipitated. Solids were filtered and the filtrate was concentrated. The residue was partitioned between dichloromethane and saturated sodium bicarbonate. The layers were separated and aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 5-35% ethyl acetate/hexanes) to give (S)-3-amino-4-chloro-5-((4-(2,4-dimethoxybenzyl)morpholin-3-yl)methoxy)benzonitrile (53 mg) as a oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])([O:13][CH3:14])=[O:12]>CC(N(C)C)=O.N1C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:19])[NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:16]=1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cccc(C(=O)Nc2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C
Yield: 97.2 %

Procedure:
In a 1-liter 3-necked flask fitted with an inlet tube for nitrogen, a magnetic stirrer, a dropping funnel and a thermometer there were introduced 76 g (0.5 moles) of p-nitroaniline in 600 ml of dimethylacetamide and 80 ml of pyridine. (Both solvents had previously been dried over a molecular sieve 3A). Over a period of 45 minutes 99.2 g (0.5 moles) of 3-carbomethoxybenzoyl chloride in 100 ml of dimethylacetamide were added with stirring and cooling, care being taken that the temperature did not rise to above 15° C. In the process a yellow precipitate was formed. After all the ingredients had been added, stirring was continued for 1 more hour at 20° C. The reaction mixture was poured into 2 l of ice water, filtered, washed 6 times with water and finally with methanol. After drying at 70° C. and a pressure of 133 Pa 146 g of the envisaged product were obtained in a yield of 97%. The melting point was 206°-207.6° C. In an analogous manner there were prepared:
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][C@H:7]1[C:11](=[O:12])[O:10][C@@H:9]2[CH2:13][CH:14]=[CH:15][C@H:8]12.[OH-:16].[Na+].[BH4-].[Na+].Cl.[Na+].[Cl-]>C1COCC1.O.C1COCC1.[Hg](OC(C)=O)OC(C)=O>[OH:16][C@H:14]1[CH2:13][C@H:9]2[O:10][C:11](=[O:12])[C@H:7]([CH3:6])[C@H:8]2[CH2:15]1
Reactant: [OH-]
Reactant: C[C@H]1C(=O)O[C@@H]2CC=C[C@@H]21
Agent: CC(=O)O[Hg]OC(C)=O
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C(=O)O[C@@H]2C[C@H](O)C[C@@H]21
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a ice-cold yellow solution of Hg(OAc)2 (1.45 g, 4.57 mmol) in THF:H2O (2.5:1 ratio, 23 mL) was added perchloric acid (˜0.7 mL) until the solution became colorless. A solution of lactone 116 (350 mg, 2.54 mmol) in THF (7 mL) was then added at 0° C. and the reaction was stirred for 1 h. Additional Hg(OAc)2 (646 mg, 2.03 mmol) similarly pretreated with perchloric acid in THF:H2O (2.5:1, 10 mL) was added and stirring was continued for 2 h at 0° C. The pH of the mixture was then adjusted to ˜10 by addition of a 1M aqueous NaOH solution. Stirring was then continued for 1 h at room temperature. The solution was cooled to 0° C. and NaBH4 (145 mg, 3.81 mmol) was added in small portions. After 1 h, the reaction mixture was acidified to pH=2 with concentrated HCl and stirring was continued for 1 h. The reaction solution was saturated with NaCl, and the aqueous phase extracted several times with EtOAc. The combined organic phase was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 2% MeOH in CH2Cl2 to yield alcohol 117 (252 mg, 64%) as a colorless oil. TLC: Rf=0.31 (CHCl3/MeOH=9/1); [α]D20+53.5 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 4.98 (dt, J=8.0, 14.9 Hz, 1H), 4.55 (m, 1H), 2.69 (qd, J=3.9, 7.6 Hz, 1H), 2.58 (m, 1H), 2.55 (m, 1H), 2.09 (d, J=15.0 Hz, 1H), 1.94 (m, 2H), 1.83 (m, 1H), 1.26 (d, J=7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 181.0, 83.8, 74.6, 51.2, 45.5, 43.9, 41.3, 18.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(O)(=O)C>[CH3:21][S:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CS(=O)(=O)Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl N-(4-aminobutyl)carbamate (13.8 g, 73.4 mmol) and triethylamine (15.3 mL, 110 mmol) was cooled to 0° C. Methanesulfonyl chloride (6.3 mL, 81 mmol) was added, and the reaction was allowed to warm to ambient temperature and stirred overnight. Aqueous acetic acid (200 mL of 10%) was added. The organic layer was then separated and washed with water (200 mL), saturated aqueous sodium bicarbonate (200 mL), water (200 mL), and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to provide 18.9 g of tert-butyl [4-(methanesulfonylamino)butyl]carbamate as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]#[CH:11].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][SH:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].[Na]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1/[CH:10]=[CH:11]\[CH:19]([S:20][CH:19](/[CH:11]=[CH:10]\[C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[F:9])[C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)[C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1
Reactant: C#Cc1c(F)cc(F)cc1F
Reactant: O=[N+]([O-])c1ccc(CS)cc1
Agent: [Na]
Product: O=[N+]([O-])c1ccc(C(/C=C\c2c(F)cc(F)cc2F)SC(/C=C\c2c(F)cc(F)cc2F)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of 2,4,6-trifluorophenylacetylene (0.02 mol), 4-nitrobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to General Procedure 2 to form (Z)-2,4,6-trifluorostyryl-4-nitrobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to General Procedure 2.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:28][C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:14][CH:13]=1)[C:7]([O:9]C)=[O:8]>CO.O1CCCC1>[CH:23]1[C:22]2[N:21]([CH2:20][CH2:19][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH:6]([C:7]([OH:9])=[O:8])[C:5]([OH:35])=[O:4])=[CH:17][CH:16]=3)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 64 h
Yield: 75.5 %

Procedure:
A 1 N aqueous solution of sodium hydroxide (3 mL) was added to a solution of 2-{4-(2-phenoxazine-10-yl-ethoxy)-benzyl]-malonic acid dimethyl ester (150 mg, 0.3 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (3 mL). The mixture was stirred for 64 h at room temperature. The title compound (95 mg, 72%) was isolated by filtration and washed with a mixture of MeOH/THF: mp 303-307° C.; 1H NMR (300 MHz, D2O): δ2.96 (d, 2H), 3.35 (t, 1H), 3.75-3.95 (bs, 2H), 4.18 (m, 2H), 6.55-6.90 (m, 10H), 7.15 (d, 2H).