Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)([CH3:3])[CH3:2].O.[CH3:17][O:18][CH:19]=[C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Br)[C:21]([O:23][CH3:24])=[O:22].COC=C(C1C=CC=CC=1CON1C(=O)C=C(C(F)(F)F)N=C1OC(C)C)C(OC)=O>C1(C)C=CC=CC=1.[Cu-]=O>[CH3:17][O:18][CH:19]=[C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][O:11][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Agent: O=[Cu-]
Agent: COC=C(C(=O)OC)c1ccccc1COn1c(OC(C)C)nc(C(F)(F)F)cc1=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC=C(C(=O)OC)c1ccccc1COc1cc(C(F)(F)F)nc(OC(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.3 %

Procedure:
2.22 g of 2-isopropoxy-6-trifluoromethyl-4-hydroxypyrimidine and 0.72 g of copper(I) oxide were suspended in 30 ml of toluene. The suspension was refluxed until no water was recognized to form, while formed water was being taken into a quantitative water receiver. 3.08 g of methyl 3-methoxy-2-(2-bromomethylphenyl)acrylate was added at an instance. The reaction was carried out for 5 hours at reflux of toluene. Then the solution was cooled down to room temperature. Insoluble matter was filtrated and further washed with 20 ml of acetone twice. The mixed solution of the obtained filtrate and washings was analyzed with high-performance liquid chromatography. The reaction yield was 22.3% and as for byproducts 0.7% for methyl 3-methoxy-2-[2-(2-isopropoxy-6-trifluoromethylpyrimidin-4-on-3-yloxymethyl)phenyl]acrylate and 77% for 4-(α-methoxy) methylen-2H-chromen-3(4H)-one.
Reaction SMILES: P(Br)(Br)Br.[C:5]([NH:15][C@:16]([CH3:33])([C:30]([OH:32])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]=[O:26])=[C:20]([O:27][CH:28]=[O:29])[CH:19]=1)(OCC1C=CC=CC=1)=[O:6]>C(OCC)C>[CH3:33][C@:16]1([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]=[O:26])=[C:20]([O:27][CH:28]=[O:29])[CH:19]=2)[C:30](=[O:32])[O:31][C:5](=[O:6])[NH:15]1
Reactant: C[C@@](Cc1ccc(OC=O)c(OC=O)c1)(NC(=O)OCc1ccccc1)C(=O)O
Agent: BrP(Br)Br
Solvent: CCOCC
Product: C[C@@]1(Cc2ccc(OC=O)c(OC=O)c2)NC(=O)OC1=O
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Phosphorous tribromide (0.81 g, 3 mmol) in dry ethylether (5 ml) is added dropwise to a solution of (S)-N-carbobenzyloxy-3-(3,4-diformyloxyphenyl)-2-methylalanine (0.4 g, 1 mmol) in dry ethylether (10 ml). After stirring 3 hours at 20°-25° under dry nitrogen, the reaction mixture is diluted with dry petroleum ether (40°-60°) (100 ml) and refrigerated 18 hours. The solvent is decanted from the gum which has separated. The gum is dissolved in methylene chloride (2 ml) and precipitated with ethyl ether as a gum. The product (B) is separated and dried 0.1 mm/25° for 3 hours over phosphorous pentoxide to afford 0.24 g (80%) of gummy solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]3[CH2:35][C@H:34]4[C@:36]5([CH2:40][N:39]([CH2:41][C:42]([F:45])([F:44])[F:43])[S:38](=[O:47])(=[O:46])[NH:37]5)[C@H:31]([CH2:32][CH2:33]4)[CH2:30][C:29]=3[CH:48]=2)O1>>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:5]1[CH:6]=[C:2]([C:25]2[CH:26]=[CH:27][C:28]3[CH2:35][C@H:34]4[C@:36]5([CH2:40][N:39]([CH2:41][C:42]([F:45])([F:44])[F:43])[S:38](=[O:46])(=[O:47])[NH:37]5)[C@H:31]([CH2:32][CH2:33]4)[CH2:30][C:29]=3[CH:48]=2)[N:3]=[CH:4]1
Reactant: Brc1c[nH]cn1
Reactant: OB(O)c1ccccc1F
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4ccccc4F)cn3)cc2C1

Procedure:
Prepared from 4-bromo-1H-imidazole, 2-fluorophenylboronic acid and homochiral boronate from Example 24 Step 1 following the procedures in Example 76 Steps 1 and 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:5]=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[I:18]I>CCCCCC.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:5]=[C:4]([F:12])[C:3]=1[I:18]
Reactant: II
Reactant: C=CCCc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCCc1cc(F)c(I)c(F)c1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
