Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1.[O:31]1CCC[CH2:32]1.C(OCC)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC>[C:12]([N:8]1[CH:9]=[CH:10][N:11]=[C:7]1[CH2:6][CH:32]=[O:31])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC=O
Product: O=CCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.75 h

Procedure:
1.6 M of n-Butyllithium in hexane (7.5 mL) was added dropwise to a solution of 2-Methyl-1-trityl-1H-imidazole (3.244 g, 10.00 mmol) in Tetrahydrofuran (100.0 mL, 1233 mmol) at −76° C. The dark red mixture was stirred for 45 min. Ethyl formate (4.039 mL, 50.00 mmol) was added quickly and the mixture (turned yellowish) was stirred for 20 min. 6 ml of 5% aq. citric acid were added and the mixture was mixed with 60 ml of aq citric acid and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4 and concentrated in vacuum. Pale yellow semisolid material (2.025 g, 57.5%) was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:10][C:9]([CH2:11][OH:12])=[N:8][CH:7]=1.O[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:16][CH:15]=1>>[N:23]1([CH2:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:12][CH2:11][C:9]3[S:10][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[CH:7][N:8]=3)=[CH:15][CH:16]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: OCc1ncc(-c2cccs2)s1
Product: c1csc(-c2cnc(COc3ccc(CCCn4ccnc4)cc3)s2)c1
Yield: 66 %

Procedure:
In substantially the same manner as in Working Example 146, 5-(2-thienyl)-2-thiazolylmethanol was mesylated and then reacted with 1-[3-(4-hydroxyphenyl)propyl]imidazole to obtain 2-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-(2-thienyl)thiazole. The yield was 66%. Recrystallization from ethyl acetate-hexane gave orange prisms, mp 82-84° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[CH:12]([O-:14])=O.[NH4+:15].[OH-].[Na+]>C(O)=O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:15]=[CH:12][O:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: Brc1ccc(-c2cocn2)cc1
Temperature: 25 °C
Yield: 25.7 %