0.41 mol 1,3 difluoro-5-(3-butenyl)-benzene was added to a dry round bottom flask with 300 ml anhydrous tetrahydrofuran. After cooling under a nitrogen atmosphere to −70° C. a solution of 0.46 mol of n-butyllithium in 280 ml hexane was added. After stirring at −70° C. for 30 minutes a mixture of 0.46 mol of Iodine in 200 ml tetrahydrofuran was added slowly over 2 hours. The reaction was left to warm to room temperature overnight. The reaction was quenched by pouring onto ice/hydrochloric acid mixture. The layers were separated and the aqueous layer extracted twice with diethyl ether (2×100 ml). The combined organic layers were washed with 50 g sodium thiosulphate in 200 ml water to remove excess iodine, then with water (2×50 ml) and dried over anhydrous sodium sulphate. Removal of the solvent yielded 126 g of the title compound as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1C=O.[CH2:13]([Mg]Cl)[CH2:14]C.C([O:20][CH2:21][CH3:22])C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[CH:6][C:7]([CH:21]([OH:20])[CH2:22][CH2:13][CH3:14])=[CH:8][CH:9]=1
Reactant: CCOCC
Reactant: CCC[Mg]Cl
Reactant: COC(=O)c1ccccc1C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(O)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
Formyl-benzoic acid methyl ester (1.00 g, 6.10 mmol) was dissolved in tetrahydrofuran (15 mL), under argon, and chilled to 0° C. A 2.0 M solution of propyl magnesium chloride in diethyl ether (3.05 mL, 6.1 mmol) was added dropwise and the reaction continued to stir at 0° C. for 45 min. 1.0 M aqueous hydrochloric acid solution (10 mL) was added to the reaction and the solution stirred vigorously for 10 min. The solution was diluted with ethyl acetate (100 mL), washed with 1.0 M aqueous hydrochloric acid solution (20 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to a clear oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 4-(1-hydroxy-butyl)-benzoic acid methyl ester (610 mg, 48%) as a clear oil: H1-NMR (400 MHz, CDCl3) δ 0.94 (3H, t, J=7.2 Hz), 1.22-1.52 (2H, m), 1.62-1.84 (2H, m), 2.00 (1H, s), 3.91 (3H, s), 4.74 (1H, t, J=6.8 Hz), 7.40 (2H, d, J=8.4 Hz), 7.99 (2H, d, J=8.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(C(=O)OC)c1
Yield: 100 %

Procedure:
Using General Procedure A: A solution of 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.402 g, 1.50 mmol), 4-bromomethyl-isophthalic acid dimethyl ester (0.603 g, 2.10 mmol), KI (63 mg, 0.38 mmol), and DIPEA (0.60 mL, 3.44 mmol) in DMF (7.5 mL) was heated at 60 ° C. for 24 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 710 mg (99%) of COMPOUND 52 as a white solid. 1H NMR (CDCl3) δ 1.63-1.77 (m, 3H), 2.09 (br s, 1H), 2.34-2.52 (m, 8H), 3.84 (s, 6H), 4.02 (s, 2H), 4.18 (d, 2H, J=11.1 Hz), 6.82 (dd, 2H, J=4.8, 7.5 Hz), 7.14 (d, 2H, J=7.5 Hz), 7.72 (s, 2H), 7.92 (s, 1H), 8.22 (d, 2H, J=4.8 Hz); 13C NMR (CDCl3) δ 19.32, 25.66, 28.30, 50.13, 52.23, 52.36, 67.14, 122.20, 126.83, 128.07, 130.49, 131.08, 131.33, 132.14, 138.08, 146.90, 149.71, 159.50, 166.88, 167.23; ES-MS m/z 474 (M+H). Anal. Calcd. For C28H31N3O4.0.3H2O: C, 70.21; H, 6.65; N, 8.77. Found: C, 70.17; H, 6.60; N, 8.72.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.O.[CH:11](=[O:14])[CH2:12][CH3:13]>CO>[OH:14][CH:11]([C:7]1[O:8][C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:6]=1[OH:9])[CH2:12][CH3:13]
Reactant: Cc1cc(=O)c(O)co1
Reactant: CCC=O
Solvent: O
Solvent: CO
Product: CCC(O)c1oc(C)cc(=O)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
Allomaltol (12.6 g, 100 mmol, 1 eq.) was added to 100 ml water and the pH of the solution was adjusted to 10.5 using 50% aqueous sodium hydroxides. Propionaldehyde (8.7 g, 150mmol, 1.5 eq.) dissolved in 50 ml methanol was slowly added dropwise over 1 hour and the solution allowed to stir at room temperature for 48 hours. After adjustment to pH 1 with 37% hydrochloric acid, the reaction mixture was evaporated to dryness and the residue taken up into 300 ml of dichloromethane. The organic layer was washed with water (150 ml), dried over anhydrous sodium sulphate, filtered and concentrated to yield the crude product. Recrystallisation from toluene afforded the pure product (14.5 g, 78.9%) as a white crystalline solid. m.p. 134-136° C. [lit. 132-135° C. Ellis (1993)].
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:18](I)[CH3:19]>CN(C=O)C>[C:3]([N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)[CH2:18][CH3:19])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CCI
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 1.15 g, 29.5 mmol) in DMF (50 mL) at 0° C. was added a solution of 2-(N-Boc-amino)-6-picoline in DMF (30 mL). The reaction was stirred at 0° C. for 15 min; then ethyl iodide (4.6 g, 30 mmol) was added. The reaction mixture was stirred at RT overnight; then was concentrated in vacuum. The residue was diluted with H2O and extracted with CH2Cl2 (3×50 mL). Drying (MgSO4), concentration, and silica gel chromatography (20% EtOAc/hexane) gave the title compound as colorless oil: MS (ES) m/e 237 (M+H)+.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:21])[CH3:20])#[CH:11]>>[C:19]([N:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: N#Cc1ccc(I)cc1
Reactant: C#Cc1ccccc1NC(C)=O
Product: CC(=O)n1c(-c2ccc(C#N)cc2)cc2ccccc21
Yield: 36 %

Procedure:
The general procedure was used to convert 4-iodobenzonitrile and N-(2-ethynylphenyl)acetamide to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 36% yield. 1H NMR (300 MHz, DMSO) δ 8.16-8.13 (d, J=8.4, 1H), 7.95-7.92 (d, J=8.6, 2H), 7.76-7.73 (d, J=8.4, 2H), 7.67-7.65 (d, J=7.7, 1H), 7.42-7.36 (dt, J=7.3, 1.5, 1H), 7.33-7.28 (dt, J=7.7, 1.1, 1H) 6.94 (s, 1H), 2.28 (s, 3H). 13C NMR (75 MHz, DMSO) δ 171.42, 139.15, 139.09, 137.98, 133.23, 130.31, 129.57, 126.25, 124.40, 121.99, 119.54, 116.08, 113.63, 111.49, 28.56. Anal. Calcd. for C17H12N2O: C, 78.44; H, 4.65; N, 10.76. Found C, 78.19; H, 4.63; N, 10.68. m.p.: 158-160° C.
Reaction SMILES: [Cl:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][NH:5][C:6](=[O:31])[N:7]([C@H:9]([CH2:15][O:16][C:17](=[O:30])[NH:18][C:19]1[N:20]=[CH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=2)[CH2:10][CH2:11][C:12](O)=[O:13])[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:61]([O:65][C:66]([N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)=[O:67])([CH3:64])([CH3:63])[CH3:62].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][NH:5][C:6](=[O:31])[N:7]([C@H:9]([CH2:15][O:16][C:17](=[O:30])[NH:18][C:19]1[N:20]=[CH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=2)[CH2:10][CH2:11][C:12]([N:71]1[CH2:72][CH2:73][N:68]([C:66]([O:65][C:61]([CH3:64])([CH3:62])[CH3:63])=[O:67])[CH2:69][CH2:70]1)=[O:13])[CH3:8]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1cc2cc(F)ccc2cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of (S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)pentanoic acid (83 mg, 0.160 mmol, 1.0 equiv) in DMF (1 mL) were added HBTU (72 mg, 0.191 mmol, 1.2 equiv.), tert-butyl-1-piperazine carboxylate (59 mg, 0.320 mmol, 2.0 equiv.) and DIEA (83 μL, 0.480 mmol, 3.0 equiv.). The reaction mixture was stirred 1 h at RT and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-tert-butyl 4-(4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)pentanoyl)piperazine-1-carboxylate (61 mg, 55%). LRMS (M+H+) m/z 689.3.