Procedure:
To a stirred solution, of 2,4′-dibromoacetophenone (9.66 g, 34.8 mmol) in formic acid (42 ml) was added ammonium formate (7.58 g. 120.6 mmol), and the mixture was heated at reflux temperature for 3 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 50% NaOH aqueous solution. The whole was extracted with CH2H2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (2.0 g, 26% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:10]Br>C(=S)=S.C(OCC)C>[Br:10][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[OH:9]
Reactant: Oc1cc(F)cc(F)c1
Reactant: BrBr
Solvent: S=C=S
Solvent: CCOCC
Product: Oc1cc(F)cc(F)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of 2.6 gm (20 mMol) 3,5-difluorophenol in 20 mL carbon disulfide was cooled to 0° C. and then a solution of 1.02 mL (20 mMol) bromine in 10 mL carbon disulfide was added dropwise over 30 minutes. After stirring for an additional 30 minutes, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with 200 mL diethyl ether and was washed sequentially with aqueous sodium metabisulfite and saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was vacuum distilled to provide 2.5 gm (60%) of 2-bromo-3,5-difluorophenol (b.p.=65° C. (5 mm Hg)).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].[C:6]([O-:9])(=[O:8])[CH3:7].[Na+].C(O)(=O)C>C(#N)C.[Ru](Cl)(Cl)Cl>[C:6]([O:9][CH:4]1[NH:1][C:2](=[O:5])[CH2:3]1)(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: O=C1CCN1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)OC1CC(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
0.71 g of azetidine-2-one and 0.82 g of anhydrous sodium acetate were suspended in 20 ml of acetonitrile and cooled to -5°, to which 10 ml of acetonitrile containing 0.26 g of ruthenium trichloride.3H2O was added. 3.8 ml of acetic acid containing 40% peracetic acid was carefully dropped thereto so as to maintain the temperature not higher than 0° C., then continuously stirred at 0° C. for 30 minutes. The solvent was distilled off under reduced pressure at a temperature not higher than 40° C., and subjected to silica gel chromatography (eluent: n-hexane: ethyl acetate=1:1) for purification to obtain 0.92 g of the title compound (yield 71%).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27]C)=[O:26])[CH2:19][CH2:18]3)=[CH:5][CH:4]=1)[CH3:2].O[Li].O>C1COCC1.CO.O>[CH2:1]([C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19][CH2:18]3)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(OCCCOc2ccc3c(c2)CC[C@H]3CC(=O)OC)c(C)n1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(OCCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)c(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
To a solution of methyl ((1S)-5-{3-[(6-ethyl-2-methyl-3-pyridinyl)oxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 246) in a mixture of THF (3 mL) and MeOH (˜0.2 mL), was added LiOH.H2O (15 mg, 0.36 mmol) in water (1 mL). The mixture was stirred for 12 h at rt, the solvents were evaporated, and the residue was suspended in a small volume of water. The aqueous solution was acidified to pH<3 using HCl (1 N aqueous solution), and then it was extracted with excess EtOAc. The organic layer was dried, concentrated and purified by preparative HPLC to give 18 mg (16%) of the product as a solid. 1H NMR (400 MHz, CDCl3): δ 7.16-6.88 (m, 3H), 6.71 (s, 1H), 6.62 (dd, 1H), 4.12-4.0 (m, 4H), 3.52-3.40 (m, 1H), 2.90-2.62 (m, 6H), 2.52-2.26 (m, 4H), 2.23-2.12 (m, 2H), 1.78-1.64 (m, 1H), 1.08 (t, 3H).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1/[CH:18]=[CH:19]/[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Li])CCC.[CH3:42][Sn:43](Cl)([CH3:45])[CH3:44].[NH4+].[Cl-]>C1COCC1>[CH2:25]([C:24]1[CH:23]=[C:22]([Sn:43]([CH3:45])([CH3:44])[CH3:42])[S:21][C:20]=1/[CH:19]=[CH:18]/[C:14]1[S:15][C:16]([Sn:43]([CH3:45])([CH3:44])[CH3:42])=[CH:17][C:13]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCCCc1ccsc1/C=C/c1sccc1CCCCCCCCCCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1cc([Sn](C)(C)C)sc1/C=C/c1sc([Sn](C)(C)C)cc1CCCCCCCCCCCC
Temperature: -78 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
(E)-1,2-Bis(3-dodecylthienyl)ethylene (12) (10.4 mmol, 2.00 g) was dissolved in anhydrous THF (43.2 mL) and cooled to −78° C. under nitrogen. n-Butyllithium (21.84 mmol, 13.7 mL) was then added dropwise. The resulting solution was warmed to room temperature over 30 min and stirred at that temperature for 3 h. The mixture was then cooled to −78° C. before trimethyltin chloride (21.84 mmol, 4.35 g) in anhydrous THF (26 mL) was added dropwise. After addition, the mixture was warmed to room temperature over 4 h and stirred for additional 20 h at room temperature. The reaction mixture was poured into saturated NH4Cl solution (100 mL) and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude solid was recrystallized from ethanol to give desired product 13 in 73% yield. 1H-NMR (CDCl3, 400 MHz) ppm 0.36 (s, 18H) ppm 0.88 (t, 6H, J=6.9 Hz) ppm 1.30 (m, 36H) ppm 1.59 (td, 4H, J=7.3 Hz, J=14.9 Hz) ppm 2.65 (m, 4H) ppm 6.94 (s, 2H) ppm 7.00 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[N:10]=1)=S)C.Cl.NO.CC[N:26](C(C)C)C(C)C>CO.CCO>[S:17]1[CH:18]=[CH:19][C:15]([C:11]2[N:10]3[N:26]=[C:6]([NH2:5])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=2)=[CH:16]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cccc(-c2ccsc2)n1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2cccc(-c3ccsc3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A suspension of ethyl({[6-(3-thienyl)pyridin-2-yl]amino}carbonothioyl)carbamate (4.0 g; 13.01 mmol; 1.0 eq.), hydroxylamine hydrochloride (4.52 g; 65.1 mmol; 5.0 eq.) and DIEA (6.55 mL) in MeOH/EtOH (1:1, 120 mL) was stirred at rt for 2 hours and then at 70° C. for 3 hours. Solvents were removed under reduced pressure, the residue was taken up in dioxane/water (1:1) and filtered to give the title compound as a white powder (2.3 g; 82%). HPLC, Rt: 1.75 min. (purity 94.8%). LC/MS, M+(ESI): 217.3.
Reaction SMILES: [H-].[Na+].[P:3]([O-:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Br)[CH3:22]>CN(C=O)C>[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][P:3]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:20])[CH3:22]
Reactant: CCOC(=O)CCCBr
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCP(=O)(OCc1ccccc1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60%, 2.52 g, 63 mmol) in DMF (60 mL) was added dibenzyl phosphite (12 mL, 48.45 mmol). After 15 minutes of stirring, ethyl-4-bromobutyrate was added and the mixture was stirred for 48 h at room temperature. The DMF was removed by evaporation. The residue was partitioned between brine, ammonium chloride and ether. The water phase was extracted several times with ether. The recombined organic layer was extracted with brine, dried over sodium sulfate, filtered and evaporated. The residue was flashed using 50% ethyl acetate in hexanes to afford the product as a colorless oil. 1H-NMR(CDCl3, 400 MHz: 1.23(t, J=7.2 Hz, 3H); 1.77-2.04(m, 4H); 2.37(m, 2H); 4.10(q, J=7.2 Hz, 2H), 5.03(m, 4H); 7.31(m, 10H). 31P-NMR(CDCl3, 400 MHz): 32.78.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]#[N:14])[CH2:10][CH:9]2[CH2:11][OH:12])=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>C1COCC1>[NH2:14][CH2:13][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:10][CH:9]1[CH2:11][OH:12]
Reactant: N#CC1(c2ccc(Br)cc2)CC1CO
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCC1(c2ccc(Br)cc2)CC1CO
Temperature: 80 °C
Yield: 72.6 %