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([CH2:16]OS(C)(=O)=O)[O:8]1)(=O)=O.[NH4+:22].[OH-].Cl>C(#N)C>[CH:9]12[O:8][CH:7]([CH2:6][NH:22][CH2:16]1)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)OCC1OC(COS(C)(=O)=O)c2ccccc21
Agent: Cl
Agent: [OH-]
Solvent: CC#N
Product: c1ccc2c(c1)C1CNCC2O1
Temperature: 100 °C

Procedure:
Methanesulfonic acid 3-methanesulfonyloxymethyl-1,3-dihydro-isobenzofuran-1-ylmethyl ester (12.1 g, 36 mmol) and conc. NH4OH (50 mL) was dissolved in acetonitrile (100 mL) and heated at 100° C. in a sealed vessel for 2 h. The reaction was then cooled, adjusted to pH 5-6 with 1 N HCl and extracted with diethyl ether (100 mL). The aqueous layer was then basified with 10 N NaOH and extracted with diethyl ether (2×100 mL). The later organic layer was dried over MgSO4, filtered, concentrated and purified with silica gel chromatography (0-15% MeOH in CH2Cl2) to obtain 12-Oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a brown, viscous oil (5.1 g, 88%). MS (m/e) 162 (M+1); HPLC (93%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:55])[NH:15][C@@H:16]([C:28](=[O:54])[N:29]([C@@H:31]([C:43]2[O:47][N:46]=[C:45]([C:48](OCCC)=[O:49])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:56][NH2:57]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:55])[NH:15][CH:16]([C:28](=[O:54])[N:29]([CH:31]([C:43]2[O:47][N:46]=[C:45]([C:48](=[O:49])[NH:57][CH3:56])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCOC(=O)c1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1noc(C(Cc2ccc3ccccc3c2)N(C)C(=O)C(Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
4-((1R)-1-{N-[(1R)-1-(3-Propoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (0.80 g, 1.07 mmol) was dissolved in 33% methylamine in ethanol and stirred at 90° C. for 18 h in a closed reaction vessel. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica (60 g) using ethyl acetate and heptane (7:3) as eluent to give 0.15 g of 4-(1-{-N-[1-(3-methylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)-ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([CH2:15][C:16](=[O:18])[CH3:17])(=O)[CH3:13].[CH2:19]([O:21][C:22](=[O:31])[CH:23]=[C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[NH2:25])[CH3:20].C(O)(C)C.CCOCC>C(O)C>[CH2:19]([O:21][C:22]([C:23]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:15]([C:16](=[O:18])[CH3:17])[C:12]([CH3:13])=[N:25][C:24]=1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:31])[CH3:20]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=C(N)N1CCCC1
Solvent: CC(C)O
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C1=C(N2CCCC2)N=C(C)C(C(C)=O)C1c1cccc([N+](=O)[O-])c1
Yield: 44 %

Procedure:
Heating a solution of 7.6 g of 3-nitrobenzaldehyde, 5.0 g of acetylacetone and 9.2 g of 3-pyrrolidino-3-aminoacrylic acid ethyl ester in 50 ml of ethanol for 2 hours yields 2-pyrrolidino-6-methyl-4-(3-nitrophenyl)-5-acetyl-4,5-dihydropyridine-3-carboxylic acid ethyl ester of melting point 130° C. (isopropanol/ether).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]3[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.I[CH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>CN(C)C=O>[CH:20]([C:18]1[N:19]=[C:15](/[CH:14]=[CH:13]/[C:11]2[CH:10]=[CH:9][N:5]3[C:6](=[O:8])[CH:7]=[C:2]([O:1][CH2:33][CH:34]4[CH2:38][CH2:37][O:36][CH2:35]4)[N:3]=[C:4]3[CH:12]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(O)nc3c2)n1
Reactant: ICC1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)cc(OCC4CCOC4)nc3c2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4H-pyrido[1,2-a]-pyrimidin-4-one (210 mg, 0.670 mmol) was suspended in dimethylformamide (6.0 ml), added with diisopropylethylamine (600 μl) and 3-(iodomethyl)tetrahydrofuran (334 μl), and stirred overnight at 80° C. The reaction solution was further added with diisopropylethylamine (600 μl) and 3-(iodomethyl)tetrahydrofuran (334 μl) and stirred overnight at 80° C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0→100:1→100:2→100:5, v/v) to obtain the title compound (277 mg, quantitative).