Procedure:
To a solution of 1-(4-bromo-phenyl)-2-hydroxymethyl-cyclopropanecarbonitrile (12.8 g, 51.0 mmol) in anhydrous THF (150 mL) was added BF3.OEt2 (10.15 mL, 0.2 mL per mmol) and the reaction mixture was heated at 80° C. Borondimethylsulphide complex (63.4 mL, 126.9 mmol, 2M in THF) was added to the reaction mixture and heated 80° C. for 4 h. Reaction mixture was quenched by 10% hydrochloric acid at 0° C. till effervescence vanishes. The reaction mixture was washed with diethyl ether (2×70 mL) and the aqueous layer was neutralized with solid sodium bicarbonate till pH 8. The neutralized aqueous layer was extracted with ethyl acetate (3×200 mL), dried over anhydrous sodium sulphate and concentrated to yield the title compound (9.49 g, 73%) as brown oil which was used as such in the next step.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[Cl:25])=[CH:22][CH:21]=[CH:20][CH:19]=2>ClCCl>[Cl:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH:14][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Butyryl chloride (3.77 mL, 1.3 eq) and triethylamine (5.85 mL, 1.3 eq) were added sequentially to a chilled (0° C.) solution of 3-amino-4-chloroquinoline (5.0 g, 1.0 eq) in dichloromethane (100 mL). The reaction mixture was warmed to ambient temperature and then allowed to stir overnight. The reaction mixture was quenched with aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 6.5 g of N-(4-chloroquinolin-3-yl)butyramide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12]Cl)=[C:7]([CH3:15])[C:6]([O:16][CH3:17])=[C:5]([O:18][CH3:19])[C:4]=1[O:20][CH3:21].[CH3:22][O:23][C:24](/[CH:26]=[CH:27]/[C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)=[O:25]>>[CH3:1][O:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([O:18][CH3:19])[C:6]([O:16][CH3:17])=[C:7]([CH3:15])[C:8]=1[CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH:27]=[CH:26][C:24]([O:23][CH3:22])=[O:25])=[CH:33][CH:32]=1.[CH3:1][O:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([O:18][CH3:19])[C:6]([O:16][CH3:17])=[C:7]([CH3:15])[C:8]=1[CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH:27]=[CH:26][C:24]([OH:25])=[O:23])=[CH:33][CH:32]=1
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Reactant: COc1c(C)c(CC=C(C)CCl)c(OC)c(OC)c1OC
Product: COC(=O)C=Cc1ccc(OCC(C)=CCc2c(C)c(OC)c(OC)c(OC)c2OC)cc1
Product: COc1c(C)c(CC=C(C)COc2ccc(C=CC(=O)O)cc2)c(OC)c(OC)c1OC