Reaction SMILES: O1C=CC=C1.[C:6]([O:10][CH2:11][CH3:12])(=O)[CH:7]=[CH2:8].[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14]>[I-].[Zn+2].[I-]>[C@@H:6]12[O:10][C@@H:11]([CH:8]=[CH:7]1)[CH2:12][C@H:14]2[C:13]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(C)=O
Reactant: C=CC(=O)OCC
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccoc1
Product: CCOC(=O)[C@@H]1C[C@@H]2C=C[C@H]1O2
Temperature: 40 °C
Yield: 46.5 %

Procedure:
A flask was charged with zinc iodide (1.010 ml, 14.98 mmol), then heated with a heat gun under high vacuum for 5 minutes. The flask was charged with furan (5.09 ml, 69.9 mmol) and ethyl acrylate (5.43 ml, 49.9 mmol), then covered in foil and heated at 40° C. for 48 hours. The solution was then diluted with ethyl acetate and washed with 10% aqueous Na2SO3. After drying with Na2SO4 and filtration, the solvents were removed under reduced pressure then purified by silica gel chromatography (RediSep Gold 80 g, gradient elution 0-50% EtOAc:Heptane) to afford (1R,2R,4R)-ethyl 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylate (3.91 g, 23.25 mmol, 46.5% yield) as a clear colorless oil (2.5:1 mixture of endo and exo isomers). 1H NMR (400 MHz, CHLOROFORM-d) δ=6.44 (dd, J=1.7, 5.8 Hz, 1H), 6.41-6.38 (m, 1H), 6.38-6.34 (m, 1H), 6.24 (dd, J=1.6, 5.8 Hz, 1H), 5.19 (dd, J=0.7, 1.6 Hz, 1H), 5.18-5.16 (m, 1H), 5.08 (dd, J=0.7, 4.6 Hz, 1H), 5.02 (ddd, J=0.7, 1.7, 4.7 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 4.10 (ttd, J=3.6, 7.1, 10.7 Hz, 1H), 3.11 (ddd, J=3.8, 4.9, 9.1 Hz, 1H), 2.42 (dd, J=3.9, 8.5 Hz, 1H), 2.17 (td, J=4.4, 11.2 Hz, 1H), 2.11 (ddd, J=4.7, 9.3, 11.4 Hz, 1H), 1.60 (dd, J=3.8, 11.5 Hz, 1H), 1.56 (dd, J=8.6, 11.6 Hz, 1H), 1.29 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 1H)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:14]O)[S:12][CH:13]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:19].O>C1(C)C=CC=CC=1>[Br:19][CH2:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: BrP(Br)Br
Reactant: OCc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(-c2csc(CBr)n2)cc1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
To the solution of [4-(4-Trifluoromethyl-phenyl)-thiazol-2-yl]-methanol (0.13 g, 0.50 mmol) in 2 ml of toluene was added PBr3 (0.072 ml, 0.752 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 1% EtOAc-Hexane) to get the desired product (0.04 g, 25%). The other derivatives were also prepared by the same general method.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[C:21]2[C:22](=[O:26])[NH:23][N:24]=[CH:25][C:20]=2[CH:19]=[N:18][CH:17]=1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH2:37][CH2:38]O.C(Cl)Cl>C1COCC1.O>[Cl:15][C:16]1[C:21]2[C:22](=[O:26])[N:23]([CH2:38][CH2:37][C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:27]=3)[N:24]=[CH:25][C:20]=2[CH:19]=[N:18][CH:17]=1
Reactant: OCCc1ccc2ccccc2n1
Reactant: O=c1[nH]ncc2cncc(Cl)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1c2c(Cl)cncc2cnn1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To 69.3 mg (0.264 mmol) in THF was added diisopropylazodicarboxylate (94 mg, 0.463 mmol) in THF under ice-cooling and under nitrogen. Then, the resulting solution was stirred for 30 min at room temperature to give a suspension. 8-Chloropyrido[4,3-d]pyridazin-1(2H)-one (24 mg, 0.132 mmol) in THF and then 2-(quinolin-2-yl)ethanol (22.89 mg, 0.132 mmol) in THF were added and the reaction mixture was stirred overnight at room temperature. The total amount of THF was 60 mL. Then, the reaction mixture was mixed with DCM and water. The organic phase was washed with 1N HCl and the organic phase was discharged. The aqueous phase was basified by 1N NaOH and extracted with DCM. The organic phase was dried and concentrated to give 34 mg (76%) of the title compound as bright beige solid. LC-MS: m/e 337.1 (M+H)+.