Procedure:
Using 1,2,3,4-tetramethoxy-5-methyl-6-(4-chloro-3-methyl-2-butenyl)benzene and methyl p-hydroxycinnamate and following the procedure described above, there were obtained methyl 4-[4-(2,3,4,5-tetramethoxy-6-methylphenyl)-2-methyl-2-butenyloxy]cinnamate (Compound 11) and 4-[4-(2,3,4,5-tetramethoxy-6-methylphenyl)-2-methyl-2-butenyloxy)-cinnamic acid (Compound 12).
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][C@H:9]([CH3:12])[N:8]2[C:13]([O:15]C(C)(C)C)=O)=[N:4][CH:3]=1.Cl.[CH3:21][O:22][C:23]([NH:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])C(O)=O)=O.[CH3:33]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[I:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][C@H:9]([CH3:12])[N:8]2[C:13](=[O:15])[C@@H:26]([NH:25][C:23]([O:22][CH3:21])=[CH2:33])[CH:30]([CH3:32])[CH3:31])=[N:4][CH:3]=1
Reactant: C[C@H]1CC[C@@H](c2ncc(I)[nH]2)N1C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1ncc(I)[nH]1)C(C)C)OC
Reaction time: 3 h
Yield: 94.2 %

Procedure:
A round bottom flask was charged with (2S,5S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (1.5 g, 3.98 mmol) and treated with an excess of hydrochloric acid (100 mL of 4.0M in dioxane). The mixture was stirred vigorously for 3 hours in which time a precipitate formed and the solvent was removed in vacuo. To a mixture of the crude intermediate, (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.836 g, 4.77 mmol), HATU (1.81 g, 4.77 mmol) in dichloromethane (25 mL), diisopropylethylamine (3.46 mL, 19.9 mmol) was then added dropwise and was stirred over night under nitrogen. The reaction mixture was partitioned ethyl acetate and saturated sodium bicarbonate. The organic layer was dried with sodium sulfate, the solvent removed in vacuo. The crude product was purified by column chromatography to yield (2S)-1-[(2S,5S)-2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl]-2-[(1-methoxyethenyl)amino]-3-methylbutan-1-one as a white solid (1.63 g, 3.75 mmol, 94%). LCMS-ESI+: calc'd for C15H23IN4O3: 434.08 (M+). Found: 435.51 (M+H+).
Reaction SMILES: [ClH:1].CCOCC.[C:7]([O:11][C:12](=[O:39])[C@@H:13]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:29][NH:30]C(OC(C)(C)C)=O)[C:20]1=[O:38])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[ClH:1].[C:7]([O:11][C:12](=[O:39])[C@@H:13]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH2:29][NH2:30])[C:20]1=[O:38])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N([C@@H](CCC(N)=O)C(=O)OC(C)(C)C)C2=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CCC(N)=O)N1C(=O)c2cccc(CN)c2C1=O
Reaction time: 5 h
Yield: 97 %

Procedure:
2N HCl/ether (14 mL) was added to a stirred solution of (2S)-2-[4-(t-butoxycarbonylamino-methyl)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyric acid t-butyl ester (2.5 g, 5.4 mmol) in CH2Cl2 (25 mL). The mixture was stirred for 5 hours. Solid was collected by filtration to give (2S)-2-(4-aminomethyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl butyric acid t-butyl ester hydrochloride (2.1 g, 97%): 1H NMR (DMSO-d6) δ 1.37 (s, 9H), 2.08-2.37 (m, 4H), 4.47-4.51 (m, 2H), 4.73-4.79 (dd, J=4.6 and 10.0 Hz, 1H), 6.73 (s, 1H), 7.25 (s, 1H), 7.92-8.03 (m, 3H), 8.68 (s, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:31])[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:16]2[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:15]=2[O:14]1>ClCCl>[C:29]([C:26]1[CH:27]=[CH:28][C:15]2[O:14][C:13]([CH3:31])([CH3:12])[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N+:20]=3[O-:9])[C:16]=2[CH:25]=1)#[N:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C=C(c2ccccn2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)C=C(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 17 h
Yield: 43.2 %

Procedure:
406 mg of m-chloroperbenzoic acid were added to a solution of 524 mg of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile in 15 ml of dichloromethane at room temperature. After stirring at room temperature for 17 hours the solution was washed with sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:4) for the elution. There were obtained 240 mg of 2-(6-cyano-2,2-dimethyl-2H1-benzopyran-4-yl)pyridine N-oxide of melting point 187°-189° C. after recrystallization from ethyl acetate.
Reaction SMILES: C=C.[C:3]([CH2:16][C:17](I)([F:19])[F:18])([C:6]([C:9]([C:12]([F:15])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4].CC1CC[C@@H]([C:28]([CH3:30])=C)CC=1.C(CC(CCI)(F)F)(C(C(C(F)(F)F)(F)F)(F)F)(F)F.S(=O)(=O)(O)[OH:52]>>[C:3]([CH2:16][C:17]([CH2:30][CH2:28][OH:52])([F:19])[F:18])([C:6]([C:9]([C:12]([F:15])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4]
Reactant: C=C(C)[C@H]1CC=C(C)CC1
Reactant: O=S(=O)(O)O
Reactant: FC(F)(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C=C
Agent: FC(F)(CCI)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: OCCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 240 °C
Reaction time: 1.5 h

Procedure:
C4F9CH2CF2CH2CH2OH was produced by introducing ethylene (25 g, 0.53 mol) was introduced to an autoclave charged with C4F9CH2CF2I (217 g, 0.87 mol) and d-(+)-limonene (1 g), and then the reactor was heated at 240° C. for 12 hours. Product was obtained via vacuum distillation 81˜91° C. at 19˜24 mmHg in 62% yield. Fuming sulfuric acid (70 mL) was added slowly to 50 g of C4F9CH2CF2CH2CH2I and mixture was stirred at 60° C. for 1.5 h. The reaction was quenched with ice-cold 1.5 wt % Na2SO3 aqueous solution and heated at 95° C. for 0.5 h. The bottom layer was separated and washed with 10 wt % aqueous sodium acetate and distilled to provide compound of formula C4F9CH2CF2CH2CH2OH: by 54-57° C. at 2 mmHg (267 Pascals).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.CC1(C)C(C)(C)OB([C:19]2[CH:31]=[CH:30][C:22]3[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=3[CH:20]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[NH:6]1[C:7]2[C:3](=[C:2]([C:19]3[CH:31]=[CH:30][C:22]4[N:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[S:25][C:21]=4[CH:20]=3)[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1
Reactant: Brc1cccc2[nH]ncc12
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
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: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cccc4[nH]ncc34)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
4-Bromo-1H-indazole (96.8 mg, 0.491 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (193.2 mg, 6.072 mmol), and tetrakis(triphenylphosphine)palladium(0) (51.5 mg, 44.6 μmol) were suspended in 1,4-dioxane (2.0 mL) and sodium carbonate (0.50 mL, 2M in water, 1.0 mmol) was added. The flask was fit with a reflux condensor and placed in a preheated oil bath (95° C.) and stirred under nitrogen overnight. The mixture was then cooled to RT and filtered through a pad of Celite® (diatomaceous earth). The filtrate was concentrated and purified on HPLC (10-95% MeCN/water with 0.1% TFA over 40 minutes) to give N-(6-(1H-indazol-4-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 309 (MH+). Calculated exact mass for C16H12N4OS: 308.
Reaction SMILES: C([N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(O)C.[OH-].[OH-].[Pd+2]>[CH:18]1([NH:8][CH2:9][C:10]([F:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(F)CNC1CCCC1
Yield: 84.8 %

Procedure:
A solution of ethyl 3-(benzyl(cyclopentyl)amino)-2-fluoro-2-methylpropanoate (3.5 g, 11.4 mmol) in ethanol (30 mL) was hydrogenated with Pd(OH)2 (20%, 400 mg, 0.57 mmol) in presence of TFA (11.4 mmol) at atmospheric pressure for 20 h. The reaction mixture was filtered through celite. The filtrate was concentrated and diluted to EtOAc/H2O, aqueous layer was basified to pH=11-12 by 1N NaOH. The organic layer was then dried and concentrated to give the product (2.1 g, 85%) as light yellow liquid. [M+H] calc'd for C11H20FNO2, 218. found 218.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:7].[CH2:8](O)[CH2:9][O:10][CH2:11][CH2:12]O>[Ni]>[O:4]1[CH2:5][CH2:6][N:1]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[CH2:2][CH2:3]1
Reactant: OCCOCCO
Reactant: N
Reactant: C1COCCN1
Agent: [Ni]
Product: C1CN(CCOCCN2CCOCC2)CCO1
Yield: 70 %

Procedure:
Zh. Vses. Khim. Obshchest. 14(5), 589-90 (1969) (Chem. Abstr. 72: 66879m) describes the formation of morpholine in a yield of 70% by gas-phase reaction of diethylene glycol with NH3 over a nickel catalyst in the presence of H2. Among other by-products, bis(2-morpholinoethyl) ether was isolated in a yield of from 5 to 7%